Coagulation / transfusion medicine Flashcards

Question

What are the main anticoagulant proteins?

Answer 1

o Antithrombin o Protein C o Tissue Factor Pathway Inhibitor

Answer 2

FALSE - they are directly or indirectly antiinflammatory.

Answer 3

o Inhibits thrombin formation o Inhibits FXa o Less inhibitory effects on FIXa and FVIIa-TF complex o Most effective when bind to heparin-like GAGs (heparan sulfate) or when exposed to exogenous heparins (thrombin inhibition increased x 1,000) o In absence of heparins and in presence of thrombin -> AT + TM will bind and inhibit thrombin.

Answer 4

o Systemic inflammation or critical illness: consumption (because of thrombin generation), decreased production (negative acute phase protein), or degradation by neutrophil elastase. o Urinary loss of AT also may occur in animals with glomerulonephritis.

Answer 5

o Inhibits FVa and FVIIIa -> inhibition accelerated x20 when cofactor protein S is present o Activated when TM binds thrombin on endothelium, mainly of microcirculation -> becomes APC o Endothelial protein C receptor (EPCR) accelerates thrombomodulin binding thrombin o TM + thrombin has 3 main functions: * Helps generate APC * Prevents thrombin from acting on fibrinogen and PLT * Will generate TAFI - thrombin activatable fibrinolysis inhibitor -> inhibits fibrinolysis

Answer 6

o Decreased hepatic production of protein C and protein S o Decrease activation of protein C due to the effects of inflammatory cytokines on the endothelium and thrombomodulin. o TNF alpha downregulates the expression of TM o Elastase (produced by endotoxin activated neutrophils) cleaves TM from endothelium o Circulating or soluble TM less effective than when complexed with EPCR on endothelium. o Soluble TM is increased in people with sepsis and independently predicts the presence of DIC, MODS, and mortality.

Answer 7

o Released primary from endothelial cells o Other sources of TFPT - platelets, mononuclear cells, cardiac myocytes, fibroblasts, vascular smooth muscle, megakaryocytic. o Inhibits FVIIa-TF complex o Inhibits FXa with protein S as cofactor o Decreased TFPI - worsens coagulopathy due to protein S deficiency in people.

Answer 8

o Circulating plasminogen is incorporated in the clot and converted to plasmin via tPA and urokinase (fibrinolytic activators) o Plasmin will break down the fibrin meshwork of the clot o tPA and urokinase - released from endothelial cells upon activation / injury of endothelium. o Plasminogen effects are decreased by endogenous plasminogen activator inhibitor (PAI-1) o TNF alpha and IL1B increase PAI-1 > tPA -> balance towards decreased fibrinolysis

Answer 9

FALSE o A hypercoagulable state is not identified until a thrombotic event occurs or the patient develops DIC, limiting the opportunity to intervene with specific therapies. o In fact, detecting the presence of a thrombus or thromboembolus is one of the only means for a clinician to learn definitively that pathologic coagulation is occurring.

Answer 10

o Traditional coagulation tests, such as PLT count, activated partial thromboplastin time (aPTT), and prothrombin time (PT), are most accurate for hypocoagulability and do not reliably identify a predisposition towards hypercoagulability. o Prolongations of aPTT/PT and decreased platelet count may appear in patients with hypercoagulability, although this usually is due to consumption of platelets and coagulation factors after unregulated thrombin generation. o In practice, a drop in circulating platelet count accompanied by a prolongation of at least 20% in baseline aPTT in an at-risk patient should raise concern of consumptive coagulopathy and prompt further investigation.

Answer 11

o Identifying a rise in procoagulant elements (MPs, fV, or VIII activities, or fibrinogen) o Identifying a decrease in endogenous anticoagulants (AT, protein S and C, or TFPI) o Identifying a decrease in fibrinolysis (decreased tPA; increased α2-antiplasmin, PAI-1, TAFI) o Markers of ongoing thrombin generation (thrombin-AT complex [TAT], prothrombin activation fragment [F1+2], or fibrinopeptides A and B) or lysis of fibrin clots (fibrin [-ogen] degradation product [FDP] or D-dimer) may be used.

Answer 12

o TEG and ROTEM o They evaluates the time to initial fibrin cross-linking, rate of clot formation, and the viscoelastic characteristics of the clot formed. o Hypercoagulable samples clot more quickly, with a faster rate of clot formation

Answer 13

o A coagulation test that focuses on the thrombin generation potential (endogenous thrombin potential, ETP) in a sample. o Hypercoagulable samples exhibit a greater ETP for CAT.

Answer 14

o Platelet contributions to a hypercoagulable state may be inferred by assessing markers of platelet activation (P-selectin expression, platelet-neutrophil aggregates) or documentation of hyperfunctional platelets in response to standard stimuli. o Detection of specific proteins on platelets or other cir- culating cells requires advanced techniques such as flow cytometry. o Flow cytometric techniques also can be used to document the pres- ence of procoagulant MPs

Answer 15

o Many of the processes by which inflammation affects coagulation are interrelated o Glycocalyx shedding and EC activation leads to compromised production of local regulators (e.g., NO) and increased expression of procoagulant molecules (e.g., UL-vWF or TF) and adhesion molecules (e.g., P-selectin), with derangement of anticoagulant defenses. o TM may be damaged by multiple mechanisms (leading to decreased activation of protein C), and AT is less effective because of decreased concentrations and impaired interactions with an endothelium that has been denuded of GAGs. o TFPI similarly may have impaired EC localization. o In addition, an exuberant release of PAI-1 resulting from inflammatory cytokine release can slow fibrinolysis and further impede coagulation defenses

Answer 16

o Patients with sepsis develop an initial hypercoagulable phase, followed by a much longer hypocoagulable phase resulting from consumption. o The majority of patients described in the veterinary literature display a hypocoagulable phenotype with evidence of prior clot formation. o In dogs with septic peritonitis, the presence of coagulopathy (defined by prolongations of PT or aPTT, or a platelet count of 100,000/μl or less) is associated independently with increased odds of death. o Although less is known about coagulopathy in cats, inflammatory conditions (pancreatitis and sepsis) are recognized as two of the top three identified causes of DIC in cats. o Dogs with sepsis have significantly prolonged aPTT and/or PT, along with higher FDP and D-dimer concentrations than control dogs. o Septic dogs also have lower protein C and AT activities, further supporting a consumptive coagulopathy. Septic dogs with continually decreasing levels of protein C and AT proteins had a worse outcome. o TAFI is increased in dogs with bacterial sepsis and other inflammatory conditions (e.g., neoplasia), resulting in downregulation of fibrinolysis.

Answer 17

o In people, the thrombophilia associated with PLN appears to be multifactorial. o Platelets are hyperaggregable and exhibit increased markers of activation (P-selectin). o Soluble factors show increases in fVIII activity and fibrinogen concentration, whereas vWF levels and fV are elevated variably. o The loss of endogenous anticoagulant potential centers on low AT activity, which occurs in people and dogs. o Despite this consistent finding, AT activity fails to uniformly predict thrombotic risk across studies in people. o Protein C levels are variable in patients with PLN, and several studies have documented elevated levels of TFPI, suggesting that this anticoagulant is not likely a significant component of the thrombophilia. o In people, levels of TAFI can be increased, along with PAI-1, suggesting a decreased fibrinolytic state. o People have a propensity toward development of renal vein thrombosis, and increased markers of endothelial activation have been documented. o These suggest some involvement of a local mechanism (e.g., endothelial activation or abnormal renal blood flow) contributing to the overall thrombophilia.

Answer 18

o TEG tracings more hyper coagulable o Increased fibrinogen, alpha2-antiplasmin and protein C activities o Decreased AT activity

Answer 19

46% to 80% 45%

Answer 20

o Coagulation abnormalities consistent with a hypercoagulable state o Low AT activity, elevated FDPs and D-dimer, and markedly elevated fibrinogen concentration o TEG studies have documented hypercoagulability, primarily on the basis of an increased clot strength (maximal amplitude or MA). Fibrinogen, platelet count and function, and hematocrit are key contributors to the MA. o Circulating TF is also a likely contributor -> upregulation of TF gene expression in whole blood, although the source of the TF has not been determined. Increased TF could come from numerous sources or from stimulation of EC TF expression by cell- free heme. o Free heme can also decrease the bioavailability of NO and upregulate EC adhesion molecules (e.g., E-selectin). o Hemolyzed erythrocytes augment thrombin generation in vitro, an effect attributed to erythrocyte-derived MPs or procoagulant erythrocyte membrane

Answer 21

o Elevated activities of fVIII and vWF, heightened levels of PAI- 1 and elevated activities of factors IX, XI, and XII. o In contrast to veterinary patients, many people with HAC suffer from comorbidities (e.g., obesity, diabetes mellitus, and hypertriglyceridemia) that are also prothrombotic conditions. o Dogs with HAC are represented in most case series describing thrombotic conditions (aortic thrombosis, PTE, splenic or portal vein thrombosis). Despite these observations, a consistent cause or definable procoagulant state has not been identified.

Answer 22

FALSE o Thrombosis secondary to cardiac disease is reported infrequently in dogs but has been associated with dilated cardiomyopathies and atrial fibrillation.

Answer 23

o Left atrial (LA) and LA appendage enlargement is associated with numerous structural changes, culminating in a procoagulant phenotype, such as increased TF and vWF on areas of denuded or damaged endothelium. o Growth hormones (e.g., VEGF), which are increased in people with AF, may promote the upregulation of TF. o Through atrial enlargement, shear stress is decreased (stasis), reducing the release of NO.

Answer 24

o A systemic hypercoagulable state occurs in 50% of cardiomyopathic cats with spontaneous echocardiographic contrast (or “smoke”) with or without a LA thrombus, and in 56% of cats with ATE and LA enlargement. o vWF : Ag (vonWillebrand factor antigen) concentrations were elevated in only the cats with ATE, and the presence of hypercoagulability was not related to LA size or the presence of congestive heart failure. o These results are echoed by an earlier study that revealed changes consistent with a hypercoagulable state in 45% of cats with hypertrophic cardiomyopathy. o Platelets from cats with cardiomyopathy required significantly lower doses of ADP to result in irreversible aggregation compared with control cats.

Answer 25

Hemangiosarcoma Mammary carcinoma Adenocarcinoma of the lung

Answer 26

o TF has been identified on malignant cells and in tumor vasculature, and tumor cells have the ability to shed TF-bearing MPs. o TF supports thrombophilia and also plays a key role in regulation of integrin function responsible for tumor angiogenesis. o In mice, TF blockade results in decreased angiogenesisand tumor growth, through modulation of VEGF. o TF expression on histopathology samples is an independent predictor of poor overall or relapse-free survival for many tumor types in people. o TF expression has been evaluated in canine cell lines of mammary tumors, pancreatic carcinoma, pulmonary adenocarcinoma, prostatic carcinoma, and sarcomas (osteosarcoma and fibrosarcoma). TF was highly expressed in all but osteosarcoma; o Tumors of epithelial origin (mammary carcinoma and pulmonary adenocarcinoma) expressed the highest levels. These tumors also shed TF-bearing microparticles into tissue culture supernatants.

Answer 27

Fibrinogen and D-dimer

Answer 28

50.4% 17.3%

Answer 29

Tissue factor

Answer 30

o TBI patients have elevated monocyte TF expression for the first 24 hours, which then quickly returns to normal. o Enhanced thrombin generation has been documented as blood passes the vasculature of the brain. In a study of people with severe isolated TBI, patients had prolonged aPTT and PT; elevated D-dimer, TAT, and F1+2; and low AT, platelets, and fibrinogen upon presentation. o Procoagulant MPs after TBI are increased significantly in CSF and blood. These MPs were primarily of EC and platelet origin, adding evidence to the likely contribution of cerebrovascular endothelial activation or injury. o Although local procoagulant factors initiate coagulation, inflammatory cytokines and procoagulant MPs provide a means for dissemination of the condition, leading to a systemic response. o Studies have suggested a state of platelet hypofunction in brain injured patients. This is opposed to non–brain-injured trauma patients who generally have increased platelet reactivity. o The cause of the platelet dysfunction in TBI patients has not been identified. o Eight experimental cats with TBI-induced coagulopathy secondary to bullet-inflicted brain injury showed a decreased platelet count and decreased platelet clumping, possibly suggesting a decreased reactivity of the cats’ platelets. A decreasing fibrinogen was also present throughout the experiment.

Answer 31

Treat the underlying condition!

Answer 32

o Antithrombin -> mixed results in people o Recombinant activated protein C (rAPC) -> benefits experimentally but not in people, removed from market. o Recombinant TFPI (rTFPI) -> benefits experimentally, not in clinical trials. o Recombinant soluble TM (rTM) -> maybe benefit on survival, unknown.

Answer 33

o Drugs that inhibit PLT function -> aspirin or clopidogrel o Drugs that inhibit thrombin formation -> UFH, LMWH

Answer 34

o Bleeding disorders are conditions that result in inappropriate hemostasis, causing or predisposing to bleeding. o Some coagulopathies result in spontaneous bleeding, but many are subclinical and hemorrhage occurs only after an invasive procedure.

Answer 35

o Primary hemostasis, involving the interaction between platelets and endothelium resulting in the formation of a platelet plug. o Secondary hemostasis, a system of proteolytic reactions involving coagulation factors and resulting in the generation of fibrin polymers, which stabilize the platelet plug to form a mature thrombus. o Fibrinolysis is the dissolution of the fibrin clot to restore vascular patency.

Answer 36

o Primary hemostasis immediately follows vascular damage. Platelets adhere to subendothelial collagen via the platelet GPVI receptor, or to collagen-bound von Willebrand factor (vWF) via the GPIb receptor. o Adherence triggers a cascade of cytosolic signaling that stimulates platelet arachidonic acid metabolism and the release of granular contents (activation). o Thrombin, generated by secondary hemostasis, is also a powerful platelet agonist. o Activated platelets release secondary agonists, TxA2, ADP, and serotonin, which recruit and activate additional platelets, thus amplifying and sustaining the initial response. o The final common pathway for all agonists is the activation of the platelet integrin αIIbβ3 receptor (formerly known as glycoprotein IIbIIIa receptor). Agonist binding induces a conformational change in the receptor, exposing binding domains for fibrinogen. o Binding results in interplatelet cohesion and aggregation. Aggregated platelets constitute the primary hemostatic plug and provide a stimulus and framework for secondary hemostasis.

Answer 37

o In vitro tests do not accurately reflect in vivo hemostasis. o Hemostatic testing makes high demands on sampling procedure; improper technique leads to artifactual results. o Tests should always be performed and interpreted carefully, along with the clinical findings, and with their limitations in mind.

Answer 38

o Platelet counts detect quantitative platelet disorders (thrombocytopenia, low PLT number). o Pseudothrombocytopenia is a common artifact that occurs when platelets in blood are not adequately counted. This usually results from platelet aggregation during sample collection and is especially common in cats. o Even in the absence of platelet clumping, pseudothrombocytopenia is frequent with automated PLT counts in cats because of the considerable overlap between erythrocyte and PLT volumes in this species, and in dogs and cats when large platelets are present. o For these reasons, low PLT counts should always be confirmed by blood smear examination.

Answer 39

o The bleeding time is the duration of hemorrhage resulting from the infliction of a small standardized injury involving only microscopic vessels and reflects in vivo primary hemostasis. o The buccal mucosal bleeding time (BMBT) is the only reliable and reproducible method in small animals.

Answer 40

o Sedation is generally not required, except in cats and nervous dogs. o The patient is restrained in lateral recumbency and a strip of gauze is tied around the maxilla to fold up the upper lip, sufficiently tight to cause moderate mucosal engorgement. o A spring-loaded device is used to make two 1-mm–deep incisions in the mucosa of the upper lip. o The incisions should be made at a site devoid of visible vessels and inclined so that the blood flows toward the mouth. o Shed blood is blotted carefully with filter paper, taking extreme care not to disturb the incisions. o The BMBT is the time from incision to cessation of bleeding.

Answer 41

o It is indicated in patients with a suspected primary hemostatic defect when the PLT count is adequate. o It is prolonged in dogs with von Willebrand disease (vWD) and nonsteroidal antiinflammatory drug –induced thrombopathia. o The BMBT also is used for the preoperative screening of patients considered at risk for vWD or other thrombopathias.

Answer 42

o It is influenced by hematocrit and blood viscosity and has appreciable inter- and intraoperator variability (up to 2 minutes). o It is a poor predictor of surgical bleeding.

Answer 43

o It evaluates the extrinsic and common pathways, specifically factors II, V, VII, X and fibrinogen. o Because of the short half-life of factor VII, the PT is sensitive to vitamin K deficiency or antagonism.

Answer 44

o II, VII, IX and X o Protein C and protein S

Answer 45

o The APTT evaluates the intrinsic and common pathways. o Only factors VII and XIII are not evaluated. o It is more sensitive to heparin than is the PT.

Answer 46

o They are in vitro plasma-based tests, represented by the cascade model of coagulation, and do not accurately represent in vivo hemostasis. o As such, they are not predictive of bleeding.

Answer 47

They are generated when fibrinogen, soluble fibrin, or cross-linked fibrin is lysed by plasmin.

Answer 48

o Elevated concentrations indicate increased fibrinolysis and/or fibrinogenolysis. o Because clearance is by hepatic metabolism and the mononuclear phagocytic system, disorders of these systems also result in elevated FSP concentrations. o FDPs can inhibit coagulation and induce platelet dysfunction, contributing to a bleeding tendency. o They are commonly detected with DIC but are not specific for the condition; elevated concentrations are also described in dogs with thromboembolism (TE), neoplasia, IMHA, hepatic dysfunction, sepsis/SIRS, heat stroke, trauma, heart failure, and GDV.

Answer 49

When fibrin is cross linked by FXIIIa

Answer 50

o In contrast to other FSPs, which indicate only the activation of plasmin, D-dimers indicate the activation of thrombin and plasmin and are specific for active coagulation and fibrinolysis. o The half-life of D-dimers is short (approx. 5 hours); therefore elevated concentrations indicate recent or ongoing fibrinolysis.

Answer 51

o D-dimers are a sensitive indicator of thrombotic conditions, such as DIC and thromboembo- lism (TE), and are more sensitive than are FSPs. o They have good negative predictive value, but the absence of elevated D-dimers does not preclude a diagnosis of DIC. o Conversely, elevated D-dimer concentrations are not specific; elevated concentrations are demonstrated in dogs with DIC, TE, neoplasia, hepatic disease, renal failure, cardiac failure, internal hemorrhage, and after surgical procedures.

Answer 52

o Fibrinogen concentration is usually determined via the Clauss method, a functional assay based on the time for fibrin clot formation after the addition of excess thrombin. o Decreased concentrations (hypofibrinogenemia) can be inherited or acquired. o Acquired disorders are described with hemodilution, massive transfusion, hepatic dysfunction, DIC, and sepsis and after thrombolytic therapy. o Hypofibrinogenemia generally does not result in prolongation of standard coagulation tests (PT, aPTT) until fibrinogen is markedly decreased (less than 50 to 100 mg/dl).

Answer 53

o The thrombin time (TT) tests functional fibrinogen, via measure of the time taken for a standardized thrombin solution to convert fibrinogen to fibrin. o The TT is prolonged with hypofibrinogenemia, dysfibrinogenemia, or in the presence of factors that inhibit fibrin polymerization (e.g., heparin, FDPs).

Answer 54

o The viscoelastic properties of the blood clot are evaluated, from initiation of coagulation, through amplification and propagation, to fibrinolysis. o Information is generated regarding the strength and stability of the clot and the dynamics of its formation and breakdown. o Compared with routine hemostatic tests, these methodologies provide global assessment of hemostasis as determined by the interplay of plasma and cellular components, more closely reflecting in vivo hemostasis.

Answer 55

o The thromboelastograph consists of a plastic cup and a pin suspended by a torsion wire. o A sample of citrated blood is placed in the cup with calcium chloride (at 37° C), and the cup is elevated so that the pin hangs in the sample. o The cup is then oscillated around the vertical axis. o When fibrin strands form between the pin and the cup, the torque (twisting force) generated is transmitted to a transducer, which converts the signal data for computer display of the TEG tracing. o Testing is routinely performed 30 minutes after sampling. Reliable and reproducible results also can be obtained at 120 minutes, but results are statistically different from 30 minutes.

Answer 56

o The reaction time (R) represents the enzymatic portion of coagulation (secondary hemostasis). o The clotting time (K) represents clot kinetics, largely determined by clotting factors, fibrinogen, and platelets. o The angle (α) depends largely on fibrinogen, as well as platelets and factors. o The maximum amplitude (MA) represents the ultimate strength of the fibrin clot, dependent primarily on platelet aggregation (platelet number and function) and, to a lesser extent, fibrinogen. o MA is used to derive the clot shear elastic modulus G, where G=5000×MA/(100−MA) and is a measure of the overall coagulant status. o Fibrinolysis is measured by the extent of clot lysis at 30 and 60 minutes after MA (LY30 and LY60, respectively).

Answer 57

o Naive citrated samples o Samples activated with recombinant human TF

Answer 58

Similar to TEG, ROTEM provides information on initial fibrin formation (clotting time, CT), kinetics of fibrin formation (clotting formation time, CFT; angle, α), maximum fibrin clot strength (maximum clot firmness, MCF), and clot lysis at 30 and 60 minutes (CL30 and CL60)

Answer 59

o Limitations of TEG and ROTEM are the inability to detect vWD and insensitivity to antiplatelet drugs. o The methodologies are also affected by blood viscosity; polycythemia results in hypocoagulable tracings and anemia produces hypercoagulable tracings.

Answer 60

o They are classified as disorders of primary or secondary hemostasis, or both, based on the pathophysiology of the hemostatic defect. o Disorders of primary hemostasis result from decreased circulating platelet numbers (thrombocytopenia), from platelet dysfunction (thrombopathia) or, rarely, from a vascular anomaly (vasculopathy). o Disorders of secondary hemostasis result from low concentration or activity of coagulation factors. o Inherited disorders are almost invariably a single defect in the hemostatic mechanism, whereas acquired disorders, which are more common, frequently affect more than one aspect of hemostasis. o Disorders of fibrinolysis (hyperfibrinolysis) can also cause, or contribute to, clinical bleeding. Hyperfibrinolysis is demonstrated in DIC and in massive trauma and is suspected to be the primary mechanism of delayed postoperative bleeding in Greyhound dogs.

Answer 61

o Refers to the syndrome resulting from blood loss, consumption of coagulation factors and platelets, and intravascular volume replacement. o During hypovolemic shock, reduced intravascular hydrostatic pressure results in shifts of coagulation factor-deficient interstitial fluids into the plasma. o This is compounded by aggressive resuscitation with IV fluids and/or massive red blood cell transfusion and further exacerbated by synthetic colloids, particularly hydroxyethyl starches (hetastarch).

Answer 62

40% to 60%

Answer 63

o The mechanisms of dilutional coagulopathy are multiple. o Fibrinogen is the first factor to become critically reduced. Fibrinogen is required in substantially higher concentrations than other factors, but the limited increase in synthesis cannot compensate for increased breakdown. o The resultant hypofibrinogenemia decreases thrombin formation and fibrin polymerization, decreasing the speed, strength, and stability of clot formation. o This effect is seen with even moderate blood loss and hemodilution. The magnitude of effect is determined by the severity of the hypofibrinogenemia and the type of resuscitative fluid used. o At fibrinogen levels below 50 mg/dl no clot is formed; clot formation occurs almost linearly up to 300 mg/dl. o Hetastarch demonstrates the most pronounced hemodilution effects because it also affects vWF and fVIII.

Answer 64

o Thrombocytopenia and the dilution of coagulation factors affect coagulation at a later point in resuscitation than does hypofibrinogenemia. o After replacement of one blood volume of platelet-deficient fluid, only 35% to 40% of platelets remain in the circulation. o In the patient with a normal platelet count before resuscitation, this dilution may not be clinically significant. o Prolongation of PT and aPTT occurs in human patients after replacement of two blood volumes. Prolongations were demonstrated in 70% of dogs after massive transfusion, but a correlation to transfused volumes was not made. o Fibrinolysis is affected by hemodilution. Progressive dilution of α2-antiplasmin and fXIII reduces fibrin cross-linking and prolongs the half-life of plasmin. o Plasminogen activator inhibitor is also decreased, resulting in prolonged tPA activity. The net result is enhanced fibrinolysis.

Answer 65

o Hypothermia, as results from hypoperfusion, evaporation from exposed body cavities during surgery, or the infusion of cold resuscitation fluids, leads to a reversible hypocoagulability. o Platelets are extremely temperature sensitive. o Evidence suggests that the bleeding tendency observed in humans at mildly reduced temperatures (33° to 37° C) results primarily from decreased vWF-mediated platelet adhesion. o At temperatures below 33° C, reduced platelet function and enzyme activity occur, with TF-fVIIa complex activity decreasing linearly. o Because conventional coagulation tests are performed at 37° C hypothermia-induced coagulopathy may be difficult to detect.

Answer 66

o Acidemia, as occurs with hypoperfusion or massive transfusion of CPDA-stored red cells, results in increased fibrinogen degradation and impaired coagulation protein activity. o fXa-Va complex activity is decreased by 50% at pH 7.2, and 70% at pH 7.0. o At a pH of 7.0, factor VIIa activity is also decreased by more than 90%. o The coagulopathy is not reversed with correction via buffer administration.

Answer 67

1) Does the patient have a bleeding disorder or is bleeding the result of local factors? 2) If the patient does have a bleeding disorder, what is the nature of the hemostatic defect: primary hemostasis, secondary hemostasis, fibrinolysis, or a combination of these? 3) Is the defect inherited or acquired? These questions usually can be answered easily based on information gleaned from the history, physical examination, and routine hemostatic testing.

Answer 68

o Severe inherited disorders are generally apparent within the first 6 months of life. o Milder forms, such as vWD, may not be diagnosed until surgery, trauma, or concurrent disease intervenes. o A history of repeated bleeding episodes suggests an inherited disorder.

Answer 69

o Some inherited disorders (e.g., hemophilia) and many acquired disorders (e.g., thrombocytopenia, vitamin K deficiency) produce spontaneous bleeding. o Other conditions (e.g., vWD, factor VII deficiency, fibrinolytic disorders) more commonly require some form of trauma to make the impairment apparent.

Answer 70

o Defects of primary hemostasis are characterized by ecchymosis and/or spontaneous bleeding from mucosal surfaces (e.g., epistaxis, gingival bleeding, hyphema, hematuria, melena). Petechiae are typical of thrombocytopenia rather than thrombopathia. o Defects of secondary hemostasis are usually characterized by single or multiple hematomas and bleeding into SQ tissue, body cavities, muscles, or joints. o Some acquired disorders, such as DIC, defy this classification because multiple hemostatic defects are present. o vWD usually has the characteristics of a primary hemostatic defect but, in its most severe form, may mimic a secondary hemostatic disorder.

Answer 71

o An initial diagnostic panel should include, at minimum, platelet enumeration/estimation, PT, and aPTT. o D-dimer and fibrinogen concentrations are also recommended. o This testing is generally sufficient to confirm a hemostatic defect and to characterize the defect as a disorder of primary hemostasis, secondary hemostasis, or both. o With characterization of the hemostatic defects, a concise list of differential diagnoses can be constructed and further diagnostic workup efficiently pursued.

Answer 72

1. Recognize and treat shock and any other life-threatening conditions. 2. Control local bleeding, if possible. 3. Restore normal hemostasis via blood product transfusion, medications, reversal of hypothermia, and/or control of other precipitating or contributing factors. 4. Monitor for stability of coagulation parameters; correct as needed. 5. Monitor for new or ongoing sources of blood loss. 6. Monitor for complications associated with new or ongoing blood loss (e.g., intrapulmonary hemorrhage).

Answer 73

o It contains hemostatic factors equivalent to the plasma from which it was obtained and is indicated for the treatment and prevention of bleeding associated with acquired and inherited disorders of secondary hemostasis. o An exception is heparin-induced bleeding, because the hemorrhagic diathesis is caused by factor inhibition, not deficiency; moreover, antithrombin in FFP may enhance heparin effects.

Answer 74

o Cryoprecipitate is prepared from FFP and contains fVIII, vWF, fibrinogen, and fibronectin in 10% of the original plasma volume. o CP is indicated for the management of patients with vWD, factor VIII deficiency, hypofibrinogenemia, and dysfibrinogenemia. o Strong evidence in human patients indicates a beneficial role of CP in the management of dilutional coagulopathy and trauma-induced coagulopathy

Answer 75

Fresh whole blood

Answer 76

o Platelet transfusion in veterinary medicine is usually therapeutic, indicated for the management of uncontrolled or life-threatening bleeding resulting from severe thrombocytopenia or thrombopathia. o Even with immune-mediated thrombocytopenia (ITP), in which transfused platelets are rapidly destroyed, a negligible increase in platelet count may provide adequate, life-saving hemostasis. o Prophylactic platelet transfusions should be considered in dogs with severe thrombocytopenia or thrombopathia before surgery.

Answer 77

DDAVP TXA EACA

Answer 78

o Desmopressin is a synthetic vasopressin analog that induces, via V2 receptors, the release of subendothelial vWF stores. o DDAVP is used for the management of thrombopathia of various causes in humans. In dogs, DDAVP is used as adjunctive treatment of bleeding associated with canine type 1 vWD, as well as for presurgical prophylaxis (administered 30 minutes before surgery). o Injectable or intranasal DDAVP is administered at 1 to 4 mcg/kg SC or IV. Onset of action is delayed approximately 30 minutes, and duration of effect is usually 2 hours. The effects of repeated doses are diminished because vWF stores are depleted. o The efficacy of DDAVP is variable and its effects short- lived; the patient should be closely monitored and blood products made available.

Answer 79

o Epsilon- aminocaproic acid (EACA) and tranexamic acid (TEA) are lysine analogs; they block the binding and activation of plasminogen and also exert antiinflammatory effects through interleukin inhibition. o TXA is approximately 10 times more potent than EACA. o TXA and EACA appear to have comparable efficacy with minimal risk of adverse events o EACA neutralizes experimentally induced hyperfibrinolysis in dogs and has a wide therapeutic index. o EACA has been shown to reduce postoperative bleeding in Greyhound dogs when administered preemptively at 15 to 40 mg/kg q8h.

Answer 80

Thrombocytopenia is confirmed by a low platelet count, verified by blood smear examination.

Answer 81

o No o The bleeding threshold is not predictable from the count alone and depends on factors such as platelet function, secondary hemostasis, and the presence of precipitating trauma. o Spontaneous bleeding generally does not occur until platelet counts fall below 30,000 to 50,000/μl, unless a concomitant bleeding disorder exists. o In the patient with spontaneous bleeding, a platelet count of more than 50,000/μl should prompt investigation for another contributing hemostatic defect. o Platelet counts as low as 5000/μl can occur without bleeding.

Answer 82

o Less o Patients with ITP tend to bleed less than patients with equivalent counts from other causes because of the presence of young, hyperfunctional platelets.

Answer 83

Cavalier King Charles Spaniels Greyhound

Answer 84

o Vascular disorders are an uncommon cause of bleeding. o In the patient with a primary hemostatic disorder and adequate platelet numbers, a platelet function defect is likely. o A prolonged BMBT in a patient with adequate platelet count confirms thrombopathia. o The drug history should be carefully appraised because numerous drugs can cause or contribute to thrombopathia. o Diseases known to affect platelet function should be excluded. If no obvious cause of acquired thrombopathia can be found, a hereditary disorder is suspected.

Answer 85

Deficiency of vitamin K dependent factors (II, VII, IX and X)

Answer 86

FI FII FX And with vitamin K factors deficiency

Answer 87

o Cryoprecipitate is ideal for deficiencies of factors VIII and fibrinogen. o Cryosupernatant is indicated for deficiencies of factors II, VII, IX, X, and XI. o Where these products are not available, FFP is an acceptable option.

Answer 88

o Factor XII deficiency is an asymptomatic condition of dogs and cats. It is the most common factor deficiency in cats, with a reported prevalence of 2.1%. o Because FXII is involved in contact factor activation but is not essential for in vivo hemostasis, deficiency results in significant prolongation of the aPTT but no hemorrhagic tendency. o FXII deficiency is usually diagnosed incidentally and must be distinguished from pathologic causes of aPTT prolongation.

Answer 89

o Dietary insufficiency is rare but has been reported in neonates or with prolonged TPN administration. o Broad-spectrum oral antimicrobial drugs can inhibit vitamin K synthesis. o Decreased absorption can result from severe gastrointestinal disease, hepatopathy, pancreatic insufficiency, or biliary obstruction. o Vitamin K antagonism occurs with warfarin therapy or anticoagulant rodenticide toxicity. These compounds inhibit vitamin K epoxide reductase, leading to a relative vitamin K deficiency.

Answer 90

o PT prolongation occurs first, reflecting the short half-life of fVII (4 to 6 hours). o Prolongation of the aPTT follows when other factors are depleted (approximately 2 days).

Answer 91

The liver plays a pivotal role in hemostasis by synthesizing clotting factors, coagulation inhibitors (antithrombin, protein C), and fibrinolytic proteins, as well as by clearing activated factors, enzyme- inhibitor complexes, and FDPs.

Answer 92

Primarily because of impaired hepatic synthesis of thrombopoietin

Answer 93

o DIC rarely occurs secondary to hepatic disease. o They have similar hemostatic defects and pattern of laboratory anomalies, therefore distinguishing these conditions can be challenging. o Fibrinogen levels tend to be lower, and D-dimer concentrations higher, in DIC compared with hepatic disease

Answer 94

o Approximately 25% of severely injured patients are presented with a clinically significant coagulopathy that develops minutes after the initial traumatic insult. o This coagulopathy, termed the acute coagulopathy of trauma and shock (ACoTS), is associated with a fourfold increase in mortality. o Resuscitation-associated coagulopathy (RAC) develops later in the posttraumatic period secondary to hypothermia, worsening acidosis, and hemodilution resulting from the administration of intravenous fluids and/or blood transfusion.

Answer 95

o ACoTS is caused by tissue trauma, shock, sympathoadrenal activation, and inflammation. o Shock with tissue hypoperfusion appears to be the major driver of ACoTS, with the extent of hypoperfusion directly correlated with the degree of coagulopathy. o Higher injury severity increases the incidence and severity of coagulopathy in hypoperfused patients. o Fibrinolysis is activated early after injury. Hypoperfusion is believed to result in increased expression of thrombomodulin on the surface of endothelial cells. The resultant increases in activated protein C (APC) inactivate fVIIa and fVa and promote fibrinolysis through the inhibition of plasminogen activator inhibitor-1 (PAI-1). o In addition, endothelial activation and injury lead to the release of tPA, endogenous heparinization from glycocalyx shedding, and increased vascular permeability. Recent studies show that fibrinogen concentrations are decreased in injured patients on admission, even preceding significant fluid resuscitation, and are associated with poor outcomes.

Answer 96

o RAC occurs in the period after injury, as a result of persistent hypothermia, acidemia, and hemodilution. o These effects result in multiple hemostatic derangements that include hypofibrinogenemia, platelet dysfunction, thrombocytopenia, and decreased enzymatic activity.

Answer 97

o Traditional plasma-based coagulation tests, such as the PT and aPTT, do not accurately reflect the in vivo coagulopathy. o The PT appears to be more sensitive than the aPTT in identifying enzymatic disorders in these patients, but these tests do not detect hyperfibrinolysis or platelet dysfunction and are not prolonged until fibrinogen falls to exceedingly low levels. o Viscoelastic testing (TEG and ROTEM) have proved superior in predicting coagulopathy and in guiding plasma and platelet transfusions.

Answer 98

o Newer protocols, termed “damage control resuscitation,” focus on the prevention of coagulopathy through permissive hypotension, limiting fluids, and delivering higher ratios of plasma and platelets. o The goal of permissive hypotension is to minimize dilutional coagulopathy secondary to fluid administration by maintaining a lower systemic blood pressure. o In humans with penetrating injuries, maintaining a target MAP of 50 mm Hg, compared with 65 mm Hg, was associated with a decreased incidence of coagulopathy, decreased blood product use, and improved survival. o Intravascular volume support is achieved preferentially via red cell and FFP transfusion, with plasma administered as early as possible. Several studies have shown the clinical benefit of aggressive hemostatic resuscitation using the empiric transfusion ratio of FFP:RBC over 1:1.

Answer 99

o DIC is characterized by the systemic activation of coagulation, leading to widespread microvascular thrombosis, which compromises organ perfusion and can contribute to organ failure. o The ongoing activation of coagulation may exhaust platelet and coagulation factors, resulting in a hypocoagulable state and bleeding.

Answer 100

DIC invariably occurs as a complication of an underlying disorder; sepsis and the systemic inflammatory response syndrome (SIRS) are the most common causes in humans and dogs

Answer 101

o It can range from asymptomatic (nonovert DIC) to signs of organ failure associated with microvascular thrombosis to fulminant bleeding (overt DIC). o Bleeding occurs in a minority of patients with DIC; organ dysfunction is more common.

Answer 102

Hypercoagulable 22% Hypocoagulable

Answer 103

o DIC represents a dynamic continuum, and findings depend on where that patient lies on the continuum at that point in time. o Hemostatic tests are not specific for DIC. Neither a gold standard nor consensus for the diagnosis of DIC exists in animals. o Hemostatic tests are best evaluated together, and in light of clinical findings. Diagnosis is generally based on the presence of an underlying condition that could trigger DIC, together with three or more of the following anomalies: thrombocytopenia, prolongation of the PT, aPTT or TT, elevated D-dimers, hypofibrinogenemia, reduced antithrombin activity, and/ or evidence of red blood cell fragmentation (schistocytes) on blood smear examination. o The diagnosis of DIC by routine laboratory testing is restricted to identification of the overt coagulopathic stage of the disease. o TEG enables identification of the more common hypercoagulable phase. Differentiation between hypercoagulable and hypocoagulable patients has been demonstrated; higher mortality rates occur in hypocoagulable dogs

Answer 104

o The prevalence of postoperative bleeding in Greyhound dogs far exceeds that of other breeds. Bleeding rates of 26% have been reported in Greyhounds after routine gonadectomy, compared with 0 to 2% in other dog breeds. o Bleeding is delayed 36 to 72 hours after surgery. o In some dogs, bleeding progresses to a generalized bleeding disorder associated with clinical signs of illness, profuse widespread bleeding, mild thrombocytopenia, hemolysis, and increased hepatic and muscle enzyme activities. o No significant differences have been identified between bleeders and nonbleeders with respect to platelet count, platelet function, PT, aPTT, fibrinogen concentration, D-dimer, factor XIII, and plasminogen. o Antiplasmin and antithrombin activities have been shown to be significantly lower in dogs that bled compared with those that did not. These findings, together with the delayed onset of the bleeding suggest anomaly of the fibrinolytic system or endothelial dysfunction, rather than a primary or secondary hemostatic disorder.

Answer 105

o Postoperative bleeding in Greyhound dogs is reduced by the prophylactic use of EACA. o Dogs that did not receive preemptive EACA after limb amputation were 5.7 times more likely to bleed than dogs that did receive EACA. o Of 100 elective gonadectomies in retired racing Greyhound dogs, bleeding occurred in 30% of the placebo group compared with only 10% of the EACA group. o In both studies, EACA was administered at 500- to 1000mg total dose (15 to 40 ml/ kg) every 8 hours for 5 days, beginning immediately or soon after surgery. An increased likelihood of bleeding associated with body weight suggests that higher dose rates may be more effective.

Answer 106

IMHA Neoplasia Feline panleukopenia

Answer 107

5% 13% 23% 59%

Answer 108

29% 20% 7% 20%

Answer 109

o Include tickborne infections such as Rocky Mountain spotted fever, anaplasmosis, babe- siosis, and ehrlichiosis. o Other commonly incriminated infectious causes include leishmaniasis, leptospirosis, heartworm disease, feline immunodeficiency virus, feline leukemia virus, feline infectious peritonitis, and sepsis. o Systemic inflammatory diseases, including neoplasia and subsequent DIC, and systemic thrombosis can cause thrombocytopenia. o Immune-mediated mechanisms cause the most severe form of thrombocytopenia. One study has identified platelet-bound antibodies in thrombocytopenic dogs with a multitude of underlying conditions, including infectious and neoplastic causes, pancreatitis, hepatitis, and SIRS. This suggests many conditions can cause immune-mediated destruction of circulating platelets.

Answer 110

o Clinically significant bleeding as a result of low platelet numbers can be observed when platelet count drops below 25 to 50 × 10^9/L. o Clinical signs of thrombocytopenia include petechiae and ecchymoses, frequently seen on oral mucous membranes, ear pinnae, or in the inguinal area. o Mucosal bleeding is also common, causing epistaxis, hyphema, hematemesis, melena, hematochezia, and hematuria. o CNS signs resulting from cerebral and spinal cord bleeds may be seen, and prolonged bleeding or excessive bruising may follow venipuncture or trauma.

Answer 111

1) Decreased production 2) Consumption 3) Sequestration 4) Increased destruction.

Answer 112

May be caused by immune-mediated disease, drugs or toxins, infectious agents, irradiation, hypoadrenocorticism, neoplasia, and myelophthisis.

Answer 113

1) Decreased production via bone marrow suppression and/or 2) Increased platelet destruction by immune-mediated processes. o Non–immune- mediated thrombocytopenia develops more gradually as megakaryocytes are suppressed and replacement of senescent platelets falters. Immune-mediated thrombocytopenia likely develops more quickly

Answer 114

o By several proposed mechanisms. o The first is hapten-dependent antibody formation, caused by the drug binding covalently to platelet membrane proteins, causing antibody production and drug-specific immune reaction. Examples of drugs that use this mechanism include penicillins and cephalosporins. o Other drugs can induce production of antibodies that bind to platelet membrane proteins (most commonly glycoprotein [GP] IIbIIIa/integrin αIIbβ3) in the presence of the drug, or optimize interactions between antibodies and platelet antigen. Examples of drugs that use this mechanism include quinine, vancomycin, sulfonamides, rifampin, and fluoroquinolones. o Other drugs induce production of auto-antibodies that react with platelets even in the absence of the drug, such as sulfonamides.

Answer 115

Non–immune-mediated mechanisms include bone marrow suppression or toxicity; examples include phenobarbital, chloramphenicol, penicillins, cephalosporins, chemotherapeutics, methimazole, azathioprine, and albendazole.

Answer 116

o In dogs and cats with thrombocytopenia that does not respond to treatment, pancytopenias, and in those animals with signs suspicious for neoplasia. o Bone marrow cytology and histopathology allow for assessment of megakaryocyte population and distribution as well as myeloid and erythroid precursors, submission for FeLV testing, and detection of fibrosis or neoplastic cell populations.

Answer 117

o Platelet counts decrease with excessive consumption, such as during significant hemorrhage and DIC. o Blood loss leading to platelet consumption and loss can be due to coagulopathies, such as vitamin K antagonist rodenticide toxicity and massive trauma. o DIC is a syndrome characterized by systemic microthrombosis caused by systemic infection or inflammation, tissue necrosis and trauma, capillary stasis, vascular damage, or release of pro-coagulant factors.

Answer 118

o Splenomegaly and splenic congestion, neoplasia, and severe hypothermia can cause sequestration of platelets in the spleen. o Splenic sequestration usually causes a mild thrombocytopenia.

Answer 119

o ITP is an autoimmune disorder in dogs that can be primary (idiopathic) or secondary to neoplastic, infectious, toxic, or inflammatory causes. o Vaccines have been cited as a cause in children and implicated as an inciting cause in dogs. o Type II hypersensitivity results in destruction of platelets and/or megakaryocytes after antiplatelet and/or antimegakaryocyte antibody attachment, and immunoglobulin opsonization and subsequent phagocytosis by the reticuloendothelial system. o Idiopathic ITP is a diagnosis of exclusion and is reported in 5% of all thrombocytopenic dogs and 2% of thrombocytopenic cats. o Reported mortality rates for idiopathic ITP range from 25% to 30%. Primary ITP appears to be rare in cats.

Answer 120

o Immunosuppression - steroids o Glucocorticoids have a broad range of actions, down-regulating Fc receptors on macrophages, preventing release of the proinflammatory cytokines IL-1 and IL-6, reducing antigen presenting and processing, reducing antibody adhesion onto epitopes, and directly inhibiting T-cell function.

Answer 121

Increases platelet counts by causing release of platelets from megakaryocytes (the microtubule system of the megakaryocyte controls the release of new platelets into circulation) and impairing phagocytosis of opsonised platelets by impairing microtubule assembly in macrophages.

Answer 122

Because of the possibility of exacerbation of hemoparasitic infections such as babesiosis and hemotropic mycoplasmosis.

Answer 123

o No o Platelet transfusions are indicated when life-threatening bleeding occurs as a result of severe thrombocytopenia. o In dogs with ITP, which is the most common cause of severe thrombocytopenia, platelet transfusions are given uncommonly because of the belief that transfused platelets are marked rapidly for destruction, and the resultant increase in platelet count is negligible. o In the case of life- threatening hemorrhage, however, a platelet transfusion may help to slow or stop bleeding.

Answer 124

Fresh whole blood (FWB), platelet-rich plasma (PRP), fresh platelet concentrate (PC), cryopreserved platelets, and lyophilized platelets.

Answer 125

o Canine PRP is harvested from fresh whole blood after centrifugation at 1000 × g for 4 minutes (i.e., a relatively slow spin compared with that necessary for separation of fresh frozen plasma). o The supernatant PRP can be used for platelet transfusion.

Answer 126

o Platelet rich plasma can be expressed into a satellite bag and centrifuged further at 2000 × g for 10 minutes to produce a platelet concentrate. o PC is obtained either by sequential centrifugations of PRP or by plateletpheresis. o This product contains a high concentration of platelets (1475 ± 430 × 10^9/L) in a relatively small volume and thus differs from PRP, which generally contains a lower number of platelets in a larger volume.

Answer 127

One unit of whole blood-derived PRP or PC per 10 kg dog results in a maximum platelet increase by 40 × 10^9/L

Answer 128

o Fresh whole blood is indicated for thrombocytopenic patients that are concurrently anemic. o A dose of 10 ml/kg of FWB results in a maximum platelet increase of 10 × 10^9/L. o The efficacy of platelet transfusion can be monitored by checking platelet counts 1 and 24h posttransfusion, as well as by monitoring the severity of clinical bleeding or other markers of hemorrhage.

Answer 129

o No o Fresh platelet products have a short shelf life; fresh whole blood can be stored at room temperature (22° C) for up to 8 hours, whereas PRP and PC can be stored at room temperature for up to 5 days under continuous gentle agitation.

Answer 130

o Freeze-dried or lyophilized platelets are fixed by a cross-linking agent so that they can withstand the processes of dehydration and rehydration. o A lyophilized canine platelet product, which can be stored at 4°C for up to 12 months, has been studied for canine patients. One study found it to be safe and easy to use. o Because of the shorter lifespan of lyophilized platelets (minutes), their indication is for arresting active hemorrhage rather than for preventing future hemorrhage or raising platelet count.

Answer 131

An immune response to foreign antigens after exposure to genetically different cells or tissues from members of the same species.

Answer 132

o Alloimmunization can occur after repeated platelet transfusions as a result of development of lymphotoxic antibodies in the recipient. o Although the necessity for repeat platelet transfusions is uncommon in veterinary patients, leukoreduction of platelet products can remove the donor’s antigen presenting cells (APC) and decrease the incidence of alloimmunization.

Answer 133

o Inherited - intrinsic or extrinsic o Acquired

Answer 134

o The lack of a functional protein needed for platelet adhesion and aggregation. o The platelets are normal in structure and function.

Answer 135

vonWillebrand's Disease (vWD) in dogs and humans

Answer 136

o It is caused by a deficiency or dysfunction of von Willebrand factor (vWF), a plasma protein of variably sized multimers that mediates platelet hemostatic function, as well as circulates with and stabilizes Factor VIII (FVIII). o Platelets contain only a small amount of vWF in dogs, whereas the richest source is in the endothelial cells.

Answer 137

o Type I is a quantitative reduction in vWF. All multimers are present; however, the concentration is less than adequate for appropriate hemostasis. o Type II vWD patients have measurable reductions in vWF, but the subset of large multimers is scant. This causes a qualitative reduction in vWF because the large multimers are essential for effective hemostatic function. o Type III vWD patients have an absolute lack of vWF altogether. Inheritance is autosomal dominant or recessive in type I but autosomal recessive in types II and III. o No sex predilection has been found.

Answer 138

o Mucosal bleeding (epistaxis, melena, hematuria, gingival hemorrhage) or excessive cavity bleeding after surgery (hemoabdomen, scrotal hematoma) or trauma. o Petechiae and ecchymoses are uncommon. o The clinical signs are worse with type III dogs and can be variable with type I. o In general, the lower the vWF concentration, the higher the risk of bleeding. o However, type II dogs can have severe bleeding because the lack of the high molecular weight vWF multimers is essential to support platelet adhesion.

Answer 139

o Diagnosis of vWD usually begins with suspicious bleeding after vascular injury. o The typical physical examination finding in a known breed affected with vWD leads the clinician to measure a manual and automated platelet count. o Thrombocytopenia must be ruled out before continuation through the ensuing coagulation work-up. o The buccal mucosal bleeding time (BMBT) is the best in vivo assessment of primary hemostasis. However, it is not specific for vWD. Normal BMBT results are less than 3 minutes. A prolonged result is consistent with intrinsic thrombocytopathia or von Willebrand’s disease. o Therefore the measurement of the vWF:antigen concentration is essential to prove the diagnosis of vWD.

Answer 140

o Treatment for a patient with a confirmed diagnosis of vWD is completed with plasma products rich in vWF. o Cryoprecipitate (1 unit/10 kg body weight IV within 8 hours of thaw) is the best choice for transfusion therapy. o Fresh frozen plasma is also an effective therapy for vWD. o Fresh whole blood can be used if the vWD patient is also profoundly anemic in an effort to provide red blood cells and vWF. However, the use of red blood cell–free products prevents sensitization to red blood cell antigens and reduces the risk of volume overload. o For therapy outside of transfusions, avoidance of injury or use of drugs that can impair platelet function is a must. o Desmopressin acetate is used to stimulate endothelial V2 receptors to release intracellular stores of vWF.

Answer 141

o Type 1 vWD patients have some response to DDAVP. o Types II and III have little to no response to DDAVP.

Answer 142

Those inherent to platelets.

Answer 143

o An autosomal recessive disease that manifests as prolonged bleeding times in the presence of normal platelet concentrations. o It is reported in humans and cats but not dogs and is classified as an intrinsic platelet storage pool deficiency. o Patients with CHS have altered lysosomal granule formation and abnormal degranulation in neutrophils and platelets. o Platelet dense granules and/or their constituents are lacking in this disease. Because of this, aggregation response to collagen is absent. o Treatment with platelet concentrates has been shown to correct abnormal oral mucosal bleeding times

Answer 144

o Found in humans and dogs. o Characterized in Otterhounds and Great Pyrenees dogs. o The primary defect leads to a deficiency in the number of the αIIbβ3 integrin. o Mucosal bleeding (epistaxis, gingival and gastrointestinal hemorrhages) and prolonged bleeding times are present because of the lack of fibrinogen binding to this essential integrin. o Successful therapy with perioperative platelet-rich plasma administration has been published in a dog with Glanzmann’s thromboasthenia. o Thrombasthenia = weak platelets

Answer 145

o Yes o Clot retraction is determined by the placement of 5 ml of whole blood into a sterile glass tube (without any anticoagulant). A wooden applicator is inserted into the tube and blood. o The tube then is sealed with plastic paraffin film before incubation at 37°C. o The assessment of clot formation and clot retraction is noted over 8 to 24 hours. Within 2 to 4 hours a normal clot retracts markedly. o Results are recorded as complete clot retraction (retraction occurred and serum was found surrounding the clot) or failed clot retraction (no serum was found surrounding the clot).

Answer 146

o Greater Swiss Mountain Dog o The lack of a functional P2Y12 receptor prevents activation via ADP-induced outside-in signaling for fibrinogen binding on the platelet surface at the αIIbβ3 integrin. o This is important because of the growing use of clopidogrel as an antithrombotic agent. Clopidogrel blocks ADP from binding at the P2Y12 receptor, reducing platelet activation.

Answer 147

Reported in Landseers, Basset Hounds, and Spitz dogs

Answer 148

o Has been found in related and unrelated German Shepherd Dogs. Autosomal recessive. o Inability for phosphatidylserine to be externalized for the creation of a procoagulant surface. These dogs also have a decreased microparticle release compared with nonaffected GSD. o The clinical findings from CSS dogs include epistaxis, postoperative hemorrhage, and spontaneous soft tissue hemorrhage. o Diagnosis requires flow cytometry. o Spontaneous hemorrhage in these dogs cannot be prevented by treatment; however, perioperative dimethylsulfoxide cryopreserved PRP transfusions plus a postoperative antifibrinolytic agent has been used with success.

Answer 149

o Idiopathic asymptomatic macrothrombocytopenia in Cavalier King Charles Spaniels (CKCS) is another inherited autosomal recessive platelet defect. o A mutation in β1-tubulin likely leads to altered proplatelet formation in megakaryocytes. o It also has been reported in related Norfolk Terriers. o CKCS have not been found to have any clinical bleeding or any abnormalities on platelet aggregation testing.

Answer 150

o Drugs o vWD o Uremia

Answer 151

o In people, secondary to aspirin, ticlopidine, clopidogrel, as well as some antibiotics and nonsteroidal antiinflammatory drugs. o These findings may be similar in dogs and cats; however, not all antiinflammatory drugs have a similar effect on laboratory measurements of hemostasis. o DDAVP has been used IV to reverse acquired acetylsalicylic acid-induced coagulopathy in three dogs.

Answer 152

o vWD is encountered less commonly as an acquired disorder and is caused by defects in vWF concentration, structure, or function that is not directly inherited. o They are the result of other medical conditions in humans (and likely in animals), such as autoimmune clearance or inhibition of vWF (i.e., myeloproliferative diseases, some cancers, immune-mediated diseases), increased shear-induced proteolysis of vWF (i.e., cardiovascular lesions or pulmonary hypertension), or increased binding of vWF to platelets and other cell surfaces. o In veterinary patients hypothyroidism and treatment with hydroxyethyl starch and dextran solutions also have been implicated in acquired vWD. o Other drugs reported to lead to the syndrome of acquired von Willebrand’s disease in humans include ciprofloxacin, griseofulvin, and valproic acid.

Answer 153

o Uremic patients are well recognized to have prolonged BMBT and delayed formation of the primary hemostatic plug. These abnormalities are due to defects in platelet adhesion, secretion, and aggregation. o Defects in vWF function are thought to play a major role. Uremic patients have been found to have normal to increased vWF levels, but platelet function can be improved in the uremic patient by transfusion of cryoprecipitate or administration of DDAVP. o In addition, uremic patients produce increased levels of NO and prostacyclin that can alter vascular tone and platelet function. o Some of the uremic toxins are believed to act as direct platelet inhibitors by competing for receptor binding. o Anemia, a common finding in uremic patients, also is believed to play an important role in altering platelet interactions with the vessel walls and reduced NO scavenging ability. o Many of these platelet function defects can be reversed by dialysis, suggesting that much of the acquired thrombocytopathy of uremia is due to circulating uremic toxins

Answer 154

o Alpha granules - adhesion molecules (P-selectin, vWF), coagulation factors (FV, FVII) o Dense granules - ADP, histamine, serotonine, Ca2+, Mg2+ epinephrine o Several protein membranes can be stored in the granules and be expressed with activation

Answer 155

o Inflammatory pathways o Immunity & anaphylaxis o Turbo growth and metastasis o Angiogenesis o Endothelial interaction - maintenance - important to maintain normal endothelial function -> stabilize intracellular junctions (VE cadherin bonds). Spontaneous petechia and GI bleed is because lack of PLT causes unstable endothelial bonds.

Answer 156

In 3 zones: peripheral zone, sol-gel zone and an organelle zone

Answer 157

o Has a thicker glycocalyx (GP–polysaccharide covering) than other blood cells, and it has randomly distributed apertures of the open canalicular system. o The glycocalyx is the site of first contact with the surrounding milieu. It contains surface GPs required for the interaction of platelets with subendothelial structures of the injured vessel wall, PLT activation, PLT adhesion and aggregation, as well as clot retraction. o In particular, the mobile receptor complexes GPIb-IX-V and integrin αIIbβ3 are abundantly expressed on the surface of resting PLT and are of great importance in hemostasis o Below the glycocalyx is the lipid bilayer -> incompressible and unstretchable. Consequently, additional membrane needed for platelet spreading must be provided by the internalized membrane parts of the open canalicular system. o It contains tissue factor (TF), which is exposed on the platelet surface in its inactive form along with negatively charged phosphatidylserine following platelet activation. o Activated PLT release TF-bearing MP capable of binding coagulation factors Va, VIIa, and Xa to their surface phosphatidylserine. Through the interaction of these coagulation factors with the TF, thrombin generation is enhanced on the surface of activated PLT as well as on platelet-derived MP. o The platelet’s submembrane area -> under the lipid bilayer and is of great importance. It contains a system of thin actin filaments (contractile cytoskeleton) which is required for PLT shape change and the translocation of receptors and particles over the platelet’s surface. o In the submembrane compartment, the cytoplasmic domains of all transmembrane receptors interact with proteins, many of which are associated with calmodulin, myosin, and actin filaments. They regulate the signaling processes required for platelet activation.

Answer 158

o The transparent yet viscous matrix inside platelets is labeled the sol-gel zone. o It resembles liquid gel and contains organized microtubules and microfilaments, randomly distributed glycogen, a few smooth and clathrin-coated vesicles, as well as secretory organelles. o Microtubules are arranged in circumferential coils close to the cell wall, thereby forming a system that supports the membrane contractile cytoskeleton. o Actin microfilaments in the sol-gel zone form the cytoplasmic actin filament cytoskeleton, in which all organelles are suspended and which keeps organelles apart from each other and from the cell wall in the resting platelet. o Following platelet activation, the cytoplasmic actin system constricts the microtubule coils moving α-granules and dense bodies to the platelet center, which may ultimately result in the secretion of their contents through the open canalicular system.

Answer 159

o Three major types of secretory organelles are present in platelets: α-granules, dense granules, and lysosomes. o In addition, platelets contain simple mitochondria, which are important for their energy metabolism, glycosomes, and tubular inclusions.

Answer 160

o Alpha granules: 50-80 per PLT (most frequent)

Answer 161

o 3-8 per platelet

Answer 162

o 0-3 per platelet

Answer 163

o The open canalicular system is a part of the platelet’s surface membrane, which extends toward the interior of the platelet and in doing so forms a tubular structure, which exerts three major functions. o Its channels can be used for the transport of plasma components such as fibrinogen to α-granules. o Can also serve as route for the release of granular contents during platelet activation. o The channels of the open canalicular system can be evaginated and thereby provide membrane parts needed for platelet spreading following platelet adhesion to an injured vessel wall. o Through this mechanism, activated platelets are able to increase their surface area more than fourfold compared with resting discoid platelets.

Answer 164

o The open canalicular system is a part of the platelet’s surface membrane, which extends toward the interior of the platelet and in doing so forms a tubular structure, which exerts three major functions. o Its channels can be used for the transport of plasma components such as fibrinogen to α-granules. o Can also serve as route for the release of granular contents during platelet activation. o The channels of the open canalicular system can be evaginated and thereby provide membrane parts needed for platelet spreading following platelet adhesion to an injured vessel wall. o Through this mechanism, activated platelets are able to increase their surface area more than fourfold compared with resting discoid platelets.

Answer 165

o Following platelet activation, membrane- bound granule proteins are expressed on the platelet surface, whereas soluble granule proteins are released into the extracellular compartment. o Most of the membrane-bound proteins are already present on the surface of resting platelets, for example, integrins such as αIIbβ3, immunoglobulin family receptors such as GPVI, Fc receptors (FcR), platelet endothelial cell adhesion molecule, the GPIb-IX-V complex, tetraspanins, CD36, and Glut-3. o However, some membrane-associated proteins including fibrocystin L, CD109, and P-selectin are exclusively expressed on the surface of activated, rather than resting, platelets. In particular, platelet surface P-selectin expression is therefore widely used as a sensitive flow cytometric marker of platelet activation

Answer 166

o Following platelet activation, platelet granules accumulate in the cell center during platelet shape change, and may fuse with one another. o In a further step, granules fuse with the open canalicular system releasing their contents into its channels and thereby finally to the extracellular space. o Another mechanism of granule release is the direct fusion of platelet granules with the plasma membrane. o The platelet cytoskeleton is also involved in granule secretion. Actin polymerization facilitates granule secretion during platelet activation. o Similar to other cells, the increase of intracellular Ca2+ supports granule secretion in platelets. o Finally, several protein C kinase take part in the platelet release reaction.

Answer 167

o Platelet surface glycoprotein o GPIb-IX-V propagates the adhesion of activated platelets to endothelial cells and subendothelial structures of the injured vessel wall, mainly by binding its most important ligand VWF, which is itself able to bind collagen. o Another ligand for GPIb-IX-V is thrombospondin, which seems to mediate platelet adhesion at high shear rates in the absence of VWF. o GPIb-IX-V has procoagulant activity on activated platelets by providing binding sites for α-thrombin, factor XI, and high-molecular- weight kininogen.

Answer 168

o GPVI is the major signaling receptor for collagen on human platelets. o GPVI belongs to the immunoglobulin superfamily of receptors. o Platelets adhere to exposed collagen fibers by binding of immobilized VWF to GPIb-IX-V. o This allows binding of collagen to low-affinity GPVI and results in intracellular signals with subsequent inside-out activation of integrins including α2β1 and αIIbβ3 as well as further clustering of GPVI.

Answer 169

o Platelet surface integrin αIIbβ3 (previously termed GPIIb/IIIa) is transformed from its resting low-affinity state to a high- affinity receptor as the final step of platelet activation and subsequently mediates platelet aggregation at a molecular level. o Agonist-induced platelet activation triggers intracellular signaling ultimately resulting in the transformation of the extracellular domain of αIIbβ3 into a high-affinity receptor for fibrinogen and VWF. o By binding fibrinogen or multivalent VWF, activated αIIbβ3 enables platelet–platelet interactions and consequently the formation of platelet aggregates.

Answer 170

o vWs and collagen induced platelet activation o Thrombin - activates PLT via PARs receptors (G coupled protein receptors) o ADP - activates platelets via P2Y1 and P2Y12 receptors (G coupled protein receptors) - coactivation of both is necessary for full platelet aggregation.

Answer 171

o Deficiencies in the initial components of the intrinsic pathway (FXII, HMWK, or PK) cause marked prolongation of the aPTT, but they are not associated with a tendency for bleeding in mice or humans. o Furthermore, FXII is clearly not required for normal hemostasis because some mammalian species (such as whales and dolphins) do not have this protein. o FXI (hemophilia C) is associated with variable hemostatic deficits in humans. o In contrast, deficiency in FVIII and FIX results in the serious bleeding tendencies seen with hemophilia A and B, despite the fact that these patients have an intact extrinsic pathway. o Similarly, deficiency of the primary enzyme of the extrinsic pathway (FVII) can be associated with bleeding, despite the presence of an intact intrinsic pathway.

Answer 172

o Primarily via the contribution of membrane surfaces to coagulation processes.

Answer 173

o Other coagulation proteins (FVII, FIX, FX, prothrombin, protein C, protein S, protein Z) contain glutamic acid (Gla) residues that allow for binding of the protein to a membrane surface via interaction between calcium and negatively charged phospholipids. o Calcium binding of the Gla regions of these proteins requires that their Gla residues be carboxylated via the vitamin K cycle in the liver. o Without complete carboxylation, these Gla proteins do not develop the required ability to properly bind calcium. o As calcium binding is necessary for interaction of the Gla residues with the membrane surface, Gla proteins that have not been adequately carboxylated are unable to properly bind the activated membrane surface. o The importance of carboxylation in membrane binding is dramatically illustrated by the profound adverse impact that vitamin K antagonists, such as warfarin, have on the ability of Gla proteins to function in hemostasis.

Answer 174

o In the inactive resting membrane state, neutral phospholipids (primarily phosphatidylcholine, sphingomyelin, and sugar-linked sphingolipids) are located on the external leaflet of the membrane, and phosphatyldserine (PS) and phosphatidylethanolamine (PE) are localized to the inner surface of the membrane. o This membrane asymmetry is essential and tightly controlled under normal conditions. o When cells are activated or injured, they shuffle the PS and PE to the outer membrane leaflet. This membrane phospholipid shuffling is controlled by a variety of enzymes. Flippase actively transports PS from the external to the internal leaflet while floppase transports PC in the opposite direction. These ATP-dependent enzymes maintain asymmetry in the resting state. o When a cell is activated or injured (such as occurs when platelets are exposed to platelet activators, or when other cell types are stimulated to undergo apoptosis) the enzyme scramblase actively shuffles the phospholipids between the 2 surfaces in response to increased concentrations of calcium in the cytosol. This results in the appearance of PS and PE on the external membrane surface.

Answer 175

o The expression of PS and PE on the cell surface has a profound impact on the procoagulant properties of the membrane surface. o It is known that the presence of PS on the membrane markedly increases the speed of some coagulation reactions. Less PS is required for maximum speed when PE is present. o It is currently thought that Gla proteins preferentially bind to PS clusters on the membrane surface, and that PE aids in grouping PS into these clusters. o The expression of PS (particularly with PE) on the external leaflet turns the cell membrane into a procoagulant surface. Because coagulation reactions occur very slowly on membranes that do not contain PS, resting cells are essentially incapable of supporting the coagulation cascade. o Under normal physiologic conditions cells do not express a procoagulant membrane. Consequently, generation of coagulation enzymes is extremely slow, and insufficient to generate enough fibrin to form a clot. o Production of thrombin is consequently limited to surfaces of cells in an injured area that have been triggered to express a procoagulant membrane. As a result, the ability of cells to control the nature of their membrane surface constitutes a powerful method of regulating coagulation reactions.

Answer 176

o Microparticles (MPs) are intact vesicles derived from cells which are surrounded by membranes. They arise when activated or apopototic cells shed bits of membrane. o Cytokines (TNF, IL6), thrombin, shear stress, and hypoxia can stimulate MP formation. o Under normal conditions MPs are primarily derived from endothelial cells, platelets and monocytes, but in certain disease states, MPs may arise from granulocytes and erythrocytes. o The quantity of circulating MPs is increased in certain illnesses such as diabetes mellitus, sepsis, and cardiovascular disease and may contribute to pathologic coagulation in a variety of disorders. o MPs contain cell surface proteins similar to those found on their parent cell (eg, ultra large vWF monomers on endothelial cell-derived MPs, P-selectin on platelet-derived MPs, TF on monocyte-derived MPs) that can participate in coagulation reactions, especially when the MP expresses a procoagulant membrane.

Answer 177

o Nonactivated resting endothelial cells express a number of other anticoagulant proteins on their surface. These include heparan sulfated proteoglycans, thrombomodulin, and tissue factor pathway inhibitor. o Endothelial cells produce HSPGs, a small amount of which is expressed on the luminal surface in contact with the flowing blood. The HSPGs are a binding site for antithrombin (AT), which then is fully capable of inactivating thrombin produced in the vicinity of the HSPG. The inactivation of thrombin by HSPG-AT is similar to that by heparin-AT which we exploit clinically when administering soluble (nonmembrane bound) forms of heparin. o Resting endothelial cells also express TM on their surface. Thrombin, once bound to TM, converts from a procoagulant to an anticoagulant protein because the thrombin-TM complex rapidly activates protein C (aPC). aPC (with its cofactor protein S [ProS]) then irreversibly cleaves FVa and FVIIIa, preventing their further participation in generation of additional new thrombin molecules. o aPC-ProS also inactivates plasminogen activator inhibitor 1 (PAI-1) which ultimately upregulates lysis of any fibrin that is formed. It is important to note that expression of TM is 100-fold higher in capillary endothelium as compared with endothelium in the major vessels. Therefore, any thrombin circulating in large vessels will be quickly extracted when the blood passes through a capillary. o TFPI on the endothelial cell surface prevents additional thrombin generation by acting as an upstream inhibitor of FXa and FVIIa. It irreversibly binds to FXa, then forms a quaternary complex between TFPI, FXa, FVIIa, and TF, preventing further generation of thrombin

Answer 178

o TF bearing cells o Platelets

Answer 179

o Initiation o Amplification o Propagation

Answer 180

Tissue factor

Answer 181

o Cells expressing TF are generally localized outside the vasculature, which prevents initiation of coagulation under normal flow circumstances with an intact endothelium. o Some circulating cells (eg, monocytes or tumor cells) and MPs may express TF on their membrane surface, but this TF under normal conditions is thought to be inactive or encrypted.

Answer 182

FVIIa 1% FVII FVIIa All other coagulation proteins circulate solely as zymogens

Answer 183

o The TF-FVIIa complex then activates additional FVII to FVIIa, allowing for even more TF-FVIIa complex activity, which then activates small amounts of FIX and FX. o Although it occurs slowly, FV can be activated directly by FXa. o The FXa generated by TF-FVIIa binds to the few generated molecules of its cofactor FVa to form the prothrombinase complex, which subsequently cleaves prothrombin and generates a small amount of thrombin. o Any FXa that dissociates from the membrane surface of the TF-bearing cell is rapidly inactivated by either TFPI or AT. o The FXa generated is consequently effectively restricted to the surface of the TF-bearing cell on which it was generated. o However, the FIXa generated can dissociate and move to the surface of nearby platelets or other cells. FIXa is not inhibited by TFPI, and much more slowly inhibited by AT than is FXa. o Because TF is always expressed in the perivascular space, any FVIIa that leaves the vasculature through minor breaks in the endothelial barrier will bind to TF and potentially initiate coagulation.

Answer 184

Coagulation progresses only when the injury allows platelets and larger proteins to leave the vascular space and adhere to the TF-bearing cells in the extravascular area.

Answer 185

o Once a small amount of thrombin has been generated on the surface of a TF-bearing cell (the initiation phase), that thrombin diffuses away from the TF-bearing cell and is available for activation of platelets that have leaked from the vasculature at the site of injury. o Binding of thrombin to platelet surface receptors causes extreme changes in the surface of the platelet, resulting in shape change, shuffling of membrane phospholipids to create a procoagulant membrane surface, and release of granule contents that provide additional fuel for the fire. o Platelet granules contain a large number of proteins and other substances that include raw materials for clotting reactions and agonists to induce further platelet activation. o Calcium may induce clustering of PS (increasing the procoagulant nature of the membrane), and promotes binding of coagulation proteins to the activated membrane surface. o In addition to activating platelets, the thrombin generated in the initiation phase cleaves FXI to FXIa and activates FV to FVa on the platelet surface. o Thrombin also cleaves von Willebrand factor off of FVIII (they circulate bound together), releasing it to mediate platelet adhesion and aggregation. The released FVIII is subsequently activated by thrombin to FVIIIa.

Answer 186

o Once a few platelets are activated in the amplification phase, the release of the granule contents results in recruitment of additional platelets to the site of injury. o The propagation phase occurs on the surface of these platelets. Expression of ligands on their surface results in cell–cell interactions that lead to aggregation of platelets. o FIXa that was generated by TF-FVIIa in the initiation phase can bind to FVIIIa (generated in the amplification phase) on the platelet surface. Additional FIXa is generated due to cleavage of FIX by FXIa that was generated during amplification on the platelet surface. o Once the intrinsic tenase complex forms (FIXa– FVIIIa) on the activated platelet surface, it rapidly begins to generate FXa on the platelet. o FXa was also generated during the initiation phase on the TF-bearing cell surface. As this FXa is rapidly inhibited if it moves away from the TF-bearing cell surface, it can not easily reach the platelet surface. o The majority of FXa must therefore be generated directly on the platelet surface through cleavage by the intrinsic tenase complex. o The FXa generated on platelets then rapidly binds to FVa (generated by thrombin in the amplification phase) and cleaves prothrombin to thrombin. o This prothrombinase activity results in a burst of thrombin generation leading to cleavage of fibrinopeptide A from fibrinogen. When enough thrombin is generated with enough speed to result in a critical mass of fibrin, these soluble fibrin molecules will spontaneously polymerize into fibrin strands, resulting in an insoluble fibrin matrix.

Answer 187

o Thrombin will activate FXIII to FXIIIa -> will cross-link fibrin strands and add strength and elasticity to the clot. o Some of the thrombin generated will bind to thrombomodulin on the endothelial cell surface. The TM/thrombin complex will have several functions. o TM/Thrombin will activate thrombin activatable fibrinolysis inhibitor (TAFI) -> TAFI will remove terminal lysin residues from fibrin -> lysin is target of many fibrinolytic proteins, making fibrin more resistant to fibrinolysis. o TM/Thrombin -> will activate PC (aPC). aPC forms a complex with cofactor protein S, which will cleave FVa and FVIIIa -> shuts down new generation of thrombin.

Answer 188

o Inevitably, some proteases diffuse away from the vicinity of the activated platelets and are carried downstream. o The lack of a procoagulant membrane on resting endothelial cells that are located away from the site of injury prevents efficient generation of thrombin by any FXa that diffuses away from the cell surface and is carried through the vasculature. o FXa and thrombin are also effectively inhibited by the endothelial cell surface associated anticoagulant systems including AT and TFPI. o Furthermore, thrombin generation is limited because aPC/ProS is a much better inactivator of FVa on the endothelial cell surface than on the platelet surface. This means that aPC/ProS is efficient at limiting thrombin generation on healthy resting endothelial cells, but not efficient at inhibiting generation of thrombin on activated platelets.

Answer 189

Population - define population of interest Intervention - treatment choice of interest, Comparison - represents the alternative treatment choice we wished to compare Outcome - patient-centered measures such as reductions in thrombosis, diminished organ dysfunction, or improvements in survival were prioritized

Answer 190

o Patient o Exposure o Comparison o Outcome o Questions formatted to compare the effect of exposure to the risk factor or development of the disease (Exposure) versus remaining disease free (Comparison) on development of thrombosis (Outcome). o Example: In dogs (P), is the development of cardiac disease (E) as opposed to remaining disease free (C) associated with the development of thrombosis (O)?

Answer 191

o Immune-mediated hemolytic anemia (dogs only) - strongly associated with the development of thrombosis in dogs. We recommend antithrombotic therapy for dogs with IMHA. o Protein-losing nephropathy (dogs only) - associated with the development of thrombosis in dogs. We recommend antithrombotic therapy for dogs with PLN. o Pancreatitis (dogs only) - severe pancreatitis, in particular acute necrotizing pancreatitis, may be associated with the development of thrombosis in dogs. We suggest that antithrombotic therapy be considered for dogs with acute pancreatic necrosis, particularly when concurrent prothrombotic conditions are present. o Glucocorticoid administration (dogs only) - corticosteroid administration favors a hypercoagulable state. Treatment with corticosteroids may be associated with the development of thrombosis in dogs, in particular those with other risk factors for thrombosis. We suggest that antithrombotic therapy be considered for dogs receiving corticosteroids where other risk factors for thrombosis exist.

Answer 192

o Hyperadrenocorticism (dogs only) - is associated with the development of thrombosis in a small subset of dogs only. We suggest HAC alone does not warrant antithrombotic therapy in the majority of dogs, unless other risk factors for thrombosis exist. o Cancer (dogs only) - in particular (adeno)carcinoma, is associated with the development of thrombosis in a small subset of dogs only -> insufficient evidence to support routine anticoagulation of dogs with cancer. We suggest that antithrombotic therapy be considered for dogs with cancer where hypercoagulability is demonstrated, or where other risk factors for thrombosis exist. o Sepsis (dogs only) - is associated with the development of thrombosis in a small subset of dogs only -> insufficient evidence to support routine anticoagulation of dogs with sepsis. We suggest that antithrombotic therapy be considered for dogs with sepsis where hypercoagulability is demonstrated, or where other risk factors for thrombosis exist. o Cerebrovascular disease - is more likely to result from a thrombotic event rather than be the cause of one. We suggest that antithrombotic therapy be considered when an ischemic stroke is identified and a concurrent medical condition associated with a risk for thrombosis is present. o Heart disease (cats) - is strongly associated with a risk of ATE. Cats with a history of ATE, left atrial (LA) dilation, spontaneous echocontrast, or reduced LA appendage flow velocity may be at particular risk. We recommend antithrombotic therapy for cats with cardiomyopathy, particularly in those with the above risk factors. o Heart disease (dogs) - is not associated with a high risk for the development of thrombosis. We suggest that antithrombotic therapy be considered in individual dogs where other risk factors for thrombosis exist.

Answer 193

o Dogs with IMHA or PLN. o Cats with cardiomyopathy and associated risk factors o Dogs or cats with >1 disease/risk factor for thrombosis (eg,pancreatitis with sepsis).

Answer 194

o Dogs or cats with a single risk factor/disease. o Dogs or cats with known risk factor conditions that, with treatment, are likely to resolve in days to weeks.

Answer 195

o Antiplatelet agents versus anticoagulants for VTE (dogs) - We suggest that anticoagulants may be more effective than antiplatelet agents for venous thromboembolism (VTE) prevention in dogs in general and in dirofilariasis specifically. o Antiplatelet agents versus anticoagulants for ATE (dogs) - We suggest that antiplatelet agents may be more effective than anticoagulants for the prevention of ATE in dogs. We suggest that anticoagulants may also be effective for prevention of ATE in dogs. o Antiplatelet agents versus anticoagulants for VTE (cats) - no evidence-based recommendations can be made regarding the use of antiplatelet agents for VTE in cats. We suggest that anticoagulants rather than antiplatelet agents be used for the prevention of VTE in cats. o Antiplatelet agents versus anticoagulants for ATE (cats) - We recommend that antiplatelet agents be used for the prevention of ATE in cats. No evidence-based recommendations can be made regarding the use of anticoagulants for ATE in cats.

Answer 196

o Clopidogrel versus aspirin (dogs) - there is insufficient evidence to make strong recommendations regarding clopidogrel versus aspirin in dogs. We suggest that clopidogrel may be more effective than aspirin in dogs at risk for ATE. o Clopidogrel versus aspirin (cats) We recommend that clopidogrel be used instead of aspirin in cats at risk for ATE. There is no evidence on which to base recommendations regarding the use of aspirin or clopidogrel in cats at risk for VTE. o New antiplatelet agents versus clopidogrel or aspirin (dogs) - There is insufficient evidence to make recommendations regarding the use of new antiplatelet agents versus clopidogrel or aspirin in dogs. We suggest that both abciximab and ticagrelor appear safe and may be efficacious antiplatelet agents in dogs. o New antiplatelet agents versus clopidogrel or aspirin (cats) - There is insufficient evidence to make recommendations regarding the use of new antiplatelet agents versus clopidogrel or aspirin in cats. We suggest that abciximab appears safe and may be efficacious as an antiplatelet agent in cats.

Answer 197

o UFH versus LMWH (dogs) - there is insufficient evidence to make strong recommendations regarding the use of UFH versus LMWH in dogs. We suggest that LMWH may be used in preference to UFH because of the positive safety profile of LMWH and more reliable bioavailability of the LMWH products compared to UFH. o UFH versus LMWH (cats) - No evidence-based recommendations can be made regarding the use of UFH versus LMWH in cats. We suggest that LMWH may be used in preference to UFH because of the documented efficacy of LMWH and the positive safety profile of LMWH. o Direct Xa inhibitors versus UFH (dogs) - There is insufficient evidence to make strong recommendations regarding the use of the direct Xa inhibitors versus UFH in dogs. We suggest the direct Xa inhibitors may be used in preference to UFH based on evidence of equivalent efficacy, combined with reliable pharmacokinetics and the ease of oral dosing. o Direct Xa inhibitors versus UFH (cats) - No evidence-based recommendations can be made regarding the use of the direct Xa inhibitors versus UFH in cats. We suggest that the direct Xa inhibitors can be considered in cats based on reliable pharmacokinetics and a favorable preliminary safety profile.

Answer 198

o Direct Xa inhibitors versus LMWH (dogs) - there is insufficient evidence to make strong recommendations regarding the use of the direct Xa inhibitors versus LMWH in dogs. We suggest that use of either the direct Xa inhibitors or LMWH in dogs is reasonable. o Direct Xa inhibitors versus LMWH (cats) - no evidence-based recommendations can be made regarding the use of the direct Xa inhibitors versus LMWH in cats. We suggest that use of either the direct Xa inhibitors or LMWH in cats is reasonable. o UFH versus warfarin and LMWH versus warfarin (dogs and cats) - there is insufficient evidence to make strong recommendations regarding the efficacy of heparin products versus warfarin in dogs or cats.We suggest that UFH or LMWH be used in preference to warfarin. o Direct Xa inhibitors versus warfarin (dogs and cats) - no evidence-based recommendation can be made regarding the efficacy of direct Xa inhibitors versus warfarin in dogs or cats. We suggest that the direct Xa inhibitors be used in preference to warfarin in both dogs and cats.

Answer 199

o Combination anticoagulant and antiplatelet therapy for VTE (dogs) - We suggest that administration of aspirin or clopidogrel in addition to LMWH or individually adjusted UFH therapy may be considered in dogs at high risk of VTE, where the risk of clot formation is felt to outweigh the increased risk of bleeding resulting from combination therapy. o Combination anticoagulant and antiplatelet therapy for VTE (cats) - there is insufficient evidence to make strong recommendations regarding combination anticoagulant and antiplatelet agent therapy in cats. We suggest that combination therapy may be considered where there is a high risk of thrombosis and the risk of clot formation is felt to outweigh the increased risk of bleeding resulting from combination therapy. o Combination antiplatelet and anticoagulant therapy for ATE (dogs) - there is insufficient evidence to make strong recommendations for or against the use of combination antiplatelet and anticoagulant therapy in dogs at risk for ATE. We suggest that administration of clopidogrel or aspirin with LMWH may be considered in dogs at risk for ATE. o Combination antiplatelet and anticoagulant therapy for ATE (cats) - no evidence-based recommendations can be made regarding the addition of anticoagulants to antiplatelet agents for ATE in cats. We suggest that administration of clopidogrel in combination with LMWH may be considered in cats at risk for ATE.

Answer 200

o Aspirin (dogs) - we suggest that oral aspirin may be effective for prevention of ATE in dogs. No evidence-based recommendations can be made for a specific aspirin dosage in dogs. We suggest that aspirin be given for 2–3 days before full therapeutic effects of aspirin are anticipated, although commencement of aspirin therapy after an arterial insult may still be effective at preventing thrombosis. No recommendations can be made for, or against, use of aspirin for VTE in dog o Aspirin (cats) - we recommend against aspirin as a sole antithrombotic in cats at risk for ATE. No recommendations can be made concerning appropriate aspirin dosage in cats.

Answer 201

o Clopidogrel (dogs) a. We recommend clopidogrel at 1.1–3mg/kg PO every 24h for the prevention of ATE in dogs. b. We suggest a single oral loading dose (4–10mg/kg) may be useful for obtaining therapeutic plasma concentrations more rapidly. c. No recommendations can be made for, or against, use of clopidogrel as a sole agent for VTE in dogs. Clopidogrel (cats) a. We recommend clopidogrel at 18.75mg total PO every 24h for prevention of ATE in cats. b. We suggest a single oral loading dose (37.5mg total) may be useful for obtaining therapeutic plasma concentrations more rapidly. c. No recommendations can be made for, or against, use of clopidogrel for VTE in cats.

Answer 202

o Warfarin (dogs) - we suggest that warfarin should not be used in dogs because it inconsistently improves outcomes and is commonly associated with bleeding complications. o Warfarin (cats) - no evidence-based recommendations can be made regarding the use of warfarin in cats at risk for thrombosis. We suggest that warfarin should not be used in cats because of marked interindividual variation coupled with a narrow therapeutic index.

Answer 203

Unfractionated heparin (dogs) a. UFH can be effectively administered by the IV or SC routes in dogs. b. Optimal UFH dose likely varies in individual dogs to maximize antithrombotic effects and minimize hemorrhagic complications. c. We suggest an initial IV dosing scheme of 100 U/kg bolus, then 480–900 U/kg every 24h (20–37.5 U/kg every hour) constant rate infusion in dogs. d. We suggest an initial SC dosage of UFH of 150–300 U/kg every 6h in dogs. e. We recommend that UFH is not administered by inhalation or PO in dogs. Unfractionated heparin (cats) a. Only a SC route of administration of UFH has been investigated in cats. b. We suggest an initial SC dosage of UFH of 250U/kg every 6h in cats.

Answer 204

Dalteparin (dogs) a. We suggest an initial SC dosage of 100–175U/kg every 8h in dogs. b. Minor bleeding may be noted at the doses reported above, but serious bleeding is unlikely. Dalteparin (cats) a. In cats, frequent SC administration is likely necessary for maintenance of the human target anti-Xa range. b. We suggest lower dosages compared to dogs may be acceptable at increased frequency, for example, 75 U/kg SC every 6 hours. c. Bleeding complications, usually minor and self-limiting, may occur with a variety of dosing schemes.

Answer 205

Enoxaparin (dogs) a. We suggest enoxaparin at a dosage of 0.8mg/kg SC every 6h is safe and well tolerated in dogs. b. This dose may not achieve anti-Xa levels considered to be therapeutic in people in all breeds of dog. c. Only minor bleeding complications have been reported in association with enoxaparin use in dogs. Enoxaparin (cats) a. We suggest enoxaparin at a dosage of 0.75–1 mg/kg SC every 6 12h should be considered in cats with a risk of VTE. b. We suggest enoxaparin be administered every 6 hours to reduce interindividual variation in peak anti-Xa activity.

Answer 206

Fondaparinux (dogs and cats) a. No studies of fondaparinux in dogs were identified. b. A dose of fondaparinux of 0.06 or 0.20mg/kg SC every 12hours was sufficient to achieve a peak plasma anti-Xa activity in cats considered effective in people, without bleeding complications.

Answer 207

Rivaroxaban (dogs) a. Based on preliminary data, rivaroxaban appears safe and well tolerated in dogs. b. We suggest a dosage of 1–2mg/kg per day in dogs. Rivaroxaban (cats) a. Based on preliminary data, rivaroxaban appears safe and well tolerated in cats. b. We suggest a dosage of 0.5–1mg/kg per day in cats.

Answer 208

a. Adjusting therapy to achieve platelet inhibition via platelet aggregometry in dogs receiving aspirin therapy can be considered. b. Some evidence suggests that in dogs receiving aspirin, platelet inhibition detectable via aggregometry (various agonists) is associated with reduced risk of ATE. c. Monitoring techniques are currently too varied to provide uniform recommendations at this time.

Answer 209

a. We suggest that warfarin should not be used in dogs or in cats. b. If warfarin is used, we recommend monitoring warfarin therapy ideally with PTINR (PT—prothrombin time; INR—international normalized ratio) to achieve a target of 2–3 or 1.5–2.0 times the base- line PT. c. Close therapeutic monitoring, particularly early in the course of therapy, is indicated to maximize efficacy and reduce the risk of complications.

Answer 210

a. We recommend anti-Xa activity for UFH monitoring in dogs because evidence supporting the use of other monitoring tests (eg, activated clotting time, activated partial thromboplastin time, thromboelastography, and Sonoclot) is limited at this time. b. An anti-Xa target of 0.35–0.7U/mL is recommended in dogs to minimize thrombosis risk and improve outcome, although minor hemorrhage may still occur. c. There is insufficient evidence to make a strong recommendation for a specific anti-Xa target in cats. d. We suggest an anti-Xa target of 0.35–0.7U/mL is reasonable in cats until more evidence is available.

Answer 211

a. There is insufficient evidence to make strong recommendations for therapeutic monitoring of LMWH in dogs or cats. b. We suggest adjusting therapy in dogs, targeting anti-Xa levels of 0.5–1.0U/mL 2–4 hours after dose can be considered.

Answer 212

a. In patients at high risk for thrombosis, anticoagulation should not be discontinued for invasive procedures. b. In patients at low to moderate risk for thrombosis, consideration may be given for discontinuation of anticoagulation prior to invasive procedures.

Answer 213

High risk a. We recommend that antiplatelet therapy with a single antiplatelet agent should be continued. b. We recommend discontinuing 1 agent if animals are receiving dual antiplatelet therapy. c. We suggest that these patients are at increased risk of bleeding and that close attention be paid to surgical hemostasis. Low/moderate risk a. We recommend that antiplatelet agents should be discontinued prior to the planned procedure.

Answer 214

High risk a. We recommend that heparin therapy should not be discontinued. b. We recommend that surgery be planned to occur at nadir of anticoagulant effect (approximately 6–8 hours after prior dose if given by subcutaneous injection). c. We suggest that these patients are at increased risk of bleeding and that close attention be paid to surgical hemostasis. Low/moderate risk a. We recommend that consideration may be given to taper (UFH) or stop (LMWH) therapy prior to a procedure.

Answer 215

High risk a. We recommend against withdrawing antiplatelet agents within 5 days of a procedure. Low/moderate risk a. We recommend that antiplatelet agents be discontinued within 5 days of a procedure.

Answer 216

High risk patient a. We recommend that in patients at high risk, antithrombotic therapy should be restarted as soon as possible after surgery provided there is no evidence of ongoing bleeding. Low/moderate risk patient a. No evidence-based recommendation can be made for patients at low/moderate risk. b. We suggest that in patients at low/moderate risk, antithrombotic therapy be restarted once there is no evidence of ongoing bleeding. Patients that develop thrombosis a. We recommend that antithrombotic therapy should be initiated immediately in patients that develop thrombosis in the postoperative period.

Answer 217

Arterial blood clot is no longer identifiable a. We recommend that if the underlying causative conditions have resolved, antithrombotic therapy should be discontinued following thrombus resolution. b. In patients with unknown underlying conditions or where these conditions cannot be cured or resolved, we recommend antithrombotic therapy should be continued indefinitely. Venous blood clot is no longer identifiable a. We recommend that if the underlying causative conditions have resolved, that antithrombotic therapy should be discontinued following thrombus resolution. b. In patients with unknown underlying conditions or where these conditions cannot be cured or resolved, we recommend antithrombotic therapy should be continued indefinitely. c. In patients with a low or moderate risk of thrombosis, we suggest that the risk of hemorrhage and the ability of the animal to tolerate antithrombotic therapy should be weighed against the risk of recurrence of the prothrombotic condition.

Answer 218

Weaning of UFH therapy a. We recommend that if UFH is administered as an IV constant rate infusion, it should be tapered (weaned) rather than abruptly discontinued. b. Clinicians should consider weaning UFH therapy administered by the subcutaneous route. Weaning of LMWH therapy a. Clinicians do not need to wean LMWH therapy prior to discontinuation. Weaning of direct Xa inhibitor therapy a. Clinicians should consider weaning direct oral Xa inhibitor therapies.

Answer 219

20% to 25%

Answer 220

20% 20mL/kg 10mL/kg

Answer 221

o Splenic contraction in dogs o Intercompartmental fluid shifts take a few hours o Fluid therapy is instituted

Answer 222

o In animals with hemorrhage secondary to acquired coagulopathies (liver disease and anticoagulant rodenticide intoxications) or patients with hereditary coagulopathies and subsequent bleeding. o Sudden hemorrhage caused by the use of heparin (including accidental use of undiluted heparin flushes) or warfarin to counter thrombosis can also be corrected with FFP, although protamine and vitamin K can also rapidly reverse the heparin and warfarin effects, respectively. o The use of FFP (with or without the administration of heparin) to replace deficient coagulation factors and antithrombin in patients with IMHA or DIC is controversial. o Evidence for the use of FFP in acute pancreatitis (to replace α-macroglobulins and antiproteases) or in parvovirosis (to provide antiparvovirus antibodies and additional Ig and to stop gastrointestinal hemorrhage) is lacking. o FP is also commonly used to correct hypoproteinemias in animals with protein-losing nephropathies and enteropathies, but its effect on oncotic pressure in these animals is minimal at clinically used dosages, especially when compared with synthetic colloids. o Critically ill animals with albumin concentrations less than 1.5 g/dl may benefit from plasma therapy because this protein is an important carrier of certain drugs, hormones, metals, chemicals, toxins, and enzymes.

Answer 223

Fibrinogen Fibronectin FVIII vW factor

Answer 224

1 week <8h

Answer 225

Cryopreserved PLT are short lived and lose their function and are no longer available, but lyophilized PLT have been intermittently available and may provide adequate hemostasis.

Answer 226

o Genetic markers on erythrocyte surfaces that are species-specific and antigenic in individuals that lack the same markers. o This antigenicity results in the development of alloantibodies, so that the administration of a small volume (as little as 1 ml) of incompatible blood can result in life-threatening immune reactions.

Answer 227

To avoid neonatal isoerythrolysis (NI)

Answer 228

o Blood group systems known as DEAs - dog erythrocyte antigens o They have more than a dozen of DEAs. The most important canine blood type is DEA 1. o DEA 1 elicits a strong alloantibody response after sensitization of a DEA 1–negative dog by a DEA 1–positive transfusion. o This can lead to an acute hemolytic transfusion reaction in a DEA 1–negative dog previously transfused with DEA 1–positive blood. o Transfusion reactions against other blood types in previously transfused dogs have been described rarely. They include reactions against the DEA 4, Dal in Dalmatians and likely few other breeds, and another common RBC antigen in a Whippet. o Dalmatians lacking the Dal antigen are likely at risk of delayed and acute hemolytic transfusion reactions.

Answer 229

Blood donors

Answer 230

o Washing the RBCs three times with physiologic saline (1 part blood and 5 to 9 parts saline) may resolve autoagglutination and rouleaux formation. o Persistent autoagglutination after saline washing of the recipient’s blood negates any typing and crossmatch testing except for the immunochromatographic method.

Answer 231

o The AB blood group system and consists of three types: type A, type B, and the extremely rare type AB. Type A is dominant over B. o Cats with type A blood have the genotype a/a or a/b, and only homozygous b/b cats express the type B antigen on their erythrocytes. o In the extremely rare AB cat, a third allele recessive to a or codominant to b (or both) leads to the expression of both A and B substances. o Cats with type AB blood are not produced by mating of a cat with type A to a cat with type B unless the cat with type A carries a rare AB allele.

Answer 232

o Cats with type AB blood have been seen in many breeds, including DSH cats but particularly in Ragdolls. o The frequency of feline A and B blood types varies geographically and among breeds. o All Siamese cats have type A blood, and Turkish Vans and Angoras have equal numbers of type A and B blood. o Most DSH cats have type A blood, but the proportion of cats with type B blood can be substantially different in certain geographic areas. Thus all donor blood must be typed.

Answer 233

o All cats with type B have very strong naturally occurring anti-A alloantibodies. o Kittens receive anti-A alloantibodies through the colostrum from type B queens, and type B kittens develop high alloantibody titers (>1 : 32 to 1 : 2048) after a few weeks of age. o Anti-A alloantibodies are responsible for serious transfusion reactions and NI (neonatal isoerythrolysis) in kittens with type A and AB blood born to type B queens.

Answer 234

o Cats with type A blood have weak anti-B alloantibodies, and their alloantibody titer is usually very low (1 : 2). o However, cats with type A blood can also develop hemolytic transfusion reactions when given B blood (in part due to the anti-A antibody in the type B donor blood), but no type A or AB queen has had a litter with NI caused by A-B incompatibility.

Answer 235

o Cats with type AB blood have no alloantibodies, although it is recommended that these cats receive type A pRBCs (where almost all plasma with anti-B antibodies has been removed) if type AB blood is not available.

Answer 236

o Mik RBC antigen in some domestic shorthaired cats. It is thought that Mik-negative cats may have naturally occurring alloantibodies or produce them, leading to blood incompatibility reactions beyond the AB blood group system.

Answer 237

o It looks for the presence or absence of alloantibodies in dogs or cats without determining the blood type. o It does not replace blood typing.

Answer 238

o The major crossmatch tests for alloantibodies in the recipient’s plasma against donor cells. o The minor crossmatch tests for alloantibodies in the donor’s plasma against recipient’s RBCs. o It is of lesser importance because the donor’s plasma is mostly removed in pRBCs and will be diluted in the recipient patient (except if a type B cat is used as donor). It is also of lesser importance if all donors’ types are known and if the donors, as generally recommended, have never received transfusions (i.e., have no prior sensitization).

Answer 239

o Yes - naturally occurring anti-DEA 7 antibodies in 50% of DEA-7 negative transfusion naïve dogs. o Implicated in causing delayed TR o Not in North America

Answer 240

o Yes o A compatible crossmatch in a dog does not prevent sensitization against donor cells within 1 to 2 weeks. o A dog that was previously given a compatible transfusion from a donor dog may become incompatible with blood from the same donor 1 to 2 weeks later.

Answer 241

o Autologous (self-) transfusion refers to the donation of blood by a patient from 4 weeks to a few days before a surgical procedure with the potential for substantial surgical blood loss. Blood can also be collected immediately before surgery. o The patient’s blood is diluted with crystalloid (and colloid) solutions, and the previously drawn blood is replaced when excessive bleeding occurs during or after surgery. o Autotransfusion is another autologous transfusion technique in which shed blood salvaged intraoperatively or after intracavitary hemorrhage is reinfused intravenously after careful filtering. o Blood from longstanding (>1 hour), contaminated, or malignant hemorrhagic effusions should never be reinfused intravenously.

Answer 242

o Blood donors should be young adult, lean, and good-tempered animals; o Dogs should weigh at least 23 kg to donate 450mL (smaller dogs could be used if proportionally less blood is collected). o Cats should weigh at least 4 kg to donate 40mL of blood.

Answer 243

o PCV or hemoglobin concentration should be more than 40% and more than 13 g/dl, respectively, in canine donors. o Should be more than 30% and more than 10 g/dl, respectively, in cats.

Answer 244

o PCV or hemoglobin concentration should be more than 40% and more than 13 g/dl, respectively, in canine donors. o Should be more than 30% and more than 10 g/dl, respectively, in cats.

Answer 245

o Acepromazine o Should not be used for blood donors.

Answer 246

o Blood is collected aseptically by gravity flow or blood bank vacuum pump from the jugular vein over a 5- to 10-minute period. Plastic blood bags containing citrate- phosphate-dextrose-adenine (CPD-A1), with or without satellite bags for blood component separation, are optimal. o These commercial blood bags represent a closed collection system in which the blood does not come into contact with the environment at any time during collection or separation into blood components, thus minimizing the risk of bacterial contamination and allowing for rapid storage of the blood products. o Large plastic syringes containing 1 ml CPD-A1 or 3.8% citrate per 9 ml blood and connected via three-way stopcock to a 19-gauge butterfly needle (and blood bag) are used commonly for blood collection in cats or toy breed dogs. o This represents an open collection system in which connections allow exposure of blood to the environment and potential contamination. Because of the risk of bacterial contamination, blood collected via an open system should not be stored for more than 48 hours. o A closed collection system for cats using small collection bags has been introduced. o The maximal donated blood volume is 20mL blood/kg or one regular blood bag unit of 450 ± 50 ml per 25kg or larger dog and 10mL blood/kg or 40 mL blood (one typical feline unit) per 4kg or larger cat. o Fluid replacement is generally not needed but can be considered in cats. Feeding donors should be limited to small amounts immediately post blood collection.

Answer 247

o Blood components are prepared from a single donation of blood by simple physical separation methods, such as centrifugation, within 8 hours of blood collection. o Thereby, FWB can be separated into pRBCs, PRP or platelet concentrates, FFP, cryoprecipitate, and cryopoor plasma. o Blood component preparation is best accomplished by using plastic blood bags with satellite transfer containers to ensure sterility. o Fluctuations in storage temperature significantly alter the length of storage; FWB and pRBCs should be kept at 4 ± 2°C (39 ± 3°F) and all plasma products at less than –20° C (–4° F) using blood bank refrigerators and freezers with alarms, if possible.

Answer 248

2,3-DPG (diphosphoglyceride) Ammonia

Answer 249

These patients may also develop hypocalcemia when given large volumes of anticoagulated plasma products.

Answer 250

o Blood components that have been warmed to room or body temperature should not be recooled or stored again because of safety concerns (it affects product quality). o Similarly, partially used or opened blood bags should be used within 24 hours because of the risk of contamination and product damage. o Stored blood products should be rotated regularly and inspected; discolored units should be discarded.

Answer 251

o Temperature-controlled water bath or bowl (≤39°C [<102° F]) is used to warm the blood products. o A microwave should never be used because of the risk of regional overheating. o Care should be taken to maintain absolute sterility and not to overheat any part of the blood products.

Answer 252

o Blood bags are connected to infusion sets that have an in-line microfilter. o Long (85 cm) blood infusion sets with a drip chamber for medium to large dogs and short infusion sets that can be attached to a syringe for small dogs and cats are available. o A latex-free infusion set should be used for platelet administration to prevent aggregation. o Microfilters with 170μm pores are used commonly to remove clots and larger red blood cell and platelet aggregates. o Finer filters with 40μm pores will remove most platelets and microaggregates, but these commonly clog or become dysfunctional after filtering 50 to 100 ml of blood. o Leukocyte reduction filters may be used at the time of blood collection to decrease febrile adverse reactions to white blood cell components. They are expensive. o Sterility must be maintained when connecting the blood component bag to the infusion set and the tubing to the catheter.

Answer 253

o Blood components are best administered intravenously, although an intramedullary (intraosseous) catheter may be used when venous access cannot be obtained. o Intraperitoneal administration is not generally recommended because absorption time is delayed and RBCs get damaged in the peritoneal cavity.

Answer 254

o Concurrent administration of drugs or fluids other than physiologic saline should be avoided to prevent lysis of erythrocytes or coagulation. o Fluids containing calcium or glucose or those that are hypotonic or hypertonic should not be administered through the same intravenous line during the transfusion.

Answer 255

o The rate of transfusion depends on the cardiovascular status, hydration status, degree of anemia, comorbidities and general condition of the recipient. o The initial rate should be slow, starting with 1 to 3 ml over the first 5 minutes to observe for any transfusion reactions, even with blood-typed or crossmatched transfusions. o In animals with cardiac disease, the transfusion should be given more slowly (i.e., 4 ml/kg/hr), and close monitoring is of utmost importance. o Transfusion of a single bag should be completed within 4 hours to prevent functional loss or bacterial growth.

Answer 256

o pRBCs = BW (kg) x [(desired PCV - patient PCV)/donor PCV] x 90 (for dogs, if it is for cats, do x 60) o Whole blood (mL) = 2 x PCV rise desired (%) x BW (Kg) o 2mL of whole blood / kg will increase PCV by 1%.

Answer 257

o At least 70-80% of the transfused erythrocytes survive 24h and thereafter expected to have a normal life span (up to 70 days in the cat, 110 in the dog). o PCV and total protein should be monitored before, during, and 6 and 24 hours after transfusion.

Answer 258

o In animals with thrombocytopenia or thrombopathia, one unit of platelet concentrate (~50 ml), PRP (~200 ml), or FWB (~450 ml) will increase the platelet count by approximately 10,000/μl in a recipient weighing 30 kg. o In animals with serious or life-threatening bleeding, the platelet count should be increased to greater than 20,000 to 50,000/μl. Platelet counts should be monitored before and 1 hour and 24 hours after platelet transfusion.

Answer 259

o FFP is initially administered at a dosage of approximately 10 ml/kg to stop bleeding or prevent excessive bleeding during surgery. o In some cases, larger volumes may be needed to control bleeding and, depending on the etiology of the coagulopathy, repeated administration of FFP may be required. o Because of the short half-life of factors VII, VIII, and von Willebrand’s factor, deficient animals may need treatment 2 to 4 times daily. o Animals with other, less severe coagulopathies may be treated daily. Plasma support should be provided for an additional 1 to 3 days after the bleeding has been controlled to prevent rebleeding.

Answer 260

o Cryoprecipitate at a dosage of 1 cryo unit (~50 ml)/10 kg or 1 to 2 ml/kg body weight twice daily is ideal to treat a bleeding animal with hemophilia A or von Willebrand’s disease. o In contrast, cryo-poor plasma (6 to 10 ml/kg) is ideal for the treatment of bleeding induced by anticoagulant rodenticide poisoning because it contains the vitamin K–dependent coagulation factors.

Answer 261

o Hemolytic transfusion reactions occur when antibodies in the recipient react with the RBC surface antigen of the donor. o The immunoglobulin G or M (IgG or IgM) antibodies then activate the complement system, which leads to formation of the membrane attack complex, which can damage the lipid bilayer of the RBC membrane leading to intravascular hemolysis. o In addition, antibody or complement fragments adhering to the RBC surface increase RBC phagocytosis. If leukocytes recognize opsonized RBCs in circulation, the result is intravascular hemolysis, whereas extravascular recognition is termed extravascular hemolysis.

Answer 262

39% to 53%

Answer 263

o Blood transfusion in humans and dogs has also been shown to be associated with an inflammatory response. o During storage of whole blood or pRBCs, contaminating leukocytes undergo lysis, which releases immunomodulators such as histamine, myeloperoxidase, plasminogen activator inhibitor 1, and eosinophilic cationic protein. o These mediators contribute significantly to an inflammatory response, potentially leading to the clinical signs of systemic inflammatory response syndrome (SIRS).

Answer 264

o Storage of pRBCs -> leads to multiple deleterious changes in the RBC units, referred to as the storage lesion. o During storage, RBCs undergo a series of physiologic, biochemical, and structural alterations leading to decreased viability and aggregation and increasing the risk for oxidative damage. o There are reports of significant disturbances in energy metabolism, rheologic properties, and oxidative damage to erythrocytes. o Several of the deleterious effects seen in stored RBCs, such as hemolysis and microparticle accumulation, are associated with an increased risk of adverse reactions in the recipients following the transfusion.

Answer 265

o Biochemical changes: - Decrease in adenosin triphosphate - Decrease in 2,3-dyphosphoglycerate - Decrease activity of RBCs SNO-Hb (s-nitrosohemoglobin -> NO binded to B93 cysteine thiol residue of Hb) - Increased K in the supernatant - Ammonia accumulation - Oxidation injury o Biomechanical changes: - RBC shape change and reduced RBC deformability - Accumulation of microparticles - Adhesion to endothelial cells o Immunological changes: - Leukocyte contamination - Soluble immune response modifiers o Potential consequences: - Effects on oxygen delivery kinetics. - Transfusion of older stored RBCs was associated with a significantly increased risk of death - Independent direct association between increasing RBC storage time and risk of infection, deep vein thrombosis (DVT), ICU length of stay, and mortality in both adults and children - RBC storage times greater than 14–28 days were associated with worse outcomes. - Complications were more common in patients who received older units (>14-d old) than those who received fresher units (<14-d old). Patients given older blood had higher rates of in-hospital mortality and higher rates of extended intubation, renal failure, and sepsis. - Greater risk of developing new or progressive MODS in hemodynamically stable critically ill pediatric patients receiving stored RBCs (>2–3 wk) has also been established - Association between transfusion with RBCs stored more than 14 days and increased risk of bacterial infection after trauma.

Answer 266

o Leukoreduction involves passing whole blood or a blood component through a filter that removes donor WBCs and platelets. Removal of those cells mitigates some of the effects associated with stored blood transfusion, including febrile nonhemolytic transfusion reactions, infection, and multiple organ failure. o However, the benefit is not complete in that stored supernatant, even from leukoreduced RBCs, still contains elements associated with storage lesion, such as microparticles, free hemoglobin, and inflammatory mediators that may lead to adverse consequences in recipients. o There was a recent study published in 2020, with the aim to evaluate the incidence of acute TRs in, and the outcome of, dogs receiving either leukoreduced or nonleukoreduced PRBC transfusions. The null hypothesis was that there would be no difference in the incidence of TRs or outcome between the 2 groups. Neither the incidence of FNHTRs nor survival to discharge were found to be affected by leukoreduction.

Answer 267

o Massive transfusion is defined as the administration of 1 or more blood volumes within a 24h period. Dog blood volume is normally estimated to be 90mL/kg. cats 60mL/kg o Other definitions: Receiving 50% of one blood volume within 3-4h, 150% of one blood volume regardless of time, or 1.5mL/kg/min of blood products for 20min have also been considered massive transfusions o Potential complications are electrolyte abnormalities (hypocalcemia hypomagnesemia, hyperkalemia), hemostatic defects (thrombocytopenia, secondary coagulopathy), hypothermia, metabolic acidosis, immunosuppression, TRALI and potentially other transfusion reactions.

Answer 268

o TRALI is considered an acute immunologic reaction, characterized by hypoxemia, clear evidence of pulmonary infiltrates in thoracic imaging with no evidence of left atrial hypertension, that occurs within 6h of transfusion. o Human definitions have been revised and have divided TRALI in type I and type II. Patients are included in type I when there are no risk factors for acute respiratory distress syndrome (ARDS), whereas type II is when there are risk factors or existing mild ARDS. o Risk factors for ARDS include but are not limited to pneumonia, non-pulmonary sepsis, pancreatitis and multiple transfusions. o Differentiating between ARDS and TRALI can be challenging as their risk factors and clinical signs intertwine. o Pathophysiology of TRALI is thought to involve the “two-hit” theory. The underlying condition is the first hit, that will cause pulmonary endothelium activation and sequestration and priming of neutrophils in the lungs; the transfusion is the second hit, that will activate the primed neutrophils causing endothelial damage and leading to TRALI. o In veterinary medicine a prospective study described an incidence of 3.7% with patients developing TRALI 48h after the transfusion.

Answer 269

o A decreased incidence of FNHTRs has been documented in patients receiving multiple transfusions with LR blood compared with NLR blood (61% in NLR group vs. 2.5% in LR group). o Leukoreduction exhibits a beneficial effect on the RBC storage lesion by improving both the incidence of hemolysis and the posttransfusion recovery of LR pRBCs. o One study documented a significant decrease in hemolysis, oxidative stress, loss of membrane integrity, and microparticle formation in LR units compared with non-LR units over time. o Seven randomized controlled trials showed that LR prevented HLA alloimmunization. o A multicenter, randomized, controlled trial (603 patients) in 1997 reported double the rate of platelet alloimmunization in the group without LR compared with the group that received LR blood. o Recently LR has been shown to abrogate the detrimental effects of aged pRBC units on trauma patients during transfusion.

Answer 270

o Multiple techniques, including washing, apheresis, centrifugation, and filtration, are accepted approaches to perform LR. o Filtration has been reported to remove the vast majority of WBCs from the blood via direct adhesion of WBCs to the filter, mechanical sieving, and indirect adhesion of aggregates (WBC and platelets) to the filter. o Filtration performed at collection for both human and dog blood has been shown to remove the majority of WBCs and platelets. o Human blood is generally submitted to LR before storage in order to prevent production of inflammatory mediators during storage. In humans, use of bedside LR filters (after storage) has been associated with hypotension in some populations and is therefore rarely used clinically.

Answer 271

Hypocalcemia Hypomagnesemia Hyperkalemia

Answer 272

o Hypocalcemia and hypomagnesemia result from the citrate that is added to blood products as an anticoagulant. o After transfusion, citrate binds rapidly to both calcium and magnesium with equal affinity, resulting in decreases in ionized calcium and magnesium levels. o In one veterinary study, ionized hypocalcemia was documented in 100% of cases after massive transfusion, with severe hypocalcemia (<0.7mmol/L) noted in 20%. o Changes in ionized magnesium concentration in this study tended to parallel those of ionized calcium. o Ionized hypocalcemia has been reported to resolve quickly once perfusion is restored because citrate is metabolized rapidly by the liver. o Treatment with calcium gluconate is indicated in cases of severe hypocalcemia or when clinical signs such as hypotension, muscle tremors, arrhythmias, or prolonged QT interval manifest.

Answer 273

o Potassium levels in stored (human) blood rise over time because of inactivation of the sodium-potassium ATPase pump by the cold storage temperatures. o Humans receiving large volumes of stored blood products may therefore be at greater risk for the development of hyperkalemia. o Most dogs, with the exception of Akitas and Shiba Inus, lack significant intracellular quantities of potassium in their red blood cells and, as a result, increased potassium levels are not observed in stored canine blood. o Although this would suggest that hyperkalemia in massively transfused canine patients should theoretically be less of a concern, hyperkalemia was identified in 20% of dogs in one study, a prevalence similar to that historically reported in human patients. o It is likely that the hyperkalemia observed in canine cases resulted from similar causes, including potassium leakage into the bloodstream from damaged tissues, extracellular potassium shift secondary to acidosis, and reduced potassium excretion associated with oliguria.

Answer 274

o Thrombocytopenia o Hypofibrinogenemia o Dilution coagulopathy

Answer 275

o It is believed to result primarily from blood loss and dilution. Blood products become devoid of platelets after 2 days of storage because the cold storage temperatures cause cell oxidation and death. o Administering large volumes of these platelet-free blood products, especially after aggressive fluid resuscitation, can result in a dilutional thrombocytopenia. o Thrombocytopenia resulting from dilution is generally less severe than the level that would have been predicted by the degree of dilution (i.e., the loss and replacement of 50% of a patients blood volume does not result in a 50% decrease in platelet count) because platelets are released from stores in the lungs and spleen. o Blunt trauma, shock, sepsis, or systemic inflammation associated with the underlying injuries may also result in consumption of platelets and clotting factors. o Platelet dysfunction resulting from acidosis or hypothermia is another well-documented phenomenon after massive transfusion and may be as important as platelet numbers in determining likelihood of bleeding.

Answer 276

o When large quantities of intravenous fluids and packed red blood cells are administered to replace massive blood loss, the dilutional effects may result in prolongation of PT and aPTT. o Clotting factor consumption secondary to tissue injury may further exacerbate dilutional coagulopathy. o Hemostasis is generally maintained as long as clotting factors are at least 30% of normal, and PT and aPTT values are not prolonged above 1.5 times normal. o Exchange transfusion models predict that loss and replacement of 1 blood volume removes slightly less than 70% of circulating factors in the plasma, so theoretically transfusions of up to 1 blood volume should not be associated with abnormal bleeding tendencies. o Coagulopathy was identified in 70% of dogs after massive transfusion, although a correlation with transfused volumes could not be made because of the retrospective nature of the study.

Answer 277

o It is believed to result from altered coagulation enzyme activity, hyperfibrinolysis, and release of activated protein C secondary to tissue injury, hypoperfusion, and acidosis. o ATC has been documented before fluid resuscitation and has been associated with increased transfusion requirements, hospital stays, and mortality. o Coagulopathy after trauma has also been documented in dogs and has similarly been associated with injury severity, transfusion requirements, and outcome. o Increased FFP and platelet/RBC ratios (at least 2:1 and up to 1:1) appear to be associated with decreased mortality in human patients, but the optimum ratio is not known.

Answer 278

o Hypothermia is a common complication of massive transfusion in human patients and was observed in 69% of massively transfused dogs. o Hypothermia results from shock secondary to the underlying illness or injury and the subsequent administration of large volumes of refrigerated blood products. o Hypothermia can have profound effects on the coagulation system. o Several studies have demonstrated a strong association between severity of hypothermia and the likelihood of developing microvascular bleeding. o Although hypothermia has little effect on clotting factor levels, it has been shown to inactivate the enzymes that initiate the intrinsic and extrinsic coagulation cascades and to enhance fibrinolysis. o Severe hypothermia can also result in decreased platelet activity. Unfortunately, the contribution of hypothermia to coagulopathy is often overlooked in clinical patients because coagulation testing typically is performed at 37° C in the laboratory rather than at the patient’s body temperature.

Answer 279

o Another complication reported in the massively transfused patient is severe metabolic acidosis. o When blood is stored, glucose metabolism leads to an increase in lactic and pyruvic acids. Thus the pH of stored blood may be as low as 6.4 to 6.6. o When a patient is transfused with 1 or more blood volumes, severe acidosis can result. This is often compounded by lactic acidosis secondary to shock. o The “bloody vicious cycle” of progressive hypothermia, persistent acidosis, and inability to establish hemostasis has been recognized increasingly in human medicine as a leading cause of death after blunt trauma. o The use of rapid infusers capable of quickly administering warmed blood and fluids, the increased use of warm air blankets, and the staging of laparotomy procedures to avoid prolonged hypotension secondary to anesthesia are measures that can significantly reduce the impact of hypothermia and acidosis on the coagulation system.

Answer 280

o Immunosuppression has been well documented in human medicine after transfusion of large blood volumes. In one study of massively transfused human patients, the incidence of wound complications in the patients who survived for at least 1 week was 29.5%, 6 times the hospital average. o The mechanism by which blood transfusions reduce immune responsiveness is unclear, but donor white blood cells within the transfused blood have been implicated. o These leukocytes are believed to exert immunosuppressive effects through alloimmunization, induction of tolerance in recipient lymphocytes, and release of humoral factors that suppress immune cell function. o Experimental studies have identified decreased phagocytic cell function, decreased natural killer cell activity, decreased macrophage antigen presentation, and suppression of erythroid, myeloid, and lymphoid hematopoiesis. o Leukoreduction has been shown in clinical studies to attenuate some of these changes.

Answer 281

o Massive transfusions have also been associated with transfusion- related acute lung injury. o Blood stored under standard blood bank conditions develops microaggregates of platelets, WBCs, and fibrin that may be removed only partially when transfused through a commercial (170-micron) blood filter. o Embolization to the alveolar capillary beds has been shown experimentally to occur in dogs and may lead to acute lung injury. o In human medicine, anti- leukocyte antibodies in the donor blood have been implicated as one of the primary causes of in vivo agglutination and subsequent embolization of recipient neutrophils to the pulmonary vasculature, although this mechanism has not yet been identified in dogs.

Answer 282

o Other potential nonimmunologic complications of massive transfusions include bacterial contamination of stored blood, infectious disease transmission, and hyperammonemia. o Blood is an excellent bacterial growth medium, and contamination may result from improper collection or handling techniques. Transfusion of contaminated blood can cause signs that may be difficult to distinguish from transfusion reactions, including fever, vomiting, hypotension, hemolysis, and death. o The incidence of disease transmission in veterinary patients is not known, but the transmission of bloodborne pathogens like Ehrlichia, Babesia, and Leishmania is possible after transfusions in dogs. o Ammonia levels in stored blood rise significantly with time, so patients who receive large volumes may be at risk for hyperammonemia. Although this has not been a problem in healthy patients, those with severe liver disease or hypoperfusion secondary to shock may not be able to metabolize or excrete this ammonia and may be at greater risk

Answer 283

o Surgical management of hemorrhage is critical, but initial surgical procedures should be aimed at “damage control,” rather than definitive repair, to minimize the impact of hypothermia and acidosis associated with prolonged anesthesia. o Using a staged laparotomy approach, sources of hemorrhage or contamination are initially controlled or packed off and the patient is then recovered. Completion of surgical procedures may be performed once cardiovascular status and coagulation have returned to acceptable levels.

Answer 284

In patients with prolonged PT and aPTT or platelet counts of less than 50,000 cells/μl.

Answer 285

o Clinical signs of hypocalcemia and hypomagnesemia may be difficult to recognize in an anesthetized patient. A prolonged QT interval on an electrocardiogram or unexplained hypotension may be the first warning of a problem. o Treatment with 0.5 to 1.5mL/kg IV calcium gluconate (10%) is recommended if ionized calcium levels are less than 0.8mmol/L or when clinical signs are present.

Answer 286

EDTA Serum - RTT

Answer 287

o Agglutination o Immunochromatographic test

Answer 288

o No longer DEA 1.1 or 1.2 - only DEA 1 strong positive or weak positive

Answer 289

Breeds: o Dalmatians - 12% o Doberman Pinschers - 42% o Shih-Tzus - 57% o Dal negative is rare, most animals are Dal positive -> then we crossmatch a patient and it is incompatible with most of the donors - because it is Dal negative and donors are Dal positive.

Answer 290

o Not born with antibodies

Answer 291

o tPA and fibrin and creates a complex o Antifibrinolytic drugs (TXA and EACA) - lysin analogues, will bind to plasminogen and inhibit its binding to fibrin.

Answer 292

Two P2Y1 P2Y12

Answer 293

o Endothelial cells produce NO and PGI2 (prostacyclin) -> prostacyclin inactivate platelets o Heparan sulfate on endothelial cells -> binds to AT3, and AT3 inactivates FII, IX and X o Thrombomodulin on endothelial cells -> binds thrombin -> activates PC -> APC inactivates FV and FVIII o There are three general layers to take note of: * Endothelial cells -> NO and PGI2 * Subendothelial cells, underneath the endothelial layer. Made up of connective tissue, specifically collagen. * Smooth muscle cells with specific types of receptors -> nociceptors = pain receptors

Answer 294

1. Vascular spasm 2. Platelet plug formation 3. Coagulation 4. Clot retraction and repair 5. Fibrinolysis

Answer 295

1) Trigger o Endothelial damage o May also cause damage to the underlying tissue o Blood may leak out and decrease blood volume 2) Purpose Prevent blood loss from occurring by contracting or constricting blood vessels 3) Mechanisms a. Endothelin, secreted by injured endothelial cells, will bind on to receptor on smooth muscle, activates intracellular PIP2-Calcium mechanism causing smooth muscle contracts. That triggers vessel vasoconstriction, preventing blood loss b. Myogenic Mechanism -> direct contact or injury to smooth muscle causes smooth muscle contraction. c. Nociceptor Activation -> inflammatory chemicals are released when there’s inflammation (histamine, leukotrienes, prostaglandins). These chemicals stimulate the nociceptors. Pain reflex induces vasoconstriction.

Answer 296

o With the endothelial cells damaged, there will be a decreased release of NO and PGI2, therefore platelets will not be inactivated. That allows platelets to attach to endothelium o Damaged heparin sulfate will not be able to keep clotting factors inactivated o Damaged thrombomodulin will not be able to activate protein C, therefore PC cannot keep FV and FVIII inactivated 1) Platelet Activation - platelets are activated when GP1b binds with ultra large vWF multimers. UL-vWF secreted by injured endothelial cells from Weibel Palade bodies. WP bodies also contain P selection, IL8, FVIII and tPA. 2) Platelet chemical release - once activated, will release ¡ADP, TXA2 and serotonin 3) Platelet Aggregation - they have receptors on their membrane that specifically bind with ADP and TXA2 -> ADP and TXA2 stimulates platelets to come and aggregate at area of injured vessel. Platelets bind with other platelets via their GP2b/3a, with fibrinogen bridging them together. 4) Vascular Spasm Effect Enhancement -> TXA2 and serotonin bind to the smooth muscle, causing contraction. That triggers ↑vasoconstriction of injured blood vessels, enhancing the vascular spasm effect 5) Clinical Significance Aspirin: decreases TXA2 release Clopidogrel, Prasugrel, Ticagrelor: block ADP receptors. Abciximab: inhibits GP2b/3a inhibitors Von Willebrand Disease: decreased VWF production

Answer 297

1) Platelet Contraction - platelet contraction is stimulated once the platelet plug is anchored to injured vessel wall by fibrin mesh. Platelets contains contractile proteins (actin and myosin) When platelets contract, they pull the damaged edges of the injured blood vessel close to each other. This squeezes some serum out of the injured vessel 2) Platelet-Derived Growth Factor (PDGF) Secretion. If smooth muscle cells are damaged, PDGF triggers mitosis or proliferation of smooth muscle cells. If there is damage to connective tissue, PDGF forms connective tissue patches to regenerate collagen fibers 3) Vascular Endothelial Growth Factor (VEGF) secretion by PLT - regenerates the new endothelial lining. The blood vessel then starts to go through healing & remodeling.

Answer 298

o Breaking down fibrin mesh -> there’s a need to get rid of the clot as it may be big enough that it could occlude blood flow and possibly cause ischemia. o Endothelium expresses Tissue Plasminogen Activator (TPA). o TPA converts plasminogen into plasmin. Plasminogen is naturally occurring in the bloodstream. Plasmin breaks down fibrin mesh into fibrinogen and fibrin degradation products like D-Dimers. This process recanalizes the clotted vessel. o TPA Drugs -> ↑Plasminogen to Plasmin -> increased rate of blood clot breakdown -> given to patient who have stroke or some type of ischemic attack within hours. o Elevated D-Dimers can be indicative of blood clots and inflammation. o Antifibrinolytics (TXA)→↓Plasminogen to plasmin→↓break down of blood clot and stabilizes clot.

Answer 299

Calcium No

Answer 300

o Constitutive expression in extravascular tissues o Induced in response to inflammatory stimuli o On monocytes, platelets, circulating MPs

Answer 301

o Adverse Event - Any undesirable or unintended occurrence associated with transfusion. It includes all adverse reactions, incidents, near misses, errors, deviations from standard operating procedures and accidents o Adverse Reaction - Any unintended response in a patient associated with the transfusion of blood or blood components o Acute transfusion reaction - Adverse reactions to blood, blood components, or plasma derivatives that occur within 24 hours of administration o Delayed transfusion reaction - Adverse reactions to blood, blood components, or plasma derivatives that occur beyond 24 hours of administration o Immunologic transfusion reaction - An adverse reaction to transfusion of blood or blood component due to response from the patient’s immune system o Non-immunologic transfusion reaction - An adverse reaction to transfusion of blood or blood component caused by physical or chemical changes to the blood cells or product, contamination, or secondary to the volume infused o Imputability - The probability that an identified probable cause was the actual cause of an adverse event after the investigation of the adverse transfusion event is completed . Definite, probable, possible and doubtful. o Severity - added from the human hemovigilance module as it is not defined in the TRACS - non-severe, severe, life-threatening and death

Answer 302

Febrile non-hemolytic Respiratory Reactions - TAD, TACO, TRALI Allergic reactions Hemolytic Reactions - acute vs delayed Delayed Serologic Transfusion Reaction Transfusion Transmitted Infection Hypocalcemia/Citrate toxicity Transfusion Related Hyperammonemia Hypotensive Transfusion Reactions Post-transfusion purpura Transfusion associated graft versus host disease

Answer 303

o An acute non immunologic or immunologic TR characterized by a temperature>39 C (>102.5 F) AND an increase in temperature of >1C (1.8 F) from the pre-transfusion body temperature during or within 4 hours of the end of a transfusion where external warming, underlying patient infection, AHTR, TRALI, and TTI have been ruled out. These occur secondary to donor white blood cell or platelet antigen-antibody reactions or due to transfer of proinflammatory mediators in stored blood products. o It is a diagnosis of exclusion, the development of a fever often leads to discontinuation of the transfusion and a series of diagnostic tests. o In people, donor white blood cell or platelet antigen-antibody reactions are thought to be responsible for at least 70% of FNHTR. Transfer of inflammatory cytokines produced in stored red blood cells by white blood cells is another cause. In one study, patients that develop a FNHTR after the administration of pRBCs were seen to have higher concentrations of IL6 and IL8; however, these cytokines were not increased in the blood products. o In people, FNHTR are more common with platelet products and appear to be more common with non-leukoreduced red blood cells. o Definite: patient has no other condition that could explain fever; hemolysis not present o Probable: there are other potential causes, but transfusion is most likely o Possible: other causes are likely, but transfusion cannot be ruled out o Incidences: dogs 1.3-24.2% / cats 3.7-22.9%

Answer 304

o A new category, transfusion associated dyspnea (TAD), was developed to recognize other respiratory transfusion reactions in hemovigilance databases that could not immediately be categorized as TRALI or TACO. In some studies, over half of TAD cases were later found to meet the criteria for another pulmonary transfusion reaction. o Is an acute transfusion reaction characterized by the development of acute respiratory distress during or within 24 hours of the end of a transfusion where TACO, TRALI, allergic reaction, and underlying pulmonary disease have been ruled out. o Indicence. dogs 2-6.3% / cats 0.4-7.4%

Answer 305

o An acute, non-immunologic reaction that is secondary to an increase in blood volume mediated by blood transfusion, characterized by acute respiratory distress and hydrostatic pulmonary edema. This reaction occurs during or within 6 hours of transfusion. It is associated with clinical, echocardiographic, radiographic, or laboratory evidence of left atrial hypertension or volume overload. These patients typically have a positive response to diuretic therapy. o Differential diagnoses for TACO may include TRALI, anaphylactic reactions, bacterial contamination of the blood unit, PTE, and hemolytic transfusion reactions with pulmonary complications o Its pathogenesis involves the “two-hit” theory. The first hit is normally the underlying condition of the patient, in this case the poor adaptability to an increase in blood volume. The second hit is due to the administration of blood or blood products. Initially it was thought that the pathophysiology was similar to pulmonary hydrostatic edema, but it has been revealed to be more complicated. o Risk factors contributing to the development of TACO (first hit) include renal failure, positive fluid balance and heart failure. The second hit might be related to suboptimal fluid management, or potentially, other factors in the transfused products. Post transfusion inflammatory cytokines like IL10 or IL6 are thought to be contributing factors to the development of TACO, as both have been found in different studies to be increased post transfusion in patients suffering from TACO. One retrospective study also showed that the incidence of TACO was reduced by almost 50% by the administration of leukoreduced products; however, further studies are needed to elucidate the true pathophysiology of TACO. o Definite: Clinical signs of worsening respiratory signs, cough, dyspnea, orthopnea, pulmonary crackles; AND echocardiographic evidence includes left atrial enlargement, left ventricular dilation, or reduced ejection fraction; AND/OR radiographic evidence includes bilateral pulmonary infiltrates, pleural effusion, pulmonary edema, pulmonary venous congestion, or cardiomegaly; AND/OR laboratory evidence includes significantly elevated BNP, NT-proBNP or a BNP or NT-proBNP pre/post transfusion ratio of over 1.5x; AND no other explanation for circulatory overload. o Probable: Transfusion is likely contributing to circulatory overload, and either the patient has received other additional fluids, or, the patient has a history of cardiac insufficiency that could explain the circulatory overload, but transfusion is just as likely to have caused it. o Possible: The patient has a history of pre-existing cardiac insufficiency that most likely explains the circulatory overload o Incidence: dogs 4.7% / cats 3%

Answer 306

o Is an acute, immunologic reaction that is secondary to antigen-antibody interactions in the lungs. TRALI is characterized by acute hypoxemia with evidence of non-cardiogenic pulmonary edema on thoracic radiographs, during or within 6 hours of allogenic blood transfusion. Patients diagnosed with TRALI have no prior lung injury, no evidence of left atrial hypertension and no temporal relationship to an alternative risk factor for ARDS. o Definite: Patient had no evidence of acute lung injury prior to transfusion; AND clinical signs of respiratory distress within 6 hours of the transfusion; AND no signs of left atrial hypertension; AND no alternative risk factors for Acute Lung Injury (ALI). o Probable: N/A o Possible: Evidence of other risk factors for acute lung injury (eg, pancreatitis, aspiration pneumonia, severe sepsis, shock) during or within 6 hours of the transfusion. o Incidence: dogs 3.7% / cats - unknown

Answer 307

o Is also based on the “two-hit” theory. First-hit risk factors include shock, positive intravascular fluid balance, hepatic surgery, low IL10 concentrations, systemic inflammation.... The increase in IL6, IL8 and C-reactive protein are seen with inflammation. C-reactive protein it is thought to contribute to the first hit by increasing concentrations of proteins that will activate and sequester neutrophils into the lungs. Neutrophils, monocytes, lymphocytes, platelets, neutrophil extracellular traps (NETS), the endothelium and other immune mechanisms might also play a role in the development of TRALI. In the two hit theory, primed neutrophils and endothelium are considered part of the first hit. o The second-hit is due to the blood product transfusion by activating those neutrophils and endothelium, leading to pulmonary neutrophil infiltration and edema. The products with higher risk of causing TRALI are plasma and platelets, most likely because the bioactive mediators for TRALI lie within the plasma. o These bioactive mediators can be immunologic, like antibodies to human leukocyte antigens, anti-HLA class I or II; various human neutrophil antigens, HNA - or non-immunologic like extracellular vesicles, aged blood cells, soluble CD40, among others. 80% of TRALI cases are immunologic, only about 20% are due to non-antibody factors.

Answer 308

Type I - patients with no risk factors for ARDS and meeting the following criteria: a. Acute onset defined by I. Hypoxemia(P/F < 300 or SPO2 < 90% on room air) II. Clear evidence of bilateral pulmonary edema on imaging III. No evidence of LA hypertension on echocardiography b. Onset of pulmonary signs within 6 hours of transfusion (imaging can be documented up to 24 hours later) c. No temporal relationship to an alternative risk factor for ARDS. Other causes for ARDS should be ruled out. Type II - patients who have risk factors for ARDS or who have existing mild ARDS, respiratory status deteriorates and is suspected to be due to a transfusion reaction: a. Findings as described in categories A and B of TRALI type I b. Stable respiratory status in the 12 hours before the transfusion.

Answer 309

Plasma and plt products, possibly because the bioactive mediators of TRALI are carried in plasma.

Answer 310

o Acute immunologic reaction that is secondary to a type I hypersensitivity response to an antigen within a blood product. This reaction occurs during or within 4 hours of transfusion. o It is characterized by clinical signs varying from transient and self-limiting to life-threatening anaphylaxis. Canine type I hypersensitivity reactions typically involve erythema, urticaria, pruritus and facial/extremity/genital angioedema. GI signs (vomiting, diarrhea), and hemoabdomen with progression to collapse can also be seen. o Feline type I hypersensitivity reactions are typically respiratory (due to upper respiratory tract edema, bronchoconstriction, and excessive mucus production) although gastrointestinal signs and severe pruritus can also occur. o Plasma proteins antigens are often thought to be the triggers. A specific agent is most of the times not identified; however, IgA and haptoglobin have been described as causes in human patients that lack these proteins. o The incidence varies between blood products, reactions are more common in platelet and plasma transfusions than in packed red blood cell transfusions. Factors associated with increased risk of allergic transfusion reactions include recipient hay fever, recipient IgA or haptoglobin deficiency, younger recipient age, administration of non-leukoreduced blood products, among others. o Allergic transfusion reactions have been reported in VM and appear to be more common in dogs than cats and when plasma products are transfused, compared to pRBCs. o Definite: Occurs less than 1 hour after the start of the transfusion AND responds rapidly to cessation of transfusion and supportive treatment AND the patient has no other conditions that could explain clinical signs. o Probable: Onset is between 1 hour after start and cessation of transfusion OR the patient does not respond rapidly to cessation of transfusion and supportive treatment OR there are other potential causes present that could explain clinical signs, but transfusion is thought to be the most likely cause. o Possible: there are other conditions that could readily explain why clinical signs are present. o Incidence: dogs 0.3-6.6% / cats 0.9-3.7%

Answer 311

o Include AHTRs and DHTRs and can be immunologic or non-immunologic in nature. o Immunologic HTRs are secondary to incompatibility of the transfused product and the recipient. The magnitude of an HTR depends on multiple immunological factors to include the class and subclass (in case of IgG) of the antibody, the ability of the antibody to activate complement, the blood group specificity of the antibody, the thermal range of the antibody, the number, density and spatial arrangement of the RBC antigen sites, the antibody concentration in the plasma and the amount of antigen (RBCs) transfused. o Non-immunologic HTRs occur due to thermal, osmotic, mechanical, or chemical factors that damage transfused blood cells, causing acute or delayed hemolysis. Ex-vivo cellular damage may occur prior to transfusion as a result of bacterial contamination, prolonged storage, excessive warming, or erroneous freezing of blood unit. o Improper administration techniques, such as the addition of drugs or hypotonic intravenous fluids or trauma from extracorporeal devices may cause damage to RBCs. This ex-vivo cellular damage may lead to acute or delayed hemolysis of the transfused RBCs in the patient.

Answer 312

o Acute, non-infectious, immunologic, or non-immunologic reaction that occurs secondary to accelerated destruction of transfused or recipient RBCs and is characterized by acute hemolysis that occur during or within 24 hours of blood product administration. o Causes of AHTRs can be divided into blood type incompatibilities and other causes of damage to transfused blood cells. o Blood type incompatibilities are immunologic acute hemolytic reactions that are type II hypersensitivity reactions due to major or minor incompatibilities between donor and recipient RBCs. A - classic example would be in the case of a type A unit of blood given to a type B cat. o Non-immunologic causes of AHTRs may include thermal, osmotic, mechanical, or chemical factors that damage transfused blood cells. o Until direct or indirect antiglobulin or other confirmatory testing is available, the following diagnostic criteria must be met: o Definite: new onset of evidence of hemolysis within 24 hours: hyperbilirubinemia (1 or more of the following should be present -> icterus, total serum or plasma bilirubin concentration above reference interval, bilirubinuria in cats, or >2+ bilirubin on a urine reagent strip in dogs). Hemoglobinemia (plasma discoloration, instrument based indicators of hemolysis). Hemoglobinuria. Spherocytosis in dogs. Erythrocyte ghosts on a smear made immediately after blood collection AND inadequate increase in PCV WITH OR WITHOUT new onset of fever >39.2C, tachycardia, hypotension (SBP < 90-100mmHg) o In the absence of serologic testing to identify a causative antibody, investigation for known (blood typing) and unknown (cross-matching) incompatibility as well as potential thermal, osmotic, mechanical, or chemical factors should be performed. o Probable: There are other potential causes present that could explain acute hemolysis, but transfusion is the most likely cause o Possible: Other causes of acute hemolysis are more likely, but transfusion cannot be ruled out. o The most common cause of AHTR in dogs and cats is mismatched trans- fusion, mainly due to erroneous recipient, donor or unit identification and labeling. Non-immunologic causes are infrequently reported in the veterinary literature. o Incidence: dogs 0-6.3% / cats 0.4-6.9%

Answer 313

o A delayed, non-infectious, immunologic or non-immunologic, reaction that occurs secondary to lysis or accelerated clearance of transfused RBCs. Occurs 24 hours to 28 days after blood product administration. Immunologic DHTRs are typically caused by a secondary immune response to the donor’s RBCs. Non-immunologic HTRs occur due to thermal, osmotic, mechanical, or chemical factors that damage transfused blood cells, causing delayed hemolysis. o Definite: unexplained decrease in PCV or hemoglobin >24 hours to 28 days after transfusion AND delayed onset (24 hours - 28 days) of at least two indicators of red blood cell destruction (see AHTR definition) AND evidence of RBC alloantibodies (for immunologic types) which developed between 24 hours and 28 days after transfusion o Probable: unexplained decrease in PCV or hemoglobin >24 hours to 28 days after transfusion AND delayed onset (24 hours - 28 days) of at least two indicators of red blood cell destruction (see AHTR definition) o Possible: Other causes of a decrease in PCV or hemoglobin 24 hours to 28 days after transfusion are likely, but transfusion cannot be ruled out. o DHTR are reported in the veterinary literature following xenotransfusion of canine blood to the feline species. o Recent canine-to-feline xenotransfusion studies have revealed incompatible pretransfusion major and minor XM testing suggesting the presence of naturally occurring alloantibodies in both species. o Delayed hemolytic transfusion reactions are described following feline AB-mismatched allogeneic transfusions. While Type B cats possess high-titer, strongly antigenic IgM antibodies, Type A cats have low alloantibody titers consisting of IgG and IgM classes. The transfusion of type B RBCs into type A cats can result in DHTRs. o Unknown incidence for dogs. Cats 64% with xenotransfusions.

Answer 314

o A delayed, immunologic reaction that is secondary to the development of new clinically significant antibodies against a RBC antigen that the recipient lacks WITHOUT evidence of hemolysis. DSTRs occur 24 hours to 28 days after a transfusion. o The most well defined of these is DEA 7. DEA 4 has been further defined and is identified to produce an alloantibody that causes an acute reaction on re exposure. Delayed alloimmunization occurs 4 days to a few weeks after transfusion of Dal-positive blood to a Dal-negative recipient. o Definite: demonstration of new alloantibody formation between 24 hours and 28 days after a transfusion by either unexplained decrease in HCT/Hb > 24 hours to 28 days post transfusion AND positive DAT where DAT was negative prior to transfusion OR Serologic demonstration of a known RBC alloantibody after analysis of the transfusion history and known type incompatible blood transfusion (not currently available in veterinary medicine) o Probable: in the absence of a definite DSTR, a positive indirect coombs test with sensitized recipient sera against a sample of the donor’s RBCs that caused the DSTR to develop. This may be time sensitive depending on the alloantibody involved and its concentration in the recipient circulation. o Possible: new alloantibody formation between 24h -28 days post transfusion without hemolysis, but other exposures or underlying conditions are present that most likely explain the conversion. o Incidence - not published

Answer 315

o An acute or delayed, non-immunologic reaction secondary to the transfusion of pathogen contaminated blood or blood components. A TTI can occur hours to years after the transfusion due to the presence of the infectious agent in the blood/blood component unit collected from an infected donor, or from pathogen contamination of blood/blood component units during processing, storage or transfusion. o Clinical signs are highly dependent on pathogen transmitted and its pathogenicity for dogs and cats and the clinical status of the recipient. o Definite: ONE or more of the following: I) Laboratory evidence of a pathogen in a transfused blood product AND/OR evidence of the pathogen in the donor at the time of donation AND/OR evidence of the pathogen in an additional component from the same donation AND/OR evidence of the pathogen in an additional recipient of a component from the same donation; II) AND no other potential recipient exposure to the pathogen; III) AND EITHER evidence that the recipient was not infected with the pathogen prior to transfusion. IV) OR the identified pathogen strains are related by molecular or extended phenotypic comparison. o Probable: ONE or more of the following: I) Laboratory evidence of a pathogen in a transfused blood product AND/OR evidence of the pathogen in the donor at the time of donation AND/OR evidence of the pathogen in an additional component from the same donation AND/OR evidence of the pathogen in an additional recipient of a component from the same donation; II) AND EITHER evidence that the recipient was not infected with this pathogen prior to transfusion; III) OR no other potential exposures to the pathogen could be identified in the recipient. o Possible: Temporally associated unexplained clinical illness consistent with infection, but no pathogen is detected in the recipient. Other, more specific adverse reactions are ruled out. o Contaminants documented in veterinary blood units have included G- (E. coli, Pseudomonas spp., Serratia spp., Caulobacter spp., Ralstonia spp.) and G+ (Enterococcus spp., Propionobacterium spp., Corynebacterium spp., Leucobacter spp., Bacillus spp., Staphylococcus spp.) bacteria. o In most reported cases of blood bacterial contamination, it could not be determined if the contamination occurred during blood collection or blood bag processing and storage

Answer 316

These pathogens are documented: I) to be transmitted (experimentally or clinically) by blood transfusion or by intravenous blood injection in canine and feline patients; and/or II) to survive in stored blood units.

Answer 317

o An acute, non-immunologic reaction that is secondary to the transfusion of a large volume of blood, with citrate as the anticoagulant, and is characterized by a significant systemic hypocalcemia within hours of initiating transfusion. o Definite: patients receiving massive transfusions with impaired hepatic function. AND compared to pretransfusion levels, a decrease in ionized calcium to <0.7 mmol/L; AND development of seizures, tremors, ptosis, vomiting (nausea), hypotension, QTc prolongation, salivation, tachycardia, salivation, or facial swelling. o Probable: patients receiving massive transfusions with impaired hepatic function AND compared to pretransfusion levels, a decrease in ionized calcium to between 0.71 and 0.8 mmol/L; AND development of vomiting (nausea), QTc prolongation, salivation, tachycardia, or facial swelling. o Possible: patients receiving massive transfusions with impaired hepatic function AND compared to pretransfusion levels, a decrease in ionized calcium to between 0.81 and 0.9 mmol/L; AND development of vomiting (nausea), QTc prolongation, salivation, tachycardia, facial swelling. o Citrate is primarily metabolized by the liver, but with poor hepatic function or failure, the amount of citrate administered can exceed hepatic metabolic capacity and lead to calcium and magnesium chelation with resultant ionized hypoCa and ionized hypoMg. o Blood products that contain the greatest amount of citrate, such as fresh frozen plasma, will cause the greatest amount of calcium chelation. o A retrospective review of calcium disorders reported citrate toxicity after transfusion as the cause of hypocalcemia in 6% of cats and 4.7% of dogs

Answer 318

o Acute, non-immunologic reaction that is secondary to hyperammonemia and characterized by signs of development of encephalopathy (neurologic signs as ataxia, head pressing, circling, seizures and vomiting), during or immediately after (minutes to few hours) blood transfusion of stored blood or stored blood components. o It is a potentially life-threatening reaction in patients with liver disease (liver failure, portosystemic shunt, premature neonates with immature functioning liver) who are unable to metabolize and excrete ammonia properly. o Definite: laboratory evidence of hyperammonemia in the transfusion recipient AND onset of signs of hepatic encephalopathy during or after a transfusion in a recipient with no evidence of signs of encephalopathy prior to the transfusion AND laboratory evidence of hyperammonemia in transfused blood or blood components. o Probable: Laboratory evidence of hyperammonemia in the transfusion recipient AND onset of signs of hepatic encephalopathy during or after a transfusion in a recipient with no evidence of signs of encephalopathy prior to the transfusion. o Possible: Onset of signs of hepatic encephalopathy during or after a transfusion in a recipient with no evidence of signs of encephalopathy prior to the transfusion. o Ammonia increases significantly during storage in canine PRBC units and in feline WB and pRBCs. o Risk factors for develop transfusion-related hyperammonemia are: using outdated blood products in which ammonia has accumulated; transfusion recipients with liver disease/hepatic dysfunction including PSS that are unable to metabolize and excrete ammonia properly; premature neonates with immature liver function; and recipients receiving large transfusion volumes and with hypoperfusion secondary to shock.

Answer 319

o An acute, non-immunologic reaction that is secondary to the infusion of stimulators of vasodilation and hypotension. It is characterized by the rapid onset of significant hypotension during or shortly after the completion of a transfusion, with the absence of other causes of hypotension, and improvement with cessation of the infusion. There is usually a decrease in systolic blood pressure of at least 30mmHg from baseline. o Definite: the development of severe hypotension occurring between 15 minutes after starting the transfusion and 1 hour of stopping the transfusion AND responds rapidly to stopping the transfusion and no other conditions explain hypotension. o Probable: the development of severe hypotension within 15 minutes of starting the transfusion and 1 hour after stopping the transfusion AND the patient does not respond rapidly to supportive treatment, or there are other potential causes of hypotension. o Possible: The development of severe hypotension but other conditions or causes of hypotension could be identified. o Most commonly identified with pRBCS. It develops following activation of coagulation factor XII, which causes the conversion of high-molecular-weight kininogen to bradykinin, leading to vasodilation and increased vascular permeability. No published cases of HyTRs in dogs and cats.

Answer 320

o It is a delayed, immunologic reaction that is secondary to alloimmunization against platelet antigens. It is characterized by thrombocytopenia arising 5-12 days following transfusion of any platelet-containing blood product. Definite: Patient has no other condition that could explain the thrombocytopenia Probable: There are other possible causes but transfusion is most likely Possible: Other causes are more likely but transfusion cannot be ruled out o Only one case of PTP has been documented in the veterinary literature. It involved a 5-year-old intact male German Shepherd with hemophilia A that developed thrombocytopenia (10,000 platelets/μL) 8 days after transfusion with 450 mL of fresh whole blood and 200 mL of fresh frozen plasma. Serum taken at the time of the thrombocytopenia had positive test results for platelet-binding IgG.

Answer 321

o Transfusion-associated graft vs. host disease (TAGVHD) is an acute to delayed immunologic reaction that is secondary to donor lymphocytes engrafting on and eventually attacking host tissue. Occurs 48 hours to 6 weeks following transfusion and has a high mortality rate in human patients (>90%). o The reaction is characterized by a skin rash, diarrhea, fever, hepatic dysfunction, and bone marrow hypoplasia. In humans, it is most common in immunocompromised individuals or when special circumstances cause transient immunosuppression. Definite: Lymphocyte chimerism is identified in absence of other causes of chimerism Probable: Lymphocyte chimerism is identified; other causes of chimerism exist Possible: Chimerism negative or not investigated; other explanations more likely. o No reported risk factors of TA-GVHD in veterinary patients.

Answer 322

o The transparent yet viscous matrix inside platelets is labeled the sol-gel zone. o It resembles liquid gel and contains organized microtubules and microfilaments, randomly distributed glycogen, a few smooth and clathrin-coated vesicles, as well as secretory organelles. o Microtubules are arranged in circumferential coils close to the cell wall, thereby forming a system that supports the membrane contractile cytoskeleton. o Actin microfilaments in the sol-gel zone form the cytoplasmic actin filament cytoskeleton, in which all organelles are suspended and which keeps organelles apart from each other and from the cell wall in the resting platelet. o Following platelet activation, the cytoplasmic actin system constricts the microtubule coils moving α-granules and dense bodies to the platelet center, which may ultimately result in the secretion of their contents through the open canalicular system.

Answer 323

o DIC is characterized by the systemic activation of coagulation, leading to widespread microvascular thrombosis, which compromises organ perfusion and can contribute to organ failure. o The ongoing activation of coagulation may exhaust platelet and coagulation factors, resulting in a hypocoagulable state and bleeding.

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Coagulation / transfusion medicine Flashcards

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