Kapitel 7 - Bleeding and hemostasis Flashcards
The interaction between platelets and endothelium resulting in the formation of a platelet plug is referred to as:
Primary hemostasis
The system of proteolytic reactions involving coagulation factors os refer to as:
Secondary hemostasis
Which is the progenitor cells of platelets and how long os the lifespan of platelets?
- Megakaryocytesin the bone marrow
- 6-8 days
Briefly describe the steps in primary hemostasis
- Following endothelial disruption, platelets adhere to subendothelial collagen. Either directly or via collagen-bond vWF
- Adherence triggers a series of reactions resulting in change of shape and activation of the platelets
- Activated platelets release secondary agonists, notably TxA2 and adenosine diphosphate (ADP) which recruits more platelets
- Agonists alter the affinity of fibrinogen binding receptors resulting in aggregation and formation of a platelet plug.
What is the final common pathway for all platelets agonists?
Activation of the platelet integrin αIIbβ3 receptor.
Agonist binding to this receptor results in interplatelet cohesion and aggregation.
Name the pathways in the secondary hemostasis and what initiates them
- Extrinsic pathway, initiated by tissue factor (exposure of blood to extravascular tissue)
- Intrinsic pathway, initiated through contact activation of fXII
- Common pathway - initiated by activation of factor X to Xa
What does APTT and PT rest respectively?
- APTT: intrinsic and common pathway
- PT: extrinsic and common pathway
What enzyme cleaves fibrinogen to fibrin?
Thrombin
Name 3 endothelial inhibitors that controls platelet reactivity
- Prostacyclin (PGI2)
- Ectoadenosine diphosphatase (ecto-ADPase)
- Nitric oxide
What are 3 natural anticoagulant pathways described
- Antithrombin
- Activated protein C
- Tissue factor pathway inhibitor
What is the function of Antithrombin and where is it produced?
It inactivates coagulation proteins that escape into the circulation from a site of injury.
Antithrombin exerts its most significant anticoagulant effect by binding and inactivating thrombin and fXa
Antithrombin also inhibits neutrophil adherence and exerts potent antiinflammatory effects
Produced in the liver
What is the function of Activated protein C?
- Inactivate cofactors fVa and fVIIIa, and this slows the rate of thrombin formation.
- Enhances fibrinolysis via the inactivation of plasminogen activator inhibitor-1 (PAI-1)
- Plays a significant role in limiting inflammatory responses and decreasing endothelial cell apoptosis in response to inflammatory cytokines and ischemia
What is the function of tissue factor pathyway inhibitor and where is it synthesised?
- Binds with and inactivates FXa.
- Synthesized and expressed by endothelial cells
What predominantly controlled fibrinolysis?
- Plasminogen activator inhibitor-1 (appears to be most important)
- α2-antiplasmin
- thrombin activatable fibrinolysis inhibitor.
Name the two plasminogen activators described
Tissue-type plasminogen activator and urokinase-type plasminogen activator.
What does Buccal mucosal bleeding time test and in what conditions can be be prolonged?
The in vivo primary hemostasis
Prolonged with thrombocytopenia, thrombopathia and vasculopathy
What is the normal range of Buccal Mucosal Bleeding Time in dogs and cats?
Dogs: less than 3 min
Cats: 34-105 sek
What does Prothrombin time (PT) and activated partial thromboplastin time (APTT) test and what does prolongation indicate respectively?
What does prolonged PT and APTT indicate?
It tests the secondary hemostasis
PT prolongation indicates defective extrinsic and/or common pathways
APTT prolongation indicates defective intrinsic and/or common pathways
Which of PT and APTT is most sensitive to vit K deficiency?
PT
What are d-dimers and what does it indicate?
D-Dimers are specific degradation products of cross-linked fibrin
Indicates the activation of thrombin and plasmin and are specific for active coagulation and fibrinolysis
What is d-dimers sensitive indicators for?
Thrombotic conditions, such as disseminated intravascular coagulation and thromboembolism in dogs. They have excellent negative predictive value but are not specific (can be seen in many other diseases as well)
(The diagnostic utility of D-dimers in cats remains uncertain)
What is thromboelastogram and what is it used for?
It is a viscoelastic test that provides a visual representation of hemostasis.
Identifying hypercoagulability and hypocoagulability in various canine disorders.
What does R, K, α, MA and G value stand for in thromboelastogram?
R: The reaction time (R) represents the enzymatic portion of coagulation (secondary hemostasis). This time is from initiation of the test to the first deviations of the tracing from baseline, indicating initial fibrin formation.
K: The clotting time (K) represents clot kinetics, largely determined by clotting factors, fibrinogen, and platelets.
α: The angle (α) is dependent largely on fibrinogen, as well as on platelets and factors. This is the slope from R to K
MA: 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, on fibrinogen.
G: is a measure of the overall coagulant status.
Give two common examples when thromboelastography results should be cautiously interpreted
In case of anemia (which produces relatively hypercoagulable tracings) and polycythemia (which produces relatively hypocoagulable tracings)
Which coagulation factor is deficient in Hemophila A and Hemophilia B respectively?
Hemofilia A: Factor VIII
Hemofilia B: Factor IX
What is acute traumatic coagulopathy (ATC)?
A coagulopathy can occur within 30 minutes of trauma,
Certain injuries, including traumatic brain injury and long bone injury, pose a greater risk for acute traumatic coagulopathy development
What are the three hypotheses that are proposed to explain acute traumatic coagulopathy?
- disseminated intravascular coagulation with a hyperfibrinolytic phenotyp
- an enhanced thrombomodulin-thrombin protein C pathway,
- and catecholamine-induced endothelial damage
Name the six factors influencing the development of acute traumatic coagulopathy
- Tissue injury
- Hypoperfusion
- Systemic inflammation
- Acidemia
- Hypothermia
- Hemodilution
What is referred to as the “lethal triad” or the “trauma triad of death.”
Coagulopathy, acidosis, and hypothermia
What effect does acidemia have on coagulation?
Acidemia increases fibrinogen degradation and impairs coagulation protein activity;
fXa-Va complex activity is decreased by 50% at pH 7.2, by 70% at pH 7.0, and by 90% at pH 6.8.294
Moreover, the coagulopathy is not reversed with correction of acidemia via buffer administration
At what level of fibrinogen is no clot formed?
Below 50 mg/dl
Side note: Hetastarch demonstrates the most pronounced hemodilution effects because it influences not only fibrinogen, but also vWF and fVIII
Name some possible causes of prolonged PT and APTT
How much blood can a patient loose until the body can no longer preserve a normal blood pressure?
40 % of the blood volume
What are the 6 basic principles when managing a bleeding patient?
- Recognize and treat shock and any other life-threatening conditions.
- Rule out or correct technical sources of bleeding.
- Restore normal hemostasis via medications, transfusion of blood products, reversal of hypothermia, and/or control of other precipitating or contributing factors.
- Monitor for stability of coagulation parameters; correct as needed.
- Monitor for new or ongoing sources of blood loss.
- Monitor for complications associated with new or ongoing blood loss (e.g., intracranial hemorrhage).
Side note: Normal thromboelastography results in the face of postoperative bleeding indicate a technical cause of bleeding and are a clear indication of the need for reexploration.
When is fresh frozen plasma indicated?
For the treatment and prevention of bleeding associated with acquired disorders of secondary hemostasis and inherited factor deficiencies
(An exception is heparin-induced bleeding because the hemorrhagic diathesis is caused by factor inhibition, not deficiency; moreover, antithrombin in fresh frozen plasma may enhance the effects of heparin.)
Which factors does frozen/stored plasma contain?
Frozen (or stored) plasma retains the more stable factors II, VII, IX, and X, so it is appropriate for inherited deficiencies of these factors and for Vitamin K deficiency or antagonism
What does cryoprecipitate contain?
fVIII, vWF, fibrinogen, and fibronectin with an average factor yield of 50%, in 10% of the original plasma volume.
This concentration enables rapid administration of therapeutic factor levels.
When is cryoprecipitate is indicated?
Cryoprecipitate is indicated for the management of patients with von Willebrand disease, factor VIII deficiency, hypofibrinogenemia, and dysfibrinogenemia
Which blood products contain platelets?
Fresh whole blood, platelet-rich plasma, and platelet concentrate
(fresh whole blood remains the primary means of platelet transfusion in veterinary practice)
What’s the criteria to preserve platelet function in fresh whole blood?
It cannot be refrigerated and must be transfused within 6 hours.
What is desmopressin and how does in work?
Desmopressin is a synthetic vasopressin analogue that induces the release of subendothelial vWF stores.
It acts to increase platelet function by enhancing the release of not only vWF, but also factor VIII and plasminogen from the endothelium.
When is desmopressin used?
Desmopressin is used as adjunctive treatment of bleeding associated with canine type 1 von Willebrand disease, as well as for presurgical prophylaxis (administered 30 minutes before surgery).
It is not effective for type 2 or 3 disease.
Give examples of some anti thrombotic drugs and then whey should be discontinued before surgery
Name the 4 possible mechanisms causing thrombocytopenia
- decreased production
- increased destruction
- increased consumption
- or sequestration
At what level of platelets is the risk for spontaneous bleeding?
When platelet counts fall below 50,000/µL, but counts as low as 5000/µL can occur without bleeding
What breed can have nonpathologic thrombocytopenia?
Cavalier King Charles Spaniels
Which is the most common congenital bleeding disorder of dogs?
von Willebrand disease
Describe the 3 types of von Willebrand disease
Type 1 is characterized by the presence of all multimers, but in reduced concentrations
Type 2 von Willebrand disease is characterized by a disproportionate loss of high-molecular-weight multimers.
Type 3 is a quantitative deficiency, with an almost complete absence of vWF (<0.1%).
(a multimer (aka oligomeric protein) is a protein that’s made up of more than one polypeptide chain stuck together is called multimeric.)
Which type of Von Willebrand is most common and which breeds are overrepresented?
Type 1
Doberman Pinschers, Standard Poodles, Shetland Sheepdogs, German Shepherd Dogs, and Airedale Terriers
Which coagulations factors are vitamin K dependent?
II, VII, IX, X
Which is the most common factor deficiency in cats?
Factor XII
Is is an asymptomatic condition of dogs and cats.
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. fXII deficiency is usually diagnosed incidentally and must be distinguished from pathologic causes of APTT prolongation
Give examples of causes of vitamin K deficiency
- Broad-spectrum oral antibiotics can inhibit vitamin K synthesis. - Decreased absorption can result from severe gastrointestinal disease, hepatic disease, pancreatic insufficiency, or biliary obstruction.
- Vitamin K antagonism occurs with warfarin therapy or anticoagulant rodenticide toxicity.
What role does the liver have in coagulation?
Synthesizing clotting factors (with the exception of fVIII), coagulation inhibitors (antithrombin, protein C), and fibrinolytic proteins
Which are the three major risk factors for thrombotic tendency (Virchow’s triad)?
- Abnormalities of the vessel wall (endothelial injury),
- Abnormalities of blood flow (vascular stasis),
- Abnormalities of blood constituents that promote hemostasis (hypercoagulability).
Name conditions associated with thromboembolism in dogs
- protein-losing nephropathy
- neoplasia
- immune-mediated hemolytic anemia
- necrotizing pancreatitis
- hyperadrenocorticism
- corticosteroid therapy
- cardiac disease (primarily infective endocarditis and dirofilariasis)
- atherosclerosis
- sepsis
- diabetes mellitus
What type of thromboembolism is most commonly seen due to surgery?
Venous thromboembolism, most commonly pulmonary thromboembolism
How many patients are affected with deep vein thrombosis undergoing orthopedic surgery.
50 %
Although many thrombi are asymptomatic and resolve spontaneously, others proceed to pulmonary thromboembolism, especially in the patient with other risk factors and/or prolonged immobility.
What are some symtoms of thromboembolism?
acute onset of respiratory signs(dyspnea, tachypnea, and depression are most common), particularly if the patient has no prior evidence of respiratory disease. The presence of a potentially hypercoagulable state should increase the degree of suspicion
Which lobes are most commonly effected with pulmonary infiltration in case of thromboembolism?
In the right and caudal lobes
Note: Regional oligemia (Westermark sign) is a less common, but more specific, finding.
Best identified on ventrodorsal and dorsoventral radiographic views, where it appears as areas of increased radiolucency, representing hypovascular lung regions distal to the occlusion.
Which is the only laboratory marker with proven clinical utility in the diagnosis of pulmonary thromboembolism in human beings and is a promising test in dogs?
D-dimer concentration
A D-dimer concentration < 250 ng/mL in dogs was shown to be a reasonable predictor for the absence of pulmonary thromboembolism, although no value was 100% specific
A strong positive result, in the absence of intracavitary hemorrhage, is highly supportive of thromboembolism
(The clinical utility of D-dimer concentrations in feline pulmonary thromboembolism remains to be investigated. In a study of cats with arterial thromboembolism, only 50% had positive D-dimer results)
What test has been the gold standard for definitive diagnosis of thromboembolism?
Selective pulmonary angiography, however, is limited by the invasiveness of the procedure and the need for general anesthesia
Nonselective pulmonary angiography is simpler and safer, but less sensitive.
What is CTPA?
computed tomographic pulmonary angiography (CTPA) which has largely replaced angiography and scintigraphy for the definitive diagnosis of pulmonary thromboembolism in human beings and have been reported experimentally in dogs.
What coagulation factors does heparin inhibit?
thrombin and fXa
How does Warfarin work as an anticoagulant?
It alters the synthesis of vitamin K–dependent coagulation factors II, VII, IX, and X, as well as the anticoagulant proteins C and S.
Note: The anticoagulant effect of warfarin is not immediate because the newly synthesized inactive coagulation factors replace their functional counterparts. During the first 24 to 48 hours of therapy, only proteins with short half-lives—factor VII and protein C—are significantly affected, thus potentiating thromboembolism risk in the initial days of therapy. For these reasons, heparin therapy should overlap warfarin therapy for at least the first 2 days and until therapeutic levels of warfarin are achieved.
How does Aspirin work as an anticoagulant?
Is it an anti platelet drug and induces an irreversible functional defect in platelets by inactivating COX-1, thus suppressing the synthesis of TxA2
What is Disseminated intravascular coagulation?
Is the syndrome characterized by the systemic activation of coagulation, leading to widespread microvascular thrombosis that compromises organ perfusion and can contribute to organ failure.
The ongoing activation of coagulation may exhaust platelet and coagulation factors, resulting in a hypocoagulable state and bleeding, particularly in patients at risk for blood loss, such as surgical patients.
(Bleeding occurs in a minority of patients with disseminated intravascular coagulation; organ dysfunction is more common)
What is the diagnosis of DIC based on?
Presence of an underlying condition that could trigger disseminated intravascular coagulation, together with three or more of the following anomalies:
- thrombocytopenia
- prothrombin time (PT) and/or activated partial thromboplastin time (APTT) prolongation
- elevated levels of fibrin split products or D-dimers,
- hypofibrinogenemia
- reduced antithrombin activity,
- and/or red blood cell fragmentation
