Coag/Transfusion Flashcards
1
Q
What are three alpha 2b beta 3 (GIIb/IIIIa) receptor antagonists?
A
Abciximab eptifibatide tirofiban
2
Q
Thrombomodulin MOA? Where does it come from?
A
Binds thrombin > ACTIVATES PROTEIN C > inactivates Va and VIIIa (with cofactor protein S) & promotes fibrinolysis (inactivates PAI-1 & inhibits TAFI)Thrombomodulin from endothelium
3
Q
What is the platelet receptor for collagen?
A
GPVI
4
Q
Antiinflammatory effects of aPC
A
Inhibits apoptosis
Decrease NF-kB
Decrease inducible TF
Decrease adhesion molecules
5
Q
What suppresses fibrinolysis?
A
PAI-1TAFI
6
Q
PAI-1 upregulated by
A
TNF-a and CRP
7
Q
Heparin MOA
A
Facilitates AT-mediated inactivation of thrombin and factor Xa (also 7, 9, 11, 12)Facilitates release of TFPI from endothelial cells
PS binds to heparin-binding domain of endothelial cell matrix protein, thrombospondin
Inhibits complement and hemolysis induced thrombin generation
8
Q
What accumulates in stored blood?
A
IL-1, IL-6, IL-8, bactericidal permeability increasing protein, phospholipase A2, TNF-a
9
Q
TFPI MOA
A
inhibits EXTRINSIC pathwayTFPI from endothelium
10
Q
How long can FWB be stored?
A
8h
11
Q
How long can PC and PRP be stored?
A
5 d at 22C with gentle agitation
12
Q
What are platelet storage lesions?
A
Change in shape from discoid to spherical, generation of lactate from glycolysis with decrease in pH, release of platelet granules, decrease in fxn, reduction in posttransfusion recovery and survival
13
Q
Why should you not chill platelets?
A
chilling causes vWF receptors (GP1balpha-IX complex) on platelet surface. The integrin receptor alphaMbeta2 (C3R) of hepatic macrophages recognizes the receptor and eats the platelet
14
Q
Half life of factor II (in dogs)?
A
41 h
15
Q
Half life of factor VII (in dogs)?
A
6.2 h
16
Q
What is the platelet receptor for VWF?
A
GP 1b-IX-V
17
Q
How can giving pRBCs help with hemostasis?
A
- dispersion of platelets to periphery 2. increase plt contact with endothelium 3. release ADP 4. scavenge NO (which inhibits plts) 5. increase production of TXA2 by platelets at bleeding site
18
Q
The platelet receptor alpha 2b beta 3 (GIIb/IIIIa) binds?
A
FIBRINOGENalso vWf
19
Q
HES-induced hypocoagulability is due to?
A
- Reduced availability of alpha 2b beta 3 (GIIb/IIIIa) platelet receptors.
- Decreased vWF (and VIII)
- Altered FXIIIa fibrin crosslinking
- HES molecules coat surface of platelet limiting binding of ligands
20
Q
LMWH MOA?
A
augments inhibitory effect of antithrombin on FXa.
21
Q
What is the test of choice to monitor LMWH?
A
Anti-Xa activity
22
Q
What is the test of choice to monitor warfarin?
A
Prothrombin time (PT) / INR
23
Q
What is INR?
A
PT results vary from different manufacturers (different tissue factor properties), so INR developed to standardize results.
24
Q
What is the test of choice to monitor unfractionated heparin?
A
activated partial thromboplastin time (aPTT) or anti-Xa activity
25
How many subunits must UFH have in order to bind AT and thrombin?
18
26
A patient with an increased risk of bleeding from LMWH overdose would have a low, normal, or high anti-Xa level?
high anti-Xa level
27
List 3 secondary agonists released by activated platelets to recruit additional platelets, amplifying the initial response
Thromboxane A2, ADP, and serotonin
28
Describe 2 mechanisms for platelet adhesion
Sub endothelial collagen via Platelet glycoprotein VI, or collagen bound vWF via glycoprotein 1b receptor
29
The final common pathway for all platelet agonists is the activation of?
Platelet integrin alphaIIbbeta3 receptor (aka glycoprotein IIbIIIa receptor); this induces a conformational change and exposes binding domains for fibrinogen
30
What factors does the PT test?
II, VII, X, V, and fibrinogen
31
What is tested with an aPTT?
Factors II, V, VIII, IX, X, XI, XII, prekallikrein, HMWK, or fibrinogen
32
What are FDP's?
Fibrinogen degradation products, generated when fibrinogen, soluable fibrin, or cross-linked fibrin is lysed by plasmin.
33
List 10 causes of elevated FDPs
Neoplasia, sepsis, SIRS, DIC, hepatic dysfunction, heart failure, thromboembolism, IMHA, heat stroke, trauma, and GDV
34
What is a D-dimer?
Neo-epitope produced when soluable fibrin is crosslinked by fXIIIa. The epitope is exposed by plasmin-induced cleavage of cross-linked fibrin
35
How do D-dimers differ from FDPs?
D-dimers are specific for active coagulation and fibrinolysis; indicate the activation of thrombin and plasmin (not just plasmin like FDPs)
36
List 6 acquired causes of hypofibrinogenemia
Hemodilution, massive transfusion, hepatic dysfunction, DIC, sepsis, and after thrombolytic therapy
37
What is the thrombin time a measure of?
Tests functional fibrinogen via a measure of the time taken for a standardized thrombin solution to convert fibrinogen to fibrin
38
List 3 causes of a prolonged thrombin time
Hypofibrinogenemia, dysfibrinogenemia, or presence of factors (heparin, FSPs) that inhibit fibrin polymerization
39
What is R and what does it represent?
Reaction time; represents enzymatic portion of coagulation (secondary homeostasis)
40
What is K? What does it represent?
Clotting time; represents clot kinetics, largely determined by clotting factors, fibrinogen, and platelets
41
What is the angle? What does it represent?
The angle represents the rapidity of fibrin accumulation and cross-linking and depends largely on fibrinogen, as well as platelets and factors.
42
What is MA and what does it represent?
Maximum amplitude; it represents the ultimate strength of the fibrin clot, dependent primarily on platelet aggregation (number and function) and to a lesser extent, fibrinogen
43
What is G and what does it represent?
Clot shear elastic modulus; represents overall coagulant status
44
What is the formula to calculate G?
G= 5000XMA/(100-MA)
45
What is LY60 and what does it represent?
Extent of clot lysis at 60 minutes after MA determined by the percentage decrease in amplitude at that time after MA. Measures fibrinolysis
46
List 8 causes of thrombocytopenia from decreased platelet production
Drug induced, IM megakaryocytic hypoplasia, viral (FeLV/FIV), chronic rickettsial disease, estrogen secreting neoplasia, myelodysplasia, megakaryocytic leukemia, cyclic thrombocytopenia, radiation, idiopathic bone marrow aplasia, post vaccination
47
List 7 causes of consumption/sequestration thrombocytopenia
DIC, microangiopathies, splenic torsion/hypersplenism, sepsis, hepatic disease, severe acute hemorrhage, severe hypothermia, HUS
48
List 9 causes of acquired thrombopathia
Drugs, uremia, anemia, hepatic disease, hypothermia, colloid hemodilution, myeloproliferative disorders and paraproteinemias, erhlichiosis, snake venom, DIC
49
List 10 drugs associated with thrombocytopathia
NSAIDs (aspirin and non aspirin), carbenicillin, cephalothin, moxalactam, sulfonamides, CCB, methylxanthines, B blockers, barbiturates, heparin, HES
50
List 3 causes of acquired vascular disorders and 1 cause of inherited
Acquired- vasculitis, cushings, arteriosclerosis Inherited - Ehlers-Danlos syndrome
51
List 8 inherited causes of thrombopathia
vWD, signal transduction disorders, Glanzmann's thrombasthenia, Chediak-Higashi syndrome, selective ADP deficiency, cyclic hematopoiesis, procoagulant expression disorders, macrothrombocytopenia
52
What is vWD, what breeds are affected?
Deficiency in vWF (type 1), decreased function of large proteins (type 2), or a complete absence of vWF (type 3). Affects many dog breeds (dobies!) rare in cats
53
What breeds have signal transduction disorders been reported in?
Bassett hound, Eskimo spitz
54
What is Glanzmann's thrombasthenia and what breeds does it affect?
Otter hound, Great Pyrenees
55
What is Chediak-Higashi syndrome? Whom does it affect?
Grey Persian cats
56
Whom is affected by selective ADP deficiency?
American Cocker Spaniel
57
In what breed is cyclic hematopoiesis inherited?
Grey collie
58
In what breed is Scott syndrome reported, what is another name for this?
GSD, procoagulant expression disorder
59
In what breed is macrothrombocytopenia reported?
CKCS
60
List 8 causes of acquired secondary hemostasis disorders
Vit K deficiency, hepatic failure, DIC, pharmacologic anticoagulants, hemodilution, severe hypothermia, acidemia, shock, massive trauma
61
Hypofibrinogenemia and dysfibrinogenemia are caused by a deficiency in what factor and this is inherited in what breeds?
FI deficiency; Bernese, Borzoi, Lhasa Apso, Vizla, Saint Bernard among others
62
Factor II deficiency causes what and is inherited in what breeds?
Hypoprothrombinemia, boxer, otter hound, English cocker spaniel
63
Factor VII deficiency causes what and in what breeds?
Hypoproconvertinemia; beagle, malamute, boxer, bulldog, miniature schnauzer, mixed breeds
64
What is hemophilia A and what animals does it affect?
FVIII deficiency; GSD, mixed breed dogs, other breeds, cats; X linked, mostly males affected
65
What is hemophilia B and whom does it affect?
FIX deficiency; numerous dog breeds, cats
66
What is Stuart-Power trait and whom does it affect?
FX deficiency; American cocker spaniel, JRT, mixed breed dogs
67
FXI deficiency causes what and in what breeds?
Plasma thromboplastin antecedent deficiency; English springer Spanial, Kerry blue terrier, Great Pyrenees
68
What animals have an inherited Vit K dependent factor deficiency been reported in?
Devon Rex cats
69
What is Hageman factor deficiency, whom does it affect, and is it a pathological condition?
FXII deficiency, min poodle, standard poodle, GSP, Shar Pei, cats; no
70
What is Chediak-Higashi syndrome?
An intrinsic platelet storage pool deficiency. Patients with this have prolonged bleeding times with normal platelet concentrations. Also have altered lysosomal granule formation and abnormal degranulation in neutrophils and platelets so aggregation response to collagen is absent.
71
What is Glanzmann's thrombasthenia?
Inherited intrinsic platelet functional defect which leads to a deficiency in alphaIIbbeta3 integrin and causes lack of fibrinogen binding. Corrected with experimental bone marrow transplantation and gene therapy
72
In what breed had a P2Y12 deficiency been reported and what does this cause?
Greater Swiss Mountain Dog; prevents activation via ADP induced outside in signaling for fibrinogen binding on the platelet surface at the alphaIIbBeta3 integrin
73
What is the mutation that alters protein signal transduction in inside out-outside in integrin signaling events in Landseers, Bassetts, and Spitz dogs?
Defect in the calcium-diacylglycerol guanine nucleotide exchange factor 1 gene (CalDAG-GEF1)
74
What is Canine Scott syndrome?
A defect so the phosphatidylserine is unable to be externalized for creation of a procoagulant surface. There is also decreased micro particle release. Diagnosis requires flow cytometry to show a difference in platelet function.
75
How is Canine Scott Syndrome treated?
Peri operative dimethylsulfoxide cryopreserved PRP transfusion plus a post operative antifibrinolytic
76
Thrombin has been shown to activate which members of the PAR family?
1,3,4
77
What does PAR mean?
Protease-activated receptors
78
According to The role of tissue factor in health and disease (JVECC 2009), what are the 4 coagulation proteases that activate PARs? PARs then mediate cell activation via what?
FVIIa, FXa, thrombin, TFG-proteins
79
TF activates what PAR receptor?
PAR 2
80
FXa activates what PAR receptor?
1, and 2
81
What are the 3 main endogenous anticoagulants?
TFPI, AT, and aPC
82
How does inflammation affect protein C production?
Down regulates PC pathway through inhibition of thrombomodulin and endothelial cell protein C receptor (EPCR) transcription so reduced ability to generate aPC. Neut elastases cleave TM from endothelial cells greatly reducing thrombomodulins activity. PC also dec in severe inflamm due to increased consumption and compromised ability to synthesize PC d/t hepatic dysfunction.
83
List the anti-inflammatory effects of TFPI
Decreased leukocyte activation and dampening expression of TNF alpha
84
Describe AT's anti-inflammatory effects
AT binds to endogenous endothelial cell GAGs (heparin sulfate and dermatan sulfate) which causes increased prostacyclin formation, decreased NF KB activation and decreased leukocyte activation and adhesion to endothelial cells.
85
Thrombophilia is...
Hypercoagulability as a result of inherited or acquired causes
86
What are some causes of thrombophilia in humans?
Factor V Leiden mutation or protein C deficiency
87
What is Virchow's triad?
Hypercoagulability, blood stasis/altered blood flow, endothelial dysfunction
88
What makes up the glycocalyx?
GAG's, proteoglycans, and glycoproteins
89
Vascular endothelial cells can be activated by what?
TNF-alpha, bradykinin, histamine, thrombin, and vascular endothelial growth factor (VEGF)
90
What anticoagulants rely on the glycocalyx?
Thrombomodulin, protein C, tissue factor pathway inhibitor,heparin cofactor II
91
How does the glycocalyx function as a mechanoreceptor?
Sensing altered blood flow and releasing nitric oxide during conditions of increased sheer stress to maintain appropriate organ perfusion.
92
List 3 important effects nitric oxide has in relation to the glycocalyx
Inflammatory response, leukocyte adhesion to the endothelium, and inhibition of platelet aggregation
93
List 5 substances contained in Weibel-Palade bodies
Ultra large multimers of vWF, P-selectin, IL-8, tPA, fVIII
94
How are UL-vWF usually dealt with in health?
Quickly cleaved by ADAMTS13, a metalloproteinase and disintegrin-like with thrombospondin type 1 repeats
95
What is the function of UL vWF?
Bind platelet GP 1balpha receptors and initiate platelet tethering and activation; are more active for platelet adhesion and activation than smaller vWF multimers
96
How does tissue factor promote inflammation?
Through the activation of nuclear factor kB, leading to production of TNF-alpha
97
What happens to platelets upon activation?
Shuffle negatively charged phospholipids (phosphatidylserine and phosphatidylethanolamine) to the surface. These provide catalytic surface needed for tenase and prothrombinase complexes for the propagation phase of clot formation
98
With activation platelets greatly increase the number of copies of what on their surface?
Active fibrinogen receptor - glycoprotein IIbIIIa, aka integrin alphaIIb beta3
99
What are the contents of alpha and dense granules secreted when platelets are activated
Calcium, factor Va, serotonin, fibrinogen, P-selectin, and ADP. Feline alpha granules also release vWF
100
How does AT act?
To inhibit thrombin and fXa, lesser inhibitory effects on fIXa and the fVIIa-TF complex
101
How can AT activity be increased?
Heparins, or, in their absence, by binding to Thrombomodulin in the presence of thrombin
102
List the 3 mechanisms that can decrease AT in systemic inflammation
Consumption (due to thrombin generation), decreased production, degradation by neutrophil elastase
103
Where is TFPI found?
Endothelial cells, platelets, mononuclear cells, vascular smooth muscle, cardiac myocytes, fibroblasts and megakaryocytes
104
What is the function of the protein C system?
Important inhibitor of fVa and fVIIIa
105
How is protein C activated?
When trace amounts of thrombin bind TM located on the endothelium, predominantly in microcirculation; accelerated in presence of EPCR and cofactor protein S
106
What 3 electrolyte abnormalities might be expected with massive transfusion?
Hypocalcemia, hypomagnesemia, and hyperkalemia
107
What hemostatic defects might be associated with massive transfusion?
Thrombocytopenia, secondary dilutional coagulopathy, and hypofibrinogenemia
108
Other than electrolyte and hemostatic abnormalities, list 4 other abnormalities associated with massive transfusion
Metabolic acidosis, TRALI, hypothermia, immunosuppression, other transfusion reactions, transmission of infectious diseases
109
Describe how massive transfusion causes hypocalcemia and hypomagnesemia
Citrate (anticoag added to blood products) binds rapidly to Ca and Mg with equal affinity resulting in decreases in iCa and iMg. ICa reported to resolve quickly once perfusion is restored as citrate is rapidly metabolized by the liver
110
When is treatment with calcium glauconate indicated in regards to massive transfusion?
When hypocalcemia is severe or when hypotension, muscle tremors, arrhythmias, or prolonged QT interval are present
111
What causes hyperkalemia associated with massive transfusion?
K levels rise over time d/t inactivation of Na-K-ATPase pumps by cold storage temperatures (less likely in dogs due to lower intracellular K stores). More likely K leakage from damaged tissues, extra cellular K shift secondary to acidosis, and reduced K excretion from oliguria
112
What is the cause of thrombocytopenia associated with massive transfusion?
Blood loss and dilution (blood products devoid of platelets after 2 days due to cold storage temperatures causing cell oxidation and death
113
Why is thrombocytopenia from dilution generally less severe than what would be predicted by the degree of dilution?
Platelets are released from stores in the lungs and spleen
114
Other than dilution, list 2 other causes of thrombocytopenia related to MT
Consumption of platelets and clotting factors (secondary to shock, sepsis, SIRS, blunt trauma); platelet dysfunction resulting from acidosis or hypothermia
115
Hemostasis is generally maintained as long as clotting factors are at least _____% of normal and PT and aPTT are not prolonged above ______.
30%; 1.5 times normal
116
Loss and replacement of 1 blood volume removes ______% of circulating factors in plasma
Slightly less than 70%
117
Acute coagulopathy of trauma is believed to result from what?
Altered coagulation enzyme activity, hyperfibrinolysis, and release of activated protein C secondary to tissue hypoperfusion, tissue injury, and acidosis.
118
Ratios of FFP/platelet to RBC ratios of what have been associated with decreased mortality in human patients?
Increased (at least 2:1, up to 1:1)
119
Describe 2 ways hypothermia can lead to coagulopathy in MT
Inactivates the enzymes that initiate the intrinsic and extrinsic coag cascades and to enhance fibrinolysis. Severe hypothermia can result in decreased platelet activity.
120
What is the 'bloody viscous cycle' being recognized increasingly in human medicine as a leading cause of death after blunt trauma?
Progressive hypothermia, persistent acidosis, and inability to establish hemostasis
121
What are the 3 definitions of massive transfusion?
1. Transfusion of > 1 blood volume of blood or blood products within a 24 hour period2. Transfusion of 1/2 estimated blood volume in 3-4 hours3. Administration of 1.5 ml/kg/min of blood products over a period of 20 minutes
122
List the factor numbers and their descriptive names
I-fibrinogenII-prothrombinIII-tissue factorV- labile factorVII- proconvertinVIII- antihaemophilic factorIX- Christmas factorX- Stuart prower factorXI- plasma thromboplastin antecedentXII- hageman factorXIII fibrin-stabilizing factor, prekallikrein (fletcher factor), HMWK (fitzgerald factor)
123
What is the plasma half life of factor II?
65 hrs
124
what is the half life of factor VII?
5 hrs
125
what is the half life of factor IX?
25 hrs
126
what is the half life of factor X?
40 hrs
127
what is the half life of factor I?
90 hrs
128
what is the half life of factor V?
15 hrs
129
what is the half life of factor VIII?
10 hrs
130
what is the half life of factor XI?
45 hrs
131
what is the half life of factor XIII?
200 hrs
132
which coagulation factors require vitamin K for synthesis and Ca2+ for activation?
II, VII, IX, X
133
What is the role of endothelin?
It promotes vasoconstriction and decreases local blood flow
134
What substances other than tissue plasmin activator, act as plasminogen activators?
urokinasebradykininkallikreinsoluble fibrin (non cross linked)
135
When are D-Dimers produced?
Plasmin cleaves cross-linked fibrin into x-oligomers that are then broken down into D-dimers. They are only produced with active coagulation and subsequent fibrinolysis
136
What are the three main mechanisms that limit thrombus formation?
Antithrombin
Protein C
Fibrinolytic system
137
What anticoagulant substances are synthesized by the intact endothelium?
ThrombomodulinProtein SHeparan sulfateTissue factor pathway inhibitor
138
Where is tissue factor pathway inhibitor synthesized?
LiverEndothelial cells
139
Name 5 causes of endothelial disruption that may result in thrombus formation
SepsisSystemic inflammatory diseaseHeartwormNeoplasiaTraumaShockIV catheterizationReperfusion injury
140
Name 5 conditions that may lead to abnormal blood flow and subsequent thrombus formation
Vascular obstructionCardiomyopathyEndocarditisCHFShockHypovolemiaProlonged recumbencyHyperviscosityHypoviscosityAnatomic abnormality
141
Name 5 conditions that may lead to increased coagulability and subsequent thrombus formation
PLNCushingsIMHAPancreatitisPLESepsisNeoplasiaDICHeart disease
142
Why are animals with PLE less prone to clot formation than animals with PLN?
PLE also causes loss of AT however they cause a concurrent loss of larger proteins maintains more of a balance between procoagulant and anticoagulant factors
143
Other than obstructing flow in a vessel, what other local effects do thromboemboli have?
They release vasoactive substances (thromboxane A2 and serotonin) that induce vasoconstriction and compromise collateral blood flow development around the obstructed vessel
144
Sonoclot ACT correlates with what on TEG
R time, K time, angle
145
CR on sonoclot correlates with what on TEG
all parameters
146
What does the Sonoclot do?
Measures changes in blood viscosity by detecting a change in mechanical impendance of a tubular, disposable, plastic probe oscillating vertically in a cuvette containing whole blood or plasma
147
How is platelet function determined on Sonoclot?
Not directly, calculated value based on both teh time it takes for the signature to peak, as well as degree of clot retraction
148
What 3 variables determined on Sonoclot
ACT, clot rate (CR), and platelet function (indirectly)
149
What does CR measure on Sonoclot?
rate of fibrin formation
150
Sonoclot correlated to several TEG parameters, platelet count, and fibrinogen, but not to other commonly used coagulation tests. T/F
T
151
MOA thrombomodulin
binds thrombin changing its substrate specificity and becomes an anticoagulant by activating protein C, with its cofactor, protein S, inactivates Va and VIIIathrombomodulin from endothelium
152
MOA TFPI
inhibits extrinsic pathwayTFPI from endothelium
153
What is the initiation stage of coagulation?
TF-VIIa makes a small amount of thrombin
154
What is the prothrombinase complex?
Va-Xa
155
What is the tenase complex?
VIIIa-IXaFxn: activates X to Xa which then binds with Va on platelet surface forming the prothrombinase complex to create thrombin burst
156
Antithrombin inhibits what factors?
2, 7, 9, 10, 11, 12
157
What dramatically increases AT activity?
heparan sulfate from endothelial cells (or heparin exogenously)
158
Effects of plasmin.
cleaves fibrin creating FDPsinactivates 5, 8, 9, 11, cleaves complement C3, enhances conversion of 12 to 12a and conversion of prekallikrein to kallikrein
159
What are inhibitors of plasmin generation
a2-antiplasmin, a-2 macroglobulin
160
Heparin MOA
Facilitates AT-mediated inactivation of thrombin and factor Xa (also 7, 9, 11, 12)Facilitates release of TFPI from endothelial cellsPS binds to heparin-binding domain of endothelial cell matrix protein, thrombospondinInhibits complement and hemolysis induced thrombin generation
161
How do you monitor heparin therapy?
anti-factor Xa (gold standard) or APTT (want 1.5-2.5 x normal)
162
What can affect APTT measurement with heparin therapy?
reagent used, high fibrinogen levels, antiphospholipid antibodies, increased circulating VIII, steroids, more low molecular weight multimers (can still have anti-factor Xa activity, but reduced ability to complex with thrombin, so APTT may appear subtherapeutic when it really is)
163
How do you monitor LMWH (enoxaparin, dalteparin)?
anti Xa only - b/c they are LMW do not complex to thrombin
164
What is the vWF platelet receptor?
Gb1b-IX-V
165
What's the difference between platelet rich plasma and platelet concetrate?
PRP is made by a soft spin at 1000 x 4 min of FWB (200 mls). If you spin again (hard spin, 2000 x 10 min), get platelet concentrate (40-70 mls)
166
How many platelets are in PRP and PC?
>100 x 10^9/L
167
Non immunologic complications of blood transfusion
pyrogen-mediated fever (most common), transmission of infectious agents, vomiting, mechanical hemolysis, CHF, hypothermia, citrate toxicity, pulmonary complications
168
Immunologic reactions to blood
acute and delayed hemolytic transfusion reactions manifesting as urticaria, anaphylaxis, graft vs host dz
169
Virchows triad
blood stasis, hypercoagulable state, endothelial damage
170
What coag factors increased in cushings?
5, 10, fibrinogen
171
What IL stimulates TF?
6 - predominantly
172
Where does heparan sulfate come from?
endothelial cells
173
When AT bound to heparan sulfate on endothelium, stimulates what factors regarding inflammation?
prostacyclin I2 and NF-kB
174
Negatively charged proteins on platelet surfaces when activated.
phosphatidylserine and phosphatidylethanolamine
175
What lives in Weibel Palade bodies
vWF, VIII, p-selectin, IL-8, TPA
176
What activates endothelial cells?
TNFa, bradykinin, thrombin, histamine, VEGF
177
What is the prothrombinase complex?
Va and Xa and prothrombin (II)
178
Feline platelet alpha granules have what that is special...
vWF (not in dog alpha granules)
179
What supports decrease in fibrinolysis?
decreased tPA, increased a2 antiplasmin, PAI-1, TAFI
180
What is MPC on Advia 120?
mean platelet component - granularity of platelets, activated platelets will have released their granules, so decreased MPC may indicate hypercoagulable state
181
G =
5000 x MA / (100-MA); higher = more hypercoagulable
182
Anticoagulant effects of aPC
inactivates Va and VIIIaenhances fibrinolysis
183
Antiinflammatory effects of aPC
Inhibits apoptosis, decreases NF-kB, decreases inducible TF, decreases adhesion molecules
184
How does inflammation alter the protein C pathway?
Inhibits thrombomodulin and endothelial cell protein C receptor transcription resulting in a decreased ability to generated APC
185
PAI-1 upregulated by
TNF-a and CRP
186
What is usually elevated with chronic end stage liver dz?
fVIII and vWF
187
What does thrombomodulin do?
activates protein C
188
Where is thrombomodulin at?
endothelial cells - its a transmembrane protein
189
What converts plasminogen to plasmin?
fibrin
190
What are antifibrinolytic drivers?
PAI-1, TAFI
191
Underlying conditions that explain the bleeding tendency in patients with decompensated chronic liver disease.
1. Portal hypertension causing hemodynamic alterations2. Endothelial dysfxn3. Development of endogenous heparin-like substances from bacterial infection4. Renal failure
192
What are the PAR receptors?
PAR1 binds TFVIIa, Xa, thrombin
PAR2 binds TF-VIIa, Xa, trypsin
PAR 3 and 4 bind thrombin
193
Bentley, JVECC, 2013 on coagulation with septic peritonitis, findings?
Preop PC >60% and AT >41.5% sensitive predictors of survival.TEG survivors were more hypercoagulable
194
TRALI
Occurs within 2-6 h of blood product, no pre-existing ALI, and no temporal relationship to alternative risk factors for ALIDue to anti-leukocyte antibodies, resolves rapidly, low mortality
195
Delayed TRALI
Occurs w/i 6-72 h after transfusion, occurs in 25% of critically ill transfused patients, mortality up to 40%Trauma, burns, sepsis increased riskRisk increased with transfusion of plasma-rich products, frozen plasma, and platelets, than transfusion with pRBC
196
Massive tranfusion risk of...
ARDS/ALI
197
TRALI theories:
1. Donor antibodies to antigens on recipient leukocytes, or less likely the other way around (in humans at least)2. mediated by an interaction b/t biologically active mediators in banked blood products and the lung (classic 2 hit theory - lung endothelium of recipient primed with neutrophils from critical dz, then transfuse blood with inflammatory mediators causing endothelial damage, capillary leak, and TRALI)
198
What accumulates in stored blood?
IL-1, IL-6, IL-8, bactericidal permeability increasing protein, phospholipase A2, TNF-a
199
Leukoreduction helps to prevent..
delayed TRALI
200
Plateletpheresis yield
3-4.5 x 10^11 vs. <1 x 10^11 for whole blood derived platelets
201
DMSO cryopreserved platelets yield
50%, half life 2 days
202
What is plateletpheresis?
selective removal of platelets from the donor's blood via an automated cell separator with return of RBCs and plasma to the donorReduces exposure of recipient to multiple donors
203
Platelets in PC?
8 x 10^10 per PC unit
204
Donor concern for plateletpheresis
citrate toxicity, hypocalcemia
205
How long can FWB be stored?
8 h
206
How long can PC and PRP be stored?
5 d at 22 C with gentle agitation
207
What are platelet storage lesions?
Change in shape from discoid to spherical, generation of lactate from glycolysis with decrease in pH, release of platelet granules, decrease in fxn, reduction in posttransfusion recovery and survival
208
Why can't you chill platelets?
chilling causes vWF receptors (GP1balpha-IX complex) on platelet surface. The integrin receptor alphaMbeta2 (C3R) of hepatic macrophages recognizes the receptor and eats the plateletGalactosylation decreases
209
What is thrombosol?
mixture of amiloride, adenoseine, and sodium nitroprusside to inhibit platelets - used with DMSO to improve platelet survival
210
DMSO platelet half life
2 d, vs. 3.5 d for fresh platelets
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DMSO plt storage life
1 year
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pRBC mechanism for the role in hemostasis
1. dispersion of platelets to periphery2. increase plt contact with endothelium3. release ADP4. scavenge NO (which inhibits plts)5. increase production of TXA2 by platelets at bleeding site
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FWB contains how many platelets?
10 x 10^9 /L
214
Methods to decrease lymphocytotoxic antibodies.
leukoreductionultraviolet B irradiation
215
What diseases are most common in cats with DIC
cancer, pancreatitis, sepsis
216
What % cats have hemorrhage with DIC?
15%
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Other findings, DIC cats, JVIM 2009.
All DIC cats had high PTTMedian PT of nonsurivors * higher than survivorsNo effect of heparin or transfusion on outcomeMost cats died or euth (7% survival)
218
Incidence of prolonged PT in dogs following GI decontamination for acute anticoagulant rodenticide ingestion. JVECC, 2008, Pachtinger, findings....
Dogs presenting w/i 6 ingestion, then PT done w/i 2-6 days. Only 8.3% developed prolonged PT needing treatment (none had bleeding or needed transfusion). No diff in age, wt, time elapsed b/t treated and untreated patients found.No assc'n w/ type of anticoagulant.Trend towards smaller dogs needing vitamin K.
219
Half life of factor VII
6.2 h
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Half life of factor II (prothrombin)
41 hShould take a minimum of 2 prothrombin half lives, or 3.5 days, to express the antithrombotic effect in patients
221
TFPI inhibits...
VIIa and XaTFPI lives in endothelial cells and platelets
222
What effect does LPS have on monocytes related to coagulation?
De novo synthesis of TF on surface
223
P-selectin
tethers platelets to surfaces
P-selectin + PSGL-1 (leukocytes binding)
224
Firm adhesion of plts to neuts is fibrinogen binding, which couples the platelet...
alpha2b beta3 to CD11b/CD18 counterreceptor (MAC-1)
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vWF platelet receptor
GP 1b-V-IX
226
collagen platelet receptor
GPVI
227
thrombin platelet receptors
PAR-1 and PAR-4
228
Alpha 2b Beta3 receptor antagonists
abciximabeptifibatidetirofiban
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Drug that blocks PAR1 receptor
vorapaxar and atopaxar
230
Drugs that block P2Y12 receptor by blocking ADP from binding
thienopyridines (prodrugs): clopidogrel, prasugrel, ticlodipineirreversible: ticagrelorreversible: cangrelor
231
Endothelial prostaglandins
PGD2, PGE2, PGF2, PGI2
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Acetylation of COX-1 is ___ more effective than COX-2 by aspirin
166Xvia acetylation of Ser529 preventing binding of AA to catalytic site on COX-1
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Other effects of aspirin besides inhibition of COX-1
stimulates NO release via 15-epoxylipoxin A4 and inhibiting leukocyte endothelial reactions, enhances fibrin clot permeability and lysis by acetylating lysine residues on fibrin
234
Clopidogrel action decreased by what drug?
PPIs - omeprazole
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Replacement of chlorine with ___ enhances prasugrels action.
fluorine
236
What drug class is ticagrelor in?
cyclopentyltriazolopyrimidine
237
Picotamide MOA
dual inhibitor of TxA2 receptors and TxA2 synthesis
238
20% of blood content of FV is where
alpha granules
239
What is the protein C/protein S/thrombomodulin (TM) system?
thrombin binds thrombomodulin, which activates protein C which binds with its cofactor, protein S, and intactivates any factors Va and VIIIa
240
Protease inhibitors TFPI and ATIII are always present bound to...
heparan sulfates on endothelial surfaces
241
TFPI inhibits
Xa and VIIa
242
What is the only coagulation protein that routinely circulates in its active form?
VII (about 1% VIIa)
243
What two effects does thrombin bound thrombomodulin have?
1. activates TAFI which modifies fibrin molecules by removing their terminal lysine residue making them more resistant to fibrinolysis2. activates Protein C which then binds cofactor Protein S to inactivate Va and VIIIa
244
How does the Sonoclot work?
Measures changes in blood viscosity using a vertically oscillating probe immersed in a cuvette of whole blood. Glass beads in the cuvette activate coagulation. Results are Sonoclot Signature graphically and quantitative results are ACT, clot rate, and platelet function
245
Recommended heparin levels for anticoagulation
0.35-0.7 U/ml
246
aPTT goal with heparin
1.5-2 X baseline
247
Babski, JVIM, 2012. Sonoclot evaluation of UFH dogs
ACT prolonged, CR decreased, aPTT correlated well with AXA; however, aPTT ratio did not correlate as strongly with AXA, Sonoclot equivalent to aPTT
248
Extrinsic platelets disorders are characterized by a lack of a functional protein needed for what?
Platelet adhesion and aggregation
249
Name the most common thrombocytopathy in dogs
Von Willebrands
250
What contacts more von willebrand factor, platelets or endothelial cells?
endothelial cells (richest source of vwb)
251
How many forms of von willebrands are there?
3
252
describe type 1 von willebrands
quantitative reduction in vWF - all multimers are present. however the concentration is less than needed for hemostasis
253
Describe type 2 von willebrands
measurable reductions in vWF, but the subset of large multimers is scant. This causes qualitative reduction in vWF because the large multimers are essentials for hemostasis
254
Describe type 3 von willebrands
Absolute lack of vWF all together
255
Clinical signs of vWF disease
Mucosal bleeding (epistaxis, melena, hematuria, gingival hemorrhage) or excessive cavity bleeding
256
T/F - Petechia and ecchymosis in dogs with von willebrands is common
false
257
What is the best in vivo diagnostic for primary hemostasis
buccal mucosal bleeding time BMBT
258
Normal BMBT times are less than ______
3 minutes
259
Which blood products are recommended to treat von willebrands
plasma containing VWF (fresh frozen plasma, cryoprecipitate or fresh whole blood)
260
T/F - Patients with Chediak higashi syndrome have a normal number of platelets
true - these patients have prolonged bleeding time in the presence of normal platelet concentrations
261
Describe the platelet defect in Chediak Higashi Syndrome
Patients with CHS have altered lysosomalgranuale formation, and abnormal degranulation in neutrophils/platelets. Because of this, aggregation to collagen is absent.
262
Describe the primary defect in patients with Glanzmanns thrombasthenia
Primary defect leads to a deficiency in the number of the alpha 2b beta 3 integrin. Prolonged bleeding time occurs because of the lack of fibrinogen beinding to this integrin.
263
Describe the mechanism behind the platelet membrane disorder in greater swiss mountain dogs
mutation is presnt on P2y12 receptor which prevents activation via ADP induced outside in signaling for fibrinogen binding on the platelet surface
264
How does clopidogrel work
Clopidogrel blocks ADP from binding at the P2Y12 receptor - reducing platelet activation
265
In which breed do we most often see Canine Scott Syndrome
German shepherd dogs
266
Describe the mechansim behind Canine Scott Syndrome
Defect lies in the inability for phosphatidylserine to be externalied from the creation of a procoagulant surface
267
Name the inherited autosomal recessive platelet defect seen in Cavaliers
Idiopathic asymptomatic macrothrombocytopenia
268
Describe the mutation in idiopathic asymtopmatic macrothrombocytopenia
A mutation in B1 tubulin leads to altered proplatelet formation in megakaryocytes
269
In humans, acquired von willebrands disease can occur through what mechanisms
autoimmune disease, increased shear-induced proteolysis of vWF (cardiovascualr lesions/pulmonary hypertension, etc), or increased binding of vWF to platelets on other cell surfaces
270
In humans, name three drugs that can cause acquired von willebrands
ciprfloxacin, griseofulvin, valproic acid
271
Name two molecules in the blood of uremic patients that become increased, resulting in altered vascualr tone and platelet function
nitric oxide and prostacylin
272
Recommended dosing of cryoprecipitate for dogs with clinical bleeding secondary to von willebrands dsiease
1 unit/10 kg IV
273
Recommended dosing of fresh frozen plasma
10-20mL/kg IV
