Bleeding and hemostasis Flashcards
What are the two stages of hemostasis?
- Primary hemostasis: formation of initial platelet plug
- Secondary hemostasis: proteolytic reactions resulting in generation of fibrin polymers and stable thrombus
Describe the mechanism of primary hemostasis.
What are the two different models of secondary hemostasis?
Traditional (or cascade model), cell based model
What are the two fundamental paradigms of the cell based model of coagulation?
- Tissue factor is the primary physiologic initiator of coagulation
- Coagulation is localized to, and controlled by, cellular surfaces
Describe the cascade model of coagulation.
Describe the cell based model of coagulation.
What are the three phases of the cell based model of coagulation?
Initiation, amplification, propagation
How does the normal endothelium control platelet reactivity?
Through three known inhibitors:
1. Prostacyclin: limits platelet response to TxA
2. ecto-ADPase: metabolizes ADP released from activated platelets
3. Nitric oxide: diffuses into platelets and decreased intracellular Ca2+ flux, reducing the number and affinity of fibrinogen binding sites
What are the three natural anticoagulant pathways?
- Antithrombin
- Activated protein C
- Tissue factor pathway inhibitor
Describe the function of the three natural anticoagulant pathways.
What are the enzymes primarily responsible for fibrinolysis?
Tissue type plasminogen activator, urokinase type plasminogen activator. Both lead to the formation of plasmin which degrades fibrin.
What acts as a cofactor for plasminogen activation?
Fibrin, in an autoregulatory manner
What primarily controls/downregulates fibrinolysis?
- Plasminogen activator inhibitor (produced by platelet alpha granules)
- Thrombin activatable fibrinolysis inhibitor
- Alpha2-antiplasmin (produced by the liver)
What is the normal BMBT in a dog and cat?
Dog: less than 3 minutes
Sedate cat: 34-105 seconds
What does a prolonged BMBT indicate?
A defect of primary hemostasis
What are APTT and PT used to assess?
Secondary hemostasis
Are APTT and PT predictive of bleeding?
No
What pathways in the traditional model do the APTT, PT and ACT test?
APTT: Intrinsic and common
PT: Extrinsic and common
ACT: Intrinsic and common - less sensitive than APTT
How decreased does a single factor have to be to cause prolongation of PT/APTT?
Decreased to less than 25-30%
Is PT or APTT more sensitive in detecting vitamin K deficiency?
PT due to the short half life of factor VII
Is the PT or APTT more sensitive to heparin administration?
APTT
What is the difference between fibrin split products and D-dimers?
D-dimers are specific fibrin degradation products that indicate both active activation of thrombin and plasmin (FDPs only indicate activation of plasmin). D-dimers are consequently specific for active coagulation and fibrinolysis and are a sensitive indicator of thrombotic conditions such as DIC and thromboembolism.
Is fibrinogen typically elevated or decreased in instances acute inflammation?
Increased - it is an acute phase protein
What effect does anemia have on TEG?
Causes a relatively hypercoaguable tracing
What can effect ACT results?
Thrombocytopenia, thrombopathia, anemia, altered viscosity, incubation temperature
What can cause disorders of primary hemostasis?
Thrombocytopenia, thrombopathia or vascular anomaly
What is the definition of acute traumatic coagulopathy?
50% prolongation in either PT or APTT. Most common in dogs with increased severity of injury, decreased systolic BP, and increased lactate
What factor is deficient in hemophilia A?
Factor VIII
What are the three hypotheses to explain acute traumatic coagulopathy?
- DIC with a fibrinolytic phenotype
- Enhanced expression of the thrombomodulin thrombin protein C pathway
- Catecholamine induced endothelial damage
What are the six factors that have been identified in the development of acute traumatic coagulatopathy?
- Tissue injury
- Hypoperfusion
These are the initiating causes. - Acidosis
- Hemodilution
- Hypothermia
These result in traumatic induced coagulopathy (TIC) which propagates ATC. - Systemic inflammation
What is the lethal triad?
Coagulopathy, acidosis, hypothermia
What effect does acidemia have on fXa-Va complex activity?
fXa-Va complex activity is decreased by 50% at a pH of 7.2, 70% at pH 7.0, and 90% at pH 6.8
What is the definition of massive transfusion?
Replacement of blood components that is greater than a patients blood volume within 24 hours, or half blood volume over 3-hours
What clotting factor is most affected by hemodilution?
Fibrinogen (due to limited synthesis). At fibrinogen levels less than 50 mg/dL no clot is formed
What prolongation of PT/APTT represents a clinical bleeding risk?
1.5 times
Platelet counts below what level are a bleeding risk?
50,000/u/L
Will TEG detect thrombopathies related to von Willebrands disease?
No
What factor deficiencies can variations in PT/APTT diagnose?
What physical signs of bleeding are typically associated with primary hemostatic deficits?
Ecchymoses and spontaneous bleeding from mucosal surfaces. Petechiae are more common with thrombocytopenia rather than thrombopathia
What physical signs of bleeding are typically associated with secondary hemostatic deficits?
Large hematomas and by bleeding into the subcutaneous tissues, body cavities, muscles and joints
What are the best tests to detect hyperfibrinolysis?
TEG is the best. Markedly elevated D-dimers or low fibrinogen concentrations may also be suggestive
What is damage control resuscitation?
Aggressive correction of coagulopathies while reducing hypoperfusion, hemodilution and hypothermia. Transfusion of platelets and plasma help to prevent dilutional coagulopathy
What are the targets of damage control resuscitation?
Maintain the PT and APTT within 1.5 times normal, and the platelet count over 50,000/uL
What ratio of PRBCs, platelets and plasma is advocated in damage control resuscitation?
1:1:1
What are contraindications for hypotensive resuscitative strategies?
Traumatic brain or spinal cord injury as mean arterial pressure is closely correlated to central nervous system perfusion
What is the lifespan of platelets in the dog and cat?
6-8 days
Describe the various plasma component transfusions and their indications.
Describe the various options for platelet transfusions and their advantages/disadvantages.
When should antithrombotic drugs be discontinued prior to surgery?
What is the mechanism of action of desmopressin?
Vasopressin analogue that acts at V2 receptors to release subendothelial stores of vWF. Onset of action is 30 minutes, and DOA is 2 hours.
What is the mechanism of action of tranexamic acid and epsilon aminocaproic acid?
Lysine analogues that block the binding and activation of plasminogen (antifibrinolytics)
How much more likely were greyhounds to have clinically hemorrhage following amputation without the administration of E-aminocaproic acid in one study?
5.7 times
What are the primary causes of thrombocytopenia?
Decreased production, increased destruction, increased consumption, sequestration
What are the three types of von Willebrands disease?
Type 1: presence but decrease of all multimers
Type 2: loss of high molecular weight multimers (Shorthaired pointers)
Type 3: almost complete absence of vWF (<0.1%) (chesapeke bay retriever, shetland sheepdog, scottish terriers)
What vWF ELISA result indicates deficiency?
<50% vWF concentration as compared to the pooled control sample
What factor deficiency causes hemophilia A and B?
Factor VIII and IX (sex linked in males)
What factor deficiency can cause a marked increase in APTT without clinical hemorrhagic tendency?
Factor XII
What coagulation factors require vitamin K for activation?
II, VII, IX, X
What can cause vitamin K deficiency?
Dietary insufficiency, decreased intestinal absorption, vitamin K antagonism (warfarin)
What is the MOA of warfarin?
Antagonizes vitamin K epoxide reductase which is the enzyme responsible for vitamin K recycling
With vitamin K deficiency is APTT/PT prolonged?
Both, but PT is prolonged first due to the short half life of fVII
What level of functional hepatic mass has to be lost for decreased coagulation factor synthesis to occur?
> 70%
What constitutes Virchow’s triad?
Endothelial injury, vascular stasis, hypercoagulability
What are the characteristics of a hypercoaguable TEG tracing?
Increased G-value, decreased R and K values, increased MA and alpha values
What tests can be used to assess for evidence of hypercoaguability?
TEG is best. Can also consider antithrombin levels, fibrinogen levels, and D-dimers
What diagnostics should be considered in instances of suspected pulmonary thromboembolism?
Thoracic radiographs, arterial blood gas analysis, echocardiography, D-dimer concentration, CT angiography
What are the most common arterial blood gas abnormalities in instances of pulmonary thromboembolism?
Increased A-a ratio, hypoxemia, hypocapnia, decreased oxygen responsiveness
What thoracic radiograph findings are suggestive of PTE?
Alveolar infiltrates (particularly right and caudal lobes), Westermark sign
Are anti-platelet drugs typically used for arterial or venous thromobprophylaxis?
Arterial
Are anticoagulants drugs typically used for arterial or venous thromobprophylaxis?
Venous
What is the mechanism of action of unfractionated heparin?
Potentiation of antithrombin activity leading to inactivation of thrombin and factor fXa
What is the goal of unfractionated heparin therapy?
Prolongation of APTT by 1.5 to 2 times normal
What is the mechanism of action of low molecular weight heparin?
Smaller molecule than unfractionated heparin (4000-6500 Daltons, compared to 5000-30,000). This leads to far greater inhibition of fXa than thrombin and much more predictable results with dosing
How is the action of low molecular weight heparin monitored?
Anti-fXa activity, although TEG may be superior
Why should heparin therapy overlap warfarin therapy for the first 2 days of therapy?
Because warfarin therapy takes 24-48 hours to exert an effect (only coagulation proteins with short half lives fVII and protein C are initially impacted).
What is the goal of warfarin therapy?
A PT that is 1.25 to 1.5 times baseline
What is the antithrombotic MOA of aspirin?
Inhibits COX-1 which suppresses the synthesis of TxA2. May also suppress prostacyclin release from endothelial cells, although this is also mediated by COX-2. Therefore suggested to use low doses of aspirin that block platelet COX-1 while sparing endothelial COX-1 and 2
What is the onset of action of aspirin?
Immediate and lasts for the length of the lifespan of the platelet
What is the MOA of clopidogrel?
This is a thienopyridine that requires hepatic metabolism for active metabolite. It blocks ADP binding on the platelet.
What is the onset of action of clopidogrel?
2 days, and reaches steady state after 5-7 days.
What drugs can be used for venous thrombolysis in instances of severe, life-threatening thrombosis?
Tissue or urokinase type plasminogen activators.
Ideally should be administered via local infusions.
What is the treatment for venous thromboembolism?
1) Supportive care
2) Prevention of thrombus propagation (unfractionated heparin).
+/- thrombolysis.
What are the most common causes of DIC in cats?
Neoplasia, pancreatitis, sepsis, infectious disease.
What markers can be used for the diagnosis of DIC?
The presence of an underlying condition that could trigger DIC with three or more of the following: thrombocytopenia, elevated PT and/or APTT, elevated fibrin split products or D-dimers, hypofibrinogenemia, reduced antithrombin activity, and/or red blood cell fragmentation
In a study by Muri 2019 in VCOT, what percentage of cats following presentation for acute trauma had acute traumatic coagulopathy (ATC)? Cats with ATC were at increased risk for what?
Incidence of ATC was 15% (clotting time and clot formation time prolonged on TEG). After 24 hours more cases had a hypercoaguable state.
Cats with ATC had a significantly higher risk for receiving blood transfusions.
