Haemostasis Flashcards
What are the 3 stages of haemostasis
What cellular components are involved in primary haemostasis?
Platelets
Endothelial cells (vWF/Von Willebrand factor)
Describe the events that happen in primary haemostasis
Adhesion: platelets bind to exposed subendothelial matrix proteins (collagen and vWF) through specific surface receptors
Activation: platelets change shape and degranulated released ADP, thromboxane and clotting factors which recruit more platelets
Aggregation: fibrinogen mediates the binding of adjacent platelets forming a temporary platelet plug
What are the possible therapeutical interventions for primary haemostasis
aspirin/NSAIDs => inhibition of thromboxane production
Clopidogrel => ADP receptor agonist
What are the clinical signs of ineffective primary haemostasis?
Petechiae (small spots of bleeding under skin or MM)
Ecchymosis (bruise)
Purpura (small, red flat spots)
Haematuria
Epistaxis (Nosebleed)
What tests can be used to assess primary haemostasis?
Give examples of disorders of primary haemostasis
Thrombocytopenia (reduced platelet number)
Thrombocytosis (increased platelet number)
Thrombopathia (abnormal platelet function)
Von Willebrand Disease (vWD)
Which breeds are predisposed to inherited thrombocytopenia?
Cavalier King Charles Spaniel
Greyhounds
Describe acquired thrombocytopenia
Decreased production of platelets
Destruction of platelets (immune mediated - primary or secondary e.g., immune thrombocytopenia)
Consumption of platelets e.g., DIC
Sequestration of platelets
Loss of platelets
Describe thrombocytosis
Increased platelet production:
- neoplasia
- drugs (adrenaline, glucocorticoids)
- reactive (cytokine driven) secondary to inflammation, neoplasia, GI disease
- iron deficiency
Decreased clearance:
- splenectomy
What are the clinical signs of thromboplasia
Bleeding
Platelet count within reference interval or slightly reduced
vWf:Ag within reference interval
abnormal BMBT (buccal mucosal bleeding time)
Describe von Willebrand disease
Most common inherited disorder of haemostasis (e.g., Dobermann)
Deficient or abnormal vWf
Measurement of vWf:Ag concentrations, genetic tests (selected breeds), BMBT
Signs: Young age -> excessive bleeding at teething, spaying/neutering
What is secondary haemostasis?
Coagulation: formation of fibrin by coagulation factors on the surface of activated platelets
3 pathways: intrinsic, extrinsic, common
Describe the intrinsic pathway of secondary haemostasis
exposure of basement membrane/collagen or negative charges activates factor XII which activates a cascade of clotting factors (XI, IX, VIIIa) to initiate the common pathway to form fibrin
This pathway takes longer
Describe the extrinsic pathway of secondary haemostasis
Contact with tissue factor (thromboplastin) activated TF (tissue factor) and factor VII complex to initiate the common pathway to form fibrin
Describe the common pathway of secondary haemostasis
Clotting factor X -> V -> thrombin -> fibrin
How secondary haemostasis be inhibited?
Antithrombin inhibits factor Xa and thrombin - acts as an anticoagulant
Describe the cell-based model of coagulation
Initiation:
- tissue factor expressed on fibroblasts bind to factor VII forming TF-FVIIa complex
- TF-FVIIa complex activates factor X => produces a small amount of thrombin
Amplification:
- thrombin amplifies its own production via activation of factor XI and the co-factors V and VIII
Propagation:
- burst of thrombin generation on platelet surfaces
Fibrin formation
What is required for coagulation to occur?
Ca and activated platelets
Vit K required for synthesis of functional factors II, VII, IX and X
Where are coagulation factors synthesised?
liver
What is the effect of warfarin and rodenticide on coagulation?
inhibit the recycling of vitamin K resulting in a relative vitamin K deficiency -> anticoagulant effect (vit K required for production of some clotting factors)
What are signs of hypocoagulability?
Haematoma
haemorrhage
What are signs of hypercoagulability?
thrombosis
What tests can be done to assess secondary haemostasis?
Prothrombin time (PT)
Activated Partial prothrombin time (aPTT)
Activated clot time (ACT)
Thrombin clot time (TCT)
Fibrinogen
Describe the prothrombin time (PT) test
Assesses the extrinsic pathway by testing factor VII and the common pathway
Tissue thromboplastin is added to blood to activate the cascade
Describe the activated partial thromboplastin time test
Assesses the intrinsic and common pathways
An activator is added to a blood sample (kaolin, silica, ellagic acid) to initiate the intrinsic pathway
A platelet substitute (cephalin) is added to provide a phospholipid surface for clotting reactions
Ca is added to allow the cascade to proceed
Time to clot is recorded
Describe the activated clot time test
Tests the intrinsic and common pathways
Available as an automated in-clinic test
Tests whole blood - requires patient platelets and calcium
Activator = diatomaceous earth
Describe the thrombin clot time test
Tests common pathway
Time taken for a thrombin solution to convert fibrinogen to fibrin
Describe the use of testing fibrinogen in assessing coagulation
Measures the balance between production (inflammation) and consumption (coagulation)
Direct check of common pathway
Give examples of methods of measuring fibrinogen
Modified TCT (clotting time compared to standard curve - TCT is inversely proportional to fibrinogen conc)
Refractometer pre and post heat precipitation of fibrinogen
Fibrinogen antigen (specialised lab needed)
Total protein plasma vs serum
Test results:
PT = increased
aPTT = normal
TCT = normal
Where is the defect in secondary haemostasis and what could be causing it?
Extrinsic pathway - FVII
Inheritance, Vit K absence or antagonism (e.g., warfarin), DIC, liver failure
Test results:
PT = normal
aPTT = increase
TCT = normal
Where is the defect in secondary haemostasis and what could be causing it?
Intrinsic pathway - FXII, XI, IX, VIII
Inherited, vit K absence or antagonism, liver failure, DIC
Test results:
PT = normal
aPTT = normal
TCT = increased
Where is the defect in secondary haemostasis and what could be causing it?
Fibrinogen conversion to fibrin
Hypo/dysfibrigonaemia
Test results:
PT = increased
aPTT = increased
TCT = normal
Where is the defect in secondary haemostasis and what could be causing it?
Common pathway - FX, FII, FV
Defects in multiple pathways
Inherited, Vit K absence or antagonism, liver failure, DIC
Test results:
PT = increased
aPTT = increased
TCT = increased
Where is the defect in secondary haemostasis and what could be causing it?
Fibrinogen conversion to fibrin
Defects in multiple pathways
Severe hypofibrinogenaemia (e.g., liver failure, inherited, DIC)
Excessive heparin therapy
Give examples of inherited disorders of secondary haemostasis
Haemophilia A
Haemophilia B
Factor XII deficiency (Hageman trait)
Describe inherited haemophilia A
FVIII
Dogs (males - sex linked)
Prolonged aPTT, PT WRI
Describe inherited haemophilia B
FIX
Dogs (males - sex linked)
Prolonged aPTT, PT WRI
Describe factor XII deficiency (Hageman trait)
Cats
Prolonged aPTT, no bleeding tendencies
Give examples of acquired disorders of secondary haemostasis
Anticoagulant rodenticide toxicosis
Metabolic diseases (e.g., liver disease, neoplasia)
Describe the effect of vitamin K inhibition on secondary haemostasis
Factors II, VII, IX and X are vit K dependent
Factor VII has very short half-life
=> extended PT (very) and aPTT (moderately)
Give examples of possible sources of vitamin K inhibition leading to impacted coagulation
Rodenticide toxicosis
Liver dysfunction
Poor Vit K uptake (e.g., cholestasis, problems in biliary flow, malabsorption)
What is fibrinolysis?
the dissolution of the fibrin clot by plasmin => formation of D-dimers
Describe fibrinolysis in greyhounds
Fibrinolysis occurs too early or too quickly => bleeding a few days after surgery
blockers e.g., tranexamic acid, are effective prevention
What is DIC?
Disseminated intravascular coagulation
= uncontrolled intravascular thrombus formation and breakdown
Not a primary disease - DIC is the result of failed haemostasis
Describe the features of DIC
Secondary to inflammation, endothelial injury, trauma, bacterial sepsis
Exposure to large amounts of tissue factor and procoagulant inflammatory cytokines
Microthrombi produced (hard to detect)
Consumption of platelets and coagulation factors leads to abnormal primary and secondary haemostasis as DIC advances
What are the signs of DIC?
Thrombo-haemorrhagic clinical signs
Red cell fragmentation on smears
Thrombocytopenia
Prolonged PT and aPTT
Hypofibrinogenaemia
Increased D-dimer concentration
Give examples of global tests of haemostasis
Viscoelastic testing:
- thromboelastography (TEG)
- thromboelastrometry (TOTEM)
- viscoelastic coagulation monitor (VCM)
What are the terms used to describe the findings of viscoelastic tests of haemostasis?
Normocoagulable
Hypercoagulable
Hypocoagulable
Excessive fibrinolysis
Reduced fibrinolysis
