Lecture Four

Question 1

What is meant by the term haemostasis?

Answer 1

Haemostasis = an arrest of bleeding

Question 2

What are the protagonists involves in haemostasis?

Answer 2

platelets, fibroblasts, coagulation factors, inhibitor factors and extracellular matrix proteins

Question 3

What are the major functions of haemostasis (3) and what is the result of an error in these functions?

Answer 3

1. maintain blood in fluid state (failure causes thrombosis)
2. Arrest bleeding following a trauma (failure causes haemorrhage)
3. Remove blood when healing is complete (failure causes thrombosis)

Question 4

What are the steps that are involved in haemostasis?

Answer 4

1. Vascular spasm (contraction of the blood vessel diameter)
2. Primary platelet response (formerly primary haemostasis)
3. Initiation of thrombin generation
4. Amplification of thrombin generation
5. Propagation of thrombin generation
6. Fibrin formation
7. Fibrinolysis

Question 5

What are the two types of qualitative problems that are normally involved in haemostasis?

Answer 5

• Extrinsic platelet disorders = platelets are normal but proteins required are absent, reduced or dysfunctional
• Intrinsic platelet disorders = involving the platelets directly (e.g. abnormalities with platelet granules)

Question 6

What are the quantitative problems involved with haemostasis?

Answer 6

• Severe thrombocytopenia- too few platelets
• Thrombocytosis- too many platelets
• Coagulation factor deficiencies

Question 7

What is the function of vWF?

Answer 7

a bridge between platelets and the sub-endothelial matrix with the assistance of glycoproteins (glycoproteins not present then things will be unable to bind)

Question 8

Explain how vWF disease occurs and the three different types of it:

Answer 8

vWF circulate as linear strings and subunits. Then join to form various sizes mutlimeters (low, medium to high mw). The high mw are the most effective at supporting the platelet adhesion. Type 1 VWF involves an equal decrease in size of all multimeters = quantitative change, Type 2 = decreased size of only the large multimeters = qualitative change, type 3 = no detectable vWF

Question 9

What are the pro-coagulants involved in the primary platelet response?

Answer 9

• TxA2 (Thromboxane A2): induces vasoconstriction and enhances platelet
• ADP: mediates platelet activation and aggregation
• α2-Antiplasmin: inhibition of plasmin
• PAI-1 (Plasminogen Activator Inhibitor-1): inhibits tissue plasminogen activator (tPA) and activate protein C to promote clot stabilization
• Factors V, XI and XIII: involved in coagulation cascade

Question 10

What are the anti-coagulants involved in the primary platelet response?

Answer 10

• ATP: inhibits platelet aggregation
• TFPI (Tissue Factor Pathway Inhibitor): inhibits TF-factor VIIa of the extrinsic pathway
• Protein S: cofactor in the protein C pathway for inhibition of factors Va and VIIa

Question 11

How does the forming of the primary plug occur?

Answer 11

The forming of the primary plug is mediated by the binding of fibrinogen with GPIIB/IIIA on platelet membrane. This will be sufficient to stop the bleeding in the majority of smaller vessels however larger one’s must be stabilised through thrombin

Question 12

What is involved in GLANZMANN THROMBOASTHENIA? What are the varying degrees of it?

Answer 12

Intrinsic disorder in which the fibrinogen GPIIB/IIIA is absent on the surface of the receptor. Three main different types of this condition occur:

• Type 1 - less than 5% of receptor on surface
• Type 2 - 10-20% of receptor is present = clot retraction is detectable but reduced
• Variant - receptor may be present but dysfunctional = clot retraction may be detectable

Question 13

How does fibrinolysis occur?

Answer 13

• Injured endothelial cells release tPA (tissue plasminogen activator) causes conversion of plasminogen to plasmin
• Binding of plasminogen amplifies its conversion to plasmin (fibrin acts as cofactor for tPA)
• Binding of both plasmin/plasminogen to fibrin serves to localise fibrinolysis to the clot and prevents plasmin from non-specifically lysing other proteins
• Binding to fibrin means plasmin is protected from its major inhibitor (alpha2- antiplasmin)

Question 14

What are the inhibitors of the secondary haemostatic response?

Answer 14

• Specific – Tissue factor inhibitor (TFPI), antithrombin (AT), Protein C and Protein S
• Non-specific protease inhibitors- a2-macroglobulin, a1-antitrypsin
• Pathological- rodenticide, antibodies, coagulation factor deficiencies, snake envenomation
• Therapeutic- Warfarin, heparin, hirudin

Question 15

What is haemophilia A?

Answer 15

functional or quantitative deficiency of factor VIII

Question 16

What is haemophilia B?

Answer 16

functional or quantitative deficiency of factor IX (humans, dogs, cats)

Question 17

How does rodenticide affect the coagulation cascade?

Answer 17

inhibitors of Vitamin K- inhibits the 2, 7, 10, 9. This means that fibrin cannot be produced to stop the bleeding

Question 18

How does snake envenomation affect the coagulation cascade?

Answer 18

large amounts of anti-coagulant molecules to decrease or increase the cascade

Question 19

What is meant by DIC ?

Answer 19

Disseminated intravascular coagulation (effectively a condition whereby coagulation goes haywire). It is systemic so is not restricted to the site of injury and it is consummative (platelets and coagulation factors)

Question 20

Is DIC a secondary or a primary disease?

Answer 20

DIC will always be secondary to an underlying disease. The underlying disease could be severe inflammation or neoplasia.

These then lead to initiations by tissue factor:

• Widespread/severe endothelial injury = exposes tissue factor
• Severe organ injury - released TF/cytokine storm
• Inflammatory cytokines - induces TF expression on monocytes and also endothelial cells (no-endothelial injury)
• Cancer - unusual tissue factor expression