Haemostasis

Question 1

Briefly describe the process of platelet activation/platelet plug formation (primary hemostasis)

Answer 1

primary hemostasis: (results in platelet plug formation)
1. Vasoconstriction
2. platelet adhesion to collagen (VWF recruits)
3. platelet activation: platelets release ADP and thromboxane A2 recruiting more platelets to aggregate. thromboxane A2 and release of serotonin causes further vasoconstriction
4. platelet aggregation (platelet plug formation)

Question 2

Briefly describe the mechanism of fibrin clot formation (secondary hemostasis)

Answer 2

Secondary hemostasis: (coagulation cascade)

Intrinsic pathway (F 8, 9, 11 , 12)
1. F12 activated into F 12a -> which then activates F11 into F11a which then activates F9 into F9a which then forms a complex with F8 (needs platelet factor 3 and calcium)
2. complex of F9a and F8 activates the common pathway

Extrinsic pathway (F 7, 9)
1. damaged tissue releases tissue factor 3 (tf3) which activates F7. F7a promotes the activation of F9 in the intrinsic pathway, and can also directly activate F10 of the common pathway

Common pathway: (F 2, 5, 10, 13)
1. F10 activated by either F9a F8 complex, or F7a into F10a. F10a with FV activates the prothrombin activator which activates F2 (prothrombin) to F2a (thrombin)
2. F2a (thrombin) then activates fibrinogen to fibrin (polymerized) , F13 activated by F2a then crosslinks the fibrin polymers, forming a fibrin mesh over the platelet plug.

Question 3

What does Gla proteins do? How are they formed? What factors are included in the Gla proteins?

Answer 3

Gla proteins are required for the proteins to bind to the membrane
- ensures that fibrin formation occurs at injury and not in the flowing blood
- complexes allow: concentration, orientation, localization
- Ca2+ dependent binding to the phospholipid membranes

Gla proteins are formed by carboxylation (vitamin k dependent reaction)
-ex. prothrombin precursor -> prothrombin
- factor 2, 7, 9, 10

Question 4

What is the function of factor 13

Answer 4

activated by thrombin and Ca, acts on fibrin and plasminogen inhibitor
- cross links fibrin chains and other molec. to increase clot strength
- binds plasminogen inhibitors to fibrin to prevent plasmin from breaking down the newly formed clot

Question 5

List 5 anticoagulants

Answer 5

antiplatelet: aspirin
calcium ion chelators: citrate, EDTA
accelerators of thrombin and factor 10a inhibition by antithrombin: heparin
inhibit carboxylation of Gla proteins: warfarin (VKA)
directly inhibit thrombin and factor 10a: new oral anticoagulants

Question 6

What is fibrinolysis?

Answer 6

fibrinolysis is the digestion of clot by PLASMIN
- activated by tissue damage or coagulation
- endothelium cells secrete tissue plasminogen activator and plasminogen activator inhibitor
- both plasminogen activator and plasminogen activator inhibitor bind to fibrin clot along with antiplasmin
- tissue plasminogen activator cleaves plasminogen into plasmin which cleaves fibrin
- plasmin is neutralized by the antiplasmin

Question 7

What is a control mechanism for primary hemostasis?

Answer 7

formation of prostoglandins in endothelial cells can bind to platelets and increase cytoplasmic cAMP, resulting in decreased Calcium levels, inhibition of shape change and activation

Question 8

How is VWF cleared out? Where can things go wrong for VWF?

Answer 8

large polymers of VWF is lysed by ADAMTS13 enzyme (deficiency causes thrombotic thrombocytopenic purpura- TTP) and cleared by macrophages

VWF can go wrong in:
- synthesis
- release
- proteolysis
- clearance