4. Clotting Flashcards
What is the basic mechanism of clotting?
Primary haemostasis
- mediated by platelets
- adhesion leads to weak platelet plugs being formed
Secondary haemostasis
- stabilises the plug, via the coagulation cascade
Fibrinolysis
- regulates the extent of the thrombus
What is coagulation?
Formation of a clot via a biological amplification system
- coagulation factors are activated by proteolysis and generate thrombin
- thrombin coverts soluble fibrinogen to insoluble fibrin —> mesh over aggregated platelets
What are platelets?
- Derived from megakaryocytes
- present in peripheral blood, live for 8-10 days
- have a contractile element called thrombostenin - helps in clot retraction
What surface glycoproteins do platelets have?
What do these bind to?
GP1a —> collagen
GP1b, IIb, IIIa —> VWF
GPIIb and IIIa —> fibrinogen
What are the platelet granules?
Dense core granules
- contain ADP - an aggregation agent
- calcium - acts as a binding agent for coag factors
Alpha granules
- contain VWF, beta-thrombomodulin, platelet activating factor 4, fibrinogen
What is the mechanism of primary haemostasis?
- Vessel wall damage - disrupts endothelium and exposes collagen
- VWF binds to collagen
- VWF also binds platelets (GP1b) - platelet adhesion
- The platelet is activated, changes shape and degranulates, releasing ADP, TXA2 and calcium
- ADP induces expression of GPIIb and IIIa —> fibrinogen linker
- TXA2 —> vasoconstriction
What lab tests can be done to check primary haemostasis?
Platelet count - quantitative problems
Blood film - may detect qualitative problems
BM biopsy - assess megakaryocyte number or presence of abnormal cells
Specialised tests - platelet aggregation and VWF levels
What are the clotting factors?
- Synthesised in the liver
- most are inactive zymogens, upon activation will act as cofactors or serine protease —> coagulation amplification
- factors II, VII, IX and X need Vit K for post-translational modification
- anticoagulant factors protein C and S also need Vit k
What is the Extrinsic pathway?
- Factor VII is activated by TF
- TF is expressed by tissues, and not normally in contact with blood
- VIIa then activates IX and X
What is the intrinsic pathway?
- Factor XII is activated by subendothelial collagen and HMWK
- XIIa activates XI, and converts plasminogen to plasmin
- XIa and VIIa activate IX
- IX activates X
What is the final common pathway?
- Factors V, Xa, I (fibrinogen) and 2 (prothrombin)
- Prothrombin complex is a 4 component system - consists of FXa, V, PF3 and calcium
—> cleaves PT to thrombin
What does thrombin do?
- converts fibrinogen to fibrin
- activates fibrin stabilising factor - helps form fibrin mesh
- also acts in feedback loop to amplify the production (VIII, V, XIII, XI)
- complexes with thrombomodulin on endothelium —> activate protein C, which inactivates Va and VIIIa
- thrombin is inactivated by a natural anticoagulant ATIII
How is a clot removed?
Fibrinolysis
- tPA is released from endothelium in damage
- activates plasminogen to plasmin
Plasmin
- cleaves fibrin to fibrinogen degradation products (FDPs) - d-dimers
- degrades V and VIII
- block platelet aggregation
- a2-antiplasmin inactivates plasmin
What lab tests do we do for secondary haemostasis disorders?
PT
APTT
Correction testing
What is PT?
- measures extrinsic system and final common pathway
- Normal is 10-13 secs
- used for warfarin monitoring, evaluation synthetic liver function and to detect factor VII efficiency if APTT is normal
- INR standardises PT between labs
