Blood clotting and haemostasis
Key point
- Must be rapid, localised and regulated
Key events (interacting simultaneously)
- Platelet plug formation (at site of vessel injury)
- Clotting factor activation (and stablisation of plug with fibrin)
- Clotting control (to limit extent of clot)
- Clot fibrinolysis (to restore blood flow)
- Vessel endothelial damage > expose collagen > platelet adhesion,
activation, secretion AND thrombin generation
- Thrombin generation > platelet activation
Platelet plug phases
- Activation - by collagen and thrombin (+ ADP, adrenaline)
- Adhesion - of platelets to subendothelial matrix (via GIIb/IIIa
receptors and VWF)
- Aggregaton - of platelets (via GIIb/IIIA receptors)
- Secretion - of platelet granules (resulting in further aggregation, plug
stabilisation. vasoconstriction)
- Procoagulant activity - ^ thombin generation (via phospholipid membrane)
Platelet secretion
- ADP - platelet aggregation
- Serotonin (5HT) - platelet aggregation, paradoxical vasoconstriction
- Fibronectin, Thrombospondin - stabilises platelet aggregartes
- Fibrinogen - contributes to clotting cascade
- Thromboxane A2 (TXA2)- platelet aggregation, vasoconstriction
- Platelet-derived growth factor (PDGF) - repair tissue (also can result
in atherosclerosis)
- Protein disulfide isomerase (PDI) - activate tissue factor, fibrin
generation
Clotting cascade
Key points
Sequential activation of inactive pro-enzymes to active enzymes that catalyse
further reactions
Amplifies signal
End product is fibrin generated from fibrinogen
Clotting pro-enzymes synthesised in liver (except VWF)
Initiating event is tissue factor from endothelial injury activating extrinsic
pathwayComponents and activation
Intrinsic pathway
- Activated by -ve charged surfaces e.g. celite, kaolin, silica, partial
thromboplastin (and thrombin)
- Factor XII (12) > XI (11) > IX (9) > common pathway
- Factor XII = Hageman factor
- Calcium, phospholipd and Factor X facilitate activation of Factor VII
Extrinsic pathway
- Activated by endothelial injury > tissue factor, thromboplastin (Factor
III)
- Factor III (3) > VII (7) > common pathway
Common pathway
- Factor X (10) > V (5) > II (2) > I (1)
- Factor II = thrombin
- Factor 1 = fibrin
- Factor 10 = stuart factor
- Factor XIII (13) cross links fibrin
- Calcium (Factor IV), II, phospholipid, anti-haemophilic factor (Factor
VIII) facilitates conversion of IX > X > V
- Thrombin activates further platelets
Clot control and lysis
- Antithrombin (AT) - neutralises Factor II (thrombin), IX, X, XII, XII
- Heparin - activates AT
- Thrombomodulin - inactivates thrombin mediated fibrin formation and
results in thrombin activation of protein C
- Protein C - inactivates Factor V, VIII
- Protein S
- Tissue factor pathway inhibitor - inactivate Factor X
- Tissue Plasminogen activator - converts plaminogen to plasmin to
dissolve fibrin