The document summarizes the physiology of blood coagulation, including the five main components (vessels, platelets, coagulation factors, inhibitors, fibrinolysis) and how they work together in a complex system. It describes platelet activation and aggregation to form a platelet plug, coagulation factors that amplify to form a fibrin mesh to strengthen the clot, and fibrinolysis to prevent excessive clotting and allow blood to flow again. A balance is needed between coagulation and anticoagulation/fibrinolysis to control clotting.

1. The Physiology of coagulation How to clot But not too much

2. Basis Blood flows through intact vessels Resting state is designed to keep blood flowing Arteries: rapid flow. Injury requires a plug Rapid, localised, controlled. minimise blood flow compromise Veins: slower, intermittent flow Systemic anticoagulant clot dissolving system

3. Complex activating and inhibition system Five components Vessels Platelets Coagulation factors (clot forming) Coagulation inhibitors (clot controlling) Fibrinolysis (clot dissolving)

4. Haemostasis Vasoconstriction Platelets activated by thrombin form a platelet plug Fibrin mesh forms via activation of the coagulation system to strengthen the clot Clot dissolution via plasmin Normal blood flow past the clot

7. Platelet shape change Pseudopod formation Interact with adjacent platelets Contract later to consolidate the platelet plug in process of clot retraction

8. Platelet adhesion Platelet receptors (integrins) Glycoprotein Ib/IX Glycoprotein Ia/IIa Ligands interact with receptors Von Willebrand factor Large (high molecular weight) multimers collagen

10. Platelet release reaction Stimuli Adrenaline, collagen, ADP, thrombin Release of preformed active substances from granules ADP, serotonin, lysozyme,factor V, thrombospondin Activate the prostaglandin pathway Thromboxane A2 via cyclooxygenase Calcium release Glycoprotein IIb/II activation

11. Platelet Phospholipid Arachadonic acid Endoperoxidases Thromboxane A2 Calcium flux Phospholipase A2 Cyclooxygenase Thromboxane synthase Phosphodiesterase

12. Platelet aggregation Platelet receptor Glycoprotein IIb/IIIa Ligands Von Willebrand factor Fibrinogen IRREVERSIBLE aggregation -> Plug

15. Coagulation forms fibrin mesh Biological amplification system which converts soluble fibrinogen to an insoluble fibrin meshwork which coverts the primary platelet plug to a firm, definitive stable clot. Required local concentration of clotting factors at site of injury Surface mediated reactions on exposed collagen, platelet phospholipid or tissue factor

16. General concepts Coagulation factors act as proteases when activated (serine proteases) Zymogens (inactive eg fibrinogen) converted to enzymes/proteins by limited proteolysis Complex formation requiring calcium, phospholipid surface, cofactors Thrombin converts fibrinogen to fibrin monomer Fibrin monomer crosslinked to fibrin Forms "glue" for platelet plug

17. Cascade effect -> amplification 2x10 8 mol Fibrin mesh 1 mol

19. Coagulation cascade XII XI IX X VIII Prothrombin (II) thrombin fibrinogen fibrin STABILISED FIBRIN V, Ca, P/L VII Intrinsic pathway Extrinsic pathway XIII APTT PT

20. X Xa II (Prothrombin) IIa (Thrombin) INITIATION VIIa TF Va VIIIa Va XIa

21. AMPLIFICATION IXa Xa-Va-II Prothrombinase Platelet IXa- VIIa-X “ tenase” TF IX VIIa THROMBIN (IIa) FIBRIN

22. Fibrinogen -> fibrin Thrombin cleaves fibrinogen Fibrinopeptide release Fibrin monomers Spontaneously link to form a loose polymer Fibrin meshwork is stabilised by factor XIIIa (activated by thrombin and calcium)

24. Inhibitors: ANTI-coagulants Antithrombin III Directly inactivates serine proteases Thrombin and Xa. Also: IXa and Xia Potentiated by heparin Protein C Inhibits (cleaves) the cofactors VIIIa and Va Significantly decreases the rate of clot formation Needs to be activated

25. Protein S: Enhances activity of protein C Thrombomodulin Activated by thrombin Binds to thrombin to alter its conformation Complex activates protein C Tissue pathway factor inhibitor Inhibits FVIIa-tissue factor complex

26. Anticoagulants Too little or ineffective Extensive clot Too much Bleeding Therapeutics Heparin Activated protein C TPFI inhibitor

27. Fibrinolysis Prevents excessive fibrin deposition Allows closely coupled with fibrin formation Localised surface bound phenomenon that is catalysed by fibrin formation

28. Components: fibrinolysis Plasminogen -> plasmin Plasminogen activators Inactivators of plasminogen Inhibitors of plasmin

30. Effect of plasmin Lyses factor V and VIII Proteolysis of fibrinogen Removes small peptides Degradation of fibrin Fibrin degradation products (FDP)s D-Dimers

32. Blood Vessel: endothelium Active Haemostasis factors Von Willebrand factor Tissue factor – expressed after injury Anticoagulant factors ATIII, protein S, thrombomodulin Fibrinolysis Tissue plasminogen activator

34. Haemostatic response Vasoconstriction Initial slowing of blood flow to injured area Smooth muscle in arterioles Vasoactive substances Platelet primary plug formation Collagen/VWF Glycoprotein Ib/IX and IIb/IIIa Aggregation with arachadonic acid pathway

35. Haemostatic response Stabilsation of the platlelet plug with fibrin Tissue factor activation of coagulation cascade Thrombin burst Formation of fibrin meshwork

36. Haemostasis reaction Regulation of fibrin clot Activation of fibrinolysis Tissue plasminogen activator Plasmin -> FDPs

37. A test tube is not a person Coagulation in vivo Temperature pH Calcium That is: hypothermic , acidotic, hypocalcaemic patients don’t clot