L10: Physiological coagulation Flashcards
Balance of coagulation
Thrombosis = increase in clotting factors or lack of inhibitors
Bleeding = lack of clotting factors/platelets or increase in inhibitors (drugs)
Physiological haemostasis vs thrombosis
Physiological haemostasis:
- Blood vessel wall disrupted
- Form a thrombus to heal defect
- Platelet rich, generally size limited
Thrombosis:
- Formation of abnormal thrombus
- Vessel wall generally intact
- Venous: red cells and fibrin
- Arterial: platelet rich, occlusive
Primary and secondary haemostasis
Primary haemostasis = platelet plug formation
Secondary haemostasis = enzymatic reactions –> formation of fibrin strands –> fibrin mesh (clot) that entraps plug
Principles of coagulation
Vessel injury and platelet plug formation -> activates clotting factors (tissue factor) -> thrombin (IIa) -> thrombin converts fibrinogen (single protein) to fibrin (many molecules linked together)
Concept of enzyme catalytics
- Cleavage reaction between protease and target protein can be very inefficient
- When co-factor is present = efficient rapid cleavage
- Co-factors align proteases on lipid membrane
- Co-factors: VIIIa and Va
Physiological pathway
Coagulation occurs through tissue factor pathway first at vessel wall then on activated platelet surface
XIIa - not required for repair of damaged vessels (not physiological)
First step in coagulation: initiation complex
Occurs on disrupted subendothelial matrix, TF exposed
- TF bound to VIIa activates X to Xa and IX to IXa
- Xa converts II to IIa (thrombin, small amount)
- IIa converts VIII to VIIIa, V to Va and XI to XIa (thrombin then converts XIa to IXa via amplification loop)
Second step in coagulation: on platelet surface
- IXa (protease) and VIIIa (co-factor) convert X to Xa
- Xa (protease) and Va (co-factor) convert II to IIa (thrombin, large amount)
Require calcium and phospholipids for both
Thrombin results in formation of fibrin: fibrinogen in plasma -> cleaved by thrombin -> fibrinogen molecules link together to form fibrin
Tissue factor
Expressed on subendothelial tissues (smooth muscle, fibroblasts)
Not expressed on endothelium or cellular blood components
Thrombin
= work horse of coagulation
- Converts fibrinogen to fibrin
- Activates factor VIII, V and XI (feedback loop to IX)
- Activates XIII (cross-links fibrin)
- Activates protein C (inhibitory roll)
- Other roles in inflammation
Natural inhibitors of coagulation
(DO NOT cause inhibitory patterns in clotting tests)
Tissue factor pathway inhibitor (TFPI):
- Inactivates factor VIIa complex
Antithrombin: (requires heparin like compunds) - Inhibits thrombin - Inhibits Xa - Less efficient inhibitor of IXa and XIa
Protein C:
- Protein S is a co-factor
- Inactivates factor V
- Inactivates factor VIII
- Activated by thrombin via thrombomodulin
Vitamin K dependent proteins and action of vit K
II, VII, IX, X, protein C, protein S
Action:
- Carboxylates glutamate residues in GLA domain of vit K dep proteins
- Absence of carboxylation = failure to bind to membrane and lack of activity
- Cyclical process within liver
Vitamin K properties
- Essential for activity of proteins, deficiency results in bleeding
- Comes from diet and bowel bacteria
- Reversal of warfarin (12-24hrs)
- Newborns naturally deficient in vit K -> haemorrhagic disease of newborn (prevented by IM supplementation of vit K)
Contact activation
- NOT physiological, involved with inflammation
- In lab XIIa deficiency gives abnormal clotting tests
- XII deficiency not associated with bleeding and deficiency is mild
- Important in lab APTT
- Role in inflammation: linked to kallikrein system in innate immunity
- Role in thrombosis which is platelet-mediated
- Role in thromboses with devices e.g. plastic central lines
Fibrinogen to fibrin
- Fibrinogen has 3 chains: alpha, beta and gamma
- D domain cross-links
- Thrombin cleaves fibrinopeptides –> cross-linked to form fibrin polymer
- Stabilised by XIIIa (and Ca2+), D domains cross-linked (deficiency in XIIIa causes bleeding due to unstable clots)
