Wimmer Blood clotting II
Terms
- Anticoagulation; control of clot
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Localization controls it
Dilution of clotting factors by blood flow slows it
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What degrades FVa and FVIIIa?
- Thrombin-activated protein C (a serum protease)
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Which factors are carboxylated before released in blood?
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II (protrombin), VII, IX, X.
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What's Gla?
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gamma-carboxyglutamate.
Carboxylation PTM
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Role of Vit. K in clotting
- Reduced Vit. K (Vit. KH2): cofactor for glu carboxylation. Catalyzed by Vit. K-dependent carboxylase.
- What give some clotting factors a high affinity for Ca?
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N-terminal Gla residues.
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What does Gla do?
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Bind FXa and PT to Ca on platelet surface, along with FVa.
Proteolytic cleavage (2 cuts) of PT by Xa occur.
Active thrombin is released, localized at the site of the plug.
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What are some Vit. K antagonists, and what do they do?
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Hinders clotting; decreases Gla formation; slows factor activation
Warfarin (Coumadin) and dicoumarol are Vit. K analogs.
They completely inhibit recycling of Vit. KH2 from oxidized Vit. KO (formed in carboxylation rxn)
- What are Vit. K antagonists used for?
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prophylactic treatment of thromboembolic disorders
- What are some specific protein-inhibitor complexes?
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Antithrombin III (ATIII) (a major serpin) is a suicide inhibitor. Modifies thrombin's active site ser, terminating clotting process.
Heparin: enhances ATIII action
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Tell me about anticoagulant therapy.
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LMW heparin.
Complication: HIT (heparin induced thrombocytopenia). Antibodies bind HMW heparin-platelet complexes, activating platelets; excessive blood clotting.
Using LMW heparin minimizes HIT problem
Drug: increase anti-FXa s
- Fibrinolysis
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Plasminogen converted to plasmin by t-PA.
Plasmin cleaves fibrin clot into soluble peptide fragments.
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Why use t-PA clinically?
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to dissolve thromboses.
(also: urokinase)