• Coagulation

    by  • 18/10/2013 • Haematology

    Process of cessation of bleeding, based on primary haemostasis (platelet mediated) and secondary haemostatic processes (coagulation factors).

    Disorders of coagulation can lead to excessive bleeding (haemophillic state) or excessive clotting (throbothillic state).

    Platelet activation: InjuryvWF released from subendotheliumrecruits factor VIII and collagenplatelets bind to collagen which express surface specific glycoprotein Ia/IIa receptors (further strengthened by vWF, glycoproteins Ib/IX/V and collagen fibrils = activated platelets release ADP, serotonin, platelet-activating factor (PAF), vWF, platelet factor 4, and thromboxane A2 (TXA2), which, in turn, activate additional plateletsrelease of clacium in plateletsactivate protein kinase Cactivate PLA2modifies the integrin increasing affinity to bind fibrinogen platelets spherical to stellate = fibrinogen cross-links and aggregation of adjacent platelets.

    Coagulation cascade

    • Tissue factor pathway (extrinsic)

    • “thrombin burst,” – converting fibrinogenfibrin.
    • InjuryFVII contacts tissue factorcomplex = FVII/TFactivates FIX and FX (activation of FXa by TF-FVIIa is almost immediately inhibited by tissue factor pathway inhibitor). FXa and FVa form the prothrombinase complex = activates prothrombin to thrombin activates FV and FVIII (which activates FXI which activates FIX), and activates and releases FVIII from being bound to vWF.

    Contact activation pathway (intrinsic)

    Final common pathway – Thrombin: conversion of fibrinogen to fibrin, activates Factors VIII and V and their inhibitor protein C, and it activates Factor XIII. The coagulation cascade is maintained in a prothrombotic state by the tenase complex, until it is down-regulated by the anticoagulant pathways.

    Clotting Cascade 300x225 Coagulation

     

    IP = XII, XI, IX, VIII, X

    EP = VII

    CP = X, V, II (prothrombin) , I (fibrinogen)

     

     

    Warfarin:

     

    • Coumarin anti-coagulant, inhibits vitamin K (vit k epoxide reductase VKOR) dependant synthesis of several blood coagulation proteins = II, VII, IX, X and protein C & S.

     

    • Uses: acute DVT, recurrent DVT, artificial metal heart valves, AF.

     

    • Rapidly orally absorbed, binds to albumin, metabolises in liver,

     

    • Warfarin has a long half-life (48hrs) and need only be given once a day.

     

    • Mechanism: When VKOR is inhibited,  the coagulation factors are no longer carboxylated at certain glutamic acid residues, and are incapable of binding to the endothelial surface of blood vessels, and are thus biologically inactive. Therefore the clotting cascade is no longer functional and formation of clotting is reduced.

     

    • Monitoring: Warfarin therapy requires careful monitoring with INR to ensure it is at an optimal therapeutic dose (0.81.2). If INR 4.5-10.0, give Vit K to reverse effect of warfarin. Can also use octoplex/bioplex (freeze dried F1, 7, 9, 10)

     

    • When in therapeutic dose – PTT = prolonged and APTT = normal/prolonged

     

    • S/e: contraindicated in pregnancy – teratogenic, bleeding, necros/gangrene, osteoporosis, purple toe syndrome, interacts with various drugs including metronidazol, macrolides, simvistatin cranberry juice.

     

     

    Heparin

     

     

    • Mechanism: heparin binds to antithrombin III and creates a 5 x pentasaccahride site. Thrombin the binds this site sequesters additional 13 saccahride subunits = inhibits FXa and IIa (thrombin). FXa catalyzes the conversion of prothrombin to thrombin, so inhibition prevents fibrin clot formation and aids in the bodies natural clot lysis processes..

     

    • Uses:STEMI, AF, DVT and PE, and cardiopulmonary bypass for heart surgery

     

    • S/e: bleeding, HIT, hyperkalaemia,

     

    • Various preparations of heparin: unfractionated (reqs IV infusion, short half life, monitor dose with APTT), fractionated (LMWH = Clexane, can be given sub-cut), fondaparinux (synthetic, again sub-cut, long half life, no need to use APTT = molecule stable)

     

     

     

     

    Antiplatelets:

    • Aspirin: irreversibly binds COX1 = stops arachidonic acid being converted to prostaglandins = reduced pain sensation. Also reduces thromboxane = reduced platelet activation.
    • Clopidogrel: rec = P2Y12 rec. When bound, inhibits adenylyl cyclase.

     

     

     

    Monitoring anticoagulation:

     

    PT (~11-16 seconds):The prothrombin time is the time it takes plasma to clot after addition of tissue factor (obtained from animals).

    • This measures the quality of the extrinsic pathway (as well as the common pathway) of coagulation.
    • The speed of the extrinsic pathway is greatly affected by levels of factor VII in the body.
    • Factor VII has a short half-life and its synthesis requires vitamin K.
    • The prothrombin time can be prolonged as a result of deficiencies in vitamin K, which can be caused by warfarin, malabsorption, or lack of intestinal colonization by bacteria (such as in newborns).
    • If prolonged PT, but normal APTT = suspect warfarin therapy.

     

    INR (usually 08-1.2): The international normalised ratio is a standardised measure of the patients PT time divided by a sample of PT times from a control population. This value is then adjusted by the International Sensitivity Index (ISI).

    • The ISI value indicates how a particular batch of tissue factor compares to an internationally standardized sample. The ISI is usually between 1.0 and 2.0.

     

    Thus, INR = (PT sample/PT control) x ISI

     

     

    APTT (usually 25-39 seconds): the acivated partial thromboplastin time is a measure of the intrinsic (“contact activation”) pathway of coagulation. The blood is collected and phospholipid and calcium (to reverse the anticoagulant effect of the oxalate) are mixed with the sample. The time for a clot is then measured.

     

    Prolonged APTT may indicate:

     

     

    Other tests:

    TT (thrombin time) = addition of excess thrombin. Normal = <22seconds

    RT (reptilase time) = to detect deficiencies or abnormalities in fibrinogen levels. 

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