Coagulation cascade

coagulation pathway

1. COAGULATION CASCADE DR.M.ANEEQUE [email protected] Department of Anesthesiology SICU and Pain Management Civil Hospital Karachi

2. Coagulation is a major haemostatic function responsible for prevention and termination of bleeding following injury. It is balanced by fibrinolytic system. COAGULATION

3. MECHANISM OF BLOOD COAGULATION The blood coagulation takes place in three steps. Formation of prothombin activator in response to rupture or damage to the blood vessels. Conversion of prothombin activator to thombin . The thrombin act as an enzyme to convert fibrinogen to fibrin thread that mesh platelates , Blood cells and plasma to form the clots.

4. PATHWAY OF COAGULATION Coagulation system is divided into two pathways Extrinsic Pathway : Which begins after trauma to vascular wall and surrounding tissue. Intrinsic Pathway: Which begins in blood itself

5. FIBRINOLYSIS If coagulation is continue and un controlled then spontaneous clot formation results pathological state The process of fibrinolysis results breakdown of clot. In this tissue injury -> release of plasminogen -> plasmin which bind to fibrin and form fibrin degradation producet

6. LABORATORY MONITORING Prothrombin time (PT) Test of Extrinsive pathway Measure Vitamin K dependent factor activity (factor II, VII, IX and X) Normal value 12-14 seconds International normalize ratio (INR) Standardized PT reporting Normal value 0.8-1.2 seconds Most sensitive to alteration in factor VII levels. Prolonged decrease of normal factor VII activity.

7. ACTIVATED PARTIAL PROTHROMBIN (APTT) Test for intrinsic common pathway Depends activity of all coagulation factor except factor VII, XIII Normal value 25-35 seconds Prolonged only if coagulation factor reduced to <30% of normal

8. ACTIVATED CLOTTING TIME (ACT) Monitor heparin anti-coagulant in the cardiac vascular surgery. Normal value 90-120 seconds.

9. THROMBIN CLOTTING TIME (TCT) Reflect abnormalities in fibrinogen -> fibrin. Prolonged by heparin, low fibrinogen thrombin inhibitor.

10. BLEEDING TIME (BT) Monitor platelet function Non-specific indicator of platelet function. Unreliable No evidence as a predictor of risk of hemorrhage Useful indicator of efficacy of anti-platelet therapy. Insensitive to mild platelet defect.

11. Lab Test Component Measured Normal Value Bleeding Time Platelet Function, Vascular integrity 3-10 minutes PT I, II, V, VII, IX & X 12-14 seconds APTT I,II,V,VIII,IX,X,XI & XII except VII & XIII 24-35 seconds Thrombin Time I & II 12-20 seconds

12. COAGULATION DISORDER Congenital Disorder: Disorder of clotting may not present until challenged by trauma, surgery in adult life. Acquired Disorder: Is due to lack of synthesis of coagulation factor. Increased loss due to DIC, Massive Blood Loss. A family history of hemophilia A, B sex linked recessive, Von willbrand disease

13. In severe hemophilia A (factor VIII) bleeding occurs spontaneously. In mild hemophilia A (factor VIII) bleeding occurs only after trauma. Medical problem such as liver disease, malabsorption (Vitamin K Deficiency) infection, malignancy, DIC, auto-immune disease, systemic lupus erythematous , rheumatoid arthritis as well as medication aspirin, NSAIDS.

14. Disorder Platelet Count PT/INR APTT TT Fibrinogen Others Hemophilia A Normal Normal Increase Normal Normal Decrease VIII Hemophilia B Normal Normal Increase Normal Normal Decrease IX Vonwillebrand disease Normal Normal Increase Normal Normal Decrease VIII, VWF, Increase bleeding time Liver Disease Normal Increase Increase Normal Normal Decrease V Vitamin K deficiency Normal Increase Increase Normal Normal Decrease II, VII, IX & X Massive Transfusion Decrease Increase Increase Normal Normal / Decrease Normal FDP (Fibrinogen de-gradation product) Heparin Normal Normal Increase Increase Normal Increase ANT Xa Warfarin Normal Increase Increase Normal Normal Decrease II, VII, IX & X

15. Haemostatic Process Effected Class of Drug Specific Drug Platelet plug formation Anti Platelet drug NSAID,Clopidogrel Coagulation cascade IV anticoagulant oral anticoagulant Heparin Warferin Fibrinolysis Fibrinolytic agent Streptokinase , urokinase DRUGS EFFECTING COAGULATION

16. Prostaglandin synthesis ADP binding GPIIb / IIIa receptor Antiplatelet drug targets

17. Aspirin inhibits cyclo-oxygenase  thromboxane A2 synthesis inhibits both COX 1 and COX 2 irreversibly Should stop 7 days prior to surgery

18. COX-1 vs COX-2 inhibitors

19. GI ulceration Haemorrhage Bronchospasm Interstitial nephritis, papillary necrosis, proteinuria , renal failure Reye’s syndrome in children Adverse effects

20. Alternative to aspirin First choice for aspirin intolerance Clopidogrel Block activation of platelets by reducing ADP activation of Gp IIb / IIIa receptor complex Should stop 5 days prior to surgery

21. Heparin Glycoaminoglycan containing a mixture of sulfated muco -polysaccharides of various sizes - Un-fractionated (5000-30000 Da ) - Low molecular weight (LMWH) (1000-10000 Da )

22. Heparin - enhances the action of Antithrombin III (AT-III) (plasma protease inhibitor) 1000 fold ↑ activity - antithrombin III inhibits clotting factor proteases, Thrombin ( IIa ), IXa , Xa , XIa and XIIa , by forming stable complexes - heparin binds to AT-III and causes a conformational change thereby activating AT-III LMWH - predominantly inhibit factor Xa Mechanism of Action

23. Increased bleeding - antidote ( protamine sulfate) Heparin induced thrombocytopaenia Osteoporosis with long term high-dose administration 3-6mths Inhibit aldosterone synthesis Adverse effects

24. Unpredictable pharmacokinetics Requires regular monitoring Infusion Higher incidence of HITs Rebound ischaemia Unfractionated heparin

25. Eg Enoxaparin ; Tinzaparin More predictable pharmacokinetics Lower incidence of heparin-associated thrombocytopenia Ease of administration s/c injection No need for monitoring Possible improvement in outcomes of acute coronary syndromes Low Mol Weight Heparins

26. Highly plasma protein bound Metabolised by liver Substrate of CYP450 enzymes Excreted in urine and stool Warfarin Should stop 2-4 days prior to surgery

27. Block the Vitamin K-dependent glutamate carboxylation of precursor clotting factors II, VII, IX and X Also inhibits Proteins C & S 8-12 hour delay in action because of T1/2 of clotting factors in plasma recovery needs synthesis of new clotting factors action is reversed with vitamin K Mechanism of action

28. Bleeding Contraindicated in pregnancy - teratogenic effects, crosses placenta risk foetal haemorrhage Warfarin induced skin necrosis - paradoxical local thrombosis - increased in patients with protein C or S deficiency "Purple toes syndrome," cholesterol microembolization Hepatic dysfunction Adverse effects

29. Derived from bacterial protein Cleaves Plasminogen Low fibrin specificity Cheap Streptokinase Fibrinolytics

30. Intrinsic compound Isolated from urine or renal cell cultures Cleaves plasminogen Urokinase

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