Blood coagulation and fibrinolysis

1. Blood coagulation and fibrinolysis March 2006

3. Haemostasis • adhesion • shape change • activation and secretion • aggregation • interaction with coagulation factors

4. Drug classes 1. Anticoagulants 2. Antiplatelet drugs 3. Thrombolytic Agents

5. Anticoagulants

6. Heparin Glycosaminoglycan containing a mixture of sulfated mucopolysaccharides of various sizes - Unfractionated (5000-30000 Da) - Low molecular weight (LMWH) (1000-10000 Da)

7. Mechanism of Action • 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 • Heparins do not affect thrombin bound to fibrin or Xa bound to platelets

9. Monitoring Therapy • APTT (APTTR) (Activated Partial Thromboplastin Time) Intrinsic pathway (heparin) • PT (INR) (Prothrombin Time) Extrinsic pathway (warfarin)

10. Heparin - indications • Rapid onset of action & short half life • When immediate anticoagulation required • When quick reversal may be required • Prevention and treatment of venous thrombosis • Pulmonary embolism • Acute Coronary syndromes • Given intravenously or subcutaneously • Can be used in pregnant women

11. Adverse effects • Increased bleeding 3% - antidote (protamine sulfate) • Heparin induced thrombocytopaenia - HITs 1% up to 3 days 5% >5 days - Can precipitate thrombosis • Osteoporosis with long term high-dose administration 3-6mths • Inhibit aldosterone synthesis – rarely causes ↑K+

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

13. Low Mol Weight Heparins • 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 (Such a benefit was suggested with enoxaparin in TIMI 11B, ESSENCE, and EVET)

14. Oral Anticoagulants Sweet Clover

15. Coumarins Warfarin, Dicumarol • Mechanism of action: • 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

17. Monitoring Therapy • PT (INR) (Prothrombin Time) Extrinsic pathway (warfarin) • APTT (APTTR) (Activated Partial Thromboplastin Time) Intrinsic pathway (heparin)

18. Warfarin • Highly plasma protein bound • Metabolised by liver • Substrate of CYP450 enzymes CYP1A2 (minor), 2C8/9 (major), 2C19 (minor), 3A4 (minor); Inhibits CYP2C8/9 (moderate), 2C19 (weak) • Excreted in urine and stool

19. Indications • Prophylaxis and treatment of • venous thrombosis • pulmonary embolism • thromboembolic disorders • atrial fibrillation with risk of embolism • prophylaxis of systemic embolism post MI (LV thrombus)

20. Adverse effects • Bleeding (risk depends on both the INR and patient factors) • 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

21. Precautions • Patient compliance - eg dementia • Patient’s bleeding risk - eg falls, chronic liver disease, alcoholism, past history • Dietary factors - eg malnutrition • Drug interactions

22. Interactions • Pharmacokinetic - changes in the absorption, protein binding, and/or metabolism - metabolism/elimination via cytochrome P450 system (common) - displacement of warfarin from plasma protein-binding sites eg NSAIDs (less important) • Pharmacodynamic - alter the risk of bleeding or clotting by either effect on platelet aggregation or vitamin K catabolism

23. CYP450 and Warfarin • CYP2C8/9 inducers↓ warfarin effect eg Carbamazepine, phenobarbital, phenytoin, rifampin • CYP2C8/9 inhibitors ↑ warfarin effect eg fluconazole, gemfibrozil, ibuprofen, ketoconazole, mefenamic acid, miconazole, nicardipine, pioglitazone, amiodarone, isoniazid, losartan, omeprazole, pantoprazole • CYP2C8/9 gene polymorphism

24. Alcohol and Warfarin • Acute ethanol ingestion (binge drinking) decreases the metabolism of warfarin and increases PT/INR • Chronic daily ethanol use increases the metabolism of warfarin and decreases PT/INR

25. Food and Warfarin • The anticoagulant effects of warfarin may be decreased if taken with foods rich in vitamin K eg liver, green tea and leafy green vegetables • Vitamin E may increase warfarin effect • Cranberry juice may increase warfarin effect

26. Herbal/Nutraceuticals • Cranberry, fenugreek, ginkgo biloba, glucosamine, may enhance bleeding or increase warfarin's effect • Ginseng (American), coenzyme Q10, and St John's wort may decrease warfarin levels and effects

27. Antibiotics and Warfarin • Cytochrome P450 High risk >75% - eg Erythromycin, Clarithromycin, Ciprofloxacin, Co-trimoxazole, Metronidazole, Ketoconazole, Fluconazole • Any broad-spectrum antibiotics can suppress production of vitamin K by the gut flora

28. Management of elevated INR • INR <6 No significant bleeding - Reduce dose or hold the next dose until INR <5 • INR >6 and <8 No significant bleeding - Hold the next 1or 2 doses until INR <5 then resume lower dose • INR >8: No significant bleeding - Hold warfarin until INR <5 - Vitamin K orally 5-10 mg or 0.5mg iv if high risk for bleeding • Any INR elevation + Serious bleeding - Hold warfarin, give vitamin K (10 mg by slow I.V. infusion), and supplement with fresh plasma transfusion or prothrombin complex concentrate (factor X complex)

29. Vitamin K and Warfarin • Note: Use of high doses of vitamin K (10-15mg) may cause resistance to warfarin for more than a week • Heparin or low molecular weight heparin can be given until the patient becomes responsive to warfarin

30. Newer Anticoagulants

31. Direct Thrombin Inhibitors • Eg Hirudin, a naturally occurring anticoagulant • Bind directly to thrombin's catalytic site rather than to antithrombin III • Inhibit clot-bound thrombin • Increased risk of major hemorrhage with hirudin • Possible role in HITs

32. Ximelegatran • Oral direct thrombin inhibitor • Concerns re: hepatotoxicity • No antidote

33. Antiplatelet agents

34. Antiplatelet agents • Predominantly prevent arterial thrombosis • In acute setting of MI & ischaemic stroke • Secondary prevention of vascular events • Primary prevention when 10 yr risk >15% and BP controlled

35. Antiplatelet drug targets • Prostaglandin synthesis • ADP binding • GPIIb/IIIa receptor • Cyclic AMP

36. Antiplatelet agents Aspirin inhibits cyclo-oxygenase  thromboxane A2 synthesis inhibits both COX 1 and COX 2 irreversibly

38. COX-1 vs COX-2 inhibitors

40. Aspirin • Pros - Inexpensive Proven efficacy • Cons – Intolerance Limited potency

41. Adverse effects • GI ulceration 6-31% • Haemorrhage • Bronchospasm • Interstitial nephritis, papillary necrosis, proteinuria, renal failure • Reye’s syndrome in children CI <16yrs • Dangerous in overdose

42. Antiplatelet agents Theinopyridines eg Clopidogrel, Ticlopidine Block activation of platelets by reducing ADP activation of Gp IIb / IIIa receptor complex

43. Clopidogrel • Alternative to aspirin First choice for aspirin intolerance • In addition to aspirin in context of Primary PCI Acute coronary syndromes Secondary prevention of MI but NOT stroke

44. Adverse effects • GI upset • Bleeding • Blood dyscrasias

45. Aspirin + Clopidogrel • significant increase in major (3.7 versus 2.7 percent for aspirin alone) and minor bleeding (5.1 versus 2.4 percent) •  bleeding risk with clopidogrel plus aspirin in patients who require coronary artery bypass graft surgery (CABG)

46. Antiplatelet agents Glycoprotein IIb/IIIa inhibitors (eg abciximab, eptifibatide) – inhibit cross-bridging of platelets by fibrinogen –Fab fragment of monoclonal antibody

47. GP IIb/IIIa inhibitorsfor ACS • Among patients undergoing PCI with stenting • Periprocedural administration of GP IIb/IIIa inhibitors improves outcomes in patients with a non-ST elevation ACS • No evidence for benefit in context of thrombolysis

48. Glycoprotein IIb/IIIa inhibitors • Adverse effects Drug-induced thrombocytopaenia Bleeding Emergency CABG (abciximab-treated patients were more likely to require surgical reexploration for bleeding (12 versus 3 percent))

49. Antiplatelet agents Dipyridamole Inhibits platelet activation : by inhibiting platelet phospho-diesterase activity, stimulating prostacyclin synthesis, and blocking adensoine uptake

50. Dipyridamole • pyrimido-pyrimidine derivative • vasodilatory effects on coronary resistance vessels • increases intracellular platelet cAMP activating the enzyme adenylate cyclase, and inhibiting uptake of adenosine from vascular endothelium and erythrocytes • *even the usual oral doses of dipyridamole may enhance exercise-induced myocardial ischemia in patients with stable angina