1. BLOOD FORMING AGENTS

2. Clinical Thrombosis 2.5 million cases of deep venous thrombosis (DVT) annually> 2.5 million cases of deep venous thrombosis (DVT) annually > 600.000 cases of pulmonary embolism (PE) per year> 600.000 cases of pulmonary embolism (PE) per year > 50.000 deaths per year from PE> 50.000 deaths per year from PE > 11.000 post surgical PE deaths per year> 11.000 post surgical PE deaths per year

8. Anti Platelet Drugs DrugMechanismUses Aspirin Permanently inhibits COX-1 and COX-2 CAD ( coronary artery disease) Stroke-TIAs ( transient ischemic attack) NSAIDs Reversibly inhibits COX-1Limited Dipyridamole Inhibits PDE; increases cAMP TIAs TiclopidineClopidogrel Inhibits ADP; active metabolite TIAs; Stroke CAD; PVD ( peripheral vascular disease)

9. INHIBITORS OF PLATELET AGGREGATION

10. Platelets inhibitors - ASA Daily dose - 80-100 mg Kardiomagnil

11. ANTIPLATELET THERAPY Aspirin Indications 1)Stroke, TIA (transient ischemic attacks) 2)MI, recurrent MI 3)Unstable angina 4)CABG potency ( coronary artery bypass graft) 4)CABG potency ( coronary artery bypass graft )

12. TICLOPIDINE 1)Interferes with platelet-fibrinogen binding 2)Exerts its action for the life of the platelet 3)May prolong bleeding time 4)Useful for coronary artery stents and CVA (cerebrovascular accident) 4)Useful for coronary artery stents and CVA (cerebrovascular accident ) 5)Methylprednisolone may reverse its effect 6)Associated with TTP (thrombocytopenic purpura), neutropenia, and diarrhea

13. CLOPIDOGREL 1)Interferes with GP IIb/IIIa ( Glycoprotein IIb/ IIIa ) binding site ( Glycoprotein IIb/ IIIa ) binding site 2)Exerts its action for the life of the platelet 3)May prolong bleeding time 4)Indicated for prevention of MI, CVA (cerebrovascular accident), and vascular death 5)Fewer side effects than ticlopidine 6)Dose: 75 mg daily

14. Abciximab (ReoPro) 1)Human-mouse monoclonal antibodies 2)Binds to GP (glycoprotein) IIb/IIIa receptor on platelets 3)Half-life 10 min. 4)May block receptor for 10 days 5)Indicated for prevention of closure of coronary vessels after angioplasty 6)May cause thrombocytopenia 7)Used with heparin and ASA

15. Antiplatelet therapy

22. Mechanism of heparin action АТ ІІІІІ аАТ ІІІ Х а 55 13 АТ ІІІ – ant thrombin ІІІ ІІ а – thrombin Х а – prothrombinase (Stuart-Prover factor) 10

24. IV or SC administration only HEPARIN

25. HEPARIN (Indications) Full Dose:5000 U or 80 U/kg IV bolus, followed by 1200-1600 U/hr adjusted to therapeutic range Full Dose: 5000 U or 80 U/kg IV bolus, followed by 1200-1600 U/hr adjusted to therapeutic range 1)Acute deep venous thrombosis 2)Pulmonary emboli 2)Pulmonary emboli 3)Unstable angina and myocardial infarction 3)Unstable angina and myocardial infarction Low Dose:5000 U sq q12 h Low Dose: 5000 U sq q12 h 1)Postoperative prophylaxis of any major abdominal, thoracic, gynecologic, or orthopedic procedure 2)Immobilized medical patients >40 yrs. with CHF, CVA, malignant disease 2)Immobilized medical patients >40 yrs. with CHF, CVA, malignant disease 3)Prophylaxis for underlying hypercoagulable state 3)Prophylaxis for underlying hypercoagulable state Other Dose: 1)Extracorporeal bypass 2)Hemodialysis 2)Hemodialysis 3)After thrombolytic therapy 3)After thrombolytic therapy

26. HEPARIN (Contraindications) 1 )Thrombocytopenia 2)Aspirin or alcohol use 3)Hepatic or renal disease 4)Other platelet dysfunction 5)GI bleeding 6)Tumors

27. HEPARIN (Side Effects) 1)Major side effect is bleeding 2)Osteoporosis with prolonged use 3)Thrombocytopenia w

28. HEPARIN-INDUCED THROMBOCYTOPENIA 1)Occurs in 2-5% of patients receiving standard heparin by immune mechanism 2)May occur with minute doses, including heparin flushes 3)More common with bovine than porcine heparin 4)Asymptomatic thrombocytopenia can occur in 30- 50% of pts who develop HIT antibodies 5)~20-50% of thrombocytopenic patients develop arterial or venous thrombosis that may be life threatening

29. 1)Lepirudin 2)Argatroban HEPARIN-INDUCED THROMBOCYTOPENIA Alternative Anticoagulants- direct thrombin inhibitors

30. LOW MOLECULAR WEIGHT HEPARIN 1) Molecular weight 3,000- 7,000 D 2)Inhibits factor Xa rather than thrombin 3)Factor Xa assay used for monitoring 4)Administered subcutaneously 2 times/d 5)Probably less antigenic than standard heparin 6)Recommended for prophylaxis and treatment

32. LOW MOLECULAR WEIGHT HEPARIN 1) PT, APTT not usually prolonged 2) May be monitored with anti-factor Xa assay

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36. Indications for and Contraindications to Parenteral Anticoagulant Agents Anticoagulant AgentClassApproved & Appropriate Indications Contraindication Unfractionated heparin Enoxaparin (Lovenox) Dalteparin (Fragmin) Tinzaparin (Innohep) Antithrombin III inhibitor Low- molecular- weight heparin Treatment of venous thromboembolism or unstable angina; used when rapid reversal is important Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism or unstable angina Prophylaxis in moderate-risk or high-risk patients, treatment of venous thromboembolism ?Prophylactic treatment Regional anesthesia Pregnancy Prosthetic Heart Valves Regional anesthesia

37. Heparin-Antibiotic Interactions The cephalosporins- cefamandole, cefotetan, and cefoperazone, contain an N- methylthiotetrazole (NMTT) side chain. This NMTT group can:The cephalosporins- cefamandole, cefotetan, and cefoperazone, contain an N- methylthiotetrazole (NMTT) side chain. This NMTT group can: - Dissociate from the parent antibiotic in solution or in vivo and competitively inhibit vitamin K action, leading to prolongation of the prothrombin time and bleeding.- Dissociate from the parent antibiotic in solution or in vivo and competitively inhibit vitamin K action, leading to prolongation of the prothrombin time and bleeding. - This side chain is also associated with a disulfiram-like reaction to alcohol.- This side chain is also associated with a disulfiram-like reaction to alcohol.

41. ANTICOAGULANTS OF INDIRECT ACTION COUMARIN (Description) 1) Isolated by Link in 1939 after previous observation that cattle developed bleeding disorder after ingestion of spoiled clover 2)Is 4-hydroxycoumarin compound, similar in structure to vitamin K 3)Administered p.o., rapid GI absorption 4)Crosses placenta easily (complications!) 5)Interacts with a variety of drugs

43. LIVER

44. COUMARIN (Actions) 1) Blocks the carboxylation of the vitamin K dependent clotting proteins, factors II, VII, IX, and X, maintaining them in their inactive forms 2) Blocks the anticoagulant proteins C and S 3) Onset – 18-48 hours

45. COUMARIN Laboratory 1)Prolongs the PT and APTT 2)PT and Prothrombin index -used for monitoring

46. Prothrombin index INTERNATIONAL NORMALIZED RATIO (INR) INR = PATIENT PT CONTROL PT CONTROL PT Decrease no less than 50 %

47. COUMARIN Side Effects 1)Hemorrhage 2) Fetal abnormalities 3)Skin necrosis with deficiencies of proteins C or S usually on 3rd to 8th day of therapy

48. COUMARIN Interactions POTENTIATORS : PhenylbutazoneCimetidineOmeprazoleAmiodarone Anabolic steroids ANTAGONISTS : BarbituratesRifampinPenicillinsAntacids

53. Pharmacodynamics of fibrinolytic drugs After introduction into organism they cause lyses of fresh (24-72 hours) thrombi in arteries, veins, cavitiesAfter introduction into organism they cause lyses of fresh (24-72 hours) thrombi in arteries, veins, cavities The most effective during the first 2-3 hours after initiation of thrombosisThe most effective during the first 2-3 hours after initiation of thrombosis

54. Thrombin – only topical !!!

55. HAEMOSTATICS with systemic action Fibrinogen, Calcium chloride, vitamin К, Vikasolum

56. INHIBITORS OF FIBRINOLYSIS of direct action (Contrikal, Trasilol, Gordox) of indirect action (Ac aminocapronicum, Ac. tranexamicum, Amben)

57. Ethamsilate Stabilizes the walls of vessels

58. Urtica (Nettle)

59. Viburnum (Snow ball, Water elder)

60. Arnica (arnica)

61. Polygonum hydropiper (Water pepper)

62. Hippocastanum (Aescusan) (Horse chestnut)

63. Ginkgo biloba (Maidenhair-tree) Tanakan

64. DRUGS EFFECTING HAEMOPOESIS

65. Food products with iron MeatSoybeans Dry smoked plums Spinach Dry apricots BuckwheatRiceBread Fruits of pomegranate Iron from animal products absorbs much more better than from plants (22 % and 1 %)