1. Pathophysiology of Thrombosis Thrombosis and Thrombolysis in Acute Coronary Syndromes

2. Blood Components - Platelets Contain adhesive glycoproteins Contain adhesive glycoproteins GP Ia – binds platelets to collagen fibers GP Ia – binds platelets to collagen fibers GP Ib - binds platelets to von Willebrand factor GP Ib - binds platelets to von Willebrand factor GP IIb/IIIa - binds platelets to von Willebrand factor, and fibrinogen GP IIb/IIIa - binds platelets to von Willebrand factor, and fibrinogen

3. Blood Components - Prothrombin Prothrombin is a plasma protein that, when activated by exposure of the blood to tissue factor released from damaged arterial wall tissue, converts to thrombin. Prothrombin is a plasma protein that, when activated by exposure of the blood to tissue factor released from damaged arterial wall tissue, converts to thrombin. Thrombin in turn converts fibrinogen to fibrin. Thrombin in turn converts fibrinogen to fibrin.

4. Blood Components - Fibrinogen Fibrinogen is a plasma protein that converts to fibrin, an elastic, threadlike filament, when exposed to thrombin. Fibrinogen is a plasma protein that converts to fibrin, an elastic, threadlike filament, when exposed to thrombin. Fibrinogen + thrombin = Fibrin Fibrinogen + thrombin = Fibrin

5. Blood Components - Plasminogen Plasminogen is a plasma glycoprotein that converts to an enzyme – plasmin – when activated by tissue-type plasminogen activator (tPA) normally present in the endothelium lining the blood vessels. Plasminogen is a plasma glycoprotein that converts to an enzyme – plasmin – when activated by tissue-type plasminogen activator (tPA) normally present in the endothelium lining the blood vessels. Plasminogen + tPA = Plasmin Plasminogen + tPA = Plasmin

6. Blood Components - Plasmin Plasmin is an enzyme that dissolves fibrin strands (fibrinolysis) binding the platelets together within a thrombus (clot). Plasmin is an enzyme that dissolves fibrin strands (fibrinolysis) binding the platelets together within a thrombus (clot).

7. Tissue Components – Von Willebrand Factor Von Willebrand Factor is a protein stored in cells of the endothelium lining the arteries. When exposed to blood after an injury to the endothelial cells, VWF binds to the platelets GP receptors. Von Willebrand Factor is a protein stored in cells of the endothelium lining the arteries. When exposed to blood after an injury to the endothelial cells, VWF binds to the platelets GP receptors.

8. Tissue Components – Collagen Fibers Collagen fibers are the white protein fibers present within the intima of the arterial wall. After an injury and exposure to blood, the CF bind to the platelets directly (via GP Ia) and indirectly through VWF. Collagen fibers are the white protein fibers present within the intima of the arterial wall. After an injury and exposure to blood, the CF bind to the platelets directly (via GP Ia) and indirectly through VWF.

9. Tissue Components – Tissue Factor Tissue factor is a substance present in tissue, platelets, and leukocytes that, when released after an injury, iniates the conversion of prothrombin to thrombin. Tissue factor is a substance present in tissue, platelets, and leukocytes that, when released after an injury, iniates the conversion of prothrombin to thrombin. Tissue Factor + Prothrombin = Thrombin Tissue Factor + Prothrombin = Thrombin

10. Blood/Tissue Component Review Tissue Factor + Prothrombin = ThrombinTissue Factor + Prothrombin = Thrombin Fibrinogen + thrombin = FibrinFibrinogen + thrombin = Fibrin Plasminogen + tPA = PlasminPlasminogen + tPA = Plasmin Plasmin dissolves Fibrin.Plasmin dissolves Fibrin.

11. Thrombus Formation Phase 1: Platelet adhesion Phase 1: Platelet adhesion Phase 2: Platelet activation Phase 2: Platelet activation Phase 3: Platelet aggregation Phase 3: Platelet aggregation Phase 4: Thrombus Formation Phase 4: Thrombus Formation

13. 1. Platelet Adhesion

14. 2. Platelet Activation

15. 3. Platelet Aggregation

16. 4. Thrombus Formation

17. Phases of Thrombolysis Phase 1: Release of tPA Phase 1: Release of tPA Phase 2: Plasmin Formation Phase 2: Plasmin Formation Phase 3: Fibrinolysis Phase 3: Fibrinolysis

18. 1. Release of tPA

19. 2. Plasmin Formation

20. 3. Fibrinolysis

21. Drugs used in the treatment of Thrombosis Aspirin Aspirin Heparin Heparin Integrilin Integrilin Tenecteplase Tenecteplase Inhibits TxA2 Blocks conversion of prothrombin to thrombin GP IIb/IIIa receptor inhibitor Converts plasminogen to plasmin

22. THROMBOLYTIC PHARMACOLOGY FOR PREHOSPITAL PROVIDERS PROVIDERS

23. STREPTOKINASE BACTERIAL PROTEIN BACTERIAL PROTEIN FIRST DEVELOPED THROMBOLYTIC FIRST DEVELOPED THROMBOLYTIC CONVERTS PLASMINOGEN TO PLASMIN CONVERTS PLASMINOGEN TO PLASMIN

24. ISIS STUDY STREPTOKINASE 8.0 % MORTALITY COMPARED TO PLACEEBO AT 13.2 % STREPTOKINASE 8.0 % MORTALITY COMPARED TO PLACEEBO AT 13.2 %

25. ALTEPLASE PRODUCED BY RECOMBIANT DNA TECHNOLOGY PRODUCED BY RECOMBIANT DNA TECHNOLOGY LOWER MORTALIT RATE WITH TPA VERSUS STREPTOKINASE LOWER MORTALIT RATE WITH TPA VERSUS STREPTOKINASE STUDIED IN GUSTO 1 TRAILS STUDIED IN GUSTO 1 TRAILS

26. HIGHER RISK OF INTRACRANIAL BLEEDING WITH TPA THAN STREPTOKINASE HIGHER RISK OF INTRACRANIAL BLEEDING WITH TPA THAN STREPTOKINASE DOSE- INITIAL BOLUS OF 15 MG IV, THEN 0.75 MG/KG OVER 30 MIN NOT TO EXCEED 50 MG, THEN 0.50 MG/KG OVER 60 MIN PERIOD NOT TO EXCEED 35 MG DOSE- INITIAL BOLUS OF 15 MG IV, THEN 0.75 MG/KG OVER 30 MIN NOT TO EXCEED 50 MG, THEN 0.50 MG/KG OVER 60 MIN PERIOD NOT TO EXCEED 35 MG

27. RETEPLASE DNA TECHNOLOGY DNA TECHNOLOGY STUDIED IN INJECT TRAILS STUDIED IN INJECT TRAILS NO CHANGE ON MORTALITY COMPARED TO STREPTOKINASE OR ALTEPLASE NO CHANGE ON MORTALITY COMPARED TO STREPTOKINASE OR ALTEPLASE DOSE- 10 UNITS GIVEN OVER 2 MIN THEN REPEATED AFTER 30 MIN DOSE- 10 UNITS GIVEN OVER 2 MIN THEN REPEATED AFTER 30 MIN

28. TENECTEPLASE THIRD GENERATION VARIANT OF THE t-PA MOLECULE THIRD GENERATION VARIANT OF THE t-PA MOLECULE LESS INCIDENCE OF BLEEDING COMPLICATIONS LESS INCIDENCE OF BLEEDING COMPLICATIONS MORE AFFINTY FOR FIBRIN MORE AFFINTY FOR FIBRIN RESISTANCE TO PLASMINOGEN ACTIVATOR INHIBITOR RESISTANCE TO PLASMINOGEN ACTIVATOR INHIBITOR

29. PHARMACODYNAMICS TNKASE BINDS TO FIBRIN AND CONVERTS PLASMINOGEN TO PLASMIN TNKASE BINDS TO FIBRIN AND CONVERTS PLASMINOGEN TO PLASMIN PLASMIN THEN INHIBITS FIBRIN PLASMIN THEN INHIBITS FIBRIN

30. PHARMACOKINETICS HALF LIFE OF 20 TO 24 MIN HALF LIFE OF 20 TO 24 MIN METABOLIZED BY THE LIVER METABOLIZED BY THE LIVER EXCRETED BY THE KIDNEYS EXCRETED BY THE KIDNEYS

31. INDICATIONS AMI AMI ST ELEVATION MI ST ELEVATION MI NEW ONSET LEFT BUNDLE BRANCH BLOCK NEW ONSET LEFT BUNDLE BRANCH BLOCK ONSET OF SYMPTOMS WITHIN 12 HOURS ONSET OF SYMPTOMS WITHIN 12 HOURS

32. ACLS THROMBOLYTIC THERAPY CLASS IF CLINICAL COMPLAINTS ARE CONSITENT WITH ISCHEMIC- TYPE PAIN, ST ELEEVATION > OR = TO 1 MM IN AT LEAST 2 ANATOMICALLY CONTIGOUS LEADS, NO CONTRAINDICATIONS, AND PT IS LESS THAN 75 YEARS OLD THROMBOLYTIC THERAPY CLASS IF CLINICAL COMPLAINTS ARE CONSITENT WITH ISCHEMIC- TYPE PAIN, ST ELEEVATION > OR = TO 1 MM IN AT LEAST 2 ANATOMICALLY CONTIGOUS LEADS, NO CONTRAINDICATIONS, AND PT IS LESS THAN 75 YEARS OLD

33. ACLS Continued DOOR TO DRUG TIME GOAL < THAN 30 MINUTES DOOR TO DRUG TIME GOAL < THAN 30 MINUTES CONSIDERED CLASS II a IF PATIENTS GREATER THAN 74 YEARS OLD CONSIDERED CLASS II a IF PATIENTS GREATER THAN 74 YEARS OLD

34. CONTRAINDICATIONS ACTIVE INTERNAL BLEEDING ACTIVE INTERNAL BLEEDING HX OF CVA HX OF CVA INTRACRANIAL OR INTRASPINAL SURGERY WITHIN 2 MONTHS INTRACRANIAL OR INTRASPINAL SURGERY WITHIN 2 MONTHS TRAUMA WITHIN THE LAST 2 MONTHS TRAUMA WITHIN THE LAST 2 MONTHS INTRACRANIAL NEOPLASMS INTRACRANIAL NEOPLASMS

35. CONTRAINDICATIONS ATRIOVENOUS MALFORMATIONS ATRIOVENOUS MALFORMATIONS ANEURYSM ANEURYSM KNOWN BLEEDING DISORDERS KNOWN BLEEDING DISORDERS SEVER UNCONTROLLED HTN SEVER UNCONTROLLED HTN LEFT HEART THROMBUS LEFT HEART THROMBUS ACUTE PERICARDITIS ACUTE PERICARDITIS SUBACUTE BACTERIAL ENDOCARDITIS SUBACUTE BACTERIAL ENDOCARDITIS

36. CONTRAINDICATIONS SEVER HEPATIC DYSFUNCTION SEVER HEPATIC DYSFUNCTION PREGNANCY PREGNANCY DIABETIC HEMORRHAGIC RETINOPATHY DIABETIC HEMORRHAGIC RETINOPATHY ADVANCED AGE ADVANCED AGE PATIENTS RECEIVING ORAL ANTICOAGULANTS PATIENTS RECEIVING ORAL ANTICOAGULANTS RECENT ADMINISTRATION OF GP IIB/IIIA INHIBITORS RECENT ADMINISTRATION OF GP IIB/IIIA INHIBITORS

37. COMPLICATIONS AND SIDE EFFECTS INTERNAL BLEEDING INTERNAL BLEEDING SUPER FICIAL BLEEDING OR SURFACE BLEEDING, OBSERVEWD MAINLY AT VASCULAR PUNCTURE SITES OR SITES OF RECENT SURGICAL INTERVENTIONS SUPER FICIAL BLEEDING OR SURFACE BLEEDING, OBSERVEWD MAINLY AT VASCULAR PUNCTURE SITES OR SITES OF RECENT SURGICAL INTERVENTIONS CHOLESTEROL EMBOLI CHOLESTEROL EMBOLI REPERFUSION DYSRYHMIAS REPERFUSION DYSRYHMIAS

38. DRUG INTERACTIONS PTS ROUTINELY TREATED WITH ASA AND HEPARIN PTS ROUTINELY TREATED WITH ASA AND HEPARIN USE PRECAUTION WITH GP IIB/IIIA INHIBITORS, ASA,OR DYPRIDAMOLE USE PRECAUTION WITH GP IIB/IIIA INHIBITORS, ASA,OR DYPRIDAMOLE

39. GERIATRIC USE HIGHER RISK OF SIDE EFFECTS WITH PTS 75 YEARS OF AGE OR OLDER HIGHER RISK OF SIDE EFFECTS WITH PTS 75 YEARS OF AGE OR OLDER

40. HOW SUPPLIED 50 MG VIAL WITH ONE 10 ML VIAL OF STERILE WATER FOR INJECTION 50 MG VIAL WITH ONE 10 ML VIAL OF STERILE WATER FOR INJECTION MUST BE RECONSTITUTED, THEN USED IMMEDIATELY MUST BE RECONSTITUTED, THEN USED IMMEDIATELY DRUG IS GIVEN AS A BOLUS OVER 5 SEC. DRUG IS GIVEN AS A BOLUS OVER 5 SEC.

41. DOSING

42. BREAK