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Pathophysiology of Thrombosis

Pathophysiology of Thrombosis. Thrombosis and Thrombolysis in Acute Coronary Syndromes. Blood Components - Platelets. Contain adhesive glycoproteins GP Ia – binds platelets to collagen fibers GP Ib - binds platelets to von Willebrand factor

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Pathophysiology of Thrombosis

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

  2. Blood Components - Platelets • Contain adhesive glycoproteins • GP Ia – binds platelets to collagen fibers • GP Ib - binds platelets to von Willebrand factor • 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. • 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 + 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 + tPA = Plasmin

  6. Blood Components - Plasmin • 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.

  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.

  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 + Prothrombin = Thrombin

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

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

  12. 1. Platelet Adhesion

  13. 2. Platelet Activation

  14. 3. Platelet Aggregation

  15. 4. Thrombus Formation

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

  17. 1. Release of tPA

  18. 2. Plasmin Formation

  19. 3. Fibrinolysis

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

  21. THROMBOLYTIC PHARMACOLOGY FOR PREHOSPITAL PROVIDERS

  22. STREPTOKINASE • BACTERIAL PROTEIN • FIRST DEVELOPED THROMBOLYTIC • CONVERTS PLASMINOGEN TO PLASMIN

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

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

  25. 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

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

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

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

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

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

  31. 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

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

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

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

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

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

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

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

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

  40. DOSING

  41. BREAK

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