Pathophysiology of Thrombosis

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Pathophysiology of Thrombosis

• Thrombosis and Thrombolysis in Acute Coronary
  Syndromes

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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

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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.

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Blood Components - Fibrinogen

• Fibrinogen is a plasma protein that converts to
  fibrin, an elastic, threadlike filament, when
  exposed to thrombin.

Fibrinogen thrombin Fibrin
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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
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Blood Components - Plasmin

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

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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.

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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.

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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
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Blood/Tissue Component Review

• Tissue Factor Prothrombin
  Thrombin
• Fibrinogen thrombin
  Fibrin
• Plasminogen tPA Plasmin
• Plasmin dissolves Fibrin.

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Thrombus Formation

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

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1. Platelet Adhesion
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2. Platelet Activation
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3. Platelet Aggregation
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4. Thrombus Formation
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Phases of Thrombolysis

• Phase 1 Release of tPA
• Phase 2 Plasmin Formation
• Phase 3 Fibrinolysis

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1. Release of tPA
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2. Plasmin Formation
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3. Fibrinolysis
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Drugs used in the treatment of Thrombosis

• Aspirin
• Heparin
• Integrilin
• Tenecteplase

• Inhibits TxA2
• Blocks conversion of prothrombin to thrombin
• GP IIb/IIIa receptor inhibitor
• Converts plasminogen to plasmin

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THROMBOLYTIC PHARMACOLOGY

• FOR PREHOSPITAL
• 
  PROVIDERS
• 
  

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STREPTOKINASE

• BACTERIAL PROTEIN
• FIRST DEVELOPED THROMBOLYTIC
• CONVERTS PLASMINOGEN TO PLASMIN

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ISIS STUDY

• STREPTOKINASE 8.0 MORTALITY COMPARED TO
  PLACEEBO AT 13.2

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ALTEPLASE

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

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• 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

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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

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TENECTEPLASE

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

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PHARMACODYNAMICS

• TNKASE BINDS TO FIBRIN AND CONVERTS PLASMINOGEN
  TO PLASMIN
• PLASMIN THEN INHIBITS FIBRIN

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PHARMACOKINETICS

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

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INDICATIONS

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

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ACLS

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

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ACLS Continued

• DOOR TO DRUG TIME GOAL lt THAN 30 MINUTES
• CONSIDERED CLASS II a IF PATIENTS GREATER THAN 74
  YEARS OLD

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CONTRAINDICATIONS

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

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CONTRAINDICATIONS

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

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CONTRAINDICATIONS

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

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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

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DRUG INTERACTIONS

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

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GERIATRIC USE

• HIGHER RISK OF SIDE EFFECTS WITH PTS 75 YEARS OF
  AGE OR OLDER

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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.

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DOSING
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BREAK