Pathophysiology of Pathophysiology of ThrombosisThrombosis

Thrombosis and Thrombolysis Thrombosis and Thrombolysis in Acute Coronary Syndromesin Acute Coronary Syndromes

Blood Components - Blood Components - PlateletsPlatelets Contain adhesive Contain adhesive

glycoproteinsglycoproteins GP IaGP Ia – binds platelets – binds platelets

to collagen fibersto collagen fibers GP IbGP Ib - binds platelets - binds platelets

to von Willebrand to von Willebrand factorfactor

GP IIb/IIIaGP IIb/IIIa - binds - binds platelets to von platelets to von Willebrand factor, and Willebrand factor, and fibrinogenfibrinogen

Blood Components - Blood Components - ProthrombinProthrombin

ProthrombinProthrombin is a plasma protein is a plasma protein that, when activated by exposure that, when activated by exposure of the blood to of the blood to tissue factortissue factor released from damaged arterial released from damaged arterial wall tissue, converts to wall tissue, converts to thrombinthrombin..

ThrombinThrombin in turn converts in turn converts fibrinogen to fibrin.fibrinogen to fibrin.

Blood Components - Blood Components - FibrinogenFibrinogen

FibrinogenFibrinogen is a plasma protein that is a plasma protein that converts to converts to fibrinfibrin, an elastic, , an elastic, threadlike filament, when exposed threadlike filament, when exposed to thrombin.to thrombin.

Fibrinogen Fibrinogen ++ thrombin thrombin = = FibrinFibrin

Blood Components - Blood Components - PlasminogenPlasminogen

PlasminogenPlasminogen is a plasma glycoprotein is a plasma glycoprotein that converts to an enzyme – that converts to an enzyme – plasminplasmin – when activated by – when activated by tissue-type tissue-type plasminogen activatorplasminogen activator (tPA) normally (tPA) normally present in the endothelium lining the present in the endothelium lining the blood vessels.blood vessels.

Plasminogen Plasminogen ++ tPA = tPA = PlasminPlasmin

Blood Components - Blood Components - PlasminPlasmin

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

Tissue Components – Tissue Components – Von Von Willebrand FactorWillebrand Factor

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

Tissue Components – Tissue Components – Collagen FibersCollagen Fibers

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

Tissue Components – Tissue Components – Tissue Tissue FactorFactor

Tissue factorTissue factor is a substance is a substance present in tissue, platelets, and present in tissue, platelets, and leukocytes that, when released leukocytes that, when released after an injury, iniates the after an injury, iniates the conversion of prothrombin to conversion of prothrombin to thrombin.thrombin.

Tissue Factor Tissue Factor ++ Prothrombin = Prothrombin = ThrombinThrombin

Blood/Tissue Component Blood/Tissue Component ReviewReview

• Tissue Factor Tissue Factor ++ Prothrombin = Prothrombin = ThrombinThrombin

• Fibrinogen Fibrinogen ++ thrombin = thrombin = FibrinFibrin

• Plasminogen Plasminogen ++ tPA = tPA = PlasminPlasmin

• Plasmin dissolves Fibrin.Plasmin dissolves Fibrin.

Thrombus FormationThrombus Formation

Phase 1: Platelet adhesionPhase 1: Platelet adhesion Phase 2: Platelet activationPhase 2: Platelet activation Phase 3: Platelet aggregationPhase 3: Platelet aggregation Phase 4: Thrombus FormationPhase 4: Thrombus Formation

1. Platelet 1. Platelet AdhesionAdhesion

2. Platelet 2. Platelet ActivationActivation

3. Platelet 3. Platelet AggregationAggregation

4. Thrombus 4. Thrombus FormationFormation

Phases of ThrombolysisPhases of Thrombolysis

Phase 1: Release of tPAPhase 1: Release of tPA Phase 2: Plasmin FormationPhase 2: Plasmin Formation Phase 3: FibrinolysisPhase 3: Fibrinolysis

1. Release of tPA1. Release of tPA

2. Plasmin Formation2. Plasmin Formation

3. Fibrinolysis3. Fibrinolysis

Drugs used in the Drugs used in the treatment of Thrombosistreatment of Thrombosis AspirinAspirin HeparinHeparin

IntegrilinIntegrilin

TenecteplaseTenecteplase

Inhibits Inhibits TxA2TxA2 Blocks conversion Blocks conversion

of of prothrombin to prothrombin to thrombinthrombin

GP IIb/IIIaGP IIb/IIIa receptor inhibitorreceptor inhibitor

Converts Converts plasminogen to plasminogen to plasminplasmin

THROMBOLYTIC THROMBOLYTIC PHARMACOLOGYPHARMACOLOGY

FOR PREHOSPITAL FOR PREHOSPITAL

PROVIDERSPROVIDERS

STREPTOKINASESTREPTOKINASE

BACTERIAL PROTEINBACTERIAL PROTEIN FIRST DEVELOPED THROMBOLYTICFIRST DEVELOPED THROMBOLYTIC CONVERTS PLASMINOGEN TO CONVERTS PLASMINOGEN TO

PLASMINPLASMIN

ISIS STUDYISIS STUDY

STREPTOKINASE 8.0 % MORTALITY STREPTOKINASE 8.0 % MORTALITY COMPARED TO PLACEEBO AT 13.2 COMPARED TO PLACEEBO AT 13.2 %%

ALTEPLASEALTEPLASE

PRODUCED BY RECOMBIANT DNA PRODUCED BY RECOMBIANT DNA TECHNOLOGYTECHNOLOGY

LOWER MORTALIT RATE WITH TPA LOWER MORTALIT RATE WITH TPA VERSUS STREPTOKINASEVERSUS STREPTOKINASE

STUDIED IN GUSTO 1 TRAILSSTUDIED IN GUSTO 1 TRAILS

HIGHER RISK OF INTRACRANIAL HIGHER RISK OF INTRACRANIAL BLEEDING WITH TPA THAN BLEEDING WITH TPA THAN STREPTOKINASESTREPTOKINASE

DOSE- INITIAL BOLUS OF 15 MG IV, DOSE- INITIAL BOLUS OF 15 MG IV, THEN 0.75 MG/KG OVER 30 MIN THEN 0.75 MG/KG OVER 30 MIN NOT TO EXCEED 50 MG, THEN 0.50 NOT TO EXCEED 50 MG, THEN 0.50 MG/KG OVER 60 MIN PERIOD NOT MG/KG OVER 60 MIN PERIOD NOT TO EXCEED 35 MGTO EXCEED 35 MG

RETEPLASERETEPLASE

DNA TECHNOLOGYDNA TECHNOLOGY STUDIED IN INJECT TRAILSSTUDIED IN INJECT TRAILS NO CHANGE ON MORTALITY NO CHANGE ON MORTALITY

COMPARED TO STREPTOKINASE OR COMPARED TO STREPTOKINASE OR ALTEPLASEALTEPLASE

DOSE- 10 UNITS GIVEN OVER 2 MIN DOSE- 10 UNITS GIVEN OVER 2 MIN THEN REPEATED AFTER 30 MINTHEN REPEATED AFTER 30 MIN

TENECTEPLASETENECTEPLASE

THIRD GENERATION VARIANT OF THIRD GENERATION VARIANT OF THE t-PA MOLECULETHE t-PA MOLECULE

LESS INCIDENCE OF BLEEDING LESS INCIDENCE OF BLEEDING COMPLICATIONSCOMPLICATIONS

MORE AFFINTY FOR FIBRINMORE AFFINTY FOR FIBRIN RESISTANCE TO PLASMINOGEN RESISTANCE TO PLASMINOGEN

ACTIVATOR INHIBITORACTIVATOR INHIBITOR

PHARMACODYNAMICSPHARMACODYNAMICS

TNKASE BINDS TO FIBRIN AND TNKASE BINDS TO FIBRIN AND CONVERTS PLASMINOGEN TO CONVERTS PLASMINOGEN TO PLASMINPLASMIN

PLASMIN THEN INHIBITS FIBRINPLASMIN THEN INHIBITS FIBRIN

PHARMACOKINETICSPHARMACOKINETICS

HALF LIFE OF 20 TO 24 MINHALF LIFE OF 20 TO 24 MIN METABOLIZED BY THE LIVERMETABOLIZED BY THE LIVER EXCRETED BY THE KIDNEYSEXCRETED BY THE KIDNEYS

INDICATIONSINDICATIONS

AMIAMI ST ELEVATION MIST ELEVATION MI NEW ONSET LEFT BUNDLE NEW ONSET LEFT BUNDLE

BRANCH BLOCKBRANCH BLOCK ONSET OF SYMPTOMS WITHIN 12 ONSET OF SYMPTOMS WITHIN 12

HOURSHOURS

ACLSACLS

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

ACLS ContinuedACLS Continued

DOOR TO DRUG TIME GOAL < DOOR TO DRUG TIME GOAL < THAN 30 MINUTESTHAN 30 MINUTES

CONSIDERED CLASS II a IF CONSIDERED CLASS II a IF PATIENTS GREATER THAN 74 PATIENTS GREATER THAN 74 YEARS OLDYEARS OLD

CONTRAINDICATIONSCONTRAINDICATIONS

ACTIVE INTERNAL BLEEDINGACTIVE INTERNAL BLEEDING HX OF CVAHX OF CVA INTRACRANIAL OR INTRASPINAL INTRACRANIAL OR INTRASPINAL

SURGERY WITHIN 2 MONTHSSURGERY WITHIN 2 MONTHS TRAUMA WITHIN THE LAST 2 TRAUMA WITHIN THE LAST 2

MONTHSMONTHS INTRACRANIAL NEOPLASMSINTRACRANIAL NEOPLASMS

CONTRAINDICATIONSCONTRAINDICATIONS

ATRIOVENOUS MALFORMATIONSATRIOVENOUS MALFORMATIONS ANEURYSMANEURYSM KNOWN BLEEDING DISORDERSKNOWN BLEEDING DISORDERS SEVER UNCONTROLLED HTNSEVER UNCONTROLLED HTN LEFT HEART THROMBUSLEFT HEART THROMBUS ACUTE PERICARDITISACUTE PERICARDITIS SUBACUTE BACTERIAL ENDOCARDITISSUBACUTE BACTERIAL ENDOCARDITIS

CONTRAINDICATIONSCONTRAINDICATIONS SEVER HEPATIC DYSFUNCTIONSEVER HEPATIC DYSFUNCTION PREGNANCYPREGNANCY DIABETIC HEMORRHAGIC RETINOPATHY DIABETIC HEMORRHAGIC RETINOPATHY ADVANCED AGEADVANCED AGE PATIENTS RECEIVING ORAL PATIENTS RECEIVING ORAL

ANTICOAGULANTSANTICOAGULANTS RECENT ADMINISTRATION OF GP IIB/IIIA RECENT ADMINISTRATION OF GP IIB/IIIA

INHIBITORSINHIBITORS

COMPLICATIONS AND SIDE COMPLICATIONS AND SIDE EFFECTSEFFECTS

INTERNAL BLEEDINGINTERNAL BLEEDING SUPER FICIAL BLEEDING OR SUPER FICIAL BLEEDING OR

SURFACE BLEEDING, OBSERVEWD SURFACE BLEEDING, OBSERVEWD MAINLY AT VASCULAR PUNCTURE MAINLY AT VASCULAR PUNCTURE SITES OR SITES OF RECENT SITES OR SITES OF RECENT SURGICAL INTERVENTIONSSURGICAL INTERVENTIONS

CHOLESTEROL EMBOLICHOLESTEROL EMBOLI REPERFUSION DYSRYHMIASREPERFUSION DYSRYHMIAS

DRUG INTERACTIONSDRUG INTERACTIONS

PTS ROUTINELY TREATED WITH PTS ROUTINELY TREATED WITH ASA AND HEPARINASA AND HEPARIN

USE PRECAUTION WITH GP IIB/IIIA USE PRECAUTION WITH GP IIB/IIIA INHIBITORS, ASA,OR INHIBITORS, ASA,OR DYPRIDAMOLEDYPRIDAMOLE

GERIATRIC USEGERIATRIC USE

HIGHER RISK OF SIDE EFFECTS HIGHER RISK OF SIDE EFFECTS WITH PTS 75 YEARS OF AGE OR WITH PTS 75 YEARS OF AGE OR OLDEROLDER

HOW SUPPLIEDHOW SUPPLIED

50 MG VIAL WITH ONE 10 ML VIAL 50 MG VIAL WITH ONE 10 ML VIAL OF STERILE WATER FOR INJECTIONOF STERILE WATER FOR INJECTION

MUST BE RECONSTITUTED, THEN MUST BE RECONSTITUTED, THEN USED IMMEDIATELYUSED IMMEDIATELY

DRUG IS GIVEN AS A BOLUS OVER DRUG IS GIVEN AS A BOLUS OVER 5 SEC.5 SEC.

DOSINGDOSING

Patient weight TNKase (mg) Volume (ml)

< 60 kg 30 6

60 to 70 kg 35 7

70 to 80 kg 40 8

80 to 90 kg 45 9

> 90 kg 50 10

BREAKBREAK