Transcript Pathophysiology of Thrombosis

Pathophysiology of Thrombosis
Thrombosis and Thrombolysis in
Acute Coronary Syndromes
Blood Components - Platelets
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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
Blood Components - Prothrombin
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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.
Blood Components - Fibrinogen
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Fibrinogen is a plasma protein that
converts to fibrin, an elastic, threadlike
filament, when exposed to thrombin.
Fibrinogen + thrombin =
Fibrin
Blood Components - Plasminogen
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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
Blood Components - Plasmin
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Plasmin is an enzyme that dissolves
fibrin strands (fibrinolysis) binding the
platelets together within a thrombus
(clot).
Tissue Components – Von
Willebrand Factor
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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.
Tissue Components – Collagen
Fibers
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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.
Tissue Components – Tissue
Factor
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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
Blood/Tissue Component Review
• Tissue Factor + Prothrombin =
Thrombin
• Fibrinogen + thrombin =
Fibrin
• Plasminogen + tPA = Plasmin
• Plasmin dissolves Fibrin.
Thrombus Formation
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Phase
Phase
Phase
Phase
1:
2:
3:
4:
Platelet adhesion
Platelet activation
Platelet aggregation
Thrombus Formation
1. Platelet Adhesion
2. Platelet Activation
3. Platelet Aggregation
4. Thrombus Formation
Phases of Thrombolysis
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Phase 1: Release of tPA
Phase 2: Plasmin Formation
Phase 3: Fibrinolysis
1. Release of tPA
2. Plasmin Formation
3. Fibrinolysis
Drugs used in the treatment
of Thrombosis
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Aspirin
Heparin
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Integrilin
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Tenecteplase
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Inhibits TxA2
Blocks conversion of
prothrombin to
thrombin
GP IIb/IIIa receptor
inhibitor
Converts
plasminogen to
plasmin
THROMBOLYTIC
PHARMACOLOGY
FOR
PREHOSPITAL
PROVIDERS
STREPTOKINASE
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BACTERIAL PROTEIN
FIRST DEVELOPED THROMBOLYTIC
CONVERTS PLASMINOGEN TO PLASMIN
ISIS STUDY
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STREPTOKINASE 8.0 % MORTALITY
COMPARED TO PLACEEBO AT 13.2 %
ALTEPLASE
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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
RETEPLASE
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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
TENECTEPLASE
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THIRD GENERATION VARIANT OF THE
t-PA MOLECULE
LESS INCIDENCE OF BLEEDING
COMPLICATIONS
MORE AFFINTY FOR FIBRIN
RESISTANCE TO PLASMINOGEN
ACTIVATOR INHIBITOR
PHARMACODYNAMICS
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TNKASE BINDS TO FIBRIN AND
CONVERTS PLASMINOGEN TO PLASMIN
PLASMIN THEN INHIBITS FIBRIN
PHARMACOKINETICS
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HALF LIFE OF 20 TO 24 MIN
METABOLIZED BY THE LIVER
EXCRETED BY THE KIDNEYS
INDICATIONS
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AMI
ST ELEVATION MI
NEW ONSET LEFT BUNDLE BRANCH
BLOCK
ONSET OF SYMPTOMS WITHIN 12
HOURS
ACLS
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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
ACLS Continued
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DOOR TO DRUG TIME GOAL < THAN
30 MINUTES
CONSIDERED CLASS II a IF PATIENTS
GREATER THAN 74 YEARS OLD
CONTRAINDICATIONS
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ACTIVE INTERNAL BLEEDING
HX OF CVA
INTRACRANIAL OR INTRASPINAL
SURGERY WITHIN 2 MONTHS
TRAUMA WITHIN THE LAST 2 MONTHS
INTRACRANIAL NEOPLASMS
CONTRAINDICATIONS
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ATRIOVENOUS MALFORMATIONS
ANEURYSM
KNOWN BLEEDING DISORDERS
SEVER UNCONTROLLED HTN
LEFT HEART THROMBUS
ACUTE PERICARDITIS
SUBACUTE BACTERIAL ENDOCARDITIS
CONTRAINDICATIONS
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SEVER HEPATIC DYSFUNCTION
PREGNANCY
DIABETIC HEMORRHAGIC RETINOPATHY
ADVANCED AGE
PATIENTS RECEIVING ORAL
ANTICOAGULANTS
RECENT ADMINISTRATION OF GP IIB/IIIA
INHIBITORS
COMPLICATIONS AND SIDE
EFFECTS
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INTERNAL BLEEDING
SUPER FICIAL BLEEDING OR SURFACE
BLEEDING, OBSERVEWD MAINLY AT
VASCULAR PUNCTURE SITES OR SITES
OF RECENT SURGICAL
INTERVENTIONS
CHOLESTEROL EMBOLI
REPERFUSION DYSRYHMIAS
DRUG INTERACTIONS
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PTS ROUTINELY TREATED WITH ASA
AND HEPARIN
USE PRECAUTION WITH GP IIB/IIIA
INHIBITORS, ASA,OR DYPRIDAMOLE
GERIATRIC USE
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HIGHER RISK OF SIDE EFFECTS WITH
PTS 75 YEARS OF AGE OR OLDER
HOW SUPPLIED
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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.
DOSING
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
BREAK