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Intrinsic System
the direct contact of the first clotting factor (factorXII) with the damaged vessel wall activates theclotting factor and initiates the cascade
Extrinsic System tissue factor (known also as thromboplastin) is
released from the damaged vascular cell
Tissue factor directly activates clotting factor VII,which then activates subsequent factors in theclotting mechanism
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Both the intrinsic and extrinsicsystems ultimately lead to theconversion of prothrombin to
thrombin
Thrombin is an enzyme that quickly
converts the inactive fibrinogenmolecule to fibrin
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Clot Breakdown Tissue plasminogen activator (t-PA)
converts plasminogen to plasmin
Plasmin, also known as fibrinolysin, is anenzyme that directly breaks down thefibrin mesh, thus destroying the clot
(Fibrinolysis) Endogenous anticoagulant proteins:
protein C, protein S, and antithrombin III
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Anticoagulants
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Heparin (Unfractionated, LMW)
Oral Anticoagulants- Anisindione (Miradon)
- Dicumarol (generic)- Warfarin (Coumadin)
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DVT 1indication for anticoagulant therapyOther indications:
after surgical procedures (joint replacement,
mechanical heart valve replacement)
following certain cardiovascular incidents(myocardial infarction, ischemic stroke)
when patients will be relatively inactive forextended periods of time
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Heparin
1drug used in the initialtreatment of venous thrombosis
Heparin works by potentiating theactivity of a circulating proteinknown as antithrombin III
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UFH
High-molecular-weight (HMW), also knownas UFH, fractions of heparin with highaffinity for antithrombin markedly inhibit
blood coagulation by inhibiting all threefactors, especially thrombin and factor Xa
Unfractionated heparin
- Calciparin
- Liquaemin
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LMWH
Low-molecular-weight (LMW) fractions ofheparin inhibit activated factor X but haveless effect on thrombin
Low molecular weight heparins:
- Ardeparin (Normiflo)
- Dalteparin (Fragmin)- Enoxaparin (Lovenox)
- Tinzaparin (Innohep)
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Advantages
LMWHs can be administered by subcutaneousinjection into fat tissuesdecreasing theneed for repeated intravenous administration
Dosing schedules of LMWHs are typicallyeasier (once per day), compared to 2 or moredaily injections of unfractioned heparin
less risk of adverse effects such as hemorrhageand death
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primary method of treating acute venousthrombosis
LMWHs are now used routinely to prevent
or treat deep vein thrombosis (DVT)following various types of surgery ormedical conditions (ischemic stroke, CA)
More predictable pharmacokinetic profilewhich allows weighted-adjusted subQadministration s lab monitoring
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Administration and Dosage
Continuous IV infusion (infusion pump)-initial: 80100 units/kg, continuousinfusion: 1522 units/kg/hto maintain
the anti-Xa activity in the range of 0.30.7units/mL
Therapy routinely is monitored by theaPTT or PTT (activated partialthromboplastin time)
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Low-dose prophylaxis: subcutaneousadministration of heparin
5000 units every 8
12 hours. Because of the danger of hematoma
formation at the injection site, heparinmust never be administeredintramuscularly.
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Subcutaneous administration forlong term management of pts
(warfarin is CI) ex: pregnancy
35 000 U every 8-12 hours
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Prophylactic enoxaparin Subcutaneously; 30 mg twice daily or 40 mg
once daily.
Full-dose enoxaparin 1 mg/kg; subcutaneously every 12 hours ;
anti-factor Xa level of 0.51 unit/mL
Selected patients may be treated withenoxaparin 1.5 mg/kg once a day, with a targetanti-Xa level of 1.5 units/mL.
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Dalteparin 5000 units subcutaneously od
200 units/kg odforvenous disease
120 units/kg every 12 hoursacutecoronary syndrome
LMWH should be used with caution inpatients with renal insufficiency or bodyweight >150 kg.
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Monitoring of Heparin Effect
activated partial thromboplastin time (aPTT orPTT ) is necessary in patients receiving UFH
protamine titration (0.20.4 unit/mL) or anti-Xa
units (0.3
0.7 unit/mL) Weight-based dosing of the LMWH levels are not
generally measured except in the setting of renalinsufficiency, obesity, and pregnancy.
anti-Xa units (0.51 unit/mL for twice-daily 4hours after administration and ~1.5 units/mL foronce-daily)
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Adverse Effects of Heparin
Hemorrhage - 1
Increased loss of hair and reversiblealopecia
Osteoporosis, fractures andmineralocorticoid deficiencylong termtherapy
Heparin Induced Thrombocytopenia (HIT)a systemic hypercoagulable state
Caution: Allergic reaction
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Contraindications HIT Hypersensitivity to the drug
Active bleeding
Hemophilia
Significant thrombocytopenia
Purpura
Severe htn
Recent surgery of the brain, SC oreye
Pts undergoing lumbar punctureor regional anesthetic block
Intracranial hemorrhage
Infective endocarditis
Active tuberculosis
Ulcerative lesions of GItract
Threatened abortion
Visceral carcinoma
Advanced hepatic orrenal disease
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Oral Anticoagulants
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block the conversion of vitamin K epoxide tovitamin K
impairs the hepatic synthesis of several clottingfactors
dec. level of circulating clotting factors (II,VII,IX, X)
dec. blood coagulation and thrombogenesis
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Warfarin (Coumadin)
one of the most commonlyprescribed drugs
8- to 12-hour delay in the action
100% bioavailability Half life: 36 hrs
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Prevention of stroke in atrialfibrillation, clotting on new
prosthetic heart valves, and clotsin dilated cardiomyopathy
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Administration and Dosage
Initial: 510 mg
Initial adjustment of theprothrombin time takes about 1week, which usually results in amaintenance dose of 57 mg/d
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Adverse Effects and CI
Warfarin
Pregnancy
Hemorrhagic disorder in the fetus Birth defect abN bone formation
Cutaneous necrosis
Frank infarction of the breast, fatty tissues,intestine, and extremities Rare
Dicumarol
gastrointestinal distress (nausea, stomach cramps,
diarrhea)
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Other Anticoagulants
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Lepirudin (Refludan)
- a drug that directly inhibits thrombin; itcan be administered intravenously to preventexcessive clotting in conditions such as
heparin-induced thrombocytopenia
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Fondaparinux (Arixtra)
newer agent that can be administered by
subcutaneous injection to prevent DVTfollowing orthopedic procedures (hip, kneereplacement) and other surgeries
inhibits clotting factor Xa
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Ximelagatran
is new drug that is currently beingdeveloped to prevent or treat DVT. Itdirectly inhibits thrombin, but has theadvantage of oral administration
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Antithrombotic Drugs
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Standard therapy during the acutephase of myocardial infarction
Prolonged use of Aspirin one of theprimary pharmacological methodsused to prevent reinfarction and
maintain coronary artery patency
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Helps prevent the type of stroke causedby cerebral ischemia and infarction
Reduces the risk of ischemic stroke inpeople with atrial fibrillation
Prevents thrombus formation in
peripheral veins and thromboembolismfollowing surgical procedures
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Suggested daily dosage = 75 to 325mg/day
Adult Aspirin tablet = 325 mg/dayPediatric Aspirin tablet = 160 mg/day
Antithrombotic effects can be achievedat very low Aspirin doses
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Glycoprotein IIb-IIIa Inhibitors Most powerful inhibitors of platelet
activity Block (antagonize) the GP receptor on
the platelet membrane that is
stimulated by fibrinogen and otherchemical mediators
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Primarily used during balloonangioplasty and other percutaneouscoronary interventions that help re-establish coronary artery blood flow
Not typically administered orally
Abciximab (ReoPro), Eptifibatide(Integrilin), Tirofiban (Aggrastat)
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ADP Receptor Inhibitors Produce moderate inhibiton of platelet
activity
Aspirin < ADP Receptor inhibitors produce beneficial effects
Contraindication:
Hx of hemorrhagic stroke
Intracranial neoplasm
Active internal bleedingPossible aortic dissection
S ki
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Streptokinase
Most commonly used type ofthrombolytic
Indirectly activates plasmin to theprecursor molecule plasminogen
Dosage: 100,000units/hr for 24-72hrs.
U ki
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Urokinase
Directly converts plasminogen toplasmin
Dosage: 300,000units/hr for 12 hrs
Streptokinase and Urokinase
Both bring the activation ofplasmin
Ti l i i ( PA)
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Tissue plasminogen activator (t-PA)
Generic name:ALTEPLASE
Rapidly and effectively initiates clotbreakdown
Joins streptokinase as one of the primarythrombolytic agents
Used preferentially during ischemic stroke Dosage: 20mg/hr
A i t l (E i )
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Anistreplase (Eminase)
AKA: Anisoylated plasminogen-streptokinase activator complex (APSAC)
Formed by combining plasminogen with
streptokinase
More selective for clots that have alreadyformed
Less effect on systemic fibrinolysis
Dosage: 30units over 3-5mins
R l d T l
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Reteplase and Tenecteplase
Actions similar to t-PA (alteplase)
Administration through IV bolus injection
ADVERSE EFFECTS OF THROMBOLYTICDRUGS
Hemorrhage -> major adverse effect
FeverAllergic reaction (itching,nausea,headache
and other symptoms)
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Treatment of Clotting
Deficiencies
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Hemophilia
Replacing the missing clotting factor
Can be administered on a regular basis
or during acute hemorrhagic episode
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Deficiency of Vitamin K-dependentclotting factors
Treated by administering exogenousVitamin K
Available for oral or parenteraladministration
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Antifibrinolytics Prevent the activation of plasmin thus
preserving clot formation
Aminocaproic Acid (Amicar) andTranexamic Acid (cyklokapron)
For patient with hemophilia to prevent clotbreakdown when undergoing surgery
Oral or IV administration
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Adverse Effects:
Nausea Diarrhea
Dizziness
Headache
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THANK YOU and
GOD BLESS!