coagulation, drugs, and the or · 2018. 3. 31. · much of the heparin clearance occurs in the...
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Coagulation, Drugs, and the
OR
October 7, 2006
Jeffrey Chen, MD
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Girish
Girish
Fibrin
Coagulation Pathway
Coagulation Pathway
Extrinsic pathway
(Tissue factor)
Prothrombin
Thrombin
Fibrinogen
Intrinsic pathway
(Contact)
XXaXa
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Some additional information
�Factors II (prothrombin), VII, IX, and X are
vitamin K dependent. (Extrinsic pathway)
�Vitamin K is cofactor in carboxylationof factor
precursors in liver
�Clotting factors are synthesized in the liver
except for vWF–which is synthesized by the
endothelium of blood vessels.
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Heparin –Action
�Heparin acts as cofactor to antithrombin
III
�Heparin-AT III complex primarily inhibits
factor Xaand thrombin in 1:4 ratio
�The above reaction goes 1000 to 3000
times faster with heparin.
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Heparin –Elimination
�Much of the heparin clearance occurs in
the liver, so clearance is reduced in
cirrhosis or hepatitis.
�A small amount (probably LMW heparin)
is eliminated unchanged by the kidney.
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Heparin Dosing-1
�Vascular surgery: 5-7000 units loading.
Keep ACT > 250 or 2-3000 units every
hour
�For CPB load with 300 units/kg. 10k
units in pump. Adjust if necessary to
keep ACT >> 380
�Often see tachycardia and/or
hypotentionon large heparin loading
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Heparin Dosing-2
�Often needs more heparin to achieve
same effect if patient has been on
heparin
�AntithrombinIII level lower in heparinized
patients
�May need to give FFP first to boost AT
III levels if patient is refractory to
heparin
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Heparin Antidote
�Can be reversed by protaminesulfate
titrated so that 1.3 mg of protamine
sulfate is administered for every 100
units of heparin REMAININGin the
patient.
�Excess protaminemakes reheparinization
harder
�Protaminesulfate is also a weak
anticoagulant
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ProtamineReactions
�Hypotension
�Histamine release mainly from macrophages
in lung tissue
�Pulmonary hypertension
�Prostaglandin and thromboxanerelease in
lung tissue
�Anaphylactic response
�Prior exposure to protamine
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Heparin-induced Thrombocytopenia
�2ndmost common side effect after bleeding
�Immunologicallyrelated
�Occurs in 3-5% of patients 5 to 10 days after
initiation of therapy of standard heparin
�In 1/3 of pts is preceded by thrombosis
�Can be life-threatening even if treated
�Lower incidence in low molecular weight
heparin.
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Drugs Associated with
Thrombocytopenia
�Abciximab
�Acetazolamide
�Allopurinol
�Aminoglutethimide
�AmphotericinB
�Beta-LactamAntibiotics
�Carbamazepine
�Chlorothizide
�Cimetidine
�Colchicine
�Desipramine
�Diazepam
�Digitoxin
�Disopyramide
�Fluconazole
�Furosemide
�Ganciclovir
�Gold Salts
�Heparin
�Hydrochlorothiazide
�Hydroxychloroquine
�Imipenem-cilastatin
�Interferon
�Isoniazid
�LMWH
�Meclofenamate
�Milrinone
�Morphine
�NSAIDs
�Phenothiazines
�Phenytoin
�Procainamide
�Quinidine
�Quinine
�Rifabutin
�Rifampin
�Sulfanomides
�Sulfonylureas
�Ticlopidine
�Trimethoprim
�ValproicAcid
�Vancomycin
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Heparin and Pregnancy
�Heparin does not cross the placenta,
therefore it must be used instead of
warfarinin cases of requiring
anticoagulant therapy in pregnancy.
�Warfarincrosses the placenta and
induces fetal warfarinsyndrome.
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Low Molecular Weight Heparin
�Has an average mol. wt of 4,500 daltons and
15 monosaccharide units.
�Is isolated from standard heparin
�Is absorbed more uniformly
�Higher bioavailablity(greater than 90%)
�Has a longer biological half-life
�Has a more predictable dose-response
because it does not bind to plasma proteins,
macrophages, or endothelial cells.
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Low Molecular Weight Heparin
�Less likely to cause thrombocytopenia
�Can be given SC once or twice daily
without monitoring.
�Is cleared unchanged by kidney (Do not
use in renal failure!) rather than by
mononuclear phagocyte system (RE
system) as is for standard heparin.
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Warfarin-Action
�Inhibits the synthesis of Vitamin K
dependent factors (in order of potency)
�Factor II
�Factor X
�Factor VII
�Factor IX
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Warfarin-Effect
�Takes 8-12 hours before effect is
observed
�That is how long it takes for the four factors
to be used up
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Warfarin-Antidote
�Vitamin K (oral or parenteral)
�Takes time before effect of warfarin
dissipates.
�Liver needs to re-synthesize all those
factors
�FFP
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Warfarin–Administration,
Absorption, Biotransformation
�Administered orally
�Biotransformedby the liver
�Completely absorbed –crosses all
membranes
�Crosses GI mucosa
�Crosses placenta –is teratogenic
�Is found in breast milk
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Warfarin–Drug-Drug
Interactions
�Many drug-drug interactions
�The following drugs stimulate the
biotranformationof warfarin:
�Barbiturates
�Phenytoin
�Rifampin
�Alcohol (chronic ingestion)
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Warfarin–Drug-Drug
Interactions
�The following drugs inhibit warfarin
biotransformation
�Cimetidine(Tagamet)
�Disulfiram(Antibuse)
�Large amount of alcohol at one time
�Amiodarone(Cordarone)
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Argatroban
�Direct thrombin inhibitor
�Reversibly binds to thrombin active site
�Does not require antithrombinIII
�Eliminated by cP450 system in liver
�Indicated for people unable to tolerate
heparin
�No specific antidote for reversal
�Half life 39-51 minutes; full reversal in 4 hours
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ArgatrobanDosing
�Actually never tested for CPB in humans
�350 mcg/kg loading dose;
25 mcg/kg/min maintenance
�Monitor ACT as usual
�No adjustment necessary for renal
impairment
�Reduce dosing for hepatic failure
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Anti-Fibrinolytics
�Aprotinin(Trasylol)
�AminocaproicAcid (Amicar)
�TranexamicAcid
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Aprotinin
�Serine protease inhibitor (trypsin,
plasmin, and kallikrein)
�Inhibits fibrinolysis
�Inhibits platelet activation and
aggregation
�Anti-inflammatory
�Rapidly cleared from body; initial half
life 0.7 hours
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AprotininDosing
�Full Dose: 1 mLtest; 200 mLloading;
200 mLin pump; 50 mL/hr maintenance
�Half Dose: 1 mLtest; 100 mLloading;
100 mLin pump; 25 mL/hr maintenance
�Some studies show that half dose offers
no anti-inflammatory and platelet
preservation benefit
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AminocaproicAcid (Amicar)
�Inhibits fibrinolysisby inhibition of
plasminogenactivator
�Rapidly cleared in urine
�5-10 gm before and after CPB; 5-10 gm
in pump
�5 gm load; 1 gm/hr maintenance
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Anti-Platelet Therapy
�Oral Anti-platelet Therapy
�Aspirin
�Ticlopidine(Ticlid)
�Clopidogrel(Plavix)
�IV Anti-platelet Therapy
�Abciximab(Reopro)
�Tirofiban(Aggrastat)
�Eptifibatide(Integrilin)
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Aspirin
�Cyclooxygenase(Cox1, 2) inhibitor,
preventing production of prostaglandins
and thromboxaneA2
�Permanently inactivates Cox
�Inhibits platelet aggregation
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Clopidogrel(Plavix) /
Ticlopidine(Ticlid)
�Platelet ADP receptor antagonists
�Inhibit platelet aggregation/degranulation
�Plavixwidely used long term post stentingor
CVA prevention
�Hangs around a long time. Greatly increases
bleeding.
�This is the drug that scares cardiac surgeons
the most
�Almost always see apronininused in CPB
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Reopro/Integrilin/Aggrastat
�GPIIb/IIIaantagonists
�Most potent anti-platelet drugs available
�Used only in cathlab
�Prevents platelet aggregation
�Reoprowith shortest half life 30 minutes
�Encounter these drugs in cathlab crashes
�Again, apronininmay be helpful
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Coagulation Studies
�ACT
�Platelet Count
�Platelet Function Test
�aPTT
�PT/INR
�Fibrinogen Count
�Fibrin Split Products
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Activated Coagulation Time
�CeliteACT
�Normal is 100-170 seconds
�Black top tube
�Aprotininprolongs normal ACT
�Kaolin ACT
�Normal is 90-150 seconds
�Gold top tube
�Aprotininindependent
�ACT > 380 for CPB; ACT > 300 for OPCAB
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Platelet Count
�Platelet count does not tell you platelet
function
�All platelets get “stupid”after bypass
�Need to do platelet function test if you
really want to know
�Most of the time unnecessary
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PT / INR / aPTT
�PT/INR measures Vitamin K dependent
pathway, mainly factor VII
�Use INR for standardization
�Coumadintherapy
�Hi dose heparin
�aPTT
�Heparin therapy
�Hi dose coumadin
�LMWH does not increase aPTTreliably
�LMWH mainly inactivates factor Xa, but not thrombin
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Fibrinogen / Fibrin Split products
�DIC panel
�Fibrinogen down
�Fibrin Split products (d-dimer) up
�Whole different topic
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Additional information
�www.labtestsonline.org
�www.anaesthetist.com/icu/organs/blood
/c_index.htm