FCPS Anticoagulants
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8/29/2012MEDC 604 Anti-coagulants1
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DR MUHAMMAD ASHRAF ZIA
MCPS;FCPS:ASSTT.PROFESSOR
SIMS/SERVICES HOSPITAL LAHORE
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Anticoagulants
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8/29/2012MEDC 604 Anti-coagulants 3
Chemical Process of Clotting
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QUESTION ?
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LIST THE CLASSES & EXAMPLES OF
ANTICOAGULANTS ?
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Direct Thrombin (II) Inhibitors asAnticoagulant Drugs
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Bivalent: Hirudin (Bivalirudin, Lepirudin, Desirudin)
Univalent:
Argatroban Dabigatran Melagatran Ximelagatran
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Other Anticoagulant Drugs:
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Defibrotide Ramatroban Antithrombin III Protein C (Drotrecogin alfa)
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Warfarin
Acenocoumarole
Phenindione Factor Xa inhibitors Rivaroxaban
Thrombin inhibitors Ximelagatran
(Exanta) Dabigatran (Pradaxa)
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Antiplatelet drugs
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Aspirin(loprin)
Dipyridamole(persantin)
Thienopyridines Clopidogrel(plavex)
Ticlopidine(ticlid) GP IIb/IIIa antagonists Abciximab(rheopro)
Eptafibatide(integrilin)
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Heparin
unfractionated heparin, a highly sulfatedglycosaminoglycan The name heparin
comes from the Greek hepar, meaning liver as
the molecule was originally derived from canine
liver cells.
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http://en.wikipedia.org/wiki/Glycosaminoglycanhttp://en.wikipedia.org/wiki/Glycosaminoglycan -
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INDICATIONS
Acute coronary syndrome,
Atrial fibrillation
Deep-vein thrombosis and pulmonary embolism
Cardiopulmonary bypass forheart surgery.
ECMO circuit forextracorporeal life support
Hemofiltration
Indwelling central or peripheral venous catheters
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http://en.wikipedia.org/wiki/Acute_coronary_syndromehttp://en.wikipedia.org/wiki/Atrial_fibrillationhttp://en.wikipedia.org/wiki/Deep-vein_thrombosishttp://en.wikipedia.org/wiki/Pulmonary_embolismhttp://en.wikipedia.org/wiki/Cardiopulmonary_bypasshttp://en.wikipedia.org/wiki/Heart_surgeryhttp://en.wikipedia.org/wiki/ECMOhttp://en.wikipedia.org/wiki/Extracorporeal_life_supporthttp://en.wikipedia.org/wiki/Hemofiltrationhttp://en.wikipedia.org/wiki/Cathetershttp://en.wikipedia.org/wiki/Cathetershttp://en.wikipedia.org/wiki/Hemofiltrationhttp://en.wikipedia.org/wiki/Extracorporeal_life_supporthttp://en.wikipedia.org/wiki/ECMOhttp://en.wikipedia.org/wiki/Heart_surgeryhttp://en.wikipedia.org/wiki/Cardiopulmonary_bypasshttp://en.wikipedia.org/wiki/Pulmonary_embolismhttp://en.wikipedia.org/wiki/Deep-vein_thrombosishttp://en.wikipedia.org/wiki/Deep-vein_thrombosishttp://en.wikipedia.org/wiki/Deep-vein_thrombosishttp://en.wikipedia.org/wiki/Atrial_fibrillationhttp://en.wikipedia.org/wiki/Atrial_fibrillationhttp://en.wikipedia.org/wiki/Atrial_fibrillationhttp://en.wikipedia.org/wiki/Acute_coronary_syndrome -
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Mechanism of Action
Heparin binds to the enzyme inhibitor
antithrombin III (AT
results in its activation through an increase in the
flexibility of its reactive site loop.
activated AT then inactivates thrombin and other
proteases involved in blood clotting, most notably
factor Xa.
rate of inactivation of these proteases by AT canincrease by up to 1000-fold due to the binding of
heparin:
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http://en.wikipedia.org/wiki/Antithrombinhttp://en.wikipedia.org/wiki/Thrombinhttp://en.wikipedia.org/wiki/Factor_Xahttp://en.wikipedia.org/wiki/Factor_Xahttp://en.wikipedia.org/wiki/Thrombinhttp://en.wikipedia.org/wiki/Antithrombin -
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Heparin
Heparin dosage is measured in units; one unit is the quantity of heparin required to
keep 1ml of cats blood fluid for 24 hours at zero
degrees Celsius.
UFH is not absorbed orally and must beadministered intravenous infusion or
subcutaneous bolus.
Once in plasma, heparin binds to plasma proteins
endothelial cells and macrophages.
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Heparin
Clearance is non-linear, depending on a rapid,saturatable mechanism and slower renal
clearance.
Due to the variable binding and clearance of
UFH, monitoring neded activated partialthromboplastin time (APTT). An APTT ratio of1.5-2.5 is often used as a target
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Antidote to Heparin Overdose
Protamine sulfate (1 mg per 100 units of heparinthat had been given over the past four hours) has
been given to counteract the anticoagulant effect
of heparin
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http://en.wikipedia.org/wiki/Protamine_sulfatehttp://en.wikipedia.org/wiki/Protamine_sulfate -
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Fondaparinux Sodium..
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Fondaparinux Sodium synthetic analogue of the pentasacharide
fragment of heparin responsible for binding AT.
By modifying the structure, the affinity offondaparinux sodium for AT is increased, thus
increasing the half-life and specific activity.
Fondaparinux sodium has a molecular weight of
1.7kDa and is more specific for inhibition of factor
Xa than the LMWH, with no effect on thrombin
inhibition.
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Fondaparinux Sodium.Absorption is via the subcutaneous route and
half-life is around 17 hours.
A fixed dosing regime for VTE prophylaxis of
2.5mg once daily is not adjusted for body weight.
No monitoring is advised
fondaparinux sodium can be monitored with an
anti-Xa assay.
contraindicated in patients with a creatinineclearance of less than 30ml/min as it is excreted
unchanged in the urine
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Fondaparinux Sodium. Fondaparinux can not be reversed with protamine
sulphate, but as with LMWH, recombinant factor
VIIa may be effective.
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Dosage Forms And Strengths
Single-dose, prefilled syringes containing either2.5 mg , 5 mg , 7.5 mg , or 10 mg of
fondaparinux.
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QUESTION ?
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HOW TO MINIMISE THE INCIDENCE OFBLEEDING & HAEMATOMA FORMATIONASSOCIATED WITH EPIDURAL ANAESTHESIA INPATIENTS TAKING THESE DRUGS ?
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SPINAL/EPIDURAL HEMATOMAS
FACTORS RESPONSBLE
use of indwelling epidural catheters
concomitant use of other drugs that affect
hemostasis, such as non-steroidal anti-inflammatorydrugs (NSAIDs), platelet inhibitors, or otheranticoagulants
a history of traumatic or repeated epidural or spinal
puncture a history of spinal deformity or spinal surgery
that can increase the risk
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Monitor patients frequently for signs and symptomsof neurologic impairment. If neurologic compromiseis noted, urgent treatment is necessary
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WARFARIN
PROLONGED USE; stop for three days,Repeat PT,INR
LESS THAN 24 HRS USE; proceed with block
MORE THAN 24 HRS/MULTIPLE DOSES;
Stop wafarin check PT/INR
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ANTICOAGULANTS&HAEMATOMA
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ANTIPLATELETS&HAEMATOMA.
ASPIRIN&NSAID
No risk for haematoma,in otherwise normal patients
DRUGS TO BE STOPPED
TICLIDOPINE, 14 days CLOPEDOGRIL 7 days
ABCIXIMAB 48 hrs
EPTIFIBATIDE, 8 hrs
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HEPARIN&HAEMATOMA
MINIDOSE s/c prophylaxis
(5000 u s/c tds)
No contraindication
PTS NEEDING HEPARIN I/OP APPLY BLOCK 1 hr be fore dose
REMOVAL OF CATH
1 hr before dose
4 hrs after dose
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THERAPEUTIC DOSE
1000 U I/V PER HR
MONITOR APTT 6 HRLY
AVOID BLOCK REMOVAL ;stop dose & repeat aptt
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LMWH
ENOXAPRIN
MANY INCIDENCS OF HAEMATOMA REPORTED
IF BLEEDING ON BLOCK HOLD DOSE FOR NEXT24 HRS
REMOVAL OF CATH; 2 HRS BEFORE DOSE
IF DOSE ALREADY GIVEN
REMOVE CATH AFTER 10 HRS
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FIBRINOLYTIC /THROMBOLYTICS
AVOID N BLOCK
(UROKINASE,STREPTOKINASE)
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WHAT IS CONCENTATION OF V111 INFFP,CRYOPRECIPITATE & FACTOR V111 CONC..?
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liquid portion ofhuman blood that has been
frozen and preserved after a blood donationand will be used for blood transfusion
centrifuged, separated, and frozen solid at18 C (0 F) or colder within eight hours ofcollection. "FFP" is often used to mean any
transfused plasma product.
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http://en.wikipedia.org/wiki/Human_bloodhttp://en.wikipedia.org/wiki/Blood_donationhttp://en.wikipedia.org/wiki/Blood_transfusionhttp://en.wikipedia.org/wiki/Blood_transfusionhttp://en.wikipedia.org/wiki/Blood_donationhttp://en.wikipedia.org/wiki/Human_blood -
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FACTOR VIII&FFP.
ONE ML OF FFP CONTAINS 1 U OF FACTOR 8
most common inherited defect in secondaryhemostasis is factor VIII deficiency(hemophilia
A).
Symptomatic patients generally have less than 5% ofnormal factor VIII activity.
Classically, patients present with a prolonged aPTT
but a normal PT and bleeding time
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contains the labile as well as stable components coagulation,
fibrinolytic
complement systems; proteins that maintain oncotic pressure
In addition,
fats,
carbohydrates
minerals similar to those in circulation.
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http://en.wikipedia.org/wiki/Coagulationhttp://en.wikipedia.org/wiki/Fibrinolysishttp://en.wikipedia.org/wiki/Complement_systemhttp://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Oncotic_pressurehttp://en.wikipedia.org/wiki/Fathttp://en.wikipedia.org/wiki/Carbohydratehttp://en.wikipedia.org/wiki/Mineralhttp://en.wikipedia.org/wiki/Mineralhttp://en.wikipedia.org/wiki/Carbohydratehttp://en.wikipedia.org/wiki/Fathttp://en.wikipedia.org/wiki/Oncotic_pressurehttp://en.wikipedia.org/wiki/Oncotic_pressurehttp://en.wikipedia.org/wiki/Oncotic_pressurehttp://en.wikipedia.org/wiki/Proteinhttp://en.wikipedia.org/wiki/Complement_systemhttp://en.wikipedia.org/wiki/Fibrinolysishttp://en.wikipedia.org/wiki/Coagulation -
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INDICATION
Replacement of isolated factor deficiencies
Reversal of warfarin effect
Massive blood transfusion (>1 blood volume withinseveral hours)
Use in antithrombin III deficiency
Treatment of immunodeficiencies
Treatment of thrombotic thrombocytopenic purpura
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Hypofibrinogenaemia (low fibrinogen levels), ascan occur with massive transfusions
Bleeding from excessive anticoagulation - Fresh
frozen plasma contains most of the coagulationfactors and is a much better choice whenanticoagulation has to be reversed quickly.
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http://en.wikipedia.org/wiki/Hypofibrinogenaemiahttp://en.wikipedia.org/wiki/Fibrinogenhttp://en.wikipedia.org/wiki/Anticoagulationhttp://en.wikipedia.org/wiki/Anticoagulationhttp://en.wikipedia.org/wiki/Fibrinogenhttp://en.wikipedia.org/wiki/Hypofibrinogenaemia -
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Massive haemorrhage - RBCs andvolume expanders are preferred
therapies. Disseminated intravascular coagulation
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http://en.wikipedia.org/wiki/Haemorrhagehttp://en.wikipedia.org/wiki/Red_blood_cellhttp://en.wikipedia.org/wiki/Blood_substituteshttp://en.wikipedia.org/wiki/Disseminated_intravascular_coagulationhttp://en.wikipedia.org/wiki/Disseminated_intravascular_coagulationhttp://en.wikipedia.org/wiki/Blood_substituteshttp://en.wikipedia.org/wiki/Red_blood_cellhttp://en.wikipedia.org/wiki/Haemorrhage -
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Each 15 mL unit typically contains 100 IU offactor VIII, and 250 mg of fibrinogen.
also contains von Willebrand factor (vWF)
Individual products may actually have lessthan these amounts as long as the averageremains above these minimums.
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http://en.wikipedia.org/wiki/Factor_VIIIhttp://en.wikipedia.org/wiki/Fibrinogenhttp://en.wikipedia.org/wiki/Von_Willebrand_factorhttp://en.wikipedia.org/wiki/Von_Willebrand_factorhttp://en.wikipedia.org/wiki/Fibrinogenhttp://en.wikipedia.org/wiki/Factor_VIII -
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Indications
Indications
Haemophilia - Used for emergency back up whenfactor concentrates are not available.
von Willebrands's disease - Not currentlyrecommended unless last reserve.
ddAVP is first line, followed by factor concentrates.
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http://en.wikipedia.org/wiki/Haemophiliahttp://en.wikipedia.org/wiki/Von_Willebrands%27s_diseasehttp://en.wikipedia.org/wiki/Desmopressinhttp://en.wikipedia.org/wiki/Desmopressinhttp://en.wikipedia.org/wiki/Von_Willebrands%27s_diseasehttp://en.wikipedia.org/wiki/Haemophilia -
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FFP is considered to have 1 U of factor VIII activityper milliliter.
cryoprecipitate has 510 U/mL,
factor VIII concentrates have approximately 40U/Ml
Each unit of factor VIII transfused is estimated toraise factor VIII levels 2% per kilogram of body
weight.
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Twice-a-day transfusions are generallyrecommended following surgery because of therelatively short half-life of factor VIII (812 h).
Administration of DDAVP can raise factor VIII levels2- to 3-fold in some patients. EACA or tranexamicacid may also be used as adjuncts
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Dosage Calculations
Factor VIII one International Unit (IU) of FVIII per
kilogram body weight (IU/kg) will result in anincrease of recombinant factor VIII concentration inthe recipient's plasma of 1.8-2.0 IU/dL
(sometimes referred to as 1.8-2%). The rise whenusing plasma-derived FVIII is expected to be 2
IU/dL. represented by the formula:
FVIII dose (IU/kg) = (desired rise in FVIII IU/dL) 2
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Example. To increase the factor VIII from 0 to 80IU/dL, as might be required for a surgical procedurein a patient with severe haemophilia A, the factor
VIII dose
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will be 80 2 = 40 IU/kg
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F VIII C i I f i
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Factor VIII Continuous Infusion
Continuous infusions provide improved coagulationfactor cover,
associated with improved bleeding outcomes andmay use less coagulation factor
After an initial bolus injection of FVIII, an infusionis started to maintain coagulation factor levels at 70-100%, according to the following formula:
Infusion rate (IU/kg/h) = clearance (mL/kg/h) xsteady state concentration IU/mL)
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Alternatively, an infusion rate of 4.0-5.0 IU/kg/hwill produce a FVIII level of
approximately 80 IU/dL.
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Monitoring
During surgery, when prolonged courses of therapy
are administered, it is imperative that factor VIII or factor IX levels are
monitored frequently. It is useful
to check pre-operative factor levels and perform an
inhibitor screen.
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QUESTIONS?
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