Coagulation Final

7/30/2019 Coagulation Final

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HEMOSTASIS

& ANTICOAGULATION


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Components of blood clotting1) Intact Endothelial Cells

Inhibit blood clotting by antiplatelet, anticoagulant andprofibrolytic effects.

Negatively charged vascular endothelium repel platelets and

produce prostacycline and NO which are potent plateletinhibitors. Vascular endothelium further expresses several inhibitors of

plasma-mediated hemostasis, including thrombomodulin (anindirect thrombin inhibitor), heparin-like glycosaminoglycans, andtissue factor pathway inhibitor (TFPI).

Vascular endothelium synthesizes tissue plasminogen activator (t-PA), which is responsible for activating fibrinolysis

Store von Willebrand factor in cytop. granules. Make prostacyclin ~ inhibits platelet aggregation


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2) Subendothelial Cells

Contain membrane prots and extracellularmatrix prots (collagen) that normally do notcontact blood

When exposed after injury, platelets aggregateat the site by mediation of von Willebrand factor(vWF) that binds to both platelet receptors andcollagen/subendo cells


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3) Platelets After injury to vascular endothelium platelets undergo alterations

characterised by three phases.a) Adhesion - Exposure of subendothelial matrix proteins (i.e.,

collagen, vWF, fibronectin) allows for platelet adhesion to thevascular wall. Deficiency of either vWF (von Willebrand disease) orglycoprotein Ib/factor IX/factor V receptors (Bernard-Soulier

syndrome) results in a clinically significant bleeding disorder.b) Activation- platelets release granular contents (alpha bodies &

dense granules), resulting in recruitment and activation of additional platelets as well as propagation of plasma-mediatedcoagulation.

c) Aggregation- Newly active glycoprotein IIb/IIIa receptors on theplatelet surface bind fibrinogen to provide for cross-linking withadjacent platelets (platelet aggregation). Bleeding disorderassociated with hereditary deficiency these receptors: Glanzmann

thrombasthenia.


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Cell surface glycoprotein receptors on platelets

that mediate hemostatic response GPIb receptor von Willebrand Factor

GPIa/IIa or GPIV receptors collagen GPIc/IIa laminin or fibronectin GPIV receptor thrombospondin

GPIIb/IIIa receptor - fibrinogen


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4) Clotting Factors Soluble plasma proteins

Mostly made in liver

Most are serine proteases and circulate as zymogens(inactive precursors)

Cascade in which clotting factors are activated by selective

proteolytic cleavage must have an enzyme (activatedcoagulation factor), substrate (inactive precursorzymogen), cofactor (accelerator/ catalyst), and calcium.


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CLOTTING FACTORS

I Fibrinogen

II Prothrombin

III Platelet Factor 3

IV Calcium ionV Pro accelerin , Labile factor

VII Pro convertin . Stable factor

VIII Anti Haemophilic A

IX Anti Haemophilic B , Christmas factorX Stuart Power factor

XI Anti Haemophilic C

XII Hageman factor

XIII Fibrin Stabilizing factor


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Blood Vessel Injury

IX IXa

XI XIa

X Xa

XII XIIa

Tissue Injury

Tissue Factor

Thromboplastin

VIIa VII

X

Prothrombin Thrombin

Fibrinogen Fribrin monomer

Fibrin polymerXIII

Intrinsic Pathway Extrinsic Pathway


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Coagulation cascade has 2 steps1) Initiation

2) Propagation Initiation Phase :

TF VIIa small amount X to Xa small amount II to IIaIf II a not neutralized by Antithrombin 3 then triggerspropogation phase.

Propogation Phase :IIa ramps up its own formation by activating platelets andfactors (FV, FVIII), setting the stage for formation of the FVIIIa IXa complex.Formation of this FVIIIa IXa complex allows FXa generation toswitch from a TF-VIIa complex catalyzed reaction to oneproduced by the intrinsic Xase pathway.


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The intrinsic Xase complex exhibiting 50-fold higherefficiency at Xa generation.Hemophilia is characterised by intact initiation phase andabsent propagation phase.The intrinsic or contact pathway of coagulation has no role inthe earliest clotting events.The commonly used laboratory tests of soluble coagulationonly measure the kinetics of the initiation phase. Theprothrombin time (PT) and activated partial thromboplastintime (aPTT) both have as endpoints the first appearance of

fibrin gel, which occurs after completion of less than 5% of the total reaction.


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Antithrombotic mechanisms

Antiplatelet effects : Intact endothelium- prevent platelet adhetion. Prostacyclin (PGI 2) and nitric oxide Inhibits adhetion & aggregation.

Anticoagulant effects : Heparin-like molecules - Activates antithrombin 3. Antithrombin is a serine protease inhibitor (serpin ) that degrades the serine

proteases: thrombin , FIXa, FXa, FXIa, and FXIIa. Protein C - inhibits clotting by inactivating factors Va and VIIIa. Protein S - a co-factor for protein C. Thrombomodulin Activates protein C. Tissue factor pathway inhibitor (TFPI)- a cell surface protein that directly

inhibits tissue factor factor VIIa and factor Xa activities.

Fibrinolytic effects : Plasminogen activator ( t-PA ) - a protease that cleaves plasminogen to form

plasmin; plasmin, in turn, cleaves fibrin to degrade thrombi .
http://en.wikipedia.org/wiki/Antithrombinhttp://en.wikipedia.org/wiki/Serine_protease_inhibitorhttp://en.wikipedia.org/wiki/Serpinhttp://en.wikipedia.org/wiki/Serpinhttp://en.wikipedia.org/wiki/Serine_protease_inhibitorhttp://en.wikipedia.org/wiki/Antithrombin


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Prothrombotic mechanism

Platelet effects : von Willebrand factor (vWF) - essential cofactor for platelet

binding to matrix elements.

Procoagulant effects : tissue factor- expressed by fibroblast in ECM & is produced in

response to cytokines (e.g., tumor necrosis factor [TNF] orinterleukin-1 [IL-1]) or bacterial endotoxin and major contributorin extrinsic pathway.

Antifibrinolytic effects : Endothelial cells secrete inhibitors of plasminogen activator

(PAIs), which limit fibrinolysis and tend to favor thrombosis.


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Testing of coagulation Blood plasma after the addition of Tissue Factor forms a

gel-like structure (Test for prothrombin time). Numerous tests are used to assess the function of the

coagulation system: Common: aPTT, PT (also used to determine INR),

fibrinogen testing (often by the Clauss m ethod ), platelet

count, platelet function testing (often by PFA-100 ). Other: TCT, bleeding time , mixing test (whether an

abnormality corrects if the patient's plasma is mixed withnormal plasma), coagulatio n factor assays,antiphosholipid antibodies , D-dimer , genetic tests (e.g.

factor V Leiden , prothromb in mutation G20210A), diluteRussell's viper venom t ime (dRVVT), miscella neousplatelet fu nction tests, thrombo elastography (TEG orSonoclot), euglobulin lysis time (ELT).
http://en.wikipedia.org/wiki/Fibrinogenhttp://en.wikipedia.org/wiki/Partial_thromboplastin_timehttp://en.wikipedia.org/wiki/Prothrombin_timehttp://en.wikipedia.org/w/index.php?title=Clauss_method&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=Clauss_method&action=edit&redlink=1http://en.wikipedia.org/wiki/Platelethttp://en.wikipedia.org/wiki/Fibrinogenhttp://en.wikipedia.org/w/index.php?title=Clauss_method&action=edit&redlink=1http://en.wikipedia.org/wiki/PFA-100http://en.wikipedia.org/wiki/PFA-100http://en.wikipedia.org/wiki/PFA-100http://en.wikipedia.org/wiki/Platelethttp://en.wikipedia.org/wiki/PFA-100http://en.wikipedia.org/wiki/Thrombin_clotting_timehttp://en.wikipedia.org/wiki/Bleeding_timehttp://en.wikipedia.org/wiki/Mixing_testhttp://en.wikipedia.org/wiki/Antiphospholipid_antibodyhttp://en.wikipedia.org/wiki/D-dimerhttp://en.wikipedia.org/wiki/Factor_V_Leidenhttp://en.wikipedia.org/wiki/Antiphospholipid_antibodyhttp://en.wikipedia.org/wiki/Prothrombinhttp://en.wikipedia.org/wiki/Prothrombinhttp://en.wikipedia.org/wiki/Prothrombinhttp://en.wikipedia.org/wiki/D-dimerhttp://en.wikipedia.org/wiki/Dilute_Russell's_viper_venom_timehttp://en.wikipedia.org/wiki/Dilute_Russell's_viper_venom_timehttp://en.wikipedia.org/wiki/Dilute_Russell's_viper_venom_timehttp://en.wikipedia.org/wiki/Dilute_Russell's_viper_venom_timehttp://en.wikipedia.org/wiki/Prothrombinhttp://en.wikipedia.org/wiki/Dilute_Russell's_viper_venom_timehttp://en.wikipedia.org/wiki/Dilute_Russell's_viper_venom_timehttp://en.wikipedia.org/wiki/Thromboelastographyhttp://en.wikipedia.org/wiki/Thromboelastographyhttp://en.wikipedia.org/wiki/Euglobulin_lysis_timehttp://en.wikipedia.org/wiki/Euglobulin_lysis_timehttp://en.wikipedia.org/wiki/Thromboelastographyhttp://en.wikipedia.org/wiki/Euglobulin_lysis_timehttp://en.wikipedia.org/wiki/Euglobulin_lysis_timehttp://en.wikipedia.org/wiki/Euglobulin_lysis_timehttp://en.wikipedia.org/wiki/Euglobulin_lysis_timehttp://en.wikipedia.org/wiki/Euglobulin_lysis_timehttp://en.wikipedia.org/wiki/Euglobulin_lysis_timehttp://en.wikipedia.org/wiki/Thromboelastographyhttp://en.wikipedia.org/wiki/Dilute_Russell's_viper_venom_timehttp://en.wikipedia.org/wiki/Dilute_Russell's_viper_venom_timehttp://en.wikipedia.org/wiki/Prothrombinhttp://en.wikipedia.org/wiki/Factor_V_Leidenhttp://en.wikipedia.org/wiki/D-dimerhttp://en.wikipedia.org/wiki/D-dimerhttp://en.wikipedia.org/wiki/D-dimerhttp://en.wikipedia.org/wiki/Antiphospholipid_antibodyhttp://en.wikipedia.org/wiki/Antiphospholipid_antibodyhttp://en.wikipedia.org/wiki/Antiphospholipid_antibodyhttp://en.wikipedia.org/wiki/Mixing_testhttp://en.wikipedia.org/wiki/Bleeding_timehttp://en.wikipedia.org/wiki/Thrombin_clotting_timehttp://en.wikipedia.org/wiki/PFA-100http://en.wikipedia.org/wiki/PFA-100http://en.wikipedia.org/wiki/PFA-100http://en.wikipedia.org/wiki/Platelethttp://en.wikipedia.org/w/index.php?title=Clauss_method&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=Clauss_method&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=Clauss_method&action=edit&redlink=1http://en.wikipedia.org/wiki/Fibrinogenhttp://en.wikipedia.org/wiki/International_normalized_ratiohttp://en.wikipedia.org/wiki/Prothrombin_timehttp://en.wikipedia.org/wiki/Partial_thromboplastin_time


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The contact activation (intrinsic) pathway is initiated by

activation of the "contact factors" of plasma, and can bemeasured by the activated partial thromboplastin time (aPTT)test.

The tissue fa ctor (extrinsic) pathway is initiated by release of tissue factor (a sp ecific cellular lipo protein), and can bemeasured by the prothr om bin time (PT) test. PT results areoften reported as ratio (INR value) to monitor dosing of oralanticoagulants such as warfarin .

The quantitative and qualitative screeni ng of fibrinogen ismeasured by the thrombin clotting time (TCT). Measurementof the exact amount of fi brinogen prese nt in the blood isgenerally done using the Clauss method for fibrinogen testing.Many analysers are capable of measuring a "derivedfibrinogen" level from the graph of the Prothrombin time clot.

Deficiencies of fibrinogen (quantitative or qualitative) willaffect all screening tests.
http://en.wikipedia.org/wiki/Partial_thromboplastin_timehttp://en.wikipedia.org/wiki/Partial_thromboplastin_timehttp://en.wikipedia.org/wiki/Tissue_factorhttp://en.wikipedia.org/wiki/Tissue_factorhttp://en.wikipedia.org/wiki/Prothrombin_timehttp://en.wikipedia.org/wiki/Prothrombin_timehttp://en.wikipedia.org/wiki/International_normalized_ratiohttp://en.wikipedia.org/wiki/Prothrombin_timehttp://en.wikipedia.org/wiki/Warfarinhttp://en.wikipedia.org/wiki/Warfarinhttp://en.wikipedia.org/wiki/Warfarinhttp://en.wikipedia.org/wiki/Warfarinhttp://en.wikipedia.org/wiki/Thrombin_clotting_timehttp://en.wikipedia.org/wiki/Thrombin_clotting_timehttp://en.wikipedia.org/w/index.php?title=Clauss_method&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=Clauss_method&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=Clauss_method&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=Clauss_method&action=edit&redlink=1http://en.wikipedia.org/w/index.php?title=Clauss_method&action=edit&redlink=1http://en.wikipedia.org/wiki/Thrombin_clotting_timehttp://en.wikipedia.org/wiki/Warfarinhttp://en.wikipedia.org/wiki/International_normalized_ratiohttp://en.wikipedia.org/wiki/Prothrombin_timehttp://en.wikipedia.org/wiki/Prothrombin_timehttp://en.wikipedia.org/wiki/Prothrombin_timehttp://en.wikipedia.org/wiki/Tissue_factorhttp://en.wikipedia.org/wiki/Partial_thromboplastin_timehttp://en.wikipedia.org/wiki/Partial_thromboplastin_time


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Deficiencies of factor XII, high molecular

weight kininogen, and prekallikrein are notassociated with clinical bleeding but are ass.with prolongation of aPTT.

Factor XIII deficiency should be considered ina patient with a severe bleeding diathesiswho has otherwise normal coagulationscreening tests, including PT, PTT, fibrinogenlevel, platelet count, and bleeding time. Clotdissolution in 5M urea can be used as ascreen.


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Thrombus Formation

Clot is a Thrombus formed in an arterial or

venous vessel Thrombophlebitis - Both inflammation and

clots are present

Some thrombus can be superficial but itsthe DVT thats a concern embolism tolungs.


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Arterial formation - begins with platelet adhesion toarterial vessel wall Adenosine diphosphate (ADP)released from platelets more platelet aggregation

Bld. flow inhibited fibrin, platelets & RBCssurround clot build up of size structure occludesbld vessels tissue ischemia

The result of Arterial Thrombus is localized tissueinjury from lack of perfusion


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Venous Formation - Usually from slow bld flow

- Can occur rapidly. Stagnation of the blood flow initiate thecoagulation cascade production of fibrin enmeshesRBCs & platelets to form the thrombus. Venous thrombushas a long tail that can break off to produce an embolus.

These travel to faraway sites then lodge in lung (capillarylevel) inadequate O2 & CO2 exchange occur (ie.pulmonary embolism & cerebral embolism)

Oral & parenteral anticoagulants (Heparin/Warfarin)

primarily act by preventing venous thrombosis Antiplatelet drugs primarily act by preventing arterial

thrombosis


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Anticoagulants

Heparin Composition : mixture of sulfated glycosaminoglycans Mechanism of action : binds to anti thrombin and enhances its

effects by 1000 times to inactivate coagulation enzymes.

Antithrombin inhibits clotting factor proteases, especially thrombin(IIa), IXa, and Xa.

Heparin functions as a cofactor for the antithrombin-proteasereaction without being consumed.

Molecular weight : 5000-30000 Half life: IV 1 hr.

IM 3hr.


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Prepared from a. bovine lung

b. bovine or porcine gi mucosa Endogenously present in a. basophils

b. mast cellsc. liver

1 Unit of Heparin volume of heparin containing

solution that will prevent clotting of 1 ml of sheeps blood from clotting for 1 hour afteraddition of 0.2 ml of 1:100 calcium chloride.


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Pharmacokinetics Poorly lipid soluble not useful orally : does not cross

placenta Routes : iv or sc Not given im : hematoma formation

Metabolism pathway not known No suitable chemical assay Extensively bound to plasma proteins Decrease in body temp below 37C prolongs elimination

half time Hepatic and renal dysfunction prolong elimin half time Nitroglycerin increases required dose of heparin


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Lab evaluation :aPTT: Used usually to monitor heparin treatment Maintain the ratio of APTT to approx 1.5 to 2.5

times the pre drug value(approx 30-35 secs) If >120 secs omit single dose as heparin is

short acting.TCT (Thrombin clotting time): For conforming heparin induced prolongation of aPTT.


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ACT (Activated clotting time) Mainstay of heparin anti coagulation monitoring. Easy to use and reliable for high heparin conc. Influenced by hypothermia, pre existing coag defects ,

presence of contact activation inhibitors (aprotinin),thrombocytopenia.

Baseline value determineda. before heparin administrationb. 3mins afterc. every 30 mins after that

Control ACT : 90 120 secs Cardio pulm bypass : adeq ACT- >300 secs: inadeq ACT -


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Clinical uses of heparin

Prevention of venous thrombosis and pulmonaryembolism Prevention of mural thrombosis after MI Treatment of unstable angina and acute MI Prevention of coronary re thrombosis after

thrombolysis Prevent extra corporeal thrombosis during bypass Treat selected cases of DIC Treat retarded fetal growth in pregnant women


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For prophylaxis : Enoxaparin better than low dose heparin (5000 U) This dose of heparin has a risk of forming wound haematoma

but no major bleeding Prophylaxis very imp for Hip surg bcoz 1. kinking of femoral vein

and 2. altered leg vein haemodynamics

For treatment : Heparin better Treatment : 5000U iv followed by infusion of 30,000 U every 24

hrs. After an initial bolus injection of 80-100 units/kg, a continuous

infusion of about 15-22 units/kg/h is required to maintain the

aPTT at 2-2.5 times control. Heparin is anticoagulant of choice in pregnancy and patientswith prosthetic heart valves

For treatment : duration 3- 6 months For treatment of MI : 5000 U followed by infusion of 24,000 U

over 24 hrs


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Side effects

Hemorrhage most common side effect Thrombocytopenia 2 types Allergic reactions CVS changes Altered protein binding displacement of alkaline

drugs like Propranolol and diazepam. Altered cell morphology distorts morphology of

RBC & WBC.(Hct , WBC Count and ESR not altered)

Decreased anti thrombin concentrations /activity paradoxical thrombotic tendency


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HAEMORRHAGE :

Most common serious side effect Increased risk : pre existing coag defects,

other drugs(eg aspirin), need forinstrumentation, chronic alchoholism.

Advantages : easy assessment (APTT, TT),shortelimin half time , availability of antagonist

Increased incidence of epidural haematoma inpatients receiving spinal and epiduralanesthetic followed by heparinanticoagulation.


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Thrombocytopenia

THROMBOCYTOPENIA MILD SEVERE

more common Life threatning

INCIDENCE seen in 30-40% patients seen in 0.5-6% patients

PLATELET COUNT


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ALLERGIC REACTIONS: Esp seen in patients with pre existing allergies d/t animal protein. Fever , utricaria

CARDIOVASCULAR CHANGES: Occurs with rapid infusion of large dose (300 U/Kg)

before bypass Modest decrease in MAP and pulm art pr D/t heparin mediated relaxation of vasc sm musc fall

in SVR


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Contraindication HIT Hypersensitivity to the drug Active bleeding Hemophilia Significant thrombocytopenia Purpura Severe hypertension Intracranial hemorrhage Infective endocarditis

Active tuberculosis Ulcerative lesions of the gastrointestinal tract Threatened abortion Visceral carcinoma

Advanced hepatic or renal disease.


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Protamine Specific antagonist of heparin. Strongly alkaline (d/t arginine) ; positively charged. Polycationic LMW protein found in salmon sperm. Positively charged alk Protamine combines with negatively

charged acidic heparin to form a complex that is devoid of anticoagulant activity.

The complex is removed by reticuloendothelial systemwithin 20 mins.

Dose reqd : 1 - 1.3 mg for every 100U of circulatingheparin.

If given in absence of heparin interacts with platelets andproteins including fibrinogen anti coag effect

CVS S/E hypotension , pulm hypertension , allergic

reactions


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HYPOTENSION : Rapid IV histamine release facial flushing , tachycardia ,

hypotension The rate of infusion should not exceed 50 mg in any 10-minute period.

Also influenced by site of injection in dogs hist release andsubseq effects seen if injected in RA but not in LA or

peripheral vein.

PULMONARY HTN : Hep-Prot complex secr of thromboxane and serotonin

pulm vasoconstic , pulm htn , pulm edema VQ mismatchart hypoxaemia

Also broncho constriction Pre treatment with COX inhibitors eg indomethacin or aspirin

blunts increase in pulm vasc resistance.


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Alternative to protaminePLATELET FACTOR 4 stored in the alpha granules of platelets. prevents formation of active thrombin inhibitor

from heparin and anti-thrombin III. Released during platelet aggregation May be an alternative to protamine

HEPARINASE I Specific heparin degrading enzyme Lyses heparin at its alpha-glycoside linkage


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LOW MOLECULAR WEIGHT HEPARINS Enoxaparin, Dalteparin , tinzaparin Derived by chemical depolymerization of unfractionated heparin Approx one third the size of heparin Heterogenous , mean mol wt 4000 5000 daltons have equal efficacy as heparin Superior bioavailability at lower doses More predictable anti coagulant responses Less binding to endothelial cells hence..longer elimin half life Once daily dosing Therapeutic doses do not affect PT and APTT. LMW heparin levels are not generally measured except in the

setting of renal insufficiency, obesity, and pregnancy. LMWheparin levels can be determined by anti-Xa units.

Protamine neutralises 65% of anti Xa activity of LMW heparin.


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Half life : 4.5 hrs. Prophylactic enoxaparin is given

subcutaneously in a dosage of 30 mg twicedaily or 40 mg once daily. Full-dose

enoxaparin therapy is 1 mg/kg subcutaneouslyevery 12 hours. This corresponds to atherapeutic anti-factor Xa level of 0.5-1unit/mL.


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LMWHUFH

1000-100003000-30000Mol Wt range

4000-500012000-15000Mo Wt average

2:1-4:11:1 Anti Xa: anti IIa activity

No YesaPTT monitoring required

NoYesInactivation by platelet factor 4

YesNoCapable of inactivation of plateletbound factor Xa

++++++Inhibition of platelet function

No YesIncrease vascular permeability+++++Protein binding

-+++Endothelial cell binding

No YesDose dependent clearance

2-5 times longer 50-90 minElimination half life


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Activated factor X inhibitor

FONDAPARINUX Interacts with antithrombin & increases its activity 300

times. Inhibits activated factor X. Eliminated through kidney. Half life- 17-21 hrs. Monitoring not required unlesss CKD.


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DIRECT ACTIVATED FACTOR XINHIBITOR

RIVAROXABAN Oral Half life- 7-11 hrs Used in HIT Contraindicated in hepatic diseses with coagulopathy

& CKD. No antidote.

0ral anticoagulants


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0ral anticoagulants

CHEMISTRY Derivatives of 4-hydroxy coumarin. (Wisconsin Alumni Research Foundation, with"arin" from coumarin added)

Warfarin most commonly usedAdvantages : predictable onset and duration of action

Excellent bioavailability after oral administrationDisadvantages: Delayed onset of action Require regular lab monitoring Difficulty in reversing effect


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Mechanism of action Inhibits Vit K epoxide reductase blocks conversion of Vit K epoxide

to Vit K depletion of Vit K block gamma-carboxylation of severalglutamate residues in prothrombin and factors VII, IX, and X as wellas the endogenous anticoagulant proteins C and S.

Platelet activity not affected.

Pharmacokinetics

Onset 8 12 hrs Rapidly and completely absorbed Peak conc 1 hr after ingestion 97% bound to albumin hence minimal renal excretion

long elimination half time

prevents diffusion into RBC , CSF , breast milk Crosses placenta with extensive effects on fetus Metabolized to inactive metabolites and conjugated with glucuronic

acid Excreted in bile and urine


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COMPARISON OF ORAL ANTICOAGULANTS

WARFARIN DICOUMAROL PHENINDIONE

PEAK EFFECT 36 72 hrs 36-48hrs 18-24hrs

DUR AFTERDISCONT

2-5 days 2-6 days 1-2 days

INITIAL ADULTDOSE

1st day- 15mg2nd day 10 mg

1st day 200-300mg

1st day 300mg2nd day 200 mg

MAINT ADULT DOSE 2.5-10mg 25-200mg 25-200mg


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LAB EVALUATIONProthrombin time (PT) should be increased to a level

representing a reduction of prothrombin activity to 25% of normal and maintained there for long-term therapy. Whenthe activity is less than 20%, the warfarin dosage should bereduced or omitted until the activity rises above 20%.

Therapeutic range for oral anticoagulant therapy is defined interms of an international normalized ratio (INR). The INR isthe prothrombin time ratio (patient prothrombin time/meanof normal prothrombin time for lab) ISI, where the ISIexponent refers to the International Sensitivity Index, and isdependent on the specific reagents and instruments used forthe determination.


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USE : Prevent venous thrombo embolism Prevent systemic embolization in pats with prosth

heart valves or atrial fibrillation Prevent stroke , recurrent MIINCREASED EFFECT: Drugs that inhibit clearance phenylbutazone and

amiodarone Inhibit conv of Vit K 2nd and 3 rd gen cephalosporins

Added effect heparin , aspirin and NSAIDsDECREASED EFFECT: Drugs that impair gi absorption cholestyramine Drugs that increase clearance barbiturates ,

rifampicin ,


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SIDE EFFECT: Bleeding main complication Treatment Vit K 10-20 mg orally or 1-5 mg IV @

1mg/min.PT returns to normal in 4 to 24 hrs. Skin necrosis occurs between 3-8 days d/t

extensive thrombosis of venules and capillarieswithin subcut fat.

Cross placenta embryopathy , CNS damage ,fetal bleeding

Embyopathy only in 1 st trimester nasalhypoplasia,stippled epiphyses

CNS damage any trimester blindness ,agenesis of corpus callosum


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Reversal of warfarin effect : Oral or parenteral vitamin K 1 (phytonadione) Fresh-frozen plasma Prothrombin complex concentrates such as

Bebulin and Proplex T, and recombinant factorVIIa (rFVIIa).


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THROMBOLYTIC DRUGS(fibrinolytics )

Streptokinase , alteplase , anistreplase MOA convert endogenous plasminogen to plasmin that causes

fibrinolysis Goal restore circulation through a previously occluded artery or

vein Acts best on newly formed clot (platelet rich and formed by weaker

fibrinogen bonds) Since reocclusion is common hence heparin also used for 1 st 24hrs Most common side effect bleeding ( M/C ICH) Most common in patients with recent trauma or recent surgery Disadvantage not fibrin specific


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CONTRAINDICATIONS

ABSOLUTE RELATIVE

Active internal bleeding Trauma/surg > 14 days

Trauma or surgery in last 14 days Chronic severe htn

Recent head trauma or KCO IC aneurysm Active peptic ulcer disease

H/O haemorrhagic CVA Treatment with anti coagulantsSBP > 200/120 mm Hg Known bleeding diathesis

Previous allergy Sig. liver ds

Traumatic CPR Prior exposure to Streptokinase oranistreplase

Suspected aortic dissection

Diabetic hgic retinopathy

pregnancy


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STREPTOKINASE Protein produced by beta hemolytic streptococci

Does not directly convert plasminogen to plasmin Binds non covalently to p.gen formation of p.gen activator

complex acts on other p.gen mols gen of plasmin Elimin half life 23 mins Infusion decreases SVR hypotension May stimulate Ab produc subsequent allergic reactions If anti strepto Abs present then induces amnestic response Lab monitoring TT If TT not prolonged within a few hrs resistance to streptokinase

d/t high titre of anti strepto Abs. Streptokinase is administered by intravenous infusion of a loading

dose of 250,000 units, followed by 100,000 units/h for 24-72hours in acute MI.


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ANISTREPLASE ( ANISOYLATED PLASMINOGEN STREPTOKINASE ACTIVATOR COMPLEX) Synthesized with aim of longer dur of action . allows for rapid intravenous injection, greater clot selectivity (ie, more activity on

plasminogen associated with clots than on free plasminogen in the blood), and morethrombolytic activity.

Tissue plasminogen activators (t-PAs) preferentially activate plasminogen that is bound to fibrin.

Alteplase, Reteplase, Tenecteplase(Longer half life).Alteplase Synth by endothelial cells More expensive and more effective than Streptokinase in opening an infarct

related artery esp if started in 3hrs Clearance by liver Elimin half life


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COMPARISONTHROMBOLYTIC DRUGS

STREPTOKINASE ALTEPLASE ANISTREPLASE

DOSE 1.5 million U..1 hr 1.25mg/kg over 3hrs

30 U over 2-5 mins

USES ACS,PE ACS,PE ACS,PE

SITE OF ACTION P.gen P.gen P.gen

ELIMIN T 23 mins


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DIRECT THROMBIN INHITOR (anti thrombotic)

Directly binds to the active site of thrombin, thereby inhibitingthrombin's downstream effects. Suppress platelet function. Use arterial and venous thrombotic disease

Used in treatment of art thrombi and preven of venthr.emb

Inhibit free and clot bound thrombin HIRUDIN- derived from leech saliva. Recombinant Lepirudin and Desirudin Alternative to heparin in pats who req anti coag but have hep

resist or heparin induced thrombocytopenia.


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HIRUDIN XIMELAGATRAN

ARGATROBAN BIVALIRUDIN

ROUTE IV Oral IV IVEXCRETION Renal Renal hepatic hepatic

USE Hep inducedthr cytopenia

thromboPxt/t of DVT

Hep ind thrcytopenia

Coronaryinterventions

STOP B4 SURG 8hrs 24 hrs 4-6hrs 2-3 hrs

PROLONGPT/PTT

+/+ +/+ +/+ +/+

ANTIDOTE haemodialysis (-) (-) (-)


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Antiplatelet drugs Targets for platelet inhibitory drugs:(a) inhibition of prostaglandin metabolism through inhibition of

cyclooxygenase (aspirin): COX is a key enzyme involved in the synthesis of thromboxane 2

(prostaglandins). Inhibits platelet aggregation long acting because new proteins must be synthesizedDose: Low dose daily (180 mg/day): Prevents ischemic attack

(ministroke) and MI 325 mg/d for primary prophylaxis of myocardial infarction


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(b) inhibition of ADP-induced platelet aggregation (ticlopidine,

clopidogrel) no effect on PG metabolism used as alternative for patients intolerant to aspirin expensive

(c)BLOCKADE OF PLATELET GLYCOPROTEIN IIB/IIIA RECEPTORS(Abciximab, Eptifibatide, Tirofiban)

(d) Additional antiplatelet drugs (Dipyridamole , cilostazol)

DRUGS USED IN BLEEDING DISORDERS


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DRUGS USED IN BLEEDING DISORDERS

VITAMIN K Vitamin K 1 is available clinically in oral and parenteral forms. Onset of effect is delayed for 6 hours but the effect is complete by 24

hours. Treatment of depression of prothrombin activity by excess warfarin or

vitamin K deficiencyPLASMA FRACTIONS FFP Cryoprecipitate- It is used to treat deficiencies or qualitative

abnormalities of fibrinogen, such as that which occurs withdisseminated intravascular coagulation and liver disease. Alsouseful in factor VIII deficiency.

Desmopressin acetate- increases the factor VIII activity of patients with mild hemophilia A or von Willebrand disease


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FIBRINOLYTIC INHIBITORS:Aminocaproic acid (EACA)

synthetic inhibitor of fibrinolysis. It competitively inhibits plasminogen activation. It is rapidly absorbed orally and is cleared from the body by

the kidney. The usual oral dosage of EACA is 6 g four times a day. When

the drug is administered intravenously, a 5 g loading doseshould be infused over 30 minutes to avoid hypotension.

Tranexamic acid analog of aminocaproic acid and has the same properties. It is administered orally with a 15 mg/kg loading dose

followed by 30 mg/kg every 6 hours. Iv dose is 10 mg/kg followed by infusion of 1

mg/kg/hour


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SERINE PROTEASE INHIBITORS :APROTININ inhibits fibrinolysis by free plasmin.

It also inhibits the plasmin-streptokinase complex inpatients who have received that thrombolytic agent. currently approved for use in patients undergoing

coronary artery bypass grafting who are at high risk

of excessive blood loss.


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RISK STRATIFICATION OF TEHIGH RISK : Mitral or aortic valve prosthosis Stroke or TIA AF CHADS 2 > 4

VTE < 3 months Known thrombophilia

MODERATE RISK: Aortic valve (new)

CHADS 2 >2 VTE 6-12 months

LOW RISK: CHADS 2 12 MONTHS

CHADS-2 SCORINGSYSTEM

POINTS

CHF 1

HTN 1

AGE >75 1

DM 1

PRIOR STROKE OR TIA 2

A h i id i


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Anaesthetic considerationsPatient on warfarinPreoperative Discontinue warfarin at least 5 d before elective procedure. Assess INR 1 to 2 d before surgery, if >1.5, consider 1-2 mg of oral vitamin K. Reversal for urgent surgery/procedure, consider 2.5-5 mg of oral or intravenous vitamin K; for immediate

reversal, considerfresh-frozen plasma

Patients at high risk for thromboembolism Bridge with therapeutic subcutaneous LMWH (preferred) to be given 36 hrs after stopping warfarin

(eonoxaparin 1.5mg/kg BD or 1mg/kg OD) or intravenous UFH. Last dose of preoperative LMWH administered (BD- morning dose only., OD- 24 hrs before surgery, administerhalf of the daily dose)

Intravenous heparin discontinued 4 hrs before surgery No bridging necessary for patients at low risk for thromboembolism

PostoperativePatients at low risk for thromboembolism

Resume warfarin on postoperative dayPatients at high risk for thromboembolism (who received preoperative bridging therapy)

Minor surgical procedure - resume therapeutic LMWH 24 hrs postoperatively Major surgical procedure - resume therapeutic LMWH 48-72 hrs postoperatively or administer low-dose LMWH Restart warfarin on the evening of post operative day. Discontinue LMWH when INR Is therapeutic for 2 consequitive day.

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Patient on antiplatelet drugsPatients with coronary stents (on aspirin/ clopidogrel) Elective surgery postponed for the following duration

Bare metal stents: 4-6 wkDrug-eluting stents: 12 months

If surgery cannot be postponed, continue aspirin throughoutperioperative period

Patients at high risk for cardiac events (exclusive of coronarystents)

Continue aspirin throughout the perioperative period Discontinue clopidogrel at least 5 d (and preferably 10 d) before

surgery Resume clopidogrel 24 hrs postoperativelyPatients at low risk of cardiac events Discontinue antiplatelet therapy 7-10 d before surgery Resume antiplatelet therapy 24 hrs postoperatively

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Regional anaesthesia & anticoagulationPatient on unfractionated heparinProphylactic subcutaneous UFH 5000 U twice daily No contraindication to the use of neuraxial techniques.

Doses >10,000 U of UFH daily or more than twice daily

Safety not established . Needle placement 1 hr Heparin

Heparin 2-4 hrs Catheter removal 1hr Heparin

P ti t LMWH


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Patient on LMWHPreoperative

LMWH thromboprophylaxis doses :LMWH 10-12 hrs Needle placementHigher (treatment) doses :

LMWH 24hr Needle placementPostoperative

Twice daily dose :

NP 24hrs 1st

dose LMWHCatheter removal 2hrs


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once daily dose:

NP 6-8hrs 1 st dose 24 hrs 2 nd dose

LMWH 10-12 hrs Cath. rem. 2hrs LMWH

Patient on warfarin Warfarin should be stopped 4-5 days before planned proc. Catheter removed when INR > 1.5.

Coagulation Final

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