HEMOSTASIS & ANTICOAGULATION

Components of blood clotting

1) Intact Endothelial Cells
Inhibit blood clotting by antiplatelet, anticoagulant and profibrolytic effects. Negatively charged vascular endothelium repel platelets and produce prostacycline and NO which are potent platelet inhibitors. Vascular endothelium further expresses several inhibitors of plasma-mediated hemostasis, including thrombomodulin (an indirect thrombin inhibitor), heparin-like glycosaminoglycans, and tissue factor pathway inhibitor (TFPI). Vascular endothelium synthesizes tissue plasminogen activator (tPA), which is responsible for activating fibrinolysis Store von Willebrand factor in cytop. granules. Make prostacyclin ~ inhibits platelet aggregation

2) Subendothelial Cells
Contain membrane prots and extracellular matrix prots (collagen) that normally do not contact blood

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

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 the vascular wall. Deficiency of either vWF (von Willebrand disease) or glycoprotein 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-mediated coagulation. c) Aggregation- Newly active glycoprotein IIb/IIIa receptors on the platelet surface bind fibrinogen to provide for cross-linking with adjacent platelets (platelet aggregation). Bleeding disorder associated with hereditary deficiency these receptors: Glanzmann thrombasthenia.

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

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 (activated coagulation factor), substrate (inactive precursor zymogen), cofactor (accelerator/ catalyst), and calcium.

CLOTTING FACTORS
I II III Fibrinogen Prothrombin Platelet Factor 3

IV
V VII VIII IX X XI

Calcium ion
Pro accelerin , Labile factor Pro convertin . Stable factor Anti Haemophilic A Anti Haemophilic B , Christmas factor Stuart Power factor Anti Haemophilic C

XII
XIII

Hageman factor
Fibrin Stabilizing factor

Intrinsic Pathway
Blood Vessel Injury XII XI IX X XIIa XIa

Extrinsic Pathway
Tissue Injury Tissue Factor Thromboplastin

IXa
Xa

VIIa X

VII

Prothrombin
Fibrinogen

Thrombin
Fribrin monomer Fibrin polymer

XIII

 Coagulation cascade has 2 steps 1) Initiation 2) Propagation Initiation Phase : TF VIIa small amount X to Xa small amount II to IIa If II a not neutralized by Antithrombin 3 then triggers propogation phase. Propogation Phase : IIa ramps up its own formation by activating platelets and factors (FV, FVIII), setting the stage for formation of the FVIIIa IXa complex. Formation of this FVIIIaIXa complex allows FXa generation to switch from a TF-VIIa complexcatalyzed reaction to one produced by the intrinsic Xase pathway.

 The intrinsic Xase complex exhibiting 50-fold higher efficiency at Xa generation. Hemophilia is characterised by intact initiation phase and absent propagation phase. The intrinsic or contact pathway of coagulation has no role in the earliest clotting events. The commonly used laboratory tests of soluble coagulation only measure the kinetics of the initiation phase. The prothrombin time (PT) and activated partial thromboplastin time (aPTT) both have as endpoints the first appearance of fibrin gel, which occurs after completion of less than 5% of the total reaction.

Antithrombotic mechanisms
Antiplatelet effects :
Intact endothelium- prevent platelet adhetion. Prostacyclin (PGI2) 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 factorfactor 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.

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] or interleukin-1 [IL-1]) or bacterial endotoxin and major contributor in extrinsic pathway.

Antifibrinolytic effects :
Endothelial cells secrete inhibitors of plasminogen activator (PAIs), which limit fibrinolysis and tend to favor thrombosis.

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 method), 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 with normal plasma), coagulation factor assays, antiphosholipid antibodies, D-dimer, genetic tests (e.g. factor V Leiden, prothrombin mutation G20210A), dilute Russell's viper venom time (dRVVT), miscellaneous platelet function tests, thromboelastography (TEG or Sonoclot), euglobulin lysis time (ELT).

 The contact activation (intrinsic) pathway is initiated by activation of the "contact factors" of plasma, and can be measured by the activated partial thromboplastin time (aPTT) test. The tissue factor (extrinsic) pathway is initiated by release of tissue factor (a specific cellular lipoprotein), and can be measured by the prothrombin time (PT) test. PT results are often reported as ratio (INR value) to monitor dosing of oral anticoagulants such as warfarin. The quantitative and qualitative screening of fibrinogen is measured by the thrombin clotting time (TCT). Measurement of the exact amount of fibrinogen present in the blood is generally done using the Clauss method for fibrinogen testing. Many analysers are capable of measuring a "derived fibrinogen" level from the graph of the Prothrombin time clot. Deficiencies of fibrinogen (quantitative or qualitative) will affect all screening tests.

 Deficiencies of factor XII, high molecular weight kininogen, and prekallikrein are not associated with clinical bleeding but are ass. with prolongation of aPTT. Factor XIII deficiency should be considered in a patient with a severe bleeding diathesis who has otherwise normal coagulation screening tests, including PT, PTT, fibrinogen level, platelet count, and bleeding time. Clot dissolution in 5M urea can be used as a screen.

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 its the DVT thats a concern embolism to lungs.

Arterial formation - begins with platelet adhesion to arterial vessel wall Adenosine diphosphate (ADP) released from platelets more platelet aggregation Bld. flow inhibited fibrin, platelets & RBCs surround clot build up of size structure occludes bld vessels tissue ischemia The result of Arterial Thrombus is localized tissue injury from lack of perfusion

 Venous Formation - Usually from slow bld flow - Can occur rapidly. Stagnation of the blood flow initiate the coagulation cascade production of fibrinenmeshes RBCs & platelets to form the thrombus. Venous thrombus has a long tail that can break off to produce an embolus. These travel to faraway sites then lodge in lung (capillary level) 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

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-protease reaction without being consumed. Molecular weight : 5000-30000 Half life: IV 1 hr. IM 3hr.

 Prepared from a. bovine lung b. bovine or porcine gi mucosa Endogenously present in a. basophils b. mast cells c. 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 after addition of 0.2 ml of 1:100 calcium chloride.

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

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.

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 determined a. before heparin administration b. 3mins after c. every 30 mins after that Control ACT : 90 120 secs Cardio pulm bypass : adeq ACT- >300 secs: inadeq ACT - <180 secs Values misleading during bypass due to hypothermia and dilution If aprotinin present use kaolin ACT and otherwise celite ACT

Clinical uses of heparin

Prevention of venous thrombosis and pulmonary embolism 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

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 patients with 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

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

HAEMORRHAGE : Most common serious side effect Increased risk : pre existing coag defects, other drugs(eg aspirin), need for instrumentation, chronic alchoholism. Advantages : easy assessment (APTT, TT),short elimin half time , availability of antagonist Increased incidence of epidural haematoma in patients receiving spinal and epidural anesthetic followed by heparin anticoagulation.

Thrombocytopenia
THROMBOCYTOPENIA INCIDENCE PLATELET COUNT CAUSE MILD more common seen in 30-40% patients <100,000/cumm drug induced platelet aggregation SEVERE Life threatning seen in 0.5-6% patients <50,000 formation of hep PF4 antibodies (IgG) that trigger plat aggregation and resulting thrombocytopenia. after 6-10 days

ONSET

btwn 3 15 days (median 10 days)

Platelet count retrns to Diag confirmed by in vitro baseline within 4 days after plat aggreg studies discontinuation

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

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.

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 system within 20 mins. Dose reqd : 1 - 1.3 mg for every 100U of circulating heparin. If given in absence of heparin interacts with platelets and proteins including fibrinogenanti coag effect CVS S/E hypotension , pulm hypertension , allergic reactions

HYPOTENSION : Rapid IV histamine release facial flushing , tachycardia , hypotension The rate of infusion should not exceed 50 mg in any 10minute period. Also influenced by site of injection in dogs hist release and subseq 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 mismatch art hypoxaemia Also broncho constriction Pre treatment with COX inhibitors eg indomethacin or aspirin blunts increase in pulm vasc resistance.

Alternative to protamine
PLATELET 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

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. LMW heparin levels can be determined by anti-Xa units. Protamine neutralises 65% of anti Xa activity of LMW heparin.

 Half life : 4.5 hrs. Prophylactic enoxaparin is given subcutaneously in a dosage of 30 mg twice daily or 40 mg once daily. Full-dose enoxaparin therapy is 1 mg/kg subcutaneously every 12 hours. This corresponds to a therapeutic anti-factor Xa level of 0.5-1 unit/mL.

UFH
Mol Wt range Mo Wt average 3000-30000 12000-15000

LMWH
1000-10000 4000-5000

Anti Xa: anti IIa activity

aPTT monitoring required Inactivation by platelet factor 4 Capable of inactivation of platelet bound factor Xa Inhibition of platelet function Increase vascular permeability Protein binding Endothelial cell binding Dose dependent clearance

1:1
Yes Yes No ++++ Yes ++++ +++ Yes

2:1-4:1
No No Yes ++ No + No

Elimination half life

50-90 min

2-5 times longer

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.

DIRECT ACTIVATED FACTOR X INHIBITOR

RIVAROXABAN
Oral Half life- 7-11 hrs Used in HIT Contraindicated in hepatic diseses with coagulopathy & CKD. No antidote.

0ral anticoagulants
CHEMISTRY Derivatives of 4-hydroxy coumarin. (Wisconsin Alumni Research Foundation, with "arin" from coumarin added) Warfarin most commonly used Advantages : predictable onset and duration of action Excellent bioavailability after oral administration Disadvantages: Delayed onset of action Require regular lab monitoring Difficulty in reversing effect

Mechanism of action
Inhibits Vit K epoxide reductaseblocks conversion of Vit K epoxide to Vit Kdepletion of Vit Kblock gamma-carboxylation of several glutamate residues in prothrombin and factors VII, IX, and X as well as 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

COMPARISON OF ORAL ANTICOAGULANTS

WARFARIN PEAK EFFECT DUR AFTER DISCONT INITIAL ADULT DOSE 36 72 hrs 2-5 days 1st day- 15mg 2nd day 10 mg DICOUMAROL 36-48hrs 2-6 days 1st day 200300mg 25-200mg PHENINDIONE 18-24hrs 1-2 days 1st day 300mg 2nd day 200 mg 25-200mg

MAINT ADULT DOSE 2.5-10mg

LAB EVALUATION
Prothrombin 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. When the activity is less than 20%, the warfarin dosage should be reduced or omitted until the activity rises above 20%. Therapeutic range for oral anticoagulant therapy is defined in terms of an international normalized ratio (INR). The INR is the prothrombin time ratio (patient prothrombin time/mean of normal prothrombin time for lab)ISI, where the ISI exponent refers to the International Sensitivity Index, and is dependent on the specific reagents and instruments used for the determination.

USE : Prevent venous thrombo embolism Prevent systemic embolization in pats with prosth heart valves or atrial fibrillation Prevent stroke , recurrent MI INCREASED EFFECT: Drugs that inhibit clearance phenylbutazone and amiodarone Inhibit conv of Vit K 2nd and 3rd gen cephalosporins Added effect heparin , aspirin and NSAIDs DECREASED EFFECT: Drugs that impair gi absorption cholestyramine Drugs that increase clearance barbiturates , rifampicin ,

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 capillaries within subcut fat. Cross placenta embryopathy , CNS damage , fetal bleeding Embyopathy only in 1st trimester nasal hypoplasia,stippled epiphyses CNS damage any trimester blindness , agenesis of corpus callosum

Reversal of warfarin effect : Oral or parenteral vitamin K1 (phytonadione) Fresh-frozen plasma Prothrombin complex concentrates such as Bebulin and Proplex T, and recombinant factor VIIa (rFVIIa).

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 1st 24hrs Most common side effect bleeding ( M/C ICH) Most common in patients with recent trauma or recent surgery Disadvantage not fibrin specific

CONTRAINDICATIONS
ABSOLUTE Active internal bleeding Trauma or surgery in last 14 days Recent head trauma or KCO IC aneurysm H/O haemorrhagic CVA SBP > 200/120 mm Hg Previous allergy Traumatic CPR Suspected aortic dissection Diabetic hgic retinopathy pregnancy RELATIVE Trauma/surg > 14 days Chronic severe htn Active peptic ulcer disease Treatment with anti coagulants Known bleeding diathesis Sig. liver ds Prior exposure to Streptokinase or anistreplase

 Protein produced by beta hemolytic streptococci Does not directly convert plasminogen to plasmin Binds non covalently to p.gen formation of p.gen activator complexacts 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 24-72 hours in acute MI.

STREPTOKINASE

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 more thrombolytic 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 <5 mins Recommended for t/t of acute ischaemic stroke within 3hrs of onset.

COMPARISON THROMBOLYTIC DRUGS

STREPTOKINASE DOSE USES SITE OF ACTION ELIMIN T 1.5 million U..1 hr ACS,PE P.gen 23 mins ALTEPLASE 1.25mg/kg over 3 hrs ACS,PE P.gen <5 mins ANISTREPLASE 30 U over 2-5 mins ACS,PE P.gen <5mins

CLEARANCE
SUCCESS RATE ANTIDOTE HYPOTENSION ALLERGY STOP B4 SURG PROLONG OF PT/PTT

hepatic
50 70 % Anti fibrinolytics mod + 3 hrs +/+

hepatic
60 - 80 do min 1 hr +/+

hepatic
60 80 Do Min 1 hr +/+

COST

expensiv

Very expensiv

Very expensiv

DIRECT THROMBIN INHITOR

(anti thrombotic) Directly binds to the active site of thrombin, thereby inhibiting thrombin's downstream effects. Suppress platelet function. Use arterial and venous thrombotic disease Used in treatment of art thrombi and preven of ven thr.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.

HIRUDIN

XIMELAGATRA N

ARGATROBAN

BIVALIRUDIN

ROUTE
EXCRETION

IV
Renal

Oral
Renal

IV
hepatic

IV
hepatic

USE
STOP B4 SURG PROLONG PT/PTT

Hep induced thr cytopenia

8hrs +/+

thromboPx t/t of DVT

24 hrs +/+

Hep ind thr cytopenia

4-6hrs +/+

Coronary interventions
2-3 hrs +/+

ANTIDOTE

haemodialysis

(-)

(-)

(-)

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 synthesized Dose: Low dose daily (180 mg/day): Prevents ischemic attack (ministroke) and MI 325 mg/d for primary prophylaxis of myocardial infarction

(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

VITAMIN K
Vitamin K1 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 deficiency

PLASMA FRACTIONS FFP Cryoprecipitate- It is used to treat deficiencies or qualitative abnormalities of fibrinogen, such as that which occurs with disseminated intravascular coagulation and liver disease. Also useful in factor VIII deficiency. Desmopressin acetate- increases the factor VIII activity of patients with mild hemophilia A or von Willebrand disease

 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 dose should 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

SERINE PROTEASE INHIBITORS : APROTININ inhibits fibrinolysis by free plasmin. It also inhibits the plasmin-streptokinase complex in patients 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.

RISK STRATIFICATION OF TE
HIGH RISK :
Mitral or aortic valve prosthosis Stroke or TIA AF CHADS 2 > 4 VTE < 3 months Known thrombophilia

CHADS-2 SCORING SYSTEM CHF HTN

AGE >75

POINTS

1
1

MODERATE RISK:
Aortic valve (new) CHADS 2 >2 VTE 6-12 months

DM
PRIOR STROKE OR TIA

1
2

LOW RISK:
CHADS 2 <2 VTE >12 MONTHS

Patient on warfarin
Preoperative

Anaesthetic considerations

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, consider fresh-frozen plasma 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, administer half of the daily dose) Intravenous heparin discontinued 4 hrs before surgery No bridging necessary for patients at low risk for thromboembolism

Patients at high risk for thromboembolism

Postoperative
Patients at low risk for thromboembolism
Resume warfarin on postoperative day 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.

Patients at high risk for thromboembolism (who received preoperative bridging therapy)

Patient on antiplatelet drugs

Patients with coronary stents (on aspirin/ clopidogrel) Elective surgery postponed for the following duration Bare metal stents: 4-6 wk Drug-eluting stents: 12 months If surgery cannot be postponed, continue aspirin throughout perioperative period Patients at high risk for cardiac events (exclusive of coronary stents) Continue aspirin throughout the perioperative period Discontinue clopidogrel at least 5 d (and preferably 10 d) before surgery Resume clopidogrel 24 hrs postoperatively Patients at low risk of cardiac events Discontinue antiplatelet therapy 7-10 d before surgery Resume antiplatelet therapy 24 hrs postoperatively

Regional anaesthesia & anticoagulation

Patient on unfractionated heparin
Prophylactic 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

Patient on LMWH
Preoperative LMWH thromboprophylaxis doses : LMWH 10-12 hrs Needle placement Higher (treatment) doses : LMWH 24hr Needle placement Postoperative Twice daily dose : NP 24hrs 1st dose LMWH Catheter removal 2hrs

once daily dose: NP 6-8hrs

LMWH

1st dose

24 hrs 2hrs

2nd dose LMWH

10-12 hrs

Cath. rem.

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