api 2007 review - mx of vte - indian context

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JAPI VOL. 55 JANUARY 2007 www.japi.org 49

Review Article

Management of Venous Thromboembolism

R Parakh*, VV Kakkar**, AK Kakkar***, For Venous Thromboembolism (VTE) Core

Group#

Abstract

Introduction : Venous Thromboembolism is an important healthcare problem the world over, resulting insignificant morbidity, mortality and resource expenditure. The rationale for use of thromboprophylaxis isbased on solid principles and scientific evidence. Indian perspective on this topic is lacking due to the non-availability of published Indian data. This document reviews the available International and Indian data anddiscusses the relevance of recommendations for prevention and management of Venous Thromboembolism(VTE) in the Indian context.

Materials and Methods : Meetings of various specialists from different Indian hospitals in the field of

Gastrointestinal Surgery, General and Vascular Surgery, Hematology, Intensive Care, Obstetrics andGynecology, Oncology and Orthopedics were held in the months of August 2005 to January 2006. Theguidelines published by American College of Chest Physicians (ACCP),1 the International Union ofAngiology (IUA),2 and the Royal College of Obstetricians and Gynecologists (RCOG),3 were discussedduring these meetings. The relevance of these guidelines and the practical implications of following these ina developing country like India were also discussed. Any published data from India was collected from database searches and the results, along with personal experiences of the participating specialists were discussed.The experiences and impressions of the experts during these meetings have been included in this document.Data from recent sources (International Union of Angiology4 and the National Comprehensive CancerNetwork (NCCN) Practice guidelines in Oncology on Venous thromboembolic disease5) was subsequentlyalso included in this document.

Results : The suggestions formulated in this document are practical, and would intend to serve as a usefulpractical reference.

Conclusions : A number of unanswered questions remain in the field of thromboprophylaxis, and carefullydesigned research protocols may help answer some of these. Implementation of the suggestions outlined

in the document remains to be studied in theIndian context.

INTRODUCTION TO VENOUSTHROMBOEMBOLISM

Venous Thromboembolism (VTE), which consists ofDeep Vein Thrombosis (DVT) and PulmonaryEmbolism (PE), is a potentially fatal disease. Long termsequelae particularly post phlebitic syndrome (PPS) arefrequent and often disabling.6

The factors that predispose to Venous Thrombosiswere initially described by Virchow in 1856 and arecalled Virchows triad. These factors are venous stasis,

*Chairman, Dept of Vascular and Indovascular Surgery, Sir GangaRam Hospital, Delhi. **Chairman, Thrombosis Research Institute,London, ***Chairman, Surgical Sciences Centre, St. BartholomewsHospital, London. #For the Venous Thromboembolism Core Group(see Venous Thromboembolism (VTE) Study Group - pg. 68)

damage to the vessel wall and hypercoagulability.7A variety of clinical conditions are associated withincreased risk of venous thrombosis (Table 1).

DVT occurs less frequently in the upper extremitythan in the lower extremity. The incidence of upper DVTis increasing because of greater utilization of indwellingcentral venous catheters. The diagnosis of DVT of thecalf is often difficult to make at the bedside. This is sobecause only one of the multiple veins may be involved,allowing adequate venous return through the remainingpatent vessels.

The initial aim of treatment of DVT is prevention ofthrombus extension and PE. The long term goal is todecrease the incidence of recurrent VTE, PPS and chronicThromboembolic Pulmonary Hypertension.

The need for systemic thromboprophylaxis, especiallyin surgical patients is based on the high prevalenceof postoperative DVT and PE, the frequent silentpresentation of VTE and the potential for major adverse

Thromboembolism Core


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50 www.japi.org JAPI VOL. 55 JANUARY 2007

clinical outcomes.8 In acutely ill medical patients,thromboprophylaxis has shown to reduce the incidenceof VTE as seen in MEDENOX Study.9

However, the utilization of thromboprophylaxis inour country has been sub-optimal.10 One of the reasonsfor this underutilization is the perception that theincidence of VTE in the Indian subcontinent is lowerthan seen in the western world. This perception maybe due to lack of reporting of all diagnosed cases, suboptimal follow up of our patients, and the fact that amajority of thromboembolic events are clinically silent

and may be often missed unless investigated for by theclinician. Moreover, the patients may not report withthe diagnosis of VTE to their treating doctors, and maybe seen at other hospitals or departments.

Another reason for the underutilization is the fear(among the treating doctors) of bleeding complicationsassociated with thromboprophylaxis. This is anunfounded fear, since, if optimally utilized, majorbleeding episodes may be rarely encountered.

Meta analysis and randomized controlled trials (RCT)

Table 1 : Risk assessment module

VTE Risk Assessment Score Card for Surgical and Medical Patients

Patients Details

Name:

Primary Diagnosis:

Consultant:

Address & Phone No.


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have demonstrated either no increase or a small increasein the absolute rates of major bleeding with the use ofLow Molecular Weight Heparin (LMWH).8

From an economic point of view, it is difficult tojustify the routine use of thromboprophylaxis in clinicalpractice, but role of thromboprophylaxis, especiallyin orthopedic surgery, high risk pregnancies, acutely

ill medical patients, etc. cannot be ignored. Studieshave proven the cost effectiveness of this treatment8,keeping in mind the increased cost incurred duringhospitalization for treatment of a symptomatic patient.The use of Low Molecular Weight Heparin to treatselected patients with VTE outside the hospital hasthe potential to dramatically reduce the cost of healthcare.11

INCIDENCE OF VENOUSTHROMBOEMBOLISM IN INDIAN SCENARIO

Venous thrombosis may occur in more than

50% of patients undergoing surgical procedures,particularly those involving the hip and knee; and 10%to 40% of patients who undergo abdominal or thoracicoperations.12

The annual incidence of Venous Thromboembolismis approximately 0.1%; the rate increases from 0.01%among people in early adulthood to nearly 1% amongthose who are at least 60 years old.13 More than half ofthese events involve Deep Vein Thrombosis.

Patients with ischaemic stroke have an overall 42%incidence of DVT in the paretic or paralyzed leg.14

A study done in 19 centers across Asia15 showed

that rate of venographic thrombosis in the absence ofthromboprophylaxis after major joint surgery in Asianpatients was 41%, which is similar to that previouslyreported in patients in western countries. This study isfurther supported by another small study done on 88patients16 that showed the prevalence of post-operativeDVT similar to that in western population (50% - 75%).In another study DVT was detected in 10% of 146 Koreanpatients undergoing cement-less THA.17

Though the exact incidence is not known in theIndian subcontinent, the clinical relevance and incidenceis not expected to be any different from the Western

population.In one retrospective study, the incidence of VTE is

reported to be 28% in South Indian population.18 Anotherretrospective study also emphasized the significant(1.79 per thousand general population) incidence ofDVT in India.19 Contrary to this, a subsequent smallprospective study20 has shown that incidence of DVTin Indian patients is very low and is not comparablewith American and European populations. Theyfurther concluded that it is not cost effective to adviseprophylaxis in Indian patients undergoing Total HipArthoplasty (THA) / Total Knee Arthoplasty (TKA)

who have no known risk factors for DVT.

Another study done in 104 Indian patients21 revealedthat incidence of venographically proven DVT inorthopedic population is 72.2% in patients undergoingTKA followed by those with THA (42.9%) and anoverall incidence of 60% in the non-prophylaxis group.These figures are in accordance with earlier studies

both in Asia, Europe and North America showing ahigh frequency of sub-clinical DVT after major jointsurgery.

A prospective observational study on epidemiology ofvenous thromboembolism in Asian patients undergoingmajor orthopedic surgery without thromboprophylaxis(The SMART Study) done on 2420 patients reveals thatthe incidence of symptomatic VTE in Asian patientsis not low and is consistent with the rate observed inwestern countries.22

A retrospective study done on 100 patients tostudy the utilization of DVT prophylaxis in medical /

surgical intensive care units10

, highlighted the fact thatprophylaxis is not administered to roughly one outof two critically ill patients who are eligible for VTEprophylaxis. This was carried out in State of Art IntensiveCare Units in the metropolitan city of Kolkata, in India.The utilization varied from 40%-60% in different centers.This data is in accordance with some western data thatcites similar incidences of underutilization.

In a registry prospective registry on venousthromboembolic events (PROVE) conducted in 19countries23, 3526 patients with symptomatic DVT wereenrolled; out of which 667 were from India. Baseline

characteristics for Indian patients were similar to thoseobserved in the overall PROVE population. Comparedwith the overall PROVE population, the prevalence ofprevious DVT, PE, or superficial leg thrombosis wassimilar in Indian patients, but fewer Indian patientshad varicose veins (8% vs. 22%). Most enrolled Indianpatients were located in acute care hospitals whenDVT symptoms occurred (54%) or at home (43%). Thiscontrasted with the overall PROVE population in whichmost enrolled patients were at home (60%), followedby acute care hospitals (36%). DVT was found bothproximally and in the calf in 54% of Indian patients,only proximally in 17%, and only in the calf in 13%,compared with 52%, 18%, and 24% in the overall PROVEpopulation, respectively.

DVT was idiopathic in 43% of patients, followinga precipitating event in 52%, and recurrent in 6%(44%, 49%, and 9% for the overall PROVE population,respectively). Prior VTE prophylaxis had been given toonly 5% of enrolled Indian patients (12% in the overallPROVE population).23

Patients with symptomatic DVT in India in thePROVE registry had similar baseline characteristicsand medical histories to patients enrolled in othercountries. However, very few enrolled patients (5%)


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had received prophylaxis prior to their DVT event,perhaps representing poor awareness of the risks forVTE in these patients.

These findings, together with continued uncertaintyabout the natural history of post-operative DVT in Asianpopulations, re-emphasizes the need for randomized andpreferably placebo-controlled evaluations with clinical

outcome measures to establish if thromboprophylaxis isrequired after major joint surgery and other high riskindications in Asia, as it is in the west.

Radionuclide Venography with PulmonaryScintigraphy is a single modality, which can assess theentire venous tree from the popliteal, femoral, iliac vein,IVC & pulmonary arteries. Concept of total thrombusload based on above investigations may help cliniciandecide regarding further invasive interventionaltherapeutic options.24

DVT Free Hospital Project : With an aim to ensuretimely recognition of VTE, and awareness amongst

the medical community, a DVT Free hospital projectis being started in Sir Ganga Ram Hospital, which isone of the tertiary care multi-specialty hospitals inIndia. All patients admitted for surgery in any of theparticipating specialty departments would be subjectedto a risk assessment on the basis of a questionnaire andexamination findings. All patients in the high-risk groupwould undergo pre and postoperative Real time B ModeCompression Ultrasonography screening to excludeDVT. All high-risk cases would be followed up for threeyears (Personal Communication, Parakh R. 2006).

Normal Hemostasis

Accurate diagnosis and treatment of patients, eitherbleeding or thrombosed, require the knowledge of thepathophysiology of hemostasis. The process can bedivided into primary and secondary components andis initiated when trauma, surgery or disease disruptsthe vascular endothelial lining and blood is exposed tosub endothelial connective tissue.

Primary hemostasis involves platelet plug formationat the site of injury. The vessel wall injury exposes tissuefactor on the surface of the damaged endothelium.The tissue factor interacts with plasma factor VII,thus activating the coagulation cascade, which

produces thrombin by stepwise activation of a seriesof proenzymes as shown in Fig. 1. Thrombin convertssoluble fibrinogen to fibrin; activates factors V, VIII,and XI, which generates more thrombin; and stimulatesplatelets. Thrombin, by activating factor XIII, also formscross-linked bonds among the fibrin molecules, whichstabilizes the clot. Regulation of the cascade at the siteof injury is thought to be due to natural anticoagulants,such as tissue factor pathway inhibitor, the protein Cand protein S system, and antithrombin.25

A high Wells Score26 substantially increases thelikelihood of DVT and indicates that definitive diagnostic

testing is appropriate. A low Wells Score26 substantiallydecreases the likelihood of DVT and indicates that asimple noninvasive test, such as the D-dimer assay, maybe sufficient to rule out DVT.27

Secondary hemostasis consists of the reactions ofthe plasma coagulation system that results in fibrinformation. As the primary hemostasis plug is beingformed, plasma coagulation proteins are activated toinitiate secondary hemostasis.

The sequence of coagulation protein reactionsthat culminate in the formation of fibrin is describedas Cascade. The coagulation cascade is a highlycoordinated and regulated series of linked enzymaticreactions that involves the sequential activation ofplasma zymogens to resume proteases.

Two pathways of blood coagulation have beenrecognized; the extrinsic or tissue factor pathway andintrinsic or contact activation pathway. These twopathways of activation of the coagulation cascadeconverge to form a common pathway, which leadsto the generation of the pivotal coagulation enzyme

Fig. 1 : The Coagulation Cascade

Fig. 2 : Mechanisms Of Haemostatic Activation By Tumor Cells.


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thrombin. Thrombin not only catalyzes the conversionof fibrinogen to fibrin but also plays an important rolein sustaining the cascade by feedback activation ofcoagulation factors at several strategic sites.

THROMBOPHILIAThrombophilia is a term used to describe a group

of conditions in which there is an increased tendency,often repeated over an extended period of time, forexcessive clotting.

Thrombophilia are of two types: Inherited &Acquired.

Inherited Thrombophilia

Inherited Thrombophilia (Table 2) refers to a geneticproblem that causes the blood to clot more easily thanit should. Different factors in the blood clotting processmay be involved, depending on the exact type of geneticproblem present. Some types of inherited thrombophilia,such as deficiencies of antithrombin, protein S or protein

C, usually are associated with venous thrombosis inpeople less than 50 years of age, while others, such asfactor V Leiden or the prothrombin gene mutation, canpredispose to a first thrombosis in all age groups.

Factor V Leiden: It is the most common inheritedthrombophilia with its prevalence as high as 20%to 40% in patients with VTE. It results from a singlemutation in factor V gene. Interestingly it appearsto be a stronger risk factor for DVT than PE.

Prothrombin Gene Mutation: Like Factor V, PTG2021OA is associated with an increased risk ofVTE.

Antithrombin Deficiency: Inherited AntithrombinDeficiency can be due to a quantitative (type 1)or a qualitative (type 2) abnormalities. It as apredominantly a risk of VTE. Approximately 60% ofpatients with antithrombin deficiency will have anepisode of venous thrombosis by age 60 years.28

Protein C and S Deficiencies: Deficiency of thesefactors, are a risk for VTE and are usually associatedwith Factor V Leiden thrombophilia.

Homocysteine: In assessing VTE risk, 2 metaanalysisfound a 2.5 to 3 pooled odd ratio of VTE in

individuals with an elevated fasting homocysteinelevels.

Acquired Thrombophilia

There are a number of other conditions that can causea person to be at increased risk to develop a venousthrombosis. These conditions include:

Previous surgery (especially orthopedic surgery and

neurosurgery).

Trauma.

Pregnancy.

Obesity.

Use of certain medications, including birth controlpills, hormone replacement therapy etc. Thirdgeneration oral contraceptives which contain lessestrogen and a different progestin are associatedwith a two fold increased risk of VTE compared tosecond generation products.

Immobilization.

Cancer.

Heart failure.

Certain disorders of the blood, such as polycythemiavera or essential thrombocythemia.

Kidney problems, such as nephrotic syndrome.

Antiphospholipid antibodies (antibodies to certainphospholipids binding proteins like ACA, LAC etc.in the blood that can affect the clotting process).

A previous episode of thromboembolism, suchas a clot in the leg (deep vein thrombosis) or lung(pulmonary embolism).

Thrombophilia Investigation and Its Timing

A thrombophilia screen may be done on patientsat admission. Follow-up testing may be needed forpatients with functional deficiency on APT, APTT;or in case of abnormal protein C, protein S, APCR& AT-III.

The same screen may be repeated, or, advised for,at the end of the period of anti-coagulant therapy,or 4 weeks after withdrawing oral anticoagulanttherapy. At this time, patient may or may not be on

Table 2 : Genetic conditions in inherited thrombophiliaGenetic Conditions in Prevalence in patients Testing MethodInherited Thrombophilia with VTE (%)

Factor V Leiden Mutation 20-40 Screening: Activated protein C resistance(most common) Confirmation: Genetic testing

Prothrombin gene mutation 6 Genetic testing only(20210A)

Protein S Deficiency 3 Screening: Protein S profile: (activity, total/free antigen)

Protein C Deficiency 3 Screening: Protein C profile (activity and antigen)

Antithrombin Deficiency 1 Screening: Antithrombin profile (activity and antigen)

Methylene Tetra Hydro Screening: Homocysteine levelFolate Reductase (MTHFR)Gene Mutation Confirmation: MTHFR genetic testing


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bridging heparin therapy.

In cases with abnormal levels reported, acquiredcauses would need to be ruled out. Family screenmay be needed for those without any acquiredcause.

Physiological Anticoagulant Mechanisms

Several physiological anti-thrombotic mechanisms

act in concert to prevent clotting under normalcircumstances. These physiological mechanisms operateto preserve blood fluidity in the intact circulation andalso to limit blood clotting to specific focal sites ofvascular injury.

Endothelial prostaglandins, nitric oxides, ADPaseand carbon monoxides are physiological plateletinhibitory mediators. Other anti-coagulant systemswhich act at different sites in the coagulation cascadeto dampen fibrin accumulation are antithrombin, theprotein C / protein S/ thrombomodulin systems andtissue factor pathway inhibitor (TFPI) system. Fibrin

that forms despite these anticoagulant systems is thendegraded by the fibrinolytic system.

Situations faced in India and present practice

Availability and cost of these tests is a limiting factorin developing countries.

Risk stratification and incidence of thrombosis andthrombophilia needs to be established by collectingdata prospectively from multiple regional centers.

DIAGNOSTIC TESTSA detailed clinical examination and probability

estimation, either structured (e.g. Wells score26

), orunstructured, provides useful information about theprobability of DVT. In cases with a low Wells score,d dimer alone may be used to rule out DVT, whereashigh Wells score may justify other invasive tests.27 Thesensitivity and specificity of various diagnostic tests isindicated in Table 3.29

Diagnostic Tests for DVT include:

1. Non-invasive diagnostic tests

2. Invasive diagnostic tests

1. Non-Invasive Diagnostic Tests

Ultrasonography imaging has both high sensitivityand specificity for the detection of thrombus in theproximal leg veins. It can be subdivided in to threecategories:

i) Compression ultrasound screen: It is a definitive testas pressure applied by the scanning probe over theregion of interest will compress a normal vein butnot the one containing thrombus.

ii) Real time B mode compression: In this technique,normal veins appear dark, whereas a blood clot ismore echogenic. In addition, the veins are typicallydilated if DVT is present.

iii) Color Doppler imaging: It provides more informationon both the speed and direction of flow. If there is

an occlusive blood clot, it will show no flow withinthe vein segment or, if partially occlusive, there maybe limited flow surrounding the blood clot.

Venous Ultrasonography

Color Doppler Duplex Scan of the common femoralvein and popliteal vein is the most commonly usedtest to evaluate patients with suspected DVT. It isused in most of Indian studies.30

It is highly sensitive (95%) and specific (96%) forsymptomatic proximal vein thrombosis. A non-compressible segment of the vein will accuratelydiagnose DVT.

The main advantages are its low cost, ease of beingrepeated, portability of the machine, and that itcan be carried out as a bedside procedure.31 Thisstudy done for screening of DVT in post-operativeorthopedic patients when Doppler sonographyand contrast venography were compared showedsensitivity of 91.66% and 100% respectively.

Current recommendations favor the use of Duplexscanning of the entire leg. Scanning of only theproximal veins is no longer acceptable. Scanning ofproximal veins alone is acceptable only if the clinicalprobability of thrombosis is low.

Limitations of Duplex Ultrasonography

Accuracy depends on the observer.

Cannot distinguish between old clot & new clot.

Difficult to diagnose DVT in presence of significantedema or obesity.

Less accurate in detecting DVT in pelvis or in smallvessels of the calf.

Ventilation/ Perfusion (V/Q) Scan

A nuclear medicine study or V/Q scan is the primaryscreening tool for patients with suspected PE. The

most important investigation documenting the utility

Table 3 : Sensitivity and specificity of diagnostic tests fordeep vein thrombosis

Test Sensitivity (%) Specificity (%)

Contrast Venography 99 100

Real Time B-Mode Compression Ultrasonography

Symptomatic DVT 96 98

Asymptomatic DVT 62 97

Doppler Ultrasonography



Duplex Ultrasonography



Magnetic Resonance Imaging


D-Dimer [Enzymes linked

immunosorbent assay (ELISA)]


Adapted from Haines ST et al29


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of V/Q screening is the PIOPED study.32 In this study,98% of patients with PE had an abnormality on theV/Q scan.

CT or MR angiography is rapidly supplanting V/Qscanning as 52% of V/Q scanning is indeterminate.

Problems with V/Q Scanning

Bronchospasm in absence of PE that leads to

mismatching of V/Q.

Another cause of V/Q mismatch is chronic orunresolved PE.

A large central or saddle embolus may also causenegative V/Q scans.

A repeat study, three months after the initialepisode to be used as the patients new baseline isrecommended.

Combination of lung scans with RadionuclideVenography for estimation of total thrombus load isa unique and reliable basis for clinicians involved in

management of VTE.24

Helical Computerized Tomography (CT)

CT Scan is gaining acceptance as a computer basedtechnique for evaluation of PE. Some studies haveshown that it is more sensitive than V/Q scan, 87% and65% respectively.

Advantages of Helical CT

The main advantage of helical CT over othermethods is that it is very accurate for diagnosingother pulmonary diseases.

Detects large PEs, with a high specificity for

identification of main and lobar emboli.Disadvantages of Helical CT

Unable to detect smaller PEs.

Identification of suspicious appearing abnormalitiesthat require further evaluation or even biopsy butactually are benign.

Availability and cost limits its widespread use.

D-dimer

This is a non-invasive blood test to measure fibrindegradation products. The test is done using differentmethodologies at different institutions like ELISA

techniques and new rapid methods. The ELISA methodis highly sensitive (99%) for VTE when using a cut offvalue of 500 microgram/l. A lower value essentiallyexcludes VTE.

D-dimer is recommended to exclude VTE in clinicallysuspicious patients (only for its negative predictivevalue). The D-dimer is useful as an adjunct to otherdiagnostic testing but is generally not a sufficient testto diagnose PE by itself.

Positive D-dimer assay does not raise the likelihoodof DVT appreciably and therefore has limited clinicalvalue.

During the meetings the need was felt regarding theusage of Wells score26 (Table 4) for suspected PE anduse of D-dimer values, compression ultrasonography,clinical diagnosis and risk stratification for propermanagement of VTE.

Echocardiography

When pat ients wi th known PE undergoechocardiography, 40% will have abnormalitiesassociated with the right ventricle. It is not a specificinvestigation but is a valuable bed-side test for criticallyill patients with hypotension to help exclude otherdiagnosis such as myocardial infarction, vasculardisorders, etc.

New Modalities

Combining CT pulmonary venography with CTvenography may become a very useful test infuture.

MRA Magnetic resonance angiography has theadvantage of screening for DVT and PE in one test.However it is an expensive test.

Chest X-ray, ECG and arterial blood gases - Theyare non-specific but important tests for evaluatingpatients suspected of having PE.

MRI Magnetic resonance imaging is useful indetecting DVT. It is useful in patients with suspectedthrombosis of the superior and inferior vena cavaor pelvic veins.

2. Invasive Diagnostic Tests

Venography

Contrast venography remains the gold standard fordiagnosis of DVT.30

Findings consistent with DVT include an intraluminalfilling defect in two views, or an abrupt cutoff in thecontrast column in a patient with previous DVT.

It is recommended that patients with an abnormal

Table 4 : Wells criteria26

Clinical Feature Score*

Active cancer 1

Paralysis, paresis, or recent plaster immobilizationof the lower extremity 1

Immobilization for more than 3 days or major surgerywithin 4 weeks 1

Localized tenderness along the distribution of thevenous system 1

Thigh and calf swollen 1

Calf swelling by more than 3 cm when compared withthe asymptomatic leg (measured 10 cm belowtibial tuberosity) 1

Pitting edema (greater in the symptomatic leg) 1

Collateral superficial veins (nonvaricose) 1

Alternative diagnosis as likely or greaterthan that of deep vein thrombosis -2

* A score of zero or less indicates a low clinical probability;

A score of one point or more indicates a moderate-to-high clinicalprobability


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ultrasound and low clinical probability of DVTor alternatively, those with a normal ultrasoundin association with a high clinical probability forVTE, should be evaluated further by venography.This is cost effective as well as diagnosticallyconfirmative.

Radionuclide ascending venography with perfusion

lung scan is very useful in assessing the totalthrombus load in patients with VTE. This is thechosen investigative modality as it is a singleprocedure that can uniformly assess the thrombusload in the iliac, caval and pulmonary circulation,which a duplex scan with its operator dependencycannot achieve.24

Contrast can be potentially thrombogenic,nephrotoxic or can give rise to allergic manifestations.Venography is not recommended as a screeningmethod but to be used in evaluating patients withhigh clinical suspicion of DVT and a negative

ultrasound, or in those patients with a non-diagnostic ultrasound who have had a previousDVT.

Pulmonary Angiography

Pulmonary angiography remains the gold standardfor diagnosis of PE. However, the test is invasive andcostly and has its side-effects.

Gold standard but increasingly less frequentlyperformed due to the widespread availability ofCT.

Complication rate is 1.6% (0.3 mortality- mainly incritically ill patients).

False positive have been reported in: malignancy,sarcoid, Takayasus arteries and angiosarcoma.

DRUGS AFFECTING COAGULATIONClassification

1. Anticoagulants drugs

- Parenteral: Low Molecular Weight Heparin(LMWH), Unfractionated Heparin (UFH).

- Oral: Warfarin etc.

2. Antithrombotic drugs: Acetyl Salicylic Acid(Aspirin), Dipyridamole, Ticlopidine etc.

3. Thrombolytic drugs: Streptokinase, Urokinaseetc.

4. Newer anticoagu lant drugs: Fondaparinux,Idraparinux etc.

Un-fractionated Heparin

Standard Un-fractionated heparin (UFH) is highlysulfated glycosoaminoglycan that is partially purifiedfrom porcine intestinal mucosa. Its molecular weightranges from 3000 to 40,000 and averages 15,000.

UFH acts primarily by binding to antithrombin III,an enzyme that inhibits the coagulation factor thrombin

(factor IIa), Xa, IXa, XIa and XIIa. UFH however does notdirectly dissolve the thrombi that already exist.

The efficacy of UFH is limited because clot boundthrombin is protected from heparin-antithrombin IIIinhibition. Its resistance can occur because UFH bindsto plasma proteins.

An aPTT that is at least one and one half times greater

than the control value should provide a minimumtherapeutic level of unfractionated heparin.

The UFH requires monitoring due to its unpredictablepharmacokinetics and narrow therapeutic range.This is performed conventionally with the activatedpartial thromboplastin time (aPTT). However, the dosegenerally used to prevent VTE in high risk patients doesnot prolong the aPTT and therefore obviates the needfor monitoring.

Low Molecular Weight Heparin (LMWH)

These are manufactured from standard unfractionatedheparin by chemical or enzymatic depolymerizationthat yields fragments about one-third the size ofunfractionated heparin. LMWH is selective inactivatorof factor-Xa and IIa. The longer plasma half life andmore predictable anti-coagulant response of LMWHpreparations allow their administration as fixed dose,once daily or twice daily subcutaneous injectionswithout need for laboratory monitoring.

Benefits of LMWH

The introduction of LMWH has been revolutionaryfor the initial treatment of VTE. When compared withHeparin, LMWH exhibits greater bioavailability aftersubcutaneous injection, has a longer half-life andproduces more predictable anticoagulation. LMWHcan be safely given subcutaneously once or twice daily,without coagulation monitoring. Meta-analysis of trialscomparing subcutaneous intravenous heparin for initialtreatment of VTE has shown that LMWH is as effectiveas heparin.33 Two more meta-analysis and randomizedtrials have confirmed that LMWH is at least as effectiveand safe as UFH for treatment of VTE.34

Besides being convenient to use, LMWH is ideallysuited for OPD treatment of VTE, an approach whichreduces health care costs and improves patientsatisfaction and compliance.35

After more than three months of initial anticoagulanttherapy, case fatality rates for recurrent VTE is about 10%after PE and 5% after DVT. The case fatality rate withmajor bleeding during long term anticoagulant therapyfor VTE is about 10%.

Various LMWH products differ in their methodsof preparation, mean molecular weight and theiranticoagulant effects. This was seen by measuring theratio of anti factor Xa to anti factor IIa (thrombin activity).The anti Xa assay is commonly used for monitoringLMWH but its clinical relevance is in doubt.36


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In the absence of trials which would comparedifferent LMWH preparations, it is unclear whetherthese differences are clinically important.37

Comparability of Various Preparations of LMWH

Although LMWH have similar mechanisms of action,their molecular weight distributions vary (Table 5)causing differences in their inhibitory activities against

factor Xa and thrombin, their plasma protein binding

and their plasma half lives.38,39

All these studies suggest that LMWH with similarweight profiles and hence similar specific activitiesare equally effective for prophylaxis as well as fortreatment of DVT. The Tables 5 and 6 show the approvedregulatory indications and dosages for the differentLMWH available in India. The readers are referred to the

product inserts for further details of each compound.

Table 5 : Current established LMWH regimens for thromboprophylaxis

Indications Dalteparin Enoxaparin Nadroparin Parnaparin Fondaparinux(Fragmin) (Clexane) (Fraxiparine) (Fluxum) (Arixtra)

General Surgery 2500 IU s.c., 1-2 hrs 2000-4000 IU s.c., 2850 IU (0.3 ml) 3200 IU s.c. 2 hrs 2.5mg s.c., once(Mod. Risk) pre-op and once daily 1-2 hrs pre-op and s.c., 2 hrs pre-op pre-op, and 3200 IU daily not before

post-op for 5-7 days once daily post-op and once daily once daily post-op 6 hrs post op foror longer for 7-10 days post-op for 7 days for 7 days 72 days or until

or till ambulation the patient isambulant

General Surgery 5000 IU s.c., 8-12 hrs 4000 IU s.c., 12 hrs 2850 IU (0.3 ml) s.c., 4250 IU s.c., 12 hrs 2.5mg s.c., once

(High Risk) pre-op and once daily pre-op and once 2-4 hrs pre-op and pre & post-op and daily not beforepost-op for 5-7 days daily post-op once daily post-op then 4250 IU once 6 hrs post op for

or longerAlternatively, for 7-10 days for 7 days or daily for 7 days 72 days or until2500 IU s.c. 1-2 hrs till ambulation the patient ispre op and 8-12 hrs ambulantpost op. 5000 IU s.c.OD after that for5-7 days or longer

Orthopedic 5000 IU s.c., 8-12 hrs 4000 IU s.c., 12 hrs 38 IU/kg (0.2 to 4250 IU s.c.12 hrs 2.5mg s.c., onceSurgery pre-op, at 12-24 hrs pre-op and once 0.4 ml) 12 hrs pre pre & post-op daily not before(High Risk) post-op then OD for daily post-op and post op, then and then 4250 IU 6 hrs post op for

5-10 days or 2500 IU for 3 weeks OD till D3 and once daily for 72 days or until4- 8 hours after surgery 57 IU/kg (0.3- at least 10 days the patient ison day 1 and 5000 IU s.c. 0.6 ml) from D4, ambulantonce daily from day 2 OD for maximum

of 10 days

Medical Patients 5000 IU of dalteparin 4000 IU s.c., and 2.5mg s.c., once

(High Risk) s.c. once daily, for 12 once daily for daily for 6 14to 14 days or longer 6-14 days max, daysin patients with or till ambulationcontinued restrictedmobility

Other Indications During Hemodialysis During Hemodialysis During Hemodialysisand Hemofiltration Unstable Angina Unstable Angina Unstable Angina and non-Q wave and non-Q waveand non-Q wave myocardial infarction myocardial infarctionmyocardial infraction

Where no regimen is shown the corresponding indication has not been specifically tested with the corresponding LMWH. Usually the regimenstated under General surgery is then used

Refer to the manufacturers guidelines for details of administration and approved dosages in each indication.

Table 6 : Current established LMWH regimens for treatment of DVT

Dalteparin Enoxaparin Nadroparin Parnaparin Fondaparinux(Fragmin) (Clexane) (Fraxiparine) (Fluxum) (Arixtra)

100 IU s.c. twice or 200 100 IU/kg, s.c., twice 85 IU/kg 6,400 IU s.c., twice Body weight adjustedIU/kg s.c once a day daily. daily or 150 IU/kg (0.1 ml/10kg) , s.c., daily for at least dosage s.c. once dailySimultaneous anticoagulation s.c. once daily for a twice daily for a 7-10 days. After for at least 5 days andwith oral vitamin-K antagonists maximum of 10 days, usual duration of acute phase 4250- until adequate oralcan be started immediately. until therapeutic 10 days, until 6400 IU/day s.c. anticoagulation isContinue combined treatment anticoagulation therapeutic for further achieved.[5 mg foruntil the prothrombin complex (INR 2-3) has been anticoagulation 10-20 days body wt < 50 kg,tests have reached therapeutic achieved with oral has been achieved 7.5 mg for body wtlevels (usually at least 5 days). anticoagulation therapy with oral anticoagulant 50 to 100 kg, 10mg

therapy for body wt > 100 kg]

Refer to the manufacturers guidelines for details of administration and approved dosages in each indication.


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All LMWHs are different molecules and henceavailable evidence with each LMWH in a particularindication, approved regulatory status may be consideredbefore usage in a particular condition. The US FDA alsoconsiders each of these molecules to be independent andseparate drugs and not as one general group of drugs.Date of one LMWH should not be extrapolated to allothers in absence of any such evidence. The tables showall the LMWHs in question along with their approvedregulatory indications in India.

Cost Effectiveness

In North America, LMWH is 10-20 times moreexpensive than UFH.40 Accordingly from an economicpoint of view, it is difficult to justify its routine usein practice but it has been seen that LMWH is moreeffective in orthopedic surgery.41 It has also been seenthat LMWH does not cross placenta and descriptivestudies suggest that they are both safe and effective inpregnancy.42 Despite its high cost, LMWH is generally

preferred over UFH because LMWH is associated withlower incidence of HIT and probably osteoporosisduring long term use.43,44 The above results justify theroutine use of LMWH whenever indicated. Outcomeresearch studies have shown that although acquisitioncost of LMWH is higher than that of UFH, in terms ofoverall cost, LMWH is more cost effective.

The use of LMWH to treat selected patients with VTEoutside the hospital has the potential to dramaticallyreduce the cost of health care. There is need for furtherstudy in this regard to see the cost effectiveness of theuse of LMWH.

Fewer patients require treatment for postoperativeVT, thereby explaining why the analysis of costeffectiveness favors LMWH over UFH or Warfarin.

COMPLICATIONS OF HEPARINBleeding

The major complication of Heparin is bleeding andthis limits its extensive use especially in this part of theworld. Factors that predispose to increased bleeding riskinclude advanced age, serious concurrent illness, heavyconsumption of alcohol, concomitant use of aspirin andrenal failure.

Due to relatively short half life of unfractionatedheparin, simple discontinuation is usually adequate tocontrol bleeding complications.

Protamine-sulphate can be used in emergencysituations with serious bleeding. It is also effective inneutralizing the antithrombin activity of LMWH butdoes not completely reverse its anti Factor-X activity.

Heparin Induced Thrombocytopenia (HIT)

Two distinct types of thrombocytopenia are associatedwith heparin therapy, which are the non-immune

variety and the immune variety of thrombocytopenia.The dose dependent, non immune mediated type ofthrombocytopenia rarely causes severe reduction in theplatelet count or clinical complications and usually doesnot require discontinuation of Heparin.

The immune form of HIT can cause serious limb andlife threatening arterial as well as venous thrombosis. In

HIT, there may be absolute or relative thrombocytopeniaand it begins usually at least 4 days after initiation oftherapy. It may be usually 50,000 to 60,000/cu mm.However, HIT can cause severe thrombocytopeniaeven in the absence of thrombosis, Heparin inducedthrombosis can actually occur with a normal plateletcount. Immune mediated HIT can develop with lowdose heparin also.

Diagnosis of HIT

HIT remains a clinical diagnosis supported bylaboratory testing. The laboratory testing involvesfunctional assay and enzyme immunoassay of antibody

to heparin-platelet-factor-4 complexes.Management of HIT

i) Discontinue and avoid all heparin.

ii) Give a nonheparin alternativeanticoagulant suchas pentasaccharide (Fondaparinux).

iii) Test for HIT antibodies.

iv) Investigate for lower-limbdeep-vein thrombosis.

v) Avoid prophylactic platelet transfusions.

Other Side Effects of Heparin

These are dose dependent osteoporosis, skinnecrosis, alopecia, hypersensitivity reactions andhyperaldosteronism.

Advantages of LMWH over UFH

- Dose-independent clearance.

- Predictable anticoagulant response.

- No need for therapeutic monitoring apart fromplatelet counts.

- Less potential for adverse effects (decreasedbleeding potential, less thrombocytopenia, lessosteopenia).

Warfarin

It is the most frequently used oral anticoagulant. Thisis a derivative of coumarin and exerts its anti-coagulantaction as vitamin K antagonist.

Monitoring of Warfarin

The optimal therapeutic range of warfarin for theprevention of VTE and symptomatic embolism fromatrial fibrillation and tissue heart valves targets an INRof 2.0 3.0. Higher intensity anti-coagulation (INR 2.5 3.5) is required in patients with mechanical prostheticheart valves. Although warfarin has a rapid action, its


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optimal anti-thrombotic effect requires several days.So, the initial therapy is started with Heparin and thenswitched over to warfarin.

Complications

Skin necrosis may occur within the first few days butit is very rare. As with Heparin, bleeding complicationsare the most common adverse effects. It is related to the

intensity and duration of the anti-coagulant therapy.Major bleeding on warfarin occurs at a rate of 5 to 7%per year.44

NEWER ANTICOAGULANTSFondaparinux

I t i s a chemica l ly synthes ized methoxyderivative of naturally occurring anti-thrombinbinding pentasaccharide. It acts by a catalytic effectfacilitating anti-thrombin binding to activated factorX. It is administered by subcutaneous injection, and itselimination half life of 17 to 21 hours allows a once daily

dose. It does not bind platelets or platelet factor 4, sothere is no associated HIT. There is no known antidotefor reversing anticoagulant effects of Fondaparinux.

Idraparinux

This is a second generation pentasaccharide. It ismore negatively charged than Fondaparinux. It has avery long half life so it is administered subcutaneouslyon a once weekly basis. It has excellent bioavailabilityso routine coagulation monitoring is not required.46

MECHANICAL METHODS OF PROPHYLAXISMechanical methods of antithrombotic prophylaxis

are aimed at an increasing mean blood flow velocity inleg veins and reduce venous stasis. They include:

1. Graduated elastic compression stockings (GECS).

2. Intermi ttent pneumati c compression (IPC)devices.

3. Mechanical foot pumps and Foot impulsetechnology.

There are few trials of mechanical methods in medicalpatients. Unlike pharmacological methods, mechanicalmethods do not increase the risk of bleeding and maybe preferred in patients in whom bleeding risks may

outweigh the antithrombotic efficacy of pharmacologicalprophylaxis. Mechanical methods are contraindicatedin patients at risk of ischemic skin necrosis, e.g.those with critical limb ischemic or severe peripheralneuropathy.47,48 Cross-infection is a risk when devicesare re-used.

1. Graduated Elastic Compression Stockings (GECS)

GECS are commercially available as both below-knee and above-knee stockings. Most controlled trialshave used above-knee stockings.48,49,8,50-52 Studiescomparing above-knee and below-knee stockings havebeen too small to determine whether or not they are

equally effective.53-56 Hence current evidence supportsthe preferential use of above-knee stockings unlesscontraindicated (e.g. thigh circumference >81 cm,incontinence).

How to apply a compression stocking:

The stocking should be put on early in the morningpreferably before the start of the swelling.

The leg must be dry.

Sitting or lying down are the best positions to adoptwhen putting on compression stockings.

The use of rubber gloves helps protect against tearsand makes it easier to pull on.

Contraindications and cautions for use of GECS

Contraindications: Massive leg edema, pulmonaryedema, severe peripheral arterial disease, severeperipheral neuropathy, major leg deformity, dermatitisetc.

Cautions : Correct sizes, aligning toe hole under the

toe, avoid folding, not to be worn in bed.The efficacy of GEC in prevention of post operative

DVT was studied in randomized, prospective controlledtrial of 200 patients, aged 40 years and above, undergoingabdominal surgery. It was concluded that GEC provideda safe and effective method of prophylaxis againstDVT.57

2. Intermittent Pneumatic Compression (IPC)devices

IPC devices periodically compress the calf and/orthigh muscles of the leg (inflation pressures 35-40mmHg at about 10s/min)8,50 and stimulate fibrinolysis.58Compression devices are usually applied immediatelybefore or during surgery and are often replaced by GECSfollowing surgery as they can cause discomfort in theconscious patient.

Caution: Not to be used in the presence of DVT.

3. Mechanical Foot Pumps and Foot ImpulseTechnology (FIT)

The A-V impulse system foot pump has beendeveloped to provide mechanical prophylaxis inpatients who are unable to weight bear and has onlybeen used in orthopedic surgery.

RCT data suggest efficacy in prevention ofasymptomatic DVT.59-68 There is no evidence that thesedevices reduce symptomatic DVT or PE. Skin necrosishas been reported and discomfort from the device canlead to poor compliance.67 Compliance issues associatedwith the use of mechanical methods are a limiting factorin their use. These methods are especially useful inpatients who are at high risk of bleeding. These may alsobe used in combination with anti-coagulant prophylaxisto improve efficacy.48

Caution: Not to be used in the presence of DVT.


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OPINION OF VTE EXPERT GROUPREGARDING SUGGESTIONS FOR

PREVENTION AND MANAGEMENT OFVTE 2006

Suggestions

Obstetrics

Incidence in Pregnancy

The incidence of thromboembolic complications inpregnancy is under-estimated and varies between twoand five per 1000 deliveries, in published reports.69

Pregnancy and VTE

Venous Thrombosis in Pregnancy

Certain physiological changes of pregnancy whichpredispose to thrombosis are:

Increase in several plasma proteins concerned withclotting.

Increase in levels of fibrinogen, factor VII, VIII andIX.

Changes in Protein S and Protein C, which arenatural inhibitors of blood coagulation.

The pathogenesis of thrombosis in pregnancy istherefore most likely to be a product of the increasedtendency to venous thrombosis in lower limbs.This combined with a shift in the balance betweencoagulation and fibrinolysis, towards enhancedcoagulation and diminished fibrinolysis, encouragesthrombus growth.

Clinical Features

The normal discomforts of pregnancy can oftenmimic the symptoms of leg vein thrombosis. Legcramps, swelling of ankles, slight cyanosis of the legsand an increased prominence of the superficial veinson standing are often seen especially in late pregnancy.Venous Thrombosis when present will almost invariablycause more symptoms in one leg than the other andusually is in the left leg. The diagnosis of DVT is almostcertain when physical signs of calf tenderness andinduration of calf muscles with unilateral edema andincreased skin temperature of the leg are present.

In the early stages, even extensive thrombi are often

asymptomatic and their presence may first be suspectedwith occurrence of Pulmonary Embolism.

The symptoms and signs of PE are predominantlyassociated with cardiovascular and respiratory systems.The immediate effects vary from clinically silent tosudden death and depend on the condition of the patientand the size of embolus.

The clinical diagnosis of both VTE and PE in pregnancyis subject to error, and whenever possible, objective

diagnostic techniques like Duplex Ultrasonographyshould be used.

Diagnostic Requirements for treatment suggest acombination of clinical and ECG evaluation along withduplex scan. MRA in selected cases can be resorted toin life threatening situations.

Since all hospitals do not have the same facilities andexpertise, management of patients with VTE or PE ina specific manner is not possible. The approach shouldbe based on urgency of diagnosis and availability of thediagnostic procedures.

Common Suggestions to the Patient

Emphasize on pelvic rest (no intercourse) and notabsolute bed rest.

The pregnant woman lying on her back in latepregnancy is likely to aggravate venous stasis inthe legs due to the compression of the vena cava.She may be advised to rest on one side and noton her back. Venous return from the lower limbsis encouraged by elevation of the feet by 15 to 20cm.

Exercises of the affected leg promote developmentof collateral venous channels and are likely tobe major factors in preventing long term venousinsufficiency.

Early mobilization is mandatory.

Adequate hydration.

Risk category stratification for obstetric patients isindicated in Table 7.

Suggestions

All women may undergo an assessment of riskfactors for VTE before or in early pregnancy.This assessment may be repeated if the woman isadmitted to hospital or develops other intercurrentproblems (Grade C).

Women with previous VTE or a strong familyhistory of VTE may be screened for inherited and

Table 7 : Risk category stratification for obstetric patients

Category Frequency of Obstetrics*Calf Vein Proximal Vein Fatal PE (%)

Thrombosis(%) Thrombosis(%)

High Risk 40-80 10-30 >1 History of DVT/PE, Thrombophilia

Moderate Risk 10-40 1-10 0.1-1 Age>40 years

Low Risk


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acquired thrombophilia ideally before pregnancy(Grade C).

Regardless of the risk of VTE, immobilization ofwomen during pregnancy, labor and the puerperiumshould be minimized and dehydration should beavoided. Emphasis is on early ambulation and notbed rest.

Women, with previous recurrent VTE, or a previousVTE and a family history of VTE in a first degreerelative, may be offered thromboprophylaxis withLMWH in antenatal period and for at least 6 weekspostpartum (Grade B).

For women with recurrent pregnancy loss (three ormore miscarriages) and women with prior severeor recurrent pre-eclampsia, abruptions or otherwiseunexplained intrauterine death, screening forcongenital thrombophilia is suggested.

Patients with APS and no prior VTE or pregnancyloss may be considered to have an increased

risk for development of venous thrombosis andperhaps pregnancy loss. Any one of the followingapproaches is suggested:

- Low dose aspirin 75 150 mg/day.

- Surveillance.

- Prophylactic LMWH.

- Mini dose of UFH.

For pregnant patients with antiphospholipidsyndrome (APS) and a history of multiple (twoor more) early pregnancy losses or one or morelate pregnancy losses, pre-eclampsia, intra-

uterine growth retardation (IUGR) or abruption,administration of ante-partum aspirin plus a minior a moderate dose UFH or prophylactic LMWH issuggested (Grade B).

For women who are homozygous for thermo labilevariant of MTHFR, folic acid supplement priorto conception or if already pregnant, as soon aspossible and throughout pregnancy is suggested.

For women with congenital thrombophilic deficitand recurrent miscarriages, a second trimesteror later loss, severe or recurrent pre-eclampsia orabruption, low dose aspirin therapy plus either

mini dose UFH or prophylactic LMWH therapy,antenatal and postpartum for a period of 6 weeksis suggested.

Women in whom a previous VTE is estrogen related[pregnancy or the Combined Oral Contraceptive(COC)] or additional risk factors such as obesity arepresent, may be started with thromboprophylaxiswith LMWH as early as possible in pregnancy(Grade C).

Women with three or more persisting risk factorsmay be considered for thromboprophylaxis withLMWH, antenatal and for 3 to 5 days postpartum.

Women may be reassessed before or during laborfor risk factors for VTE. Age over 35 years andBMI greater than 23-25/body weight (greater than70 kg) are important independent risk factors forpostpartum VTE even after vaginal delivery. Thecombination of either of the risk factors with anyother risk factor for VTE, with the presence of twoother persisting risk factors may lead clinicians toconsider use of LMWH for 3-5 days postpartum.

For women requiring long term oral anticoagulanttherapy who are attempting pregnancy, the groupsuggested substituting UFH or LMWH for warfarinas soon as pregnancy is achieved.

Treatment of VTE during pregnancy

In women with acute VTE, the group suggestseither low dose LMWH throughout pregnancy orintra venous UFH for at least 5 days, followed byadjusted dose of UFH or LMWH for the remainderof pregnancy. Anticoagulants may be administered

for at least 6 weeks postpartum.70

In women receiving adjusted dose of LMWH orUFH therapy, heparin may be discontinued 24 hoursprior to labor (Grade C).

Placement of infra-renal IVC filter (preferablyretrievable) under duplex sonographic control canbe resorted to in dire emergencies.

In women with prosthetic heart valve, the groupsuggests

Adjusted dose of LMWH 12 hourly throughoutpregnancy in doses adjusted either to keep a 4 hourpost-injection anti Xa level at approximately 1 to 1.2u/ml or according to weight.

Adjusted dose of UFH throughout pregnancy whichis administered 12 hourly, in doses adjusted to keepthe mid interval aPTT at least twice control.

UFH or LMWH until the thirteenth week, changeto warfarin until the middle of the third trimesterand then restart UFH or LMWH (Grade C).

Long-term anticoagulant may be resumedpostpartum with all regimens.

In women with prosthetic valves at high risk, thegroup suggests the addition of low dose aspirin, 75

to 150 mg/d.Delivery and the Puerperium

For delivery by elective caesarean section, thewomen may receive a thromboprophylactic doseof LMWH on the day before delivery (Grade C).

On the day of delivery, the thromboprophylacticdose of LMWH may be given three hours post-operatively or 4 hours after removal of the epiduralcatheter (Grade C).

Where anticoagulants are contraindicated, GECstockings may be worn for at least 6 weeks following

delivery and may be combined with 75mg of aspirin


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daily (Grade C).

Breast feeding is not contraindicated with eitherLMWH, unfractionated heparin or warfarin (GradeB).

Advice on Preventing DVT for Pregnant WomenTraveling by Air

There is no data available to reach an evidence based

analysis of the risk of travel related VTE in pregnancy.However, the risk of travelers thrombosis is furtherincreased in pregnant women. The risk is greatest inthose who have previous history of VTE and/or aresuffering from thrombophilia.

The group suggests:

Calf exercises.

Ambulation inside aircraft.

Avoidance of dehydration.

Pregnant women are suggested to wear properlyfitting elastic compression stockings for long travel

time (>4 hours duration) flights or for all flights ifthey have additional risk factors or

LMWH may be given for pregnant women atincreased risk who are taking long flights on theday of travel and the day after.

Hormone Replacement Therapy (HRT) and VTE

All women commencing Hormone ReplacementTherapy (HRT) may be counseled about the riskof VTE. This will make them aware of signs andsymptoms of VTE and enable them to accessmedical help as soon as possible, if they suspectthat they have developed thrombosis.

Universal screening of women for thrombophilicdefects prior to or continuing the prescription ofHRT was suggested inappropriate.

HRT may be avoided in women with multiple pre-existing risk factors for VTE.

Selective estrogen receptor modulators may beconsidered to carry the same risk of thrombosis as

estrogen containing HRT.

HRT may be considered a risk factor for VTEwhen assessing women pre-operatively. However,HRT does not require to be routinely stoppedprior to surgery provided that appropriatethromboprophylaxis such as low dose LMWH,with or without thromboembolic deterrent stocking

is given.

GYNECOLOGIC SURGERYRisk category stratification for gynecology patients

is indicated in Table 8.

Suggestions

Low Risk: For patients undergoing majorgynecological surgery for benign disease withoutadditional risk factors, the group suggests againstthe use of specific prophylaxis other than early andpersistent mobilization and adequate hydration.

Moderate Risk: Thromboprophylaxis with LDUH

(5000 units twice a day) or LMWH (according tomanufacturers instructions), till the patient isambulatory (Grade A). IPC used continuouslymay also be considered (Grade A). Adjusted dosewarfarin may have a role when low dose heparin iscontraindicated, for eg: in HIT, but is not suggestedfor routine prophylaxis (Grade A).

High Risk: The group suggests LMWH (high riskdaily dose as per manufacturers instructions)(Grade A), LDUH (5000 units 8 hourly) (Grade A) orIPC (throughout hospital stay) (Grade B) or LMWHor low dose unfractionated heparin (LDUH) + IPC

or GEC for optimal prophylaxis (insufficient dataavailable for grading).

Higher Risk: The group suggested continuation ofprophylaxis may be continued for 2-4 weeks afterhospital discharge (to be decided on individualbasis) (Grade C).

Hematology

Asymptomatic patients with congenital thrombophilia

Table 8 : Risk category stratification for gynecology patients

Category Frequency Of GynecologyCalf Proximal Vein Fatal PE (%)

Thrombosis (%) Thrombosis (%)Major gynecological surgery, age>60*

High Risk 40-80 10-30 >1 Major gynecological surgery, age 40-60 &cancer or history of DVT/PE, thrombophilia

Major gynecological surgery, age 40-60Moderate Risk 10-40 1-10 0.1-1 Major gynecological surgery, age60

Minor gynecological surgery, age


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do not require thromboprophylaxis as a routine butmay be protected during surgery or in presence of anymedical condition associated with an increased risk ofthrombosis.

Thromboprophylaxis may be done by thefollowing:

Use of LMWH starting preoperatively andcontinuing once a day till ambulation.

UF heparin 5000 U given 1-2 hrs pre-op and thenQ8H Q12H post operatively.

D-dimers done on 7th day (discharge time) and 28thday (review time).

MEDICAL CONDITIONSRisk category stratification for medical patients is

indicated in Table 9.

Suggestions

The group suggests prophylaxis with LDUH orLMWH (Grade A) for patients with

Acute medical illness.

Admitted with congestive cardiac failure orsevere respiratory disease.

Bed confinement and one or more additionalrisk factors like Cancer, previous VTE, sepsis,acute neurological disease or inflammatorybowel disease.

Alternately, GECs or IPC may be considered incases of active bleeding or if anticoagulant iscontraindicated in patients with risk factors for VTE(Grade C).

CRITICAL CARESuggestions

LDUH or LMWH for high risk or moderate riskpatients (Grade A).

For patients where anticoagulants are contraindicated,GEC stockings with IPC may be considered asalternatives (Grade C).

In absence of contraindications, combined LDUHor LMWH with GECs/IPC may be advised (GradeC).

ORTHOPEDIC SURGERY

Elective Hip Replacement

Suggestions

The group suggested routine use of the following:

1. LMWH.

2. Fondaparinux.

3. Adjusted oral anticoagulant therapy.

4. IPC or FIT with GEC in certain patients with risk ofbleeding.

LMWH The high risk dose of LMWH may start 12hours before surgery or 12 to 24 hours after surgeryor 4-6 hours after surgery at half dose and then theusual high risk dose the following day (Grade A).

Fondaparinux Pentasaccharide, which is anindirect inhibitor of factor Xa, (2.5mg) started 6-8hours after surgery (Grade A).

Adjusted dose of oral anticoagulant started pre-operatively or evening after surgery (INR target 2.5or range 2-3) (Grade A).

Prophylaxis may be initiated either before or after

operation depending upon adopted regime andmay be continued 4-6 weeks with LMWH (GradeA) or Pentasaccharide (Grade C).

Recombinant Hirudin is approved for short-termprophylaxis and may be used in patients with HIT(Grade A).

The group suggests against the use of Aspirin,Dextran, LDUH, GEC, IPC or venous foot pump(VFP) as the only method of thromboprophylaxisin these patients (Grade A).

ELECTIVE KNEE REPLACEMENT

Suggestions Routine thromboprophylaxis using LMWH or

Fondaparinux or adjusted dose VKA (Grade A).

IPC or foot impulse technology + GEC are analternative option but more studies are needed(Grade B).

Use of any sole method of thromboprophylaxiswith aspirin, LDUH or Venous Foot Pump is notsuggested (Grade A).

HIP FRACTURE SURGERY (HFS)The group suggests the following:

Table 9 : Risk category stratification for medical patients

Category Frequency Of Medical PatientsCalf Vein Proximal Vein

Thrombosis (%) Thrombosis (%) Fatal PE (%)

High Risk 40-80 10-30 >1 Stroke, Age > 70Congestive cardiac failure

Moderate Risk 10-40 1-10 0.1-1 Shock, History of DVT/PEThrombophilia

Immobilized patient with active diseaseLow Risk


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LMWH (Grade A).

Fondaparinux (Grade A).

Adjusted dose VKA (INR range 2-3) (Grade A).

LDUH (Grade A) (Grade A).

IPC or FIT + GEC may be used when there arecontraindications to anticoagulants (Grade C).

Aspirin alone was not suggested (Grade A). If surgery is likely to be delayed, prophylaxis with

LMWH or IPC or FIT plus GEC be initiated duringtime between hospital admission and surgery(Grade C).

KNEE ARTHROSCOPYSuggestions

Routine prophylaxis is not suggested (Grade B).

High risk or prolonged surgery patients LMWHmay be given and continued until full ambulation(Grade B).

OTHER PROPHYLAXIS ISSUES IN MAJORORTHOPEDIC SURGERY

Suggestions

Timing of prophylaxis initiation

The decision of timing of prophylaxis may be basedon efficacy to bleeding tradeoffs for that particularagent. For LMWH, pre operative or post operativeinitiation, are advised (Grade A).

Duration of prophylaxis

The group suggested that patient undergoing TotalHip Replacement, Total Knee Arthroplasty or HFSreceive prophylaxis with LMWH (using a high riskdose), Fondaparinux (2.5mg OD) or a VKA (targetINR range 2-3) for at least 10 days (Grade A).

Extended prophylaxis may be given for 28 to 35days after surgery to patients undergoing THR orHFS (Grade A).

Recommended options for extended prophylaxis inTHR:

LMWH (Grade A).

VKA (Grade A).

Fondaparinux (Grade C).

Recommended options for extended prophylaxis inHFS:

Fondaparinux (Grade A).

LMWH (Grade C).

VKA (Grade C).

ISOLATED LOWER EXTREMITIES INJURIESSuggestions

The group did not suggest thromboprophylaxisroutinely in patients with isolated lower extremity

injuries (Grade A).

MULTIPLE TRAUMASSuggestions

The group suggested that all trauma patientswith at least one risk factor for VTE receivethromboprophylaxis, if possible (Grade A).

They also suggested LMWH, starting as soonas bleeding risk is acceptable (Grade A) or IPCin presence of contraindications to LMWH andcontinued until full ambulation (Grade B).

The group suggested against the use of IVC filtersas primary prophylaxis in trauma patients (GradeC).

The group suggested the continuation ofthromboprophylaxis until hospital discharge,including the period of inpatient rehabilitation(Grade C). Continuing prophylaxis after hospitaldischarge with LMWH or a VKA (target INR, 2.5;

INR range 2-3) in patients with major impairedmobility was suggested (Grade C).

ACUTE SPINAL CORD INJURIES (SCI)The group agreed to the following suggestions

Thromboprophylaxis to be provided to all patientswith acute SCI (Grade A).

Prophylaxis with LMWH in combination with IPCand /or GEC (Grade C).

IPC and/or GEC is to be used when anticoagulantprophylaxis is contraindicated (Grade C).

They suggested against the use of LDUH, GEC, orIPC as single prophylaxis modalities (Grade A).

The also suggested against the use of an IVC filtersas primary prophylaxis (Grade A). Prophylaxis maybe done only during hospitalization.

GENERAL SURGERYRisk category stratification for General Surgery

patients is indicated in Table 10.

Suggestions

Low Risk : The group suggested against the use ofspecial prophylaxis other than early and persistentmobilization (Grade C).

Moderate Risk : LDUH 5000 units commencedpre-operatively and continued twice or thricedaily or, LMWH (according to manufacturerrecommendations for moderate risk patients)(Grade A).

High Risk : LDUH 5000 units commenced pre-operatively and continued post operatively threetimes a day (Grade A) or LMWH commencedpre-operatively and continued post operatively(According to manufacturers recommendations)

(Grade A). Both may be combined with mechanical


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methods (GEC or IPC) (Grade B).

IPC with GEC compression may be used as analternative method for patients at risk for or withactive bleeding, until total ambulation (Grade A).

In selected high risk general surgery patientsincluding those who have undergone major cancersurgery, the group suggested post hospital dischargeprophylaxis with LMWH (Table 11). 71 This may bedecided on individual basis (Grade A).

In majority of the studies, the duration of prophylaxis

has been 5-7 days but extended prophylaxis may bedone for selected patients.

UROLOGICAL SURGERYSuggestions

The group suggested routine prophylaxis withLDUH twice or three times daily for patientsundergoing major, open urologic procedures (GradeA).

The group suggested against the use of specificprophylaxis other than early and persistentmobilization for patients undergoing transurethral

or other low risk urologic procedures (Grade C).

For actively bleeding patients or patients at highrisk of bleeding, the group suggested the use of GECand/or IPC at least until bleeding risk decreases(Grade C).

VASCULAR SURGERYSuggestions

In patients undergoing vascular surgery who donot have additional thromboembolic risk factors*,

routine use thromboprophylaxis was not suggested(Grade B).

For patients undergoing major vascular surgicalprocedures who have additional thromboembolicrisk factors*, prophylaxis with LDUH or LMWH(Grade C) may be given.

* Potential thromboembolic risk factors in vascular surgeryinclude advanced age, limb ischemia, long duration of surgery, and

intraoperative local trauma, including possible venous injury.

IVC Filters

The two major indications of placement of IVC filtersare:

Table 10 : Risk category stratification for general surgery patients

Category Frequency Of General Surgery

Calf Vein Proximal Vein Fatal PE (%)Thrombosis (%) Thrombosis (%)

Major general surgery, age > 60High Risk 40-80 10-30 >1 Major general surgery, age 40-60 & cancer or

history of DVT/PEThrombophilia

Major general surgery, age 40-60 without

other risk factors*Minor surgery, age > 60Moderate Risk 10-40 1-10 0.1-1 Minor surgery, age 40-60 with history of

DVT/PE or on estrogen therapy

Major general surgery, age < 40,Low Risk


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1. Major hemorrhage that precedes anti-coagulationand

2. Recurrent PE despite well documented adequateanticoagulation.

An IVC Filter prevents PE, not DVT.72 Patients withfilters after an initial PE are more than twice as likelyas non-filter patients to require re-hospitalization for

DVT. Therefore, when a filter is inserted, anticoagulantsmay also be used, whenever possible, to preventfurther thrombosis. Some patients have an immediatecontraindication to anti-coagulation, but the durationof this contraindication is uncertain. Under thesecircumstances, placement of a non-retrievable filter maybe appropriate.

They can also be used for a few days only becauseof concern for infection at the insertion site. Retrievablefilters can be left in place for 10-14 days or permanentlyif necessary for a trapped large clot or a persistentcontraindication to anti-coagulation.

REGIONAL ANESTHESIA IN THEANTI-COAGULATED PATIENTS

Suggestions

Combining neuraxial techniques with intra-operativeanti-coagulation with heparin during vascular surgerywas acceptable to the group with the followingcautions:

The technique in patients with other coagulopathiamay be avoided.

Heparin administration may be delayed for 1 hour

after needle placement. In-dwelling neuraxial catheters may be removed 2-4

hours after the last heparin dose and the patientscoagulation status is evaluated; re-heparinizationmay occur one hour after catheter removal.

Patient to be monitored post-operatively toprovide early detection of motor blockade and useof minimal concentration of local anesthetics toenhance the early detection of a spinal hematomamay be considered.

Pre-operative LMWH

P a t i e n t s o n p r e - o p e r a t i v e L M W Hthromboprophylaxis can be assumed to have alteredcoagulation. In these patients, needle placementmay occur at least 10-12 hours after LMWH dose.

Post-operative LMWH

The first dose of LMWH may be administeredno earlier than 24 hours (if twice daily dosage),postoperatively, regardless of anesthetic techniqueand only in presence of adequate surgicalhemostasis.

If OD dosage is to be given, then the first post-operative LMWH may be administered 6-8 hours

after surgery.

LAPAROSCOPIC SURGERYSuggestions

T h e g r o u p s u g g e s t e d a g a i n s t r o u t i n ethromboprophylaxis in these patients other thanaggressive mobilization (Grade A).

Those who are having additional risk factors,thromboprophylaxis may be given with LDUH,LMWH, IPC or GECs (Grade C).

NEURO SURGERYSuggestions

The group suggested that thromboprophylaxisbe routinely used in patients undergoing majorneurosurgery (Grade A).

The group suggested the use of IPC in all patientswith or without graduated compression stockings(Grade A). Addition of LMWH is associated withan increase of efficacy (Grade A) but use of LMWHis to be individualized as risk of bleeding is high.

CANCER SURGERYRisk factors for DVT in patients with cancer:

Chemotherapy.73

Hormonal therapy (e.g.: Tamoxifen in women).74,75

Surgery.76,77

Immobilization due to prolonged bed rest.78,79

Previous history of Thromboembolic event.6

Central venous catheter (CVC).80

Suggestions

In adult cancer patients who have been admittedor who are confined to bed and have one or moreadditional risk factors including chemotherapy, orsurgery, periods of immobilization, prophylaxiswith LDUH or LMWH was suggested (Grade A).Agent selection may be based on renal failure (Cr Cl< 30ml/ml) cost, ease of administration, monitoringand ability to reverse anticoagulation.

Group suggested appropriate anticoagulation (oralor parenteral) depending on affordability and

availability, for the long-term treatment of acuteVTE in cancer patients, and may be continued fora minimum of 3-6 months (Grade A).

In patients who are undergoing major cancer surgeryLDUH 5000 units commenced pre-operativelyand continued post operatively three times a day(Grade A) or LMWH commenced pre-operativelyand continued post operatively (According tomanufacturers recommendations) (Grade A). Bothmay be combined with mechanical methods (GECor IPC) (Grade B). The duration of prophylaxisneeds further study.


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In patients who have undergone major cancersurgery, the group suggested post hospital dischargeprophylaxis with LMWH. This may be decided onindividual basis. (Grade A).

The group suggests that clinicians not routinelyuse prophylaxis for long term indwelling CVCsin cancer patients (Grade B). It was specifically

suggested that clinicians not use LMWH, and fixeddose warfarin (Grade B) for this indication.

The Relative Contraindications to AnticoagulationTreatment

Recent central nervous system (CNS) bleed,intracranial or spinal lesion.

High risk for bleeding.

Active bleeding (major): more than 2 unitstransfused in 24 hours.

Chronic, clinically significant measurable bleeding> 48 hours.

Thrombocytopenia (platelets < 50,000/mcL). Recent major operation at high risk for bleeding.

BURNSSuggestions

The group suggested the use of LMWH (Grade C)as soon as it is considered safe to do so.

Burn patients with additional risk factors for VTEincluding one or more of following: advance age,morbid obesity, extensive or lower extremity burns,concomitant lower extremity trauma, use of femoralvenous catheter, and /or prolonged immobilitymay receive thromboprophylaxis, if possible (Grade C).

Long Distance Travel

10% of air travel passengers older than 50 yearsdevelop symptomless DVT during long flights.81,82

Suggestions

The group suggested the following general measuresfor long distance travelers by air where flight time>6 hours:

Avoid tight clothing (Grade C),

Avoid dehydration (Grade C), and

Perform frequent calf muscle stretchingexercises (Grade C).

For long distance travelers with additional riskfactors the group suggested either GEC or a singledose of LMWH injected prior to departure (GradeB).

The group did not suggest Aspirin for prophylaxis(Grade B).

ANTITHROMBOTIC DRUGS ANDNEURAXIAL ANESTHESIA

Suggestions

The risk of perispinal epidural hematoma may beincreased with concomitant use of antithrombotic drugswhile using neuraxial anesthesia or analgesia.

Removal of the epidural catheter, especially inpresence of an anticoagulant effect has also beenassociated with hematoma.

The Group suggests

Removal of epidural catheter when the anticoagulanteffect is at its minimum.

Anticoagulant prophylaxis may be delayed forat least 2 hours after removal of spinal needle orepidural catheter.

If prophylaxis with a VKA such as warfarincontinues, epidural analgesia may not be used forlonger than 1 or 2 days (INR should be 1.5

APTT >40 s

Platelet count


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patients.

9. Due to paucity of Oncology data in Indian context,the group strongly felt the need for appropriate

trials to study the following:a. Duration of post operative prophylaxis

b. The role oral anticoagulants in post opprophylaxis and therapy.

c. To form a registry of assessing relative risk ofVTE in different cancer patients.

Acknowledgements

Supported by an educational grant from Thrombosis Educationand Research Fund - TERF, under the auspices of the ThrombosisResearch Institute (TRI), London, U.K. This document is intendedto review the available Indian data and discuss the relevance ofInternational recommendations for prevention and management of

VTE in the Indian scenario. The development of this document isorganized under the auspices of the Thrombosis Research Institute(TRI), London, UK and supported by an educational grant fromThrombosis Education and Research Fund (TERF). We are gratefulto the following companies for their unconditional grant towards themeetings of the faculty: GlaxoSmithKline Pharmaceuticals Limited,Mumbai; Pfizer Limited, Mumbai; the Sanofi-Aventis Group, Mumbai.We also thank Alpcord Network for managing the Conference inOctober, 2005. We are thankful to Xcelerx Communications fordocumenting the discussions during the numerous meetings and forpreparing the script of the current document.

Meetings of various specialists in the field of GastrointestinalSurgery, General and Vascular Surgery, Hematology, Intensive Care,Obstetrics and Gynecology, Oncology and Orthopedics were heldin the months of August 2005 to January 2006. The experiences and

impressions of the experts during these meetings have been includedin this document.

Venous Thromboembolism is an important healthcare problemthe world over, resulting in significant morbidity, mortality andresource expenditure. The fact that studies are not available fromIndian patients does not necessarily mean that data from the Westwould not hold for our population. Further, a repetition of the samestudies as done in the West would not be needed, and may not throwany new light on the subject.

The implementation of evidence based and thoughtful prophylaxisstrategies would be beneficial to the patients in terms of accessing thebest possible care. The group felt that every hospital should developa formal strategy that addresses the prevention of thromboemboliccomplications. This may be in the form of written guidelines, which

are applicable to the needs of the attending patients.

Grades of RecommendationsThe grades of recommendations used are those that have been

used by the IUA.

Grade A recommendations are based on level 1 evidence frommore than one randomised controlled trials that have shown consistentresults (e.g., in systematic reviews), and are directly applicable to thetarget population. High quality and methodologically sound singlerandomised controlled trials have been classified as grade B.

Grade B recommendations are based on level 1 evidence fromrandomised controlled trials with less consistent results, limitedpower, or other methodological problems, or from a different groupof patients to the target population.

Grade C recommendations are based on level 2 evidence fromwell-conducted observational studies with consistent results, directly

applicable to the target population.

REFERENCES

VENOUSTHROMBOEMBOLISM (VTE) STUDY GROUPHematology : Core Group Leader : V Nair, Army Hospital (R&R), Delhi.MB Agarwal, Bombay Hospital Institute of Medical Sciences, Mumbai. A Bhave, Lilavati Hospital & Research Centre, Mumbai. Lt Col ASharma, Army Hospital (R&R), Delhi. S Shah, Jaslok Hospital, Mumbai. B George, Christian Medical College Hospital, Vellore. S Ap te ,Sahyadri Speciality Hospital, Pune.Surgery : Core Group Leader : A Choudhary, Sir Ganga Ram Hospital, Delhi.KS Vijayraghavan, Sri Ramchandra Medical College and Research Institute, Chennai.M Gore, Lokmanya Tilak Municipal Medical College,Mumbai. R Kannan, Cancer Institute, Adyar, Chennai. P Shukla, Tata Memorial Hospital, Mumbai. VK Kapoor, Sanjay Gandhi Postgraduate

Institute of Medical Sciences, Lucknow. G Srikanth, Manipal Hospital, Bangalore. CV Kantharia, King Edward Memorial Hospital,Mumbai.Oncology : Core Group Leader : P Jagannath, Raheja Hospital, Mumbai.BK Smruti, Lilavati Hospital & Research Centre, Mumbai. TB Yuvaraja, Tata Memorial Hospital, Mumbai. C Ramchandra, Kidwai MemorialInstitute of Oncology, Bangalore. S Gupta, Tata Memorial Hospital, Mumbai. BS Awasthy, Batra Hospital, New Delhi.Vascular Surgery : Core Group Leader : R Parakh, Sir Ganga Ram Hospital, DelhiM Patel, Sterling Hospital, Ahmedabad. KR Suresh, Jain Institute of Vascular Sciences, Bangalore. N Shekhar, Apollo Hospital, Chennai. DKamerkar, Ruby Hall Clinic, Pune. PR Pai, Bombay Hospital, Mumbai. P Patel, Lilawati Hospital, Mumbai. A Johri, Jaslok Hospital, Mumbai.U Vasudeva Rao, Manipal Hospital, Bangalore. N Bhushan, Manipal Hospital, Bangalore. RK Pinjala, Nizams Institute of Medical Sciences,Hyderabad. N Shastry, Apollo Hospital, New Delhi.Critical Care : Core Group Leader(s) : RK Mani, Apollo Hospital, Delhi. F Kapadia, PD Hinduja Hospital, Mumbai.R Bajwa, Regency Hospital, Kanpur. A Sarkar, Peerless Hospital, Kolkata. S Ramasubban, Apollo Gleneagles Hospital, Kolkata. Ramakrishnan,Apollo Hospitals, Chennai.Orthopedics : Core Group Leader(s) : S Agarwala, Hinduja Hospital, Mumbai. R Malhotra, All India Institute of Medical Sciences, NewDelhi.N Rajgopalan, St. Johns Medical College Hospital, Bangalore. PV Vijayaraghavan, Sri Ramchandra Medical College and Research Institute,

Chennai. SR Rao, Apurva Hospital, Rajkot. AK Maru, Madhuram Hospital, Rajkot. MS Ghosh, Kothari Medical Centre, Kolkata. MS Diggikar,B.J. Medical College, Pune. A Rajgopal, Fortis Hospital, NOIDA. KJ Reddy, Apollo Hospital, Hyderabad. S Mehta, Advanced Ortho Centre,Thane, Mumbai. PK Banerjee, Peerless Hospital, Kolkata. A Bhattacharya, AMRI Hospital, Kolkata. A Bandyopadhya, Peerless Hospital,Kolkata.Gynae & Obstetrics : Core Group Leader : SK Ghai Bhandari, Sir Ganga Ram Hospital, Delhi.NB Vaid, University College of Medical Sciences & Guru Teg Bahadur Hospital, Delhi. S Mittal, All India Institute of Medical Sciences, NewDelhi. H Khullar, Sir Ganga Ram Hospital, Delhi. I Ganguli, Sir Ganga Ram Hospital, Delhi. Tarakeshwari, Fernandez Hospital, Hyderabad.A Maheshwari, Tata Memorial Hospital, Mumbai. P Kumar, Kasturba Medical College & Hospital, Manipal. N Venkatesh, St. Philomenas,Bangalore. N Bhatacharya, Kalyani Hospital, Kolkata. JK Gupta, Apollo Gleneagles, Kolkata.


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api 2007 review - mx of vte - indian context

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