Consensus On Prophylaxis Of  Venous Thromboembolism

Ministry of Health Malaysia
Academy of Medicine Malaysia
College of Surgeons Malaysia
1999


 Contents
Expert Committee
Statement of Intent
Evidence Levels and Recommendations
Introduction
1.  Aims of this Guideline
2.  Identification of Hospital Patients at Risk of Venous Thromboembolism.
    2.1 Low Risk Groups
    2.2 Moderate Risk Groups
    2.3 High Risk Groups
3. Methods of Prophylaxis – Moderate and High Risk Groups.
    3.1 Mechanical Methods
    3.2 Pharmacological methods
4. Duration of Prophylaxis.
    4.1 In Hospital
    4.2 After Hospital Discharge
5. Specific Antithrombotic Prophylaxis :
    5.1     Moderate Risk Groups -
    5.1.1  Patients undergoing major General, Urological, Gynaecological, Cardiothoracic or Vascular
             Surgery
    5.1.2  Patients immobilised with Major Medical Illness
    5.1.3  Acute Myocardial Infarction
    5.1.4  Intracranial Neurosurgery
    5.1.5  Major Trauma
    5.2     High Risk Groups –
    5.2.1  Elective Hip Replacement
    5.2.2  Hip Fractures or Major Fractures of Lower Limb
    5.2.3  Elective Knee Replacement
    5.2.4  Major Pelvic or Abdominal Surgery for Malignancy
    5.2.5  Acute stroke with Paralysis of Lower Limb
    5.2.6  Acute Spinal Cord Injury or Disease causing Lower Limb Paralysis
    5.2.7  Critical Ischaemia or Amputation of Lower Limb
    5.3     Prophylaxis in Women Taking Oral Contraceptives or Hormone Replacement Therapy
    5.4     Prophylaxis in Pregnancy and The Puerperium
    5.4.1  Women with Past History of Venous Thromboembolism
    5.4.2  Women with Known Heritable Thrombophillic Defect
    5.4.3  Women with an Acquired Thrombophillic Defect
    5.4.4  Women with Thrombotic Risk Factors Alone
6.  Quick Reference Guide
7.  References

Table 1 :  Venous Thromboembolism
Table 2 :  Incidence of Venous Thromboembolism in Hospital patients According to Risk Group
Table 3 :  Elective Major General surgery- Indirect Comparisons
Table 4 :  Elective Hip Replacement -Indirect Comparisons
Table 5 :  Hip Fracture - Indirect Comparisons


   Expert Committee
Consensus on Prophylaxis of Venous Thromboembolism.

Chairman    : Mr Yusha’ Hj. Abdul Wahab
Secretary    : Mr Chew Loon Guan
Members    : Dato’ Dr Mrs. S.T. Kew               Dato’ Dr Alex Mathews
                     Dato’ Dr Yahya Awang               Dato’ Dr K Inbasegaran
                     Dato’ Dr Borhan Tan                   Dr Visalachy Purushotaman
                     Mr Sebastian Tong                     Dr Kok Keng Weng
                     Dr Tan Swee Looi                       Mr Zainal Ariffin Azizi
                     Dr Kok Keng Weng                    Mr Suib Ismail
                     Mr Lim Beng Kiat                       Mr Harjit Singh
                     Dr Jameela Sathar                      Dr Azmilla
                     Dr Chang Ham Long                   Dr Chin Chee Howe
                     Dr K.S. Dhillon                           Dr Mohd Roslan b Mohd Halim
                     Prof. Dr V. Sivanesaratnam         Assoc. Prof. Masbah Omar
 
 

Independent Evaluators :

Mr. Abdullah Salleh Dr N. Nivedi                                    Dr N. Nivedita
Dr Christopher Vincent Dr Sahir Sanusi                          Dr Sahir Sanusi
Dr Gerard Lim Chin Chye Dr Shong Hing Kock                Dr Shong Hing kock
Dr Hasim Mohammad
Dr Hooi Lai Seong
 

Statement Of Intent

This report is not intended to be construed or to serve as a standard of medical care. Standards of medical care are determined on the basis of all clinical data available for an individual case and are subject to change as scientific knowledge and technology advance and patterns evolve.

These parameters of practice should be considered guidelines only. Adherence to them will not ensure a successful outcome in every case, nor should they be construed as including all proper methods of care or excluding other acceptable methods of care aimed at the same results.

The ultimate judgement regarding a particular clinical procedure or treatment plan must be made by the Doctor in light of the clinical data presented by the patient and the diagnostic and treatment options available.

Significant departures from the national guideline by local protocols should be fully documented and the reasons for the differences explained.

Significant departures from the local protocols should be fully documented in the patient's case notes at the time the relevant decision is taken.

Evidence Levels and Recommendations
 
 

Level

Type of Evidence

Ia

Evidence obtained from meta-analysis of randomised controlled trials.

Ib

Evidence obtained from at least one randomised controlled trial. 

IIa

Evidence obtained from at least one well-designed controlled study without randomisation.

IIb

Evidence obtained from at least one other type of well designed quasi-experimental study. 

III

Evidence obtained from well designed non-experimental descriptive studies, such as comparative studies, correlation studies and case control studies.

IV

Evidence obtained from expert committee reports or opinions and / or clinical experiences of respected authorities.

 
 

Grade 

Recommendations

 
(Evidence  
Levels 1a,1b)
Required - at least one randomised controlled trial as part of the body of literature of overall good quality and consistency addressing the specific recommendation. 
B 
(Evidence Levels IIa,IIb,III)
Required - availability of well conducted clinical studies but no randomised clinical trials on the topic of recommendations. 
C 
(Evidence Level IV) 
Required - evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities.  
Indicates absence of directly applicable clinical studies of good quality. 

 


Introduction

Deep vein thrombosis especially of the lower limbs occur either spontaneously or inpatients admitted to hospitals either for a surgical or medical problem. It is primarily the admitted group of patients that this guideline is aimed at. The implementation of such a guideline in our local health and hospital care system has the potential to reduce significantly premature deaths, clinical disability, prolonged hospital stay, readmissions and costs.

The occurrence of deep vein thrombosis in hospitalised patients is dependent upon various risk factors. The reported incidence of deep vein thrombosis varies from 0.45% to 30%. (1 – 7) . A study done in University Hospital Kuala Lumpur reported an incidence of  76.5% (8) in Orthopaedic patients undergoing surgery.

It is obvious that deep vein thrombosis does occur and that a large proportion of them are asymptomatic. Furthermore up to 50% of asymptomatic deep vein thrombosis can lead to pulmonary embolism and in a significant number of cases, this proves to be fatal.

A recent random survey carried amongst clinicians at the First MOH-AMM Scientific Meeting revealed that only about 6% of clinicians regularly initiate deep vein thrombosis prophylaxis for their patients. Though this was a rather small sample group, it nevertheless reflects the low priority given to deep vein thrombosis prophylaxis by our local clinicians. The First MOH-AMM Scientific Meet had a pre-congress workshop on Clinical Practice Guidelines where amongst its speakers was Professor James Petrie, who is the chairman of SIGN ( Scottish Intercollegiate Guidelines Network ), whose group published the Prophylaxis of Venous Thromboembolism - A National Clinical Guideline recommended for use in Scotland. The following guideline is an adaptation from that publication of their pilot edition in September 1995 .

1. Aims of This Guideline
The aim of this national guideline is to assist individual clinicians and hospitals to produce local protocols for :
i) identification of patients at risk of venous thromboembolism
ii) routine administration and monitoring of appropriate and effective prophylaxis in such patients.

2. Identification of Hospital Patients at Risk of Venous Thromboembolism
Many practitioners recognise that the risk of venous thromboembolism increases with :
1. "Background" factors
2. Acute or subacute precipitating factors.
It is usually a combination of risk factors that predisposes a patient to deep vein thrombosis.
 
  Table 1 : Venous Thromboembolism – Risk Factors (10)

Background Factors

  • Age
  • Marked obesity ( BMI >30 )
  • Immobility ( bed rest longer than 4 days. ) 
  • Pregnancy 
  • Puerperium 
  • High dose estrogens
  • Previous DVT or PE 
  • Thrombophilia
    - Deficiency of antithrombin, protein-C or protein-S  
    - activated protein-C resistance  
    - antiphospholipid antibody or  
  • Lupus anticoagulant.

Precipitating Factors

  • Trauma or surgery, especially of pelvis, hip, lower limb. 
  • Malignancy , especially pelvic , abdominal , metastatic  
  • Heart failure 
  • Recent myocardial infarction 
  • Paralysis of lower limb(s)  
  • Severe infection  
  • Inflammatory bowel disease 
  • Nephrotic syndrome 
  • Polycythemia
  • Paraproteinemia  
  • Paroxysmal nocturnal hemoglobinurea
  • Bechet’s disease. 
  • Burns

It is recommended that all hospital patients at moderate or high risk should                                         receive specific prophylaxis.

2.1 Low-risk groups of hospital patients have a risk of DVT of less than 10% in screening studies; with
      proportionally low risk of proximal extension or pulmonary embolism ( Table 2 ) .

Such patients include :

Patients at low risk should be encouraged to mobilise early after surgery. However they do not merit the risk and cost of routine specific prophylaxis with antithrombotic drugs or mechanical devices. Table 2 : Incidence of Venous Thromboembolism in Hospital Patients According to Risk Group(10).

Group

Deep vein thrombosis

Proximal vein  thrombosis

Fatal pulmonary embolism

Low risk 

< 10%

< 1% 

0.01%

Moderate risk 

10 - 40%

1 - 10%

0.1 - 1%

High risk 

40 – 80%

10 - 30%

1 - 10%

 
2.2 Moderate-risk groups of hospital patients have an incidence of DVT in screening studies of
     10 - 40% ith a risk of fatal PE up to an average of 1%.(Table 2).

Moderate risk groups are :

In addition to early mobilisation, such patients should receive specific prophylaxis.

2.3 High-risk groups of hospital patients have an incidence of DVT in screening studies of 40 -
     80%, and an above average risk of fatal PE of 1-10%. (Table 2).

High-risk groups are :

In addition to early mobilisation, such patients should receive specific prophylaxis.

3. Methods of Prophylaxis - Moderate and High Risk Groups

3.1 Mechanical methods :
These include graduated elastic compression stockings (14) and intermittent pneumatic compression devices. They are effective in prevention of DVT in moderate-risk surgical patients ( Table 3)

Table 3. Elective Major General Surgery - Indirect Comparisons (9)
This table sets out indirect comparisons from trials based on routine fibrinogen leg scanning. Each line compares each agent against untreated controls( given no specific prophylaxis ). Such indirect comparisons are not the most reliable way to determine relative efficacy of different antithrombotic regimens. Direct comparisons ( in which patients are randomly allocated to one of two active regimens ) are more reliable ; however, few have been published. Analyses of the direct randomised comparisons indicate that differences between LMW heparins and low-dose standard heparins are not as marked as the table suggest, but are still significant. (15, 16)
 

Regimen 

Incidence of   Mean

DVT ( % )   95 % Cl

Untreated controls 

25 

24 - 26 

LMW Heparins 

4

3 - 5 

Low-dose standard heparin 

8

7 - 9 

Elastic stockings 

9

6 - 13 

Intermittent compression 

10

7 - 13 

Warfarin 

10

3 - 18 

Dextran 

16

13 - 18 

Aspirin 

20

16 - 24 

v Mechanical methods may also be combined with pharmacological prophylaxis to increase efficacy in high-risk patients.

v Unlike pharmacological prophylaxis, trials of mechanical methods have not yet been large enough to establish whether or not they significantly reduce fatal pulmonary embolism; nor have they been evaluated in medical patients. However, it seems reasonable to extrapolate efficacy from studies of DVT in surgical patients.

v Because they do not increase the risk of bleeding, mechanical methods may be preferred in patients at increased risk of bleeding from pharmacological prophylaxis.

3.2 Pharmacological methods :

 

These include :  
standard heparin ( usually in low dosage ) 
low molecular weight heparins or heparinoids. 
oral anticoagulants 
dextran 70 
aspirin

 

(a) Low dose standard heparin ( 5 000 IU, 8-12 hourly )

subcutaneously is effective in preventing DVT and PE in medical patients and in moderate-risk surgical patients. ( Table 3 ).
It has less effect on DVT in hip surgery ( Table 4 & 5 )
  Table 4 : Elective Hip Replacement - Indirect Comparisons (11) This table sets out indirect comparisons for illustrative purposes from trials based on routine venography.

Regimen

Incidence of   Mean

DVT ( % )   95 % CI

Untreated controls 

50 

46 - 55 

Adjusted dose standard heparin 

11

4 - 19 

LMW heparins 

16 

13 - 19 

Oral anticoagulants 

18 

12 - 24 

Intermittent compression 

21 

16 - 25 

Dextran 70 

30 

24 - 36 

Low-dose standard heparin 

34 

29 - 40 

Elastic stockings 

38 

30 - 46 

Aspirin 

45 

40 - 50 

  Table 5 : Hip Fracture - Indirect Comparisons (11) This table sets out indirect comparisons for illustrative purposes from trials based on routine venography.

Regimen

Incidence of   Mean

DVT ( % )   95% CI

Untreated controls 

43

38 - 49 

LMW heparins 

11

7 - 15 

Oral anticoagulants 

25

20 - 29 

Dextran 70 

30

25 - 34 

Low-dose standard heparin 

39

25 - 54 

Aspirin 

41

29 - 53

 

b)  Low molecular weight heparins and heparinoids, are also given subcutaneously for prophylaxis of
    venous thromboembolism. They are effective as once daily injections ( twice daily for parotid ).
    Compared to standard heparins, low-molecular weight heparins are significantly more effective in
    orthopaedic surgery (Table 4 & 5 ) and slightly more effective in general surgery (Table 3) without
    increasing the risk of bleeding (15, 16) .

(c) Oral anticoagulants are effective in prophylaxis of DVT and PE and have been used especially in
     hip ( Table 4 ).

Contra-indications usually include :
    - bleeding disorders
    - bleeding or potentially bleeding lesions
    - pregnancy ( due to fetal toxicity )
    - spinal or epidural analgesia.

(d) Dextran 70, seldom used in Malaysia, is given as peri-operative intravenous infusions, shows limited
    efficacy in prevention of DVT after general surgery (Table3 ) but appears more effective in preventing
    thrombosis after hip surgery (Table 4 & 5 ) and in prevention of PE.

Complications include :
    - increased risk of bleeding ( contra-indications are similar to those for heparin ).
    - risk of fluid overload.
    - allergic reactions.
    - may cause cross match difficulties.

(e) Aspirin shows limited efficacy in preventing DVT ( Table 3, 4 & 5 ) (19)

4.0 Duration of Prophylaxis
4.1 In hospital :
specific antithrombotic prophylaxis should continue for at least 5 days ( the minimum duration for prophylaxis in clinical trials ) or until hospital discharge if this is earlier than 5 days.

4.2 After hospital discharge :
increased risk of thrombo-embolism may continue for several weeks in patients with continuing risk factors ( eg. immobility, malignancy, puerperium, thrombophilias ) ( Table 1 ). In such patients, consideration should be given by the hospital team to continue prophylaxis after discharge (20), although such practice has not yet been tested in randomised trials.

5.1 Specific Antithrombotic Prophylaxis

5.1  Moderate Risk Groups :
5.1.1 Patients undergoing major general, urological, gynaecological, cardiothoracic or
        vascular surgery who are aged 40 years or more, or who have one or more other risk
        factors listed in Table 1.

These are Grade A recommendations based on level I data.(10-12)

5.1.2 Patients immobilised with major acute medical illness; eg. heart failure, chest
        infection, malignancy, diabetic acidosis or hyperosmolarity, and other conditions in
        Table 1.

These are grade A recommendations for heart failure and chest infection, and grade C recommendations for other indications - based on a large trial with non-random allocation, small randomised trials in heart failure and chest infection, and extrapolation of data from other patient groups (10 – 12).

5.1.3 Acute myocardial infarction

Recommendations for heparin and Warfarin are grade A recommendations based on level I data (10 – 12). Recommendations for intermittent pneumatic compression or graduated elastic compression stockings are grade C recommendations based on extrapolation of data from other patient groups (10 – 12).

5.1.4. Intracranial neurosurgery
The use of anticoagulants in Neurosurgery is usually contraindicated.

This is a grade A recommendation based on level I data (10 –12) .

5.1.5 Major trauma
In this group especially, the balance of thromboembolic risk and bleeding risk should be considered in the individual patient.

These are grade C recommendations based on extrapolation of data from other patient groups (10-12) .


5.2 High-risk Groups :
5.2.1 Elective hip replacement

These are grade A recommendations based on level I data (10 - 12, 21), given in descending order of perceived efficacy.

5.2.2 Hip fractures or Major fractures of lower limb
In this group especially, the balance of thromboembolic risk and bleeding risk should be considered in the individual patient.

These are grade A recommendations based on level I data. (10 - 12, 21).

5.2.3 Elective knee replacement

These are grade A recommendations based on level I data (10 – 12)

5.2.4 Major pelvic or abdominal surgery for malignancy; or major surgery, trauma or
        illness in patients with previous DVT, PE or thrombophilia.

These are grade A recommendations based on level I data. (10 – 12)

5.2.5 Acute stroke with paralysis of lower limb

These are grade C recommendations based on extrapolation of data from other patient groups.(10-12)

(intracranial bleeding should first be excluded, eg. by CT or MRI brain scanning ).

This is a grade A recommendation based on level I data. (10 - 12, 21, 22)

Warfarin is a grade C recommendation based on extrapolation of data from other patient groups: it may be in some patients for prophylaxis of recurrent thromboembolism from the heart.
An overview of the randomised trials in acute stroke indicated that whilst heparin reduced the risk of DVT, the reduction in PE and death were not statistically significant, and an increased risk of haemorrhagic transformation of cerebral infarction could not be ruled out (22). The International Stroke Trial should provide clearer evidence of the balance of risk and benefit, while routine use of heparin in acute stroke cannot be recommended.

5.2.6 Acute spinal cord injury or disease causing lower limb paralysis (eg. Guillain Barre
        syndrome)

This is a grade B recommendation based on level II data. (10-12)

5.2.7 Critical ischaemia or amputation of the lower limb

These are grade C recommendations based on extrapolation of results from other patient groups. (10-12)

5.3 Prophylaxis in Women taking oral contraceptives or hormone replacement therapy.
Whether or not to stop the combined oral contraceptive pill before major surgery is a controversial issue(10). In a recent study, the risk of post-operative venous thromboembolism increased from 0.5% to 1% for pill users versus non-users (10).

These are grade C recommendations based on epidemiological studies.

5.4 Prophylaxis in pregnancy and the puerperium.
Those factors which increase thrombotic risk in non-pregnant patients also increase the risk of thrombosis associated with pregnancy.

All the following recommendations are grade C, based on level IV studies and extrapolation of data from other patient groups. (13, 21).
 

5.4.1 Women with a past history of venous thromboembolism and no other known
        thrombotic risk factors.
Such patients require prophylaxis at least post-partum :

In women who have had a previous thrombotic event during pregnancy, consider ante-natal thromboprophylaxis ( commencing 4-6 weeks ahead of the gestation stage at which the previous thrombosis occured ) :

5.4.2 Women with a known heritable thrombophilic defect eg. deficiency of antithrombin (AT),
        protein C ( PC ) or protein S ( PS); activated protein C resistance; whether or not they
        have had a previous thrombosis.

Such patients usually merit referral to a unit experienced in managing pregnancy in thrombophilic women.
These women require thromboprophylaxis at least post-partum using the regimen outlined in 5.4.1 above.
Many women with thrombophilic defects in addition merit antenatal thromboprophylaxis.
The timing of introduction and the dose of anticoagulant must be decided on an individual basis; aiming to minimise the total exposure to heparin.

For PC and PS deficient women, subcutaneous standard heparin ( 7500-10,000 IU, 12 hourly ) or prophylactic doses of a low-molecular weight heparin commencing late second or early third trimester is appropriate.

Women with certain types of AT deficiency are at high risk of pregnancy associated thrombosis. In these patients thromboprophylaxis usually requires subcutaneous standard heparin in doses adjusted to achieve a plasma heparin concentration of 0.2-0.4 IU/ml. These patients in particular usually merit referral to a unit experienced in managing pregnancy in thrombophilic women.

5.4.3 Women with an acquired thrombophilic defect eg. antiphospholipid antibodies ( lupus
        anticoagulants or anticardiolipin antibodies ).

Those who have already had a thrombotic event should be managed as in 5.4.1 above.
Those who have had no previous thrombotic event may merit at least post-partum thromboprophylaxis as in 5.4.1 above.

5.4.4 Women with no past history of thrombosis and no known thrombophilic defect, but with
        other thrombotic risk factors particularly where these risk factors occur in combination,
        eg.:

Where heparin is contra-indicated ( eg. in a patient with osteoporosis or with heparin induced thrombocytopenia not resolving on change of therapy to a low-molecular weight heparin ) or where a patient has a mechanical heart valve prosthesis, warfarin may be used during pregnancy, replacing warfarin with heparin at least four weeks ahead of the expected delivery date and if possible avoiding the gestation period 6-12 weeks. A low-molecular weight heparin or danaparoid may be considered in patients who have heparin induced thrombocytopenia; however, cross-reactivity should be excluded.
   

References

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7.  Pezzullo-J A, Perkins A B, Cronan-J J.
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8.  Dhillon-K S, Askander-A, Doraisamy-S.
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9.  Claget G P, Anderson F A Jnr, Levine M N et al.
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10. Thromboembolic Risk Factors ( THRIFT ) Consensus Group.
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11. European Consensus Statement. Prevention of venous thromboembolism.
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12. Turnbull A, Tindall V R, Beard R W et al.
      Confidential enquiry into maternal deaths in England and Wales 1982 – 1984. London : HMSO
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13. British Society for Haematology.
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14. Wells P S, Lensing A W A and Hirsch J.
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15. Nurmohamed M T, Rosendaal F T, Buller H R, et al.
     Low molecular weight heparin versus standard heparin in general and orthopaedic surgery : a
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16. Leizorovicz A, Haugh M C, Chapius F R et. al.
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17. Wildsmith JAW and McClure JH. .Anticoagulant drugs and central nerve blockade. Anaesthesia
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18. British Soceity of Haematology.
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19. Antiplatelet Triallists' Collaboration.
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     thrombosis and pulmonary embolism by antiplatelet prophylaxis amoung surgical and medical
     patients. BMJ 1994; 308: 235-46.

20.  Arcelus J I and Caprini J A.
      Prevention after hospital discharge In Prevention of Venous Thromboembolism. Goldhaber SZ (ed),
      New York : Marcel Dekker 1993, pp 497-518.

21. Turpie A G G. Orgaran ( ORG 10172 ): a low molecular weight heparinoid. In: Prevention of Venous
      Thromboembolism. Berqvist D, Comerota AJ,Nicolaides AN, Scurr JH (eds),London: Med-Orion
      1994, pp 175-180.

22. Sandercock PAG, van den Belt A G M, Lindley R J and Slattery J.
      Antithrombotic therapy in acute stroke : an overview of the completed trials.
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23. Leyvraz P F, Bachmann F, Hoek J et al. Prevention of deep vein thrombosis after hip replacement :
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                                                                                                                               14th June 2000