Deep vein thrombosis (DVT) has two important sequelae:

• Pulmonary embolism
• Post-thrombotic syndrome (see section on Prognosis below)

Both are common disorders. A thrombus either arises spontaneously or is predisposed by such conditions as surgery, trauma or prolonged bed rest. They usually form in the deep veins of the lower limbs but may extend higher and into the pelvic veins. The intimate relationship between DVT and pulmonary embolism (PE) is such that the term venous thrombo-embolism (VTE) is often used to cover both conditions.

DVT can be very difficult to diagnose but early recognition and appropriate treatment can save many lives.

Epidemiology

• DVT or PE may occur in almost 2 in 1,000 people each year, with up to 25% of those having a recurrence. Around 5-15% of people with untreated DVT may die from PE.¹
• Male:female ratio = 1.2 to 1. When not pregnant or using oral contraceptives or HRT, women have a lower risk than men.²
• Two thirds of patients with proven PE have no symptoms of DVT and, in one third of cases, it is impossible to find the original site of a DVT without an autopsy.
• Autopsy studies demonstrate that approximately 80% of all cases of DVT and PE remain undiagnosed, even when they are the immediate cause of death.

Assessing risk

The risk factors for DVT (and hence VTE) arise from the 3 underlying components of Virchow's triad. They are:

• Venous stasis
• Hypercoagulability
• Injury to the intima of veins

One study found that 50-70% of patients had readily identifiable risk factors.³ There are many other risk factors including smoking. Risk increases with age and with obesity but these are often associated with other risk factors:

Clinical features

The clinical diagnosis of DVT can be very difficult.

• Many DVTs progress to PE without DVT being clinically apparent.
• In those with classic clinical signs, only about 50% have DVT.
• History, examination and the presence of risk factors can be unreliable in making the diagnosis, and ambulatory patients (as in primary care) may be rather different from hospital inpatients, who are the group most studied.⁶

The last factor may make the GP ask, "Is the evidence base available applicable to the patient in front of me?"

Classical features are from obstruction to venous drainage:

• Limb pain and tenderness along the line of the deep veins.
• Swelling of calf or thigh (usually unilateral). Involvement of the iliac bifurcation, the pelvic veins, or the vena cava produces leg oedema that is usually bilateral.
• Distension of superficial veins.
• Increase in skin temperature.
• Skin discolouration (erythema or occasionally purple or cyanosed).
• A palpable cord (hard, thickened palpable vein).
• Low-grade fever (said to be rare but perhaps not sought often enough).
• There may be pain upon dorsiflexion of the foot and spontaneous maintenance of the relaxed foot in abnormal plantar flexion (Homans' sign is not helpful in diagnosis as it is very non-specific).⁶

Cellulitis adds to the problem:

• Severe signs of DVT can resemble cellulitis.
• Secondary cellulitis may develop with primary DVT.
• Primary cellulitis may be followed by a secondary DVT.
• Superficial thrombophlebitis may hide an underlying DVT.

Assessment and investigations

Investigations may be classified as risk assessment or definitive diagnosis.

Risk assessment

Use a scoring system such as the Wells diagnostic algorithm to assess pre test probability:

• Refer people who are likely to have DVT for same-day assessment and management (local protocols may vary).
• For people who are unlikely to have DVT, take a blood sample for D-dimer testing if there is the local facility to do this and it is reasonably practical and safe to do so (for example the results will be reported that day).
• If patient presents "out of hours" consider subcutaneous low-molecular weight heparin now and investigations tomorrow.

D-dimers

• These are specific cross-linked products of fibrin degradation and are raised in patients with VTE. Sensitivity is high but specificity poor.
• High concentrations occur in other disorders, such as malignancy and pregnancy and in other conditions where clots form, as after surgery. The investigation of VTE in pregnancy is fraught with many difficulties.⁹
• Nevertheless, a negative test can exclude the need for further investigation.^10,11
• Several D-dimer assays are available, e.g. ELISA tests or SimpliRED whole blood agglutination test suitable for near patient testing. Some evidence suggests that D-dimer should be measured after the end of the anticoagulation period, to assess the risk of re-thrombosis.¹²

Plethysmography involves recording of changes in the size of the limb due to tissue fluid or pooled blood in the veins. Techniques include photoplethysmography (absorption of light by haemoglobin), strain gauge and electrical impedance (change in calf size or electrical impedance of skin during and after occluding venous outflow).

Definitive investigations

Imaging can be by venography, by 2-dimensional ultrasound, or by magnetic resonance imaging.

• All these tests are most sensitive when DVT is symptomatic, when thrombus causes complete venous outflow obstruction and when the clot extends into the upper thigh.
• False-negatives are highest when the thrombus is solely below the knee or above the groin, when obstruction is incomplete and when the patient is asymptomatic.

The choice of definitive test may depend upon local protocols as none is perfect.

• Duplex ultrasound is the initial investigation of choice in nearly all patients with suspected DVT.
  • Its reliability is dependent upon the skill of the user.
  • It may miss a non-occlusive thrombus in up to 40% of cases involving the iliac or pelvic veins.
  • Major axial veins of the lower limb are well displayed.
  • Compression ultrasonography is increasingly being used early in the investigative process.¹³
• Magnetic resonance venography and CT venography may be useful adjuncts.¹³
• Contrast venography has long been "the gold standard" of diagnosis for DVT.
  • An intravenous catheter is placed in a dorsal vein of the foot and contrast medium is infused into the vein.
  • A tourniquet around the leg occludes the superficial veins and forces contrast into the deep veins.
  • A positive result tends to be conclusive but a negative result is less reassuring. It is time-consuming and requires much technical skill to obtain good results.
  • It is highly invasive and has substantial morbidity and mortality unlike the other diagnostic tests for DVT.
  • Up to 10% of patients have new thrombosis shortly after a negative venogram. This may be because it missed the original DVT or because intravenous contrast can trigger thrombosis by causing endothelial injury.
  • Extravasation of contrast material into the dorsum of the foot may cause sloughing of tissue.
  • Anaphylactoid reactions to contrast material occur in 3% of patients and can cause death.

Management

A practical approach to initial management in primary care is as follows:

• Patients likely to have a DVT on the grounds of clinical suspicion or risk factors should be referred immediately to hospital.
• For people who are unlikely to have DVT, perform a D-dimer test if available.
  • If the test is positive, refer immediately for further assessment and management.
  • If the test is negative, reassure the person, and tell them to seek urgent medical advice if they develop difficulty breathing, increased breathing rate, or chest pain (since these symptoms may indicate pulmonary embolism).
  • If D-dimer testing is not available or practical, refer for same-day assessment.
• Treat the suspicion of DVT with subcutaneous low molecular weight heparins (LMWH) if no contra-indications.¹⁴
• LMWHs have made outpatient treatment of DVT possible. Trials have suggested that it is both feasible and safe.¹⁵ LMWHs are likely to be the treatments of choice for pregnant patients, although more trials are needed.¹⁶
• Patients with confirmed DVT are usually commenced on warfarin (unless contra-indicated) and the heparin can be discontinued when the warfarin is in the therapeutic range.
• Patients with a DVT should wear compression stockings to reduce the rate of post-thrombotic syndrome. In one study of 194 patients with a first episode of proximal DVT, the rate of post-thrombotic syndrome was reduced by 50% when graded compression stockings were used.¹⁷ There is evidence that the stockings provide benefit for a period of two years but compliance is low.¹⁸
• Filters in the inferior vena cava are occasionally inserted to reduce PE. The indications for their use include PE with contra-indication to anticoagulation and recurrent PE despite adequate anticoagulation. In the UK, most vena cava filters are removed 3 weeks after the period of greatest risk and are not permanent. There is no consensus about whether patients with long-term filters should receive long-term treatment anticoagulation.

Target ranges

According to the BNF:¹⁹

• A loading dose of warfarin is usually needed (check BNF for dosage guidance and interactions with current medication).
• First episode of a proximal vein thrombosis should receive anticoagulants for 6 months, with a target INR of 2.5 (±0.5 is acceptable). The duration of anticoagulation is still under debate. Use higher target of 3.5 in recurrent DVT/PE in patients who had recurrence whilst on lower dose of warfarin or with mechanical heart valves.

The British Thoracic Society concluded that if VTE arises after surgery, 4 weeks of anticoagulation should be adequate. In other settings, patients with new DVT, PE, or both, who do not have a persisting underlying cause or risk factor, should receive anticoagulants for 3 months.²⁰ In patients with no other risk factors, there is no additional benefit of anticoagulation for 6 months rather than 3.²¹

There is limited evidence that thrombolytics such as streptokinase may resolve symptoms more rapidly and preserve venous valve integrity and hence decrease the incidence of the post-phlebitic syndrome,²² although there is an increased risk of major haemorrhage.

Fondaparinux sodium is a synthetic pentasaccharide that inhibits activated factor X. This drug has been licensed in the United Kingdom for prophylaxis of VTE in patients having major orthopaedic surgery of the legs. The potential of this drug for treating DVT has not been fully evaluated.

Prognosis

• There may well be recurrence of DVT. Recurrence after the first event can be as high as 60% but halved by compression stockings.¹⁷
• Death occurs in approximately 6% of DVT cases and 12% of PE cases within 1 month of diagnosis.² Long-term outcome tends to be good if it is not associated with malignancy.²³

Post-thrombotic syndrome

• Isolated calf vein thrombophlebitis produces post-phlebitic syndrome in 20 to 40% of symptomatic cases.
• Risks associated with the syndrome include older age, obesity, a history of previous ipsilateral DVT, iliac-femoral location of the current thrombosis, failure to recover promptly from the acute symptoms, and insufficient quality of oral anticoagulant therapy.²⁴
• There is a low risk of post-thrombotic syndrome in patients with asymptomatic DVT.²⁵
  • Thrombosis destroys the valves of the deep veins, leading to chronically elevated venous pressure within the legs.
  • Valve incompetence need not be extensive to produce symptoms. Isolated incompetence of the valves in the popliteal segments leads to elevated venous pressures and over 60% of those with isolated popliteal valve failure develop severe chronic venous insufficiency.
  • The syndrome produces chronic pain, oedema, hyperpigmentation and ulceration.

Prevention

See related article on Prevention of Deep Vein Thrombosis.

Historical

• Schenk first described venous thrombosis in 1644, when he described an occlusion in the inferior vena cava.
• In 1846 Virchow recognised the association between venous thrombosis in the legs and PE. Rudolf Virchow (the name of Slavic origin, often mispronounced then as it is now, pronounced "Furko") was Professor of Pathology in Berlin in the Pathological Institute built specifically for him and was author of the most important pathology text in history, "Cellular-pathologie" in which his famous dictum "Omnis cellula e cellula" ("each cell stems from another cell") appeared for the first time. One of his many interesting original observations is that of leukaemia. He also found time to serve in the Reichstag for 13 years, as leader of the Radical Party, a persistent opponent of Bismark.

Document references

1. McManus RA, Fitzmaurice D, Murray E, et al; Thromboembolism. Clin Evid (Online). 2009 Mar 9;2009. pii: 0208. [abstract]
2. White RH; The epidemiology of venous thromboembolism. Circulation. 2003 Jun 17;107(23 Suppl 1):I4-8. [abstract]
3. Ageno W, Agnelli G, Imberti D, et al; Risk factors for venous thromboembolism in the elderly: results of the master registry. Blood Coagul Fibrinolysis. 2008 Oct;19(7):663-7. [abstract]
4. Piegsa K, Guillebaud J; Oral contraceptives and the risk of DVT. Practitioner. 1996 Sep;240(1566):544-51.
5. No authors listed; Venous thromboembolic disease and combined oral contraceptives: results of international multicentre case-control study. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Lancet. 1995 Dec 16;346(8990):1575-82. [abstract]
6. O'Donnell TF Jr, Abbott WM, Athanasoulis CA, et al; Diagnosis of deep venous thrombosis in the outpatient by venography. Surg Gynecol Obstet. 1980 Jan;150(1):69-74. [abstract]
7. Deep vein thrombosis, Clinical Knowledge Summaries (April 2009)
8. Wells PS, Anderson DR, Bormanis J, et al; Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet. 1997 Dec 20-27;350(9094):1795-8. [abstract]
9. Nijkeuter M, Ginsberg JS, Huisman MV; Diagnosis of deep vein thrombosis and pulmonary embolism in pregnancy: a systematic review. J Thromb Haemost. 2006 Mar;4(3):496-500. Epub 2005 Dec 23. [abstract]
10. Aschwanden M, Labs KH, Jeanneret C, et al; The value of rapid D-dimer testing combined with structured clinical evaluation for the diagnosis of deep vein thrombosis. J Vasc Surg. 1999 Nov;30(5):929-35. [abstract]
11. Ginsberg JS, Kearon C, Douketis J, et al; The use of D-dimer testing and impedance plethysmographic examination in patients with clinical indications of deep vein thrombosis. Arch Intern Med. 1997 May 26;157(10):1077-81. [abstract]
12. Palareti G, Legnani C, Cosmi B, et al; Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped. Thromb Haemost. 2002 Jan;87(1):7-12. [abstract]
13. Madhusudhana S, Moore A, Moormeier JA; Current issues in the diagnosis and management of deep vein thrombosis. Mo Med. 2009 Jan-Feb;106(1):43-8; quiz 48-9. [abstract]
14. van Den Belt AG, Prins MH, Lensing AW, et al; Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev. 2000;(2):CD001100. [abstract]
15. Pineo GF, Hull RD; Economic and Practical Aspects of Thromboprophylaxis With Unfractionated and Low-Molecular-Weight Heparins in Hospitalized Medical Patients. Clin Appl Thromb Hemost. 2009 Jun 10. [abstract]
16. Veraart JC, Pronk G, Neumann HA; Pressure differences of elastic compression stockings at the ankle region. Dermatol Surg. 1997 Oct;23(10):935-9. [abstract]
17. Brandjes DP, Buller HR, Heijboer H, et al; Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet. 1997 Mar 15;349(9054):759-62. [abstract]
18. Wittkowsky AK, Nutescu EA, Devine EB; Compression stockings to prevent post-thrombotic syndrome: a role for anticoagulation clinics? J Thromb Thrombolysis. 2008 Dec;26(3):248-50. Epub 2007 Nov 30. [abstract]
19. British National Formulary
20. No authors listed; Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Research Committee of the British Thoracic Society. Lancet. 1992 Oct 10;340(8824):873-6. [abstract]
21. Campbell IA, Bentley DP, Prescott RJ, et al; Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial. BMJ. 2007 Mar 31;334(7595):674. Epub 2007 Feb 8. [abstract]
22. Rogers LQ, Lutcher CL; Streptokinase therapy for deep vein thrombosis: a comprehensive review of the English literature. Am J Med. 1990 Apr;88(4):389-95. [abstract]
23. Prandoni P, Lensing AW, Prins MR; Long-term outcomes after deep venous thrombosis of the lower extremities. Vasc Med. 1998;3(1):57-60. [abstract]
24. Prandoni P, Kahn SR; Post-thrombotic syndrome: prevalence, prognostication and need for progress. Br J Haematol. 2009 May;145(3):286-95. Epub 2009 Feb 13. [abstract]
25. Persson LM, Lapidus LJ, Larfars G, et al; Asymptomatic Deep Venous Thrombosis is Associated with a Low Risk of Post-thrombotic Syndrome. Eur J Vasc Endovasc Surg. 2009 May 29. [abstract]

Internet and further reading

• Prevention and management of venous thromboembolism, Scottish Intercollegiate Guidelines Network - SIGN (December 2010)
• Management of deep vein thrombosis (DVT) as an out-patient, British Committee for Standards in Haematology (2003)
• Guidelines on use of vena cava filters, British Committee for Standards in Haematology (2006)
• Venous Thromboembolism and Hormonal Contraception, Royal College of Obstetricians and Gynaecologists (September 2010)
• Diagnosis of deep vein thrombosis in symptomatic outpatients and the potential for clinical assessment and D-dimer assays to reduce the need for diagnostic imaging, British Committee for Standards in Haematology (2003)
• Venous thromboembolism - reducing the risk, NICE Clinical Guideline (January 2010); Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital