Dr Alan Begg discusses the diagnosis, assessment, and management of thromboembolic disease in primary care

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Read this article to learn more about: 

  • how to identify people at risk of venous thromboembolism (VTE) 
  • evaluating the clinical probability of a VTE diagnosis 
  • what pharmacological interventions are available to treat VTE. 

After reading this article, ‘Test and reflect’ on your updated knowledge with our multiple-choice questions. Earn 0.5 CPD credits

 

1 Learn the epidemiology 

Venous thromboembolism (VTE) is defined as deep vein thrombosis (DVT) with or without a pulmonary embolism (PE). General practitioners should be aware that DVT is a common disease: 1 per 1000 of the general population in the UK will present with clinical symptoms of DVT each year. A DVT usually affects the deep veins of the lower limbs but thrombosis can affect other sites; it describes the formation of a thrombus in a deep vein, which partially or completely obstructs blood flow.1

A PE occurs when the thrombus dislodges and travels in the blood to the pulmonary arteries. Pulmonary emboli can significantly contribute to morbidity and mortality, with around 10% of all hospital deaths attributable to the condition.1

A DVT can result in post-thrombotic leg syndrome in about 30% of cases, with leg ulcers developing in between 2% and 10% of patients approximately 10 years after their first symptomatic DVT. One potential long-term consequence of PE is the development of chronic pulmonary hypertension.1

2 Recognise the risk factors 

Most risk factors for VTE can be identified by taking a comprehensive history along with a clinical examination.1

The incidence of first VTE rises exponentially with age, reaching an annual incidence of 1 per 100 in those aged over 80 years. An individual’s risk of VTE is increased two- to three-fold if their body mass index is >30 kg/m2, which may reflect immobility and coagulation activity.1

Provoked DVT or PE

A provoked DVT or PE occurs in a person with an antecedent (within 3 months) transient major clinical risk factor for VTE. These factors include:2

  • surgery 
  • trauma 
  • significant immobility (bedbound, unable to walk unaided, or likely to spend a substantial proportion of the day in bed or in a chair) 
  • pregnancy or puerperium 
  • taking hormonal therapy (e.g. oral contraceptive or hormone replacement therapy). 

Unprovoked DVT or PE 

A DVT or PE is considered unprovoked if it occurs in a patient with:2

  • no antecedent major clinical risk factor for VTE who is not taking hormonal therapy or 
  • active cancer, thrombophilia, or a family history of VTE, because these are underlying risks that remain constant in the patient. 

Recurrent venous thromboembolism 

A risk factor for recurrent VTE (in patients not on long-term anticoagulation) is previous unprovoked VTE, which has a recurrence rate of 5% per year. Recurrent VTE is also associated with obesity.1 Men have an increased relative risk of recurrent VTE compared with women, which may be due to sex-specific factors present at the time of the first VTE event in thrombophilic families. The difference in lifetime risk of recurrent VTE between men and women in thrombophilic families has been explained by women being younger at the time of the first venous thrombosis due to hormonal risk factors, and a longer interval between a provoked first episode of venous thrombosis and recurrence in women.3

The incidence of first VTE rises exponentially with age, reaching an annual incidence of 1 per 100 in those aged over 80 years

Know the signs and symptoms 

Individual signs and symptoms are, on their own, poor predictors of the presence or absence of DVT.4

Typical symptoms of DVT are pain in the leg, especially on deep palpation of the deep veins. The pain is often accompanied by swelling of the leg and changes to skin colour and temperature with vein distension. Both legs may be affected.4

A positive Homan’s sign is when pain occurs in the calf or popliteal region on passive, abrupt, forceful dorsiflexion of the ankle with the knee in a flexed position. Practitioners are now advised not to use this test as it can be painful and insensitive, it is non-specific, and in theory it could possibly dislodge a thrombus.4

A PE should be suspected in a person with:5

  • dyspnoea
  • tachypnoea
  • pleuritic chest pain 
  • features of DVT.

In one prospective study, one or more of the features listed above were present in 97% of people with PE.5 Other clinical features that may be present include:5

  • tachycardia
  • haemoptysis
  • syncope
  • hypotension with a systolic blood pressure <90 mmHg
  • cough and fever 
  • crepitations audible on auscultation.

Typical symptoms of DVT are pain in the leg, especially on deep palpation of the deep veins

4 Be aware of differential diagnoses

It is important to consider that only one-third of people with a clinical suspicion of a DVT have the condition.4

The list of other conditions to consider with similar presenting symptoms is extensive, and includes:4

  • physical trauma such as:
    • calf muscle tear or strain
    • haematoma in the muscle 
    • sprain or rupture of Achilles tendon
    • fracture 
  • cardiovascular conditions:
    • post-thrombotic syndrome
    • venous insufficiency
    • acute limb ischaemia 
    • vasculitis
    • right-side heart failure
  • other conditions:
    • ruptured Baker’s cyst
    • cellulitis 
    • dependent oedema or lymphatic obstruction
    • cirrhosis or nephritic syndrome 
    • compartment syndrome.

Refer to the NICE Deep vein thrombosis  Clinical Knowledge Summary4 for the full list of differential diagnoses.

Similarly, there may be other conditions that could explain possible PE symptoms, including:5

  • respiratory causes such as pneumothorax, pneumonia, and acute exacerbation of chronic lung disease
  • cardiac causes such as acute coronary syndrome, acute left ventricular failure, dissecting or rupturing aortic aneurysm, pericarditis
  • gastro-oesophageal reflux disease
  • musculoskeletal chest pain
  • any cause of a vaso-motor collapse. 

An ECG may help in the diagnosis and a chest X-ray will help to exclude other causes. Practitioners should not delay management of suspected PE for results of an ECG or chest X-ray as they are often normal in someone with a PE.5

Evaluate the clinical probability 

A validated clinical decision tool such as the Wells score should be used initially to assess the probability of a patient having DVT or PE.2

For a DVT, NICE Clinical Guideline 1442 recommends the two-level DVT Wells score.6

Clinical features and the associated point scores are listed below:

  • active cancer (treatment ongoing, within 6 months, or palliative) [1 point]
  • paralysis, paresis, or recent plaster immobilisation of the lower extremities [1 point]
  • recently bedridden for 3 days or more or major surgery within 12 weeks requiring general or regional anaesthesia [1 point]
  • localised tenderness along the distribution of the deep venous system [1 point]
  • entire leg swollen [1 point]
  • calf swelling at least 3 cm larger than asymptomatic side [1 point]
  • pitting oedema confined to the symptomatic leg [1 point]
  • collateral superficial veins (non‑varicose) [1 point]
  • previously documented DVT [1 point]

Deduct two points if an alternative diagnosis is at least as likely as DVT.

A DVT is ‘likely’ if the score is ≥2 points and ‘unlikely’ if the score is ≤1 point.2

If a PE is suspected the two-level PE Wells score7 should be used to assess the clinical probability of a PE. Points are scored as follows:2

  • there are clinical signs and symptoms of DVT (minimum of leg swelling and pain with palpation of the deep veins) [3 points]
  • an alternative diagnosis is less likely than a PE [3 points]
  • heart rate >100 beats per minute [1.5 points]
  • immobilisation for more than 3 days or surgery in the previous 4 weeks [1.5 points]
  • previous DVT/PE [1.5 points]
  • haemoptysis [1 point]
  • malignancy (on treatment, treated in the last 6 months, or palliative) [1 point].

A PE is ‘likely’ if the score is >4 points, if the score is ≤4 points a PE is ‘unlikely’.2

Confirm the diagnosis

The diagnosis of VTE is not always straightforward, but failure to diagnose and treat a VTE correctly can result in a fatal PE.2

Investigating suspected deep vein thrombosis

If a DVT is suspected and is considered ‘likely’ on the two-level DVT Wells score, the patient should have a proximal leg vein ultrasound scan carried out within 4 hours of being requested, followed by a D-dimer test if the result of the scan is negative. If this is not possible, request an ultrasound scan within 24 hours, perform a D-dimer test, and give an interim 24-hour dose of parenteral anticoagulant.2

Repeat the proximal leg vein ultrasound scan 6–8 days later for all patients with a positive D-dimer test and a negative ultrasound scan.2

If a DVT is ‘unlikely’ on the two-level DVT Wells score but the D-dimer test is positive, offer an ultrasound scan within 4 hours or an interim 24-hour dose of a parenteral anticoagulant with an ultrasound scan performed within 24 hours.2

Investigating suspected pulmonary embolism 

For patients in whom PE is suspected and the two-level PE Wells score is ‘likely’, offer an immediate computed tomography pulmonary angiogram (CTPA). If a CTPA cannot be carried out immediately, offer immediate interim parenteral anticoagulant therapy followed by a CTPA.2

If the CTPA is negative and DVT is suspected, a proximal leg scan is required.2

For patients with an ‘unlikely’ two-level PE Wells score, offer a D-dimer test. If the result is positive, offer an immediate CTPA or immediate interim anticoagulant therapy until a CTPA can be carried out.2

Failure to diagnose and treat a VTE correctly can result in a fatal PE

Offer therapeutic treatment 

Start anticoagulation treatment in patients with confirmed PE or DVT as soon as possible, with the addition of a vitamin K antagonist (VKA) within 24 hours of diagnosis.2

Anticoagulation treatment should be either low molecular weight heparin (LMWH) or fondaparinux. Unfractionated heparin is the agent of choice if there is severe renal impairment. Treatment should be continued for at least 5 days or until the international normalised ratio (INR) (adjusted by a VKA) is 2 or above for at least 24 hours, whichever is longer.2

Offer LMWH to patients with active cancer and confirmed proximal DVT or PE. After 6 months of treatment, review the continued use of anticoagulation.2

Extending VKA therapy beyond 3 months should be considered in an unprovoked PE or proximal DVT, taking into account the risk of VTE recurrence and bleeding.2

NICE technology appraisals recommend that direct oral anticoagulants (DOACs) may be used as possible alternative options for the treatment and prevention of PE and DVTs in adults.8–11

Catheter-directed thrombolytic therapy should be considered under certain conditions for people with a symptomatic iliofemoral DVT.2

Elastic graduated compression stockings should not be offered to prevent post-thrombotic syndrome or VTE recurrence after a proximal DVT.2

Ensure patients are given verbal and written information about their anticoagulation treatment, including:2

  • duration of treatment
  • side-effects
  • interactions with other medications, foods, and alcohol
  • monitoring 
  • how it may affect activities such as sport and travel.

Remember to investigate

All patients who have been diagnosed with unprovoked DVT or PE should be investigated to exclude underlying cancer, if they do not already have a cancer diagnosis.2

A physical examination guided by the patient’s full history should be carried out in those with an unprovoked DVT or PE. The following tests should be peformed:2

  • chest X-ray
  • blood tests (full blood count, serum calcium, and liver function tests)
  • urinalysis.

In those over 40 years of age, consider: 

  • an abdomino-pelvic CT scan
  • mammogram in women. 

In patients who have had an unprovoked DVT or PE, if it is planned to stop anticoagulation treatment:2

  • consider testing for antiphospholipid antibodies
  • test for hereditary thrombophilia if the patient has a first-degree relative who has had DVT or PE.

9 Consider travel-related thrombosis

Travel-related VTE risk applies as much to long-haul air travel (>4 hours) as it does to other passive modes of transport such as travel by car and rail.1

The absolute risk of an episode of flight-related VTE is estimated to be one episode in 4600 flights over 4 hours with the increased risk persisting for up to 8 weeks after travel.1 Both shorter and taller people and people who are overweight are more at risk of a flight-related VTE, as are people seated in a window seat.1 Women who are taking the combined oral contraceptive pill or are carriers of factor V Leiden are at increased risk of VTE through possible coagulation activation.1

It is uncertain whether seated exercises or anti-embolism stockings help prevent a travel-related VTE. Class 1 stockings (flight socks) may reduce subclinical events.1

Travellers should be advised to remain as ambulant as safely possible during and after journeys, and leg exercises while seated may be recommended.1 Pharmacological prophylaxis can be considered for those deemed to be at high risk of travel-related VTE, with a single dose of LMWH on the day of travel being the agent of choice.1 Patients in this group include those:1

  • who have had a previous travel-related VTE and are no longer taking warfarin
  • where travel is essential in the early post-operative period 
  • who are immobilised after a lower limb fracture.1

People being monitored on warfarin should ensure that their INR is within the therapeutic range prior to travel.1

10 Be alert to the increased risk of VTE in pregnancy

It can be difficult to diagnose DVT in pregnant women as the Wells score and D-dimer test are not validated for use during pregnancy.12

The risk of VTE in pregnancy is about four times the risk in non-pregnant women of childbearing age. The risk is highest in the third trimester and increases further in the first 6 weeks postpartum. Pregnancy is associated with the three broad categories of Virchow’s triad (stasis, vessel wall injury, and hypercoagulability), which are thought to contribute to thrombosis. The uterus can compress the left iliac vein so DVT is more common on the left side of the body during pregnancy. A previous unprovoked or oestrogen-related VTE is a strong risk factor for antepartum and postpartum VTE. Other risk factors include:12

  • body mass index >25 kg/m2
  • immobility
  • varicose veins
  • smoking 
  • age ≥35 years.

Pregnant women most commonly present with discomfort (80–95%) and oedema (80–88%) in a lower extremity. Isolated lower abdominal or pelvic pain may rarely be the presenting symptoms of a pelvic DVT.12

The approach to diagnosing DVT differs in pregnancy. Pre-test probability clinical prediction tools are not used in pregnancy and a physiological gradual increase in D-dimer occurs in pregnancy so results may give a false positive.12

To confirm a diagnosis of DVT in pregnancy, compression ultrasonography with real time imaging of the deep veins with venous compression should be performed as soon as possible to minimise the risk of PE. Doppler examination of the iliofemoral veins as part of the compression ultrasonography is recommended.12

Low molecular weight heparin (LMWH) is the anticoagulant of choice as it does not cross the placenta or enter breast milk.12 The Royal College of Obstetricians and Gynaecologists guideline on Thromboembolic disease in pregnancy and the puerperium: acute management suggests that the treatment is continued until at least 6 weeks postpartum and for a minimum duration of 3 months. Graduated elastic compression stockings are thought to be effective and are used for reducing DVT-related pain and oedema.13

Pregnant women who have an episode of VTE are at increased risk of VTE in future pregnancies and should be advised to avoid oestrogen-related oral contraception.14


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References

  1. Scottish Intercollegiate Guidelines Network (SIGN). Prevention and management of venous thromboembolism. SIGN Guideline 122. SIGN, 2010 (updated 2014). Available at: www.sign.ac.uk/assets/sign122.pdf
  2. NICE. Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. NICE Clinical Guideline 144. NICE, 2012. Available at: www.nice.org.uk/cg144
  3. Lijfering W, Veeger N, Middeldorp S et al. A lower risk of recurrent venous thrombosis in women compared with men is explained by sex-specific risk factors at time of first venous thrombosis in thrombophilic families. Blood 2009; 114 (10): 2031–2036.
  4. NICE. Deep vein thrombosis. NICE Clinical Knowledge Summary. cks.nice.org.uk/deep-vein-thrombosis (accessed 14 June 2017).
  5. NICE. Pulmonary embolism. NICE Clinical Knowledge Summary. cks.nice.org.uk/pulmonary-embolism (accessed 11 July 2017).
  6. Wells P, Anderson D, Rodger M et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003; 349: 1227–1235.
  7. Wells P, Anderson D, Rodger M et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost 2000 83 (3): 416–420.
  8. NICE. Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism. NICE Technology Appraisal 287. NICE, 2013. Available at: www.nice.org.uk/ta287
  9. NICE. Apixaban for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism. NICE Technology Appraisal 341. NICE, 2015. Available at: www.nice.org.uk/ta341
  10. NICE. Dabigatran etexilate for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism. NICE Technology Appraisal 327. NICE, 2014. Available at: www.nice.org.uk/ta327
  11. NICE. Edoxaban for treating and for preventing deep vein thrombosis and pulmonary embolism. NICE Technology Appraisal 354. NICE, 2015. Available at: www.nice.org.uk/ta354
  12. Khan F, Vaillancourt C, Bourjeily G et al. Diagnosis and management of deep vein thrombosis in pregnancy. BMJ 2017; 357: j2344.
  13. Royal College of Obstetricians and Gynaecologists (RCOG). Thromboembolic disease in pregnancy and the puerperium: acute management. RCOG Green-top Guideline 37b. RCOG, 2015. Available at: www.rcog.org.uk/globalassets/documents/guidelines/gtg-37b.pdf
  14. Faculty for Sexual and Reproductive Healthcare (FSRH). UK Medical eligibility criteria for contraceptive use | UKMEC 2016. FSRH, 2016. Available at: www.fsrh.org/standards-and-guidance/uk-medical-eligibility-criteria-for-contraceptive-use-ukmec/ G