Venous thromboembolic diseases: the management of venous thromboembolic diseases and the role of thrombophilia testing

NICE guidelines [CG144] Published date:

1 Guidance

The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.

To ensure comprehensive management and continuity when developing a programme of care for patients who are at risk of or who develop VTE, users of this guideline are encouraged to refer to NICE guidance on Venous thromboembolism: reducing the risk (NICE clinical guideline 92), Rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults (NICE technology appraisal guidance 170), Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults (NICE technology appraisal guidance 157) and Medicines adherence (NICE clinical guideline 76) (see also section 6).

Terms used in this guidance

D-dimer test D-dimer is a product formed in the body when a blood clot (such as those found in DVT or PE) is broken down. A laboratory or point-of-care test can be done to assess the concentration of D-dimer in a person's blood. The threshold for a positive result varies with the type of D-dimer test used and is determined locally. The result of the D-dimer test can be used as part of probability assessment when DVT or PE is suspected.

International normalised ratio (INR) A standardised laboratory measure of blood coagulation used to monitor the adequacy of anticoagulation in patients who are having treatment with a vitamin K antagonist.

Provoked DVT or PE in a patient with an antecedent (within 3 months) and transient major clinical risk factor for VTE – for example 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 – or in a patient who is having hormonal therapy (oral contraceptive or hormone replacement therapy).

Proximal DVT DVT in the popliteal vein or above. Proximal DVT is sometimes referred to as 'above-knee DVT'.

Renal impairment Reduced renal function that may be acute or chronic. An estimated glomerular filtration rate of less than 90 ml/min/1.73 m2 indicates a degree of renal impairment in chronic kidney disease. (For NICE guidance on the classification of chronic kidney disease see Chronic kidney disease [NICE clinical guideline 73]).

Unprovoked DVT or PE in a patient with:

  • no antecedent major clinical risk factor for VTE (see 'Provoked deep vein thrombosis or pulmonary embolism' above) who is not having hormonal therapy (oral contraceptive or hormone replacement therapy) or

  • active cancer, thrombophilia or a family history of VTE, because these are underlying risks that remain constant in the patient.

Wells score Clinical prediction rule for estimating the probability of DVT and PE. There are a number of versions of Wells scores available. This guideline recommends the two-level DVT Wells score and the two-level PE Wells score.

1.1 Diagnosis

Diagnostic investigations for deep vein thrombosis

1.1.1 If a patient presents with signs or symptoms of deep vein thrombosis (DVT), carry out an assessment of their general medical history and a physical examination to exclude other causes.

1.1.2 If DVT is suspected, use the two-level DVT Wells score (see table 1 below) to estimate the clinical probability of DVT.

Table 1 Two-level DVT Wells score a

Clinical feature

Points

Active cancer (treatment ongoing, within 6 months, or palliative)

1

Paralysis, paresis or recent plaster immobilisation of the lower extremities

1

Recently bedridden for 3 days or more or major surgery within 12 weeks requiring general or regional anaesthesia

1

Localised tenderness along the distribution of the deep
venous system

1

Entire leg swollen

1

Calf swelling at least 3 cm larger than asymptomatic side

1

Pitting oedema confined to the symptomatic leg

1

Collateral superficial veins (non-varicose)

1

Previously documented DVT

1

An alternative diagnosis is at least as likely as DVT

−2

Clinical probability simplified score

DVT likely

2 points or more

DVT unlikely

1 point or less

a Adapted with permission from Wells PS et al. (2003) Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis.

1.1.3 Offer patients in whom DVT is suspected and with a likely two-level DVT Wells score (see table 1 above) either:

  • a proximal leg vein ultrasound scan carried out within 4 hours of being requested and, if the result is negative, a D-dimer test
    or

  • a D-dimer test and an interim 24-hour dose of a parenteral anticoagulant (if a proximal leg vein ultrasound scan cannot be carried out within 4 hours) and a proximal leg vein ultrasound scan carried out within 24 hours of being requested.

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

1.1.4 Offer patients in whom DVT is suspected and with an unlikely
two-level DVT Wells score (see table 1 above) a D-dimer test and if the result is positive offer either:

  • a proximal leg vein ultrasound scan carried out within 4 hours of being requested or

  • an interim 24-hour dose of a parenteral anticoagulant (if a proximal leg vein ultrasound scan cannot be carried out within 4 hours) and a proximal leg vein ultrasound scan carried out within 24 hours of being requested.

1.1.5 Diagnose DVT and treat (see the recommendations on treatment in section 1.2) patients with a positive proximal leg vein ultrasound scan.

1.1.6 Take into consideration alternative diagnoses in patients with:

  • an unlikely two-level DVT Wells score (see table 1 above) and

    • a negative D-dimer test or

    • a positive D-dimer test and a negative proximal leg vein ultrasound scan.

  • a likely two-level DVT Wells score (see table 1 above) and

    • a negative proximal leg vein ultrasound scan and a negative D-dimer test or

    • a repeat negative proximal leg vein ultrasound scan.

Advise patients in these two groups that it is not likely they have DVT, and discuss with them the signs and symptoms of DVT and when and where to seek further medical help.

Diagnostic investigations for pulmonary embolism

1.1.7 If a patient presents with signs or symptoms of pulmonary embolism (PE), carry out an assessment of their general medical history, a physical examination and a chest X-ray to exclude other causes.

1.1.8 If PE is suspected, use the two-level PE Wells score (see table 2 below) to estimate the clinical probability of PE.


Table 2 Two-level PE Wells score a

Clinical feature

Points

Clinical signs and symptoms of DVT (minimum of leg swelling and pain with palpation of the deep veins)

3

An alternative diagnosis is less likely than PE

3

Heart rate > 100 beats per minute

1.5

Immobilisation for more than 3 days or surgery in the previous 4 weeks

1.5

Previous DVT/PE

1.5

Haemoptysis

1

Malignancy (on treatment, treated in the last 6 months, or palliative)

1

Clinical probability simplified scores

PE likely

More than 4 points

PE unlikely

4 points or less

a Adapted with permission from Wells PS et al. (2000) Derivation of a simple clinical model to categorize patients' probability of pulmonary embolism: increasing the model's utility with the SimpliRED D-dimer.

1.1.9 Offer patients in whom PE is suspected and with a likely two-level PE Wells score (see table 2 above) either:

  • an immediate computed tomography pulmonary angiogram (CTPA) or

  • immediate interim parenteral anticoagulant therapy followed by a CTPA, if a CTPA cannot be carried out immediately.

Consider a proximal leg vein ultrasound scan if the CTPA is negative and DVT is suspected.

1.1.10 Offer patients in whom PE is suspected and with an unlikely two-level PE Wells score (see table 2 above) a D-dimer test and if the result is positive offer either:

  • an immediate CTPA or

  • immediate interim parenteral anticoagulant therapy followed by a CTPA, if a CTPA cannot be carried out immediately.

1.1.11 For patients who have an allergy to contrast media, or who have renal impairment, or whose risk from irradiation is high:

  • Assess the suitability of a ventilation/perfusion single photon emission computed tomography (V/Q SPECT) scan or, if a V/Q SPECT scan is not available, a V/Q planar scan, as an alternative to CTPA.

  • If offering a V/Q SPECT or planar scan that will not be available immediately, offer immediate interim parenteral anticoagulant therapy.

1.1.12 Diagnose PE and treat (see the recommendations on treatment in section 1.2) patients with a positive CTPA or in whom PE is identified with a V/Q SPECT or planar scan.

1.1.13 Take into consideration alternative diagnoses in the following two groups of patients:

  • Patients with an unlikely two-level PE Wells score (see table 2 above) and either:

    • a negative D-dimer test or

    • a positive D-dimer test and a negative CTPA.

  • Patients with a likely two-level PE Wells score (see table 2 above) and both:

    • a negative CTPA and

    • no suspected DVT.

Advise these patients that it is not likely they have PE and discuss with them the signs and symptoms of PE, and when and where to seek further medical help.

Patients with signs or symptoms of both deep vein thrombosis and pulmonary embolism

1.1.14 If a patient presents with signs or symptoms of both DVT (for example a swollen and/or painful leg) and PE (for example chest pain, shortness of breath or haemoptysis), carry out initial diagnostic investigations for either DVT or PE, basing the choice of diagnostic investigations on clinical judgement.

1.2 Treatment

Pharmacological interventions

Deep vein thrombosis or pulmonary embolism

1.2.1 Offer a choice of low molecular weight heparin (LMWH) or fondaparinux to patients with confirmed proximal DVT or PE, taking into account comorbidities, contraindications and drug costs, with the following exceptions:

  • For patients with severe renal impairment or established renal failure (estimated glomerular filtration rate [eGFR] <30 ml/min/1.73 m2) offer unfractionated heparin (UFH) with dose adjustments based on the APTT (activated partial thromboplastin time) or LMWH with dose adjustments based on an anti-Xa assay.

  • For patients with an increased risk of bleeding consider UFH.

  • For patients with PE and haemodynamic instability, offer UFH and consider thrombolytic therapy (see recommendations 1.2.7 and 1.2.8 on pharmacological systemic thrombolytic therapy in pulmonary embolism).

Start the LMWH, fondaparinux or UFH as soon as possible and continue it for at least 5 days or until the international normalised ratio (INR) (adjusted by a vitamin K antagonist [VKA]; see recommendation 1.2.3 on VKA for patients with confirmed proximal DVT or PE) is 2 or above for at least 24 hours, whichever is longer.

1.2.2 Offer LMWH to patients with active cancer and confirmed proximal DVT or PE, and continue the LMWH for 6 months[4]. At 6 months, assess the risks and benefits of continuing anticoagulation[5].

1.2.3 Offer a VKA to patients with confirmed proximal DVT or PE within 24 hours of diagnosis and continue the VKA for 3 months. At 3 months, assess the risks and benefits of continuing VKA treatment (see recommendations 1.2.4 and 1.2.5 below).

1.2.4 Offer a VKA beyond 3 months to patients with an unprovoked PE, taking into account the patient's risk of VTE recurrence and whether they are at increased risk of bleeding. Discuss with the patient the benefits and risks of extending their VKA treatment.

1.2.5 Consider extending the VKA beyond 3 months for patients with unprovoked proximal DVT if their risk of VTE recurrence is high and there is no additional risk of major bleeding. Discuss with the patient the benefits and risks of extending their VKA treatment.

Rivaroxaban

NICE is developing technology appraisal guidance on rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism (publication expected July 2012).

Thrombolytic therapy

Deep vein thrombosis

1.2.6 Consider catheter-directed thrombolytic therapy for patients with symptomatic iliofemoral DVT who have:

  • symptoms of less than 14 days' duration and

  • good functional status and

  • a life expectancy of 1 year or more and

  • a low risk of bleeding.

Pulmonary embolism

1.2.7 Consider pharmacological systemic thrombolytic therapy for patients with PE and haemodynamic instability (see also recommendation 1.2.1 on pharmacological interventions for DVT and PE).

1.2.8 Do not offer pharmacological systemic thrombolytic therapy to patients with PE and haemodynamic stability (see also recommendation 1.2.1 on pharmacological interventions for DVT and PE).

Mechanical interventions

Proximal deep vein thrombosis or pulmonary embolism

1.2.9 Offer below-knee graduated compression stockings with an ankle pressure greater than 23 mmHg to patients with proximal DVT a week after diagnosis or when swelling is reduced sufficiently and if there are no contraindications[6], and:

  • advise patients to continue wearing the stockings for at least 2 years

  • ensure that the stockings are replaced two or three times per year or according to the manufacturer's instructions

  • advise patients that the stockings need to be worn only on the affected leg or legs.

1.2.10 Offer temporary inferior vena caval filters to patients with proximal DVT or PE who cannot have anticoagulation treatment, and remove the inferior vena caval filter when the patient becomes eligible for anticoagulation treatment.

1.2.11 Consider inferior vena caval filters for patients with recurrent proximal DVT or PE despite adequate anticoagulation treatment only after considering alternative treatments such as:

  • increasing target INR to 3–4 for long-term high-intensity oral anticoagulant therapy or

  • switching treatment to LMWH.

1.2.12 Ensure that a strategy for removing the inferior vena caval filter at the earliest possible opportunity is planned and documented when the filter is placed, and that the strategy is reviewed regularly.

1.3 Patient information

1.3.1 Give patients having anticoagulation treatment verbal and written information about:

  • how to use anticoagulants

  • duration of anticoagulation treatment

  • possible side effects of anticoagulant treatment and what to do if these occur

  • the effects of other medications, foods and alcohol on oral anticoagulation treatment

  • monitoring their anticoagulant treatment

  • how anticoagulants may affect their dental treatment

  • taking anticoagulants if they are planning pregnancy or become pregnant

  • how anticoagulants may affect activities such as sports and travel

  • when and how to seek medical help.

1.3.2 Provide patients who are having anticoagulation treatment with an 'anticoagulant information booklet' and an 'anticoagulant alert card' and advise them to carry the 'anticoagulant alert card' at all times.

1.3.3 Be aware that heparins are of animal origin and this may be of concern to some patients (see Religion or belief: a practical guide for the NHS). For patients who have concerns about using animal products, consider offering synthetic alternatives based on clinical judgement after discussing their suitability, advantages and disadvantages with the patient. [This recommendation is from Venous thromboembolism: reducing the risk (NICE clinical guideline 92]).

1.3.4 Advise patients about the correct application and use of
below-knee graduated compression stockings, how long they should be worn and when they should be replaced.

1.4 Self-management and self-monitoring for patients treated with a vitamin K antagonist

1.4.1 Do not routinely offer self-management or self-monitoring of INR to patients who have had DVT or PE and are having treatment with a VKA.

1.5 Investigations for cancer

1.5.1 Offer all patients diagnosed with unprovoked DVT or PE who are not already known to have cancer the following investigations for cancer:

  • a physical examination (guided by the patient's full history) and

  • a chest X-ray and

  • blood tests (full blood count, serum calcium and liver function tests) and

  • urinalysis.

1.5.2 Consider further investigations for cancer with an abdomino-pelvic CT scan (and a mammogram for women) in all patients aged over 40 years with a first unprovoked DVT or PE who do not have signs or symptoms of cancer based on initial investigation (see recommendation 1.5.1 above).

1.6 Thrombophilia testing

1.6.1 Do not offer thrombophilia testing to patients who are continuing anticoagulation treatment.

1.6.2 Consider testing for antiphospholipid antibodies in patients who have had unprovoked DVT or PE if it is planned to stop anticoagulation treatment.

1.6.3 Consider testing for hereditary thrombophilia in patients who have had unprovoked DVT or PE and who have a first-degree relative who has had DVT or PE if it is planned to stop anticoagulation treatment.

1.6.4 Do not offer thrombophilia testing to patients who have had provoked DVT or PE.

1.6.5 Do not routinely offer thrombophilia testing to first-degree relatives of people with a history of DVT or PE and thrombophilia.



[4] At the time of publication (June 2012) some types of LMWH do not have a UK marketing authorisation for 6 months of treatment of DVT or PE in patients with cancer. Prescribers should consult the summary of product characteristics for the individual LMWH and make appropriate adjustments for severe renal impairment or established renal failure. Informed consent for off-label use should be obtained and documented.

[5] Although this use is common in UK clinical practice, at the time of publication (June 2012) none of the anticoagulants has a UK marketing authorisation for the treatment of DVT or PE beyond 6 months in patients with cancer. Informed consent for off-label use should be obtained and documented.

[6] Prescribers should refer to specific product information and contraindications before offering graduated compression stockings.

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