DEEP VEIN THROMBOSIS

1.What validated criteria should I use in primary care to establish a patient’s risk of deep vein
thrombosis (DVT)?

In the symptomatic patient with suspected DVT, ruling the disease in or out in a primary care setting is a
challenge. Isolated clinical signs and symptoms are of limited use.[1] The best estimate is obtained
through use of clinical risk scores, which use both the patient’s history and findings on examination, and
the most validated of these is the Wells score.[2] The two level DVT Wells score is the current tool
recommended for risk assessment by the National Institute for Health and Care excellence (NICE).[3] It
has been validated within primary care and is the best available option for immediate risk assessment in
the symptomatic patient, dividing patients into either a high (likely) or a low (unlikely) risk category, as
shown in table 1.
Table 1. Two level DVT Wells score.

Clinical feature Points

Active cancer (treatment ongoing, within six months, or palliative) 1

Paralysis, paresis, or recent plaster immobilisation of the lower extremities 1

Recently bedridden for three days or more, or major surgery within 12 1

weeks requiring general or regional anaesthesia

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 Two

points or
more

DVT unlikely One

point or
less
In an asymptomatic patient, you can assess their future risk of DVT within primary care by quantifying
their inherent and acquired risk factors. Evaluate this risk using a validated tool such as
the QThrombosis® calculator, which was developed by primary care researchers from a database of
over 20 000 cases of venous thromboembolism (VTE).

2. Can all patients use the Wells clinical decision rule to assess their risk of DVT?

Only use the Wells clinical decision rule following a standard history and physical examination in a
patient in whom DVT is a diagnostic possibility. Do not apply it to all patients with leg pain and/or
swelling, in view of its limited specificity.[2, 43] The Wells criteria for establishing risk also lack
external validity in certain groups who were not included in the original 2003 study.[2] To apply the
Wells criteria, patients should therefore meet the following conditions:

 There should be clinical suspicion of acute leg DVT from the reviewing doctor after history and
examination
 Patients should not be pregnant or in the postpartum period
 Patients should be symptomatic within the preceding 72 hours of review
 Patients should not be on a treatment dose of anticoagulant (to include vitamin K antagonist, low
molecular weight heparin, or direct oral anticoagulant (DOAC)).

If these conditions are not met, or you strongly suspect DVT in a complex patient, you should consider
definitive imaging as a first line investigation. Other research teams have attempted to establish risk
prediction tools for these isolated cohorts, such as the Constans rule for upper limb DVT, and the LEFt
rule in pregnancy.[5, 6] These additional rules have not been extensively validated and are not
commonly used in general practice.

3. What is the investigation of choice to confirm DVT? When is a doppler ultrasound useful, and
when is a D-dimer test indicated?

Compression ultrasound (CUS) is well studied, and is the imaging investigation of choice in suspected
DVT.[7] It is a non-invasive, rapid, cost effective test, and is free from any harmful side effects. CUS is
usually performed as a triplex ultrasound, and includes assessment of 2D images for
anatomy/compressibility, pulsed wave, and colour doppler to study velocity and flow turbulence.

CUS can be limited to the proximal veins up to the level of the popliteal trifurcation (proximal CUS), or
include the whole leg (whole leg CUS).

 Proximal CUS has a high sensitivity when compared to contrast venography.[7] However, since
it doesn’t examine the calf, it can miss distal thrombi in the calf veins, or other pathology in the
calf. Negative proximal scans are often repeated at seven days to look for evidence of
propagating distal disease in the event of high clinical probability (likely Wells score) and a
raised D-dimer level. This can be inconvenient for patients and clinicians, as it involves an
additional appointment and the costs associated with further time off from work and/or transport
costs
 Whole leg CUS has the advantages of imaging the entire lower limb venous system in a single
sitting, and assessing the calf for alternate pathology such as calf haematoma or Baker’s cyst. An
alternate radiological diagnosis is found with whole leg assessment approximately 25% of the
time.[8] Pragmatic trials of symptomatic patients discharged without anticoagulation following a
 single negative whole leg CUS have consistently shown false negative rates of below 0.5%,
despite limited sensitivity data on comparison with venography.[9] Perhaps a greater concern
than false negatives is that a strategy incorporating whole leg CUS will diagnose approximately
twice the number of acute thrombi, thus resulting in twice the amount of therapeutic dose
anticoagulation. Increased anticoagulation naturally comes with an increased overall risk of
bleeding within this cohort. The evidence in support of anticoagulation for distal DVT is limited,
and many clinicians fear the harms of anticoagulation to outweigh the benefits in this population

To avoid CUS entirely, you can use a diagnostic strategy which incorporates D-dimer testing. Only use
D-dimer testing without CUS in patients deemed to have a low pretest probability of disease following
assessment with the Wells score, as recommended by NICE guidance.[3] If patients are “unlikely” to
have disease, a negative D-dimer test at a standard cut point effectively excludes the disease without the
need for CUS. Reporting units and standard cut points vary depending on the type of assay used.

Higher, age dependent cut points may perform with equal sensitivity in those patients over 50 years old,
but with much improved specificity.[12, 13] As such, the concept of age adjusted D-dimer thresholds is
gaining traction. These studies suggest a novel threshold of age multiplied by 10 in fibrinogen
equivalent units (FEU). So for an 80 year old patient, the cut point becomes 800 ng/ml FEU rather than
the standard 500 ng/ml FEU for those using a compatible assay. Prospective diagnostic randomised
controlled trials are lacking in this area.

There are several D-dimer point of care (POC) tests available, with some evidence for their use in the
community. These tests could theoretically reduce the need for assessment in hospital in a high
proportion of patients. Various POC D-dimer assays exist, and each has its own cut point recommended
by the manufacturer; these cut points can vary from those used in lab based clinical studies, but overall
sensitivity of point of care D-dimer testing appears to be relatively high

4. What is the most effective anticoagulation treatment for patients with DVT?

The standard treatment after diagnosis of acute DVT has been phased anticoagulation, involving daily
injections of low molecular weight heparin (LMWH) or fondaparinux at a treatment dose, alongside oral
loading with a vitamin K antagonist (VKA) such as warfarin. This remains the advice in the 2012 NICE
guidance last updated in November 2015.[3]

Newer direct oral anticoagulants (DOACs) include Factor Xa inhibitors such as rivaroxaban, apixaban,
and edoxaban, and the direct thrombin inhibitor dabigatran. They do not require regular monitoring, and
purport to have similar efficacy to standard anticoagulant treatment. These agents have all been deemed
non-inferior to warfarin for treatment of proximal DVT in large randomised controlled trials, and have
received positive technology appraisals from NICE advocating their use.

Rivaroxaban and apixaban are started in isolation, however both dabigatran and edoxaban need five
days’ parenteral anticoagulation with LMWH during the loading phase.

Currently rivaroxaban, apixaban, and edoxaban are black triangle drugs, which means limited
experience of the use of these products, and the MHRA requests that all suspected adverse reactions be
reported. You should consult the BNF for updated information on this status.
With regard to bleeding complications, all DOACS have shown an overall reduction in intracranial
bleeding when compared against standard VKA use.[18] Both edoxaban and apixaban have shown an
additional reduction in overall major bleeding episodes within large randomised datasets.[19] All
DOACS are either contraindicated, or used with caution in patients with severe hepatic or renal
impairment.[36]

 Patients with end stage renal disease (eGFR below 15 ml/min/1.73 m2) who have an acute DVT
often need admission for monitored use of either LMWH or intravenous unfractionated heparin.
This allows regular monitoring of blood levels to avoid toxicity and ongoing clinical review
 In patients with active cancer, usual practice is to maintain patients on treatment dose LMWH
for the duration of therapy, rather than oral agents. This practice is based on trial data
demonstrating improved outcomes

In light of the above, the most effective anticoagulant for DVT depends on the index disease,
comorbidities, bleeding risk, and patient preference.

5. Do we always need to anticoagulate patients who have a DVT? How do their age and any
comorbidities affect this decision? If we opt not to anticoagulate, how do we follow up these
patients?

The decision to anticoagulate any patient with a DVT is based on an individual assessment of the
risk/benefit profile. This profile incorporates four key issues:
 Location of thrombus and risks for propagation, embolisation, and recurrence
 Bleeding risk on anticoagulation
 The patient’s comorbidities
 The patient’s preference.

Patients with a proximal DVT are thought to have a high risk for embolisation, as many as 50% in one
study.[20] The average risk of major bleeding with therapeutic anticoagulation is approximately 2% to
3%.[21] As such, anticoagulation is strongly recommended in nearly all patients with proximal disease.
For patients with an unacceptably high risk of bleeding, insertion of an inferior vena cava filter is a
secondary option, but these cases should be discussed with a haematologist.[3]
Patients with a distal (calf) DVT are believed to be at lower overall risk of embolisation. Although
prospective data are limited, current reviews suggest a propagation rate of approximately 10%, and an
embolisation rate of 1% to 2% with untreated disease.[11] The risk/benefit profile therefore starts to
become more even.

Clinical scoring systems such as HASBLED and other validated tools can predict individualised
bleeding risk [22, 39]; at the same time, a clinical assessment can establish the likelihood of
complications from the DVT. Those who have unprovoked disease, severe symptoms, or those with a
large thrombus (high disease burden) may stand to benefit more from treatment. The American College
of Chest Physicians (ACCP) offers excellent guidance in this regard.[23] Consider your patient’s
preference in any decision making.

If you and your patient come to a decision not to treat their calf DVT, standard practice is serial CUS
and regular clinical review for a period of up to six weeks.[23] Imaging is conducted weekly in many
specialist centres, but frequency is decided locally. If there are no signs of propagation, and the patient is
well following a four to six week observation period, the likelihood of late complications are minimal
6. How long would you recommend anticoagulation for lower leg DVT and other thromboses?

Both the British Committee for Standards in Haematology (BCSH) and the American College of Chest
Physicians (ACCP) offer useful guidance on duration of therapy for patients with acute deep vein
thrombosis.[23, 24, 44] Duration is principally dependent on:

 Provoking factors
 Anatomical location
 Prior history.

For any proximal DVT, the recommended period of full therapeutic anticoagulation is at least three
months. If the thrombus is considered to be “provoked,” either by recent surgery or a non-surgical
transient risk factor (such as the oral contraceptive pill, pregnancy, or plaster immobilisation), then
continual anticoagulation is not routinely recommended. However, if the DVT is “unprovoked” then
consider extending the period of anticoagulation. This extended period can range from six months to
lifelong, based on the balanced risks of recurrence, major bleeding, and patient preference.

For those patients with isolated distal, or calf vein DVT, treatment recommendations vary. The BCSH
guidelines recommend six weeks of anticoagulation, based on a single randomised control trial of six
weeks versus three months of anticoagulation. The ACCP guidelines suggest conservative management
(without anticoagulation), unless concerns exist regarding the severity of symptoms, clot size, and
distribution (thrombus burden), or patient preference for treatment. In the latter cases, the ACCP
guidelines recommend three months’ treatment.

For patients with proximal DVT and active malignancy, six months of treatment with daily LMWH
injections is superior to three months.[25] In general, international guidance suggests patients should
have extended anticoagulation while the cancer is active, with continuing use being reassessed regularly
(for example annually)

7. Is there any need for investigation before stopping anticoagulation, such as a follow up
ultrasound?

The majority of centres will base decisions about stopping treatment on a combination of:
 Patient preference
 Anatomical location of index disease
 Provocation data
 Presence of malignancy
 Validated estimates of recurrence or complication.

Laboratory tests are often distorted by ongoing drug treatment prior to stopping anticoagulation.
However, certain tests do predict recurrence of unprovoked disease after treatment has stopped.[26, 27]
The DASH score for example uses the D-dimer test and clinical assessment to assess risk of
recurrence.[26] There is reasonable evidence to suggest that a raised D-dimer three weeks after stopping
oral anticoagulation, when assessed in conjunction with clinical risk factors such as increasing age and
male sex, increases the risk of recurrence. Other rules such as HERDOO2 suggest D-dimer testing
during anticoagulation.[27] The Vienna prediction model is an additional tool to evaluate the risk of
recurrence, but is limited by its complexity.[38]
Previous work has looked at the degree of residual vein obstruction (RVO) on ultrasound prior to
cessation as a predictor of recurrence. Although this is a technique likely to suffer from reliability issues,
it has potential face validity. Presence of RVO at the conclusion of treatment in unprovoked disease
provides only a modest estimate of recurrence risk.[28] There are no randomised trials assessing the net
benefit of this technique for patients, and it comes with significant time, cost, and inconvenience for
patients. There is potential for the technique to lead to over-anticoagulation and harm. As such, it is not
incorporated in any current risk prediction models, although further studies are ongoing.

8. If I suspect a lower leg DVT and I’m awaiting a scan to confirm it, is it reasonable to start a
DOAC immediately rather than heparin?

This is a difficult question, as the majority of DOAC trials only recruited patients with confirmed
venous thrombosis or pulmonary embolism, and not suspected disease. This means that we need to
extrapolate from these trials about the safety of these drugs in patients with suspected disease, although
this extrapolation is likely to be correct.

There is also little direct evidence to support the current use of LMWH over alternatives in suspected
disease, although use of parenteral LMWH is now established current practice and recommended by
NICE for patients needing to wait more than four hours for objective imaging.

Therapeutic anticoagulation with dabigatran and edoxaban is preceded by a five day LMWH lead in.As
such, these agents cannot be used as monotherapy in cases of suspected disease. However, rivaroxaban
and apixaban provide therapeutic anticoagulation as monotherapy, and as such could be used for
anticoagulation cover pending diagnosis. Currently these are both black triangle drugs, which means
limited experience of the use of these products, and the MHRA requests that all suspected adverse
reactions should be reported. You should consult the BNF for updated information on this status.

When using rivaroxaban or apixaban, the patient needs to take a treatment dose every 12 hours until the
diagnosis is confirmed or excluded. You should also consult local guidelines for advice on the use of
DOACs in primary care for DVTs in your area.

9. What should I say to patients who want a scan every week to assess the clot?

The assessment of whether or not there is any residual thrombus is challenging, and is prone to
problems with interobserver reliability.[29, 30] On serial compression ultrasound (CUS), changes in clot
structure and volume are notable only when extensive.[29] The diagnosis of recurrence/extension in a
patient on therapeutic dose anticoagulation is not without risk; current guidelines suggest increasing the
intensity of anticoagulation in this event, for example changing to low molecular weight heparin.[23]
This increases the risk of fatal intracranial bleeding and major bleeding. As such, the diagnosis of
recurrence/extension on treatment is one with significant implications, and is made on clinical
presentation rather than radiological investigation.

In some cases, such as conservatively managed calf DVT, serial CUS may have advantages. Agree clear
endpoints for propagation, and start treatment based on a transparent failure of conservative care. The
most commonly agreed cut point is propagation to or above the level of the popliteal trifurcation

10. When is it appropriate to investigate for a clotting disorder, and how should this be carried
out?
There is much discussion about thrombophilia screening to guide decision making for long term
anticoagulation in patients with unprovoked DVT. Current evidence would suggest limited benefit to
individualised prediction of risk.[

NICE has produced clear UK guidance on the role of testing for thrombophilia or antiphospholipid
syndrome in venous thromboembolism.[3] Use this guidance in shared decision making with your
patient at the end of their initial treatment period, and if the patient refuses further anticoagulation at this
stage, regardless of additional test results, then acknowledge this.

The guidance from NICE recognises that if anticoagulation is continued long term anyway, then it is
neither of clinical or economic benefit to screen for thrombophilic disease.[3] Likewise, for those
patients with provoked disease who are at low overall risk of recurrence, testing offers no additional
benefit and is not recommended after stopping anticoagulation. You should consider testing in the
following circumstances:

 Patients with unprovoked disease where it is planned to stop anticoagulation, and there is a
strong family history of venous thrombosis. Thrombophilia testing involves screening for
deficiency in three main natural anticoagulants: protein C, protein S, and antithrombin. A
positive test increases the risk of recurrence, and you should factor this into your decision
making regarding long term treatment
 Also consider testing for antiphospholipid syndrome (APS) in patients with unprovoked DVT,
with or without a strong family history of disease.

For accuracy, only screen for thrombophilia and APS following cessation of anticoagulants; these drugs
can interfere with test results.

11. How should I assess and manage a patient who is prone to recurrent DVT?

The patient who is prone to recurrent DVT is highly likely to already be taking an anticoagulant at a
treatment dose. Your assessment should focus on identification of new disease that needs a change in
management, rather than evaluation of any previous chronic thrombi. Management should focus on
early gold standard investigation (usually CUS in a patient at high clinical risk; see question 3 for more
details) where there is a strong suspicion of new VTE. Maintain therapeutic levels of anticoagulation
while awaiting the results of any investigations, rather than increasing the dose.

In patients with prior disease who are currently not receiving anticoagulation of any kind, the modified
Wells score is validated to include previous VTE as a criterion. Interpretation of CUS is challenging in
patients with chronic thrombi, so use expert sonographers and compare current images with previous
ones to avoid mislabelling of scan results. The diagnosis of recurrence is an important one, as it can
mean the difference between lifelong anticoagulation and anticoagulation for three months only.