Deep vein thrombosis

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

INITIAL

suspected or confirmed DVT of the leg with phlegmasia cerulea dolens

1st line – immediate parenteral anticoagulation plus supportive care

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1st line –

immediate parenteral anticoagulation plus supportive care

Phlegmasia cerulea dolens (PCD) is a life- and limb-threatening emergency. If it is suspected, quick action is needed; the results of investigations should not be waited for before treatment is started.[40]

Supportive therapies and parenteral anticoagulation with unfractionated heparin (UFH) should be started immediately.[40]

The affected limb should be elevated. Local resuscitation protocols should be followed, and urgent advice should be sought from the critical care team about appropriate resuscitation measures.[40]

Primary options

heparin: 80 units/kg intravenous bolus initially, followed by 18 units/kg/hour intravenous infusion, adjust dose according to aPTT; 333 units/kg subcutaneously initially, followed by 250 units/kg every 12 hours

Plus – thrombolysis or surgical thrombectomy

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Plus –

thrombolysis or surgical thrombectomy

Treatment recommended for ALL patients in selected patient group

The patient should immediately be referred to a vascular surgeon or interventional radiology. Treatment options include catheter-directed thrombolysis, pharmacomechanical-directed thrombolysis, and surgical thrombectomy (which may be combined with fasciotomy and iliac stenting), although these are generally used for phlegmasia cerulea dolens due to iliac vein DVT.[40][159][160][161]

suspected or confirmed DVT without phlegmasia cerulea dolens and no contraindications to anticoagulation: initiation-phase therapy

proximal DVT of the leg

1st line – anticoagulation

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1st line –

anticoagulation

Patients with a confirmed proximal DVT of the leg, or who present with suspected DVT and have a high probability of disease, should receive an anticoagulant dosed according to the initiation phase of therapy, unless contraindicated.[18]

Choice of agent depends on patient factors such as hepatic/renal function, pregnancy, cancer, obesity, other comorbidities, concomitant medications and drug-drug interactions, and bleeding risk. Choice may also depend on patient preference or recommendations in local guidelines.[18]

If treatment was initiated before diagnostic confirmation and DVT is subsequently excluded, anticoagulation can be discontinued.[18]

Unfractionated heparin (UFH) is recommended when interventional therapies (e.g., catheter-directed thrombolysis or pharmacomechanical intervention) may be utilized, or if the patient is at high risk of bleeding.

In stable patients the choice of initial anticoagulant is guided by the choice for the most appropriate longer-term therapy. Generally this will be a direct oral anticoagulant (DOAC), but there are exceptions for specific patient populations.

DOACs (e.g., apixaban, edoxaban, rivaroxaban, dabigatran) are generally recommended over vitamin K antagonists (usually warfarin). If a DOAC is chosen, there is either an initiation phase at a higher oral dose (apixaban and rivaroxaban), or lead-in treatment with a parenteral anticoagulant for 5-10 days while treatment is established (edoxaban and dabigatran). This is then followed by oral monotherapy at treatment-phase dosing of the chosen agent. DOACs are as effective as UFH, low molecular weight heparin (LMWH), and warfarin for the treatment of venous thromboembolism (VTE), and are generally recommended over these drugs outside of special populations.[168] No monitoring of coagulation profile is necessary, and bleeding complications are similar or less than those of warfarin, but there is a lower or similar incidence of major bleeding with pulmonary embolism.[169][170] All have a longer half-life than UFH or LMWH and a shorter half-life than warfarin, and all have a rapid onset of action. DOACs do not interact with food; however, they do undergo some drug-drug interactions. Notable drug interactions include: strong inhibitors or inducers of P-glycoprotein (with edoxaban and dabigatran); and strong inhibitors or inducers of P-glycoprotein and CYP3A4 (with apixaban and rivaroxaban).

For patients where warfarin is more appropriate, treatment with UFH, LMWH, or fondaparinux alongside the starting dose of warfarin is needed in the initiation phase, while therapeutic anticoagulation is established. In patients who will transition from UFH, LMWH, or fondaparinux to warfarin, warfarin should be started the same day that UFH, LMWH, or fondaparinux is started, unless there is a very high risk for bleeding. If bleeding risk is high, observing the patient for 1-2 days on UFH alone is advisable. Three strategies can be used to select the initial dose of warfarin: a clinical algorithm calculates the estimated stable and starting dose based on several patient characteristics; a genetic algorithm calculates the estimated stable and starting dose based on the results of genetic tests such as CYP450-2C9 genotype and VKORC1 haplotype, as well as clinical variables; a fixed-dose approach uses initiation nomograms.[172][173] [ ] Once warfarin is started, it is continued concomitantly with the parenteral anticoagulant while the dose is titrated. Subsequent dosing of warfarin is based on the international normalized ratio (INR) response to each dose. The therapeutic INR range is 2-3 (target 2.5, unless concomitantly being used for anticoagulation of mechanical heart valves). UFH, LMWH, or fondaparinux should be continued for a minimum of 5 days, and until INR is 2 or greater for at least 24 hours, at which point the UFH, LMWH, or fondaparinux can be discontinued.[18][179]

UFH is preferred when a short-acting agent is needed due to concerns about bleeding. It is usually initiated with an intravenous weight-based loading bolus followed immediately by initiation of a weight-based continuous infusion. Treatment requires monitoring of activated partial thromboplastin time (aPTT) or heparin-calibrated anti-Xa activity, which is used to titrate dose to the target range. LMWH may be used if there are indications for extended LMWH (e.g., in patients who cannot take an oral medication, patients with cancer with concomitant medications that have significant drug-drug interaction that precludes DOAC, patients with an intraluminal gastrointestinal [GI] malignancy and high risk of GI bleeding, and patients with severe liver disease where neither warfarin nor DOACs can be used). LMWH is dosed subcutaneously according to patient weight. Platelet count is regularly measured during treatment with UFH or LMWH because of the possibility of heparin-induced thrombocytopenia (HIT) as a complication.

Increased risk of bleeding: it may be preferable to treat patients who are at increased risk of bleeding (e.g., recent surgery, peptic ulceration) with intravenous UFH initially because it has a short half-life and its effect can be reversed quickly with protamine.[41] Once it is clear anticoagulation is tolerated, selection of an appropriate anticoagulation regimen can take place.

Active cancer: in patients with VTE and active cancer (cancer-associated thrombosis), a DOAC (apixaban, edoxaban, rivaroxaban) is recommended over LMWH.[18][19] LMWH, UFH, fondaparinux, rivaroxaban, or apixaban can be used for initial anticoagulation.[42] DOACs (particularly edoxaban and rivaroxaban) are associated with a higher risk of gastrointestinal bleeding than LMWH. In patients with luminal gastrointestinal cancer, the American College of Chest Physicians (ACCP) recommends apixaban or LMWH as the preferred agents.[18][181]

Renal impairment: for patients with renal impairment (i.e., creatinine clearance <30 mL/minute), intravenous or subcutaneous UFH, followed by warfarin, is the preferred anticoagulant regimen. Apixaban is approved for use in severe renal disease and has outcomes similar to UFH followed by warfarin, and represents an alternative option.[182] LMWH has unpredictable renal clearance among patients with renal failure. For patients on LMWH, laboratory monitoring of the anticoagulant effect (i.e., by anti-factor Xa assay) is generally not necessary, but should be considered in patients with severe renal impairment and those with moderate renal impairment if LMWH use is prolonged (i.e., >10 days).[183] Fondaparinux, rivaroxaban, edoxaban, and dabigatran are generally not recommended in people with severe renal impairment, and patients with creatinine clearance <25 to 30 mL/minute were excluded from large randomized controlled trials. Apixaban, edoxaban, and rivaroxaban may be used in some patients with renal impairment; however, consult local guidance as recommendations vary between countries.

Hepatic impairment: UFH or LMWH are recommended in these patients, and should be overlapped with warfarin unless cancer is present.[18] Warfarin should be used cautiously if the baseline INR is elevated; extended-duration LMWH may be preferred.[20][184] DOACs are generally not recommended in patients with hepatic impairment, especially those with moderate-to-severe impairment (Child-Pugh class B or C).[18][41]

Obesity: UFH or LMWH are options for the initiation phase of treatment in patients living with obesity. The use of actual body weight is appropriate when calculating the therapeutic dose in obese patients. Laboratory monitoring of the anticoagulant effect of LMWH (i.e., by anti-factor Xa assay) is generally not necessary, but should be considered in patients with class III obesity (body mass index [BMI] 40 or above).[20][81][183] There is no known weight limit for the use of DOACs; however, they have not been extensively studied in patients with extreme weights. The Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis recommends dabigatran and edoxaban are avoided in patients with BMI >40 kg/m² or weight >120 kg given the lack of clinical outcomes data. Rivaroxaban and apixaban can be considered in these patients.[185] Two large, retrospective, matched cohort studies showed similar outcomes in patients receiving rivaroxaban, apixaban, or dabigatran versus warfarin, though no prospective comparative evidence exists.[186][187] If DOACs are used in these patients, appropriate drug-specific monitoring may be considered, though there is limited evidence that drug-specific levels predict important clinical outcomes.[81]

Pregnancy: women who develop VTE and who are pregnant or may become pregnant can be treated with subcutaneous UFH or LMWH monotherapy.[188] Because of changes in the pharmacodynamics of subcutaneous UFH during pregnancy, LMWH is preferred.[18][189] Routine measurement of peak anti-Xa activity for pregnant or postpartum patients on LMWH is not recommended except in women at extremes of body weight (i.e., <50 kg or >90 kg) or with other complicating factors (e.g., renal impairment or recurrent VTE) that put them at high risk. Warfarin is known to cause teratogenic effects when used in pregnancy and should be avoided. If breastfeeding is planned, then LMWH is the agent of choice. Warfarin is an alternative; it is minimally secreted in breast milk, but there is extensive clinical experience suggesting no ill effect in the breastfeeding infant.[153][190] The safety of DOACs in pregnancy and lactation is not known, and they should be avoided in both situations (but can be used in the postpartum period if the patient is not breastfeeding).

Heparin-induced thrombocytopenia (HIT): in patients with HIT, anticoagulation is with argatroban. Fondaparinux, apixaban, rivaroxaban, and dabigatran have also been suggested, though they are not approved for patients with active HIT.[166][167] Argatroban is preferred for patients with HIT with high bleeding risk or renal impairment. See Heparin-associated thrombocytopenia.

Primary options

Direct oral anticoagulant (DOAC)

apixaban: 10 mg orally twice daily for 7 days, followed by 5 mg twice daily

Direct oral anticoagulant (DOAC)

edoxaban: ≤60 kg body weight: 30 mg orally once daily, starting 5-10 days after treatment with a parenteral anticoagulant; >60 kg body weight: 60 mg orally once daily, starting 5-10 days after treatment with a parenteral anticoagulant

Direct oral anticoagulant (DOAC)

rivaroxaban: 15 mg orally twice daily for 21 days, followed by 20 mg once daily

Direct oral anticoagulant (DOAC)

dabigatran etexilate: 150 mg orally twice daily, starting 5-10 days after treatment with a parenteral anticoagulant

Vitamin K antagonist

warfarin: 2-5 mg orally once daily initially, adjust dose according to target INR

Low molecular weight heparin (LMWH)

enoxaparin: 1 mg/kg subcutaneously every 12 hours; or 1.5 mg/kg subcutaneously every 24 hours

Low molecular weight heparin (LMWH)

dalteparin: 200 units/kg subcutaneously every 24 hours for 1 month, followed by 150 units/kg every 24 hours, maximum 18,000 units/day; or 100 units/kg subcutaneously every 12 hours for 1 month, followed by 150 units/kg every 24 hours, maximum 18,000 units/day

Unfractionated heparin (UFH)

Factor Xa inhibitor

fondaparinux: <50 kg body weight: 5 mg subcutaneously once daily; 50-100 kg body weight: 7.5 mg subcutaneously once daily; >100 kg body weight: 10 mg subcutaneously once daily

Direct thrombin inhibitor

argatroban: consult specialist for guidance on dose

Plus – physical activity

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Plus –

physical activity

Treatment recommended for ALL patients in selected patient group

Early walking exercise is considered safe in patients with acute DVT.[41][221] It does not increase leg symptoms acutely in patients with a previous DVT, and may help to reduce post-thrombotic syndrome.[221][222][223][224]

Consider – gradient stockings

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Consider –

gradient stockings

Treatment recommended for SOME patients in selected patient group

Gradient (graduated compression) stockings are not recommended for the prevention of post-thrombotic syndrome by the ACCP guidelines. There is no evidence that their use reduces the risk for recurrent DVT.[18] However, they may be useful for patients with acute or chronic symptoms of DVT.[18] [ ]

Not recommended for other patients.[18]

distal DVT of the leg

1st line – serial imaging of the deep veins and/or anticoagulation

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1st line –

serial imaging of the deep veins and/or anticoagulation

For patients with acute isolated distal DVT of the leg with severe symptoms or risk factors for extension, anticoagulation is recommended.[18] Risk factors for extension include: positive D-dimer, extensive thrombosis (e.g., >5 cm long; involving multiple veins; >7 mm in maximum diameter), thrombosis close to the proximal veins, absence of any reversible provoking factor, active cancer, past history of venous thromboembolism (VTE), or hospital inpatient status.[18]

For patients with acute isolated distal DVT of the leg but without severe symptoms or risk factors for extension, serial imaging (e.g., once weekly or with worsening of symptoms) of the deep veins for 2 weeks is suggested over anticoagulation.[18][164] Anticoagulation is given only if the thrombus propagates on serial ultrasound examinations.[18]

If treatment was initiated before diagnostic confirmation and DVT is subsequently excluded, anticoagulation can be discontinued.[18]

UFH is preferred when a short-acting agent is needed due to concerns about bleeding. Treatment requires monitoring of activated partial thromboplastin time (aPTT) or heparin-calibrated anti-Xa activity, which is used to titrate dose to the target range. LMWH may be used in the initiation phase pending subsequent transition to a DOAC (dabigatran or edoxaban) or warfarin in the treatment phase. LMWH is dosed subcutaneously according to patient weight. Platelet count is regularly measured during treatment with UFH or LMWH because of the possibility of heparin-induced thrombocytopenia (HIT) as a complication.

Obesity: UFH or LMWH are options for the initiation phase of treatment in patients living with obesity. The use of actual body weight is appropriate when calculating the therapeutic dose in obese patients. Laboratory monitoring of the anticoagulant effect of LMWH (i.e., by anti-factor Xa assay) is generally not necessary, but should be considered in patients with class III obesity (BMI 40 or above).[20][81][183] There is no known weight limit for the use of DOACs; however, they have not been extensively studied in patients with extreme weights. The Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis recommends dabigatran and edoxaban are avoided in patients with BMI >40 kg/m² or weight >120 kg given the lack of clinical outcomes data. Rivaroxaban and apixaban can be considered in these patients.[185] Two large, retrospective, matched cohort studies showed similar outcomes in patients receiving rivaroxaban, apixaban, or dabigatran versus warfarin, though no prospective comparative evidence exists.[186][187] If DOACs are used in these patients, appropriate drug-specific monitoring may be considered, though there is limited evidence that drug-specific levels predict important clinical outcomes.[81]

Primary options

Direct oral anticoagulant (DOAC)

apixaban: 10 mg orally twice daily for 7 days, followed by 5 mg twice daily

Direct oral anticoagulant (DOAC)

rivaroxaban: 15 mg orally twice daily for 21 days, followed by 20 mg once daily

Direct oral anticoagulant (DOAC)

dabigatran etexilate: 150 mg orally twice daily, starting 5-10 days after treatment with a parenteral anticoagulant

Vitamin K antagonist

warfarin: 2-5 mg orally once daily initially, adjust dose according to target INR

Low molecular weight heparin (LMWH)

enoxaparin: 1 mg/kg subcutaneously every 12 hours; or 1.5 mg/kg subcutaneously every 24 hours

Low molecular weight heparin (LMWH)

Unfractionated heparin (UFH)

Factor Xa inhibitor

fondaparinux: <50 kg body weight: 5 mg subcutaneously once daily; 50-100 kg body weight: 7.5 mg subcutaneously once daily; >100 kg body weight: 10 mg subcutaneously once daily

Direct thrombin inhibitor

argatroban: consult specialist for guidance on dose

Plus – physical activity

Back

Plus –

physical activity

Treatment recommended for ALL patients in selected patient group

Consider – gradient stockings

Back

Consider –

gradient stockings

Treatment recommended for SOME patients in selected patient group

Not recommended for other patients.[18]

suspected or confirmed DVT without phlegmasia cerulea dolens: contraindications to anticoagulation

proximal DVT of the leg

1st line – IVC filter

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1st line –

IVC filter

An inferior vena cava (IVC) filter can be placed in patients with acute proximal DVT (e.g., diagnosed in the preceding 1 month) who have a contraindication to anticoagulation therapy (absolute contraindications to anticoagulation include active major bleeding, severe thrombocytopenia, high bleeding risk, central nervous system lesion).[18][22][41][201][202]Kaufman JA, Barnes GD, Chaer RA, et al. Society of Interventional Radiology clinical practice guideline for inferior vena cava filters in the treatment of patients with venous thromboembolic disease. Developed in collaboration with the American College of Cardiology, American College of Chest Physicians, American College of Surgeons Committee on Trauma, American Heart Association, Society for Vascular Surgery, and Society for Vascular Medicine. J Vasc Interv Radiol. 2020 Oct;31(10):1529-44. The American College of Chest Physicians (ACCP) guidelines recommend against the use of IVC filters in addition to anticoagulation in patients with acute DVT of the leg.[18] Other guidelines consider relative indications for IVC filter use to include massive pulmonary embolism (PE) with residual deep venous thrombus in a patient at risk for further PE, free-floating iliofemoral or IVC thrombus, and severe cardiopulmonary disease and DVT (e.g., cor pulmonale with pulmonary hypertension).[203]

IVC filter placement should take place as early as possible if it is the only treatment that can be initiated. There is little evidence available to suggest the ideal time for placement. Observational studies suggest that insertion of a venous filter might reduce PE-related mortality rates in the acute phase but with an associated increase in the risk of filter-related venous thromboembolism.[207][208]

Complications associated with permanent IVC filters are common, although they are rarely fatal.[208] Early complications (including insertion-site thrombosis) occur in approximately 10% of patients. Late complications are more frequent and include recurrent DVT (approximately 20% of patients) and post-thrombotic syndrome (up to 40% of patients).[209][210] Occlusion of the IVC filter affects approximately 22% of patients at 5 years and 33% at 9 years, regardless of the use and duration of anticoagulation.[210]

Post-filter anticoagulation should be considered on a case-by-case basis according to relative and absolute contraindications.[211] Anticoagulation should be initiated if the contraindication resolves or if a risk/benefit analysis suggests this to be a reasonable course.[18] When retrievable filters are used, they should be removed as soon as it is safe to use anticoagulants.[22]

Plus – physical activity

Back

Plus –

physical activity

Treatment recommended for ALL patients in selected patient group

Consider – gradient stockings

Back

Consider –

gradient stockings

Treatment recommended for SOME patients in selected patient group

Not recommended for other patients.[18]

distal DVT of the leg

1st line – serial imaging of the deep veins

Back

1st line –

serial imaging of the deep veins

Plus – physical activity

Back

Plus –

physical activity

Treatment recommended for ALL patients in selected patient group

Consider – gradient stockings

Back

Consider –

gradient stockings

Treatment recommended for SOME patients in selected patient group

Gradient (graduated compression) stockings are not recommended for the prevention of post-thrombotic syndrome by the American College of Chest Physicians (ACCP) guidelines. There is no evidence that their use reduces the risk for recurrent DVT.[18] However, they may be useful for patients with acute or chronic symptoms of DVT.[18] [ ]

Not recommended for other patients.[18]

ACUTE

treatment-phase therapy

1st line – maintenance anticoagulation

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1st line –

maintenance anticoagulation

The American College of Chest Physicians (ACCP) guidelines recommend that patients who do not have a contraindication are given a 3-month treatment phase of anticoagulation. In general, the treatment used during the acute phase is continued into the treatment phase; direct oral anticoagulants (DOACs) are recommended over a vitamin K antagonist (usually warfarin).[18]

During the treatment phase, follow-up and reevaluation are based on the patient's level of risk for bleeding, comorbidities, and the anticoagulant agent selected.[18]

Patients taking dabigatran or edoxaban should remain on the same dose started during the initiation phase with a parenteral agent, unless renal function substantially declines, warranting discontinuation. Patients taking apixaban and rivaroxaban should have their dose adjusted to the treatment-phase dose.[41]

Patients treated with warfarin should continue to report for international normalized ratio (INR) measurements. The target range of 2-3 (target INR 2.5) is maintained, unless concomitant anticoagulation for mechanical heart valves is required.[41]

If extended low molecular weight heparin (LMWH) is used (e.g., in patients who cannot take an oral medication, patients with cancer with concomitant medications that have significant drug-drug interaction that precludes DOAC, patients with an intraluminal gastrointestinal [GI] malignancy and high risk of GI bleeding, and patients with severe liver disease where neither warfarin nor DOACs can be used), the dose depends upon the agent.[41] If dalteparin is chosen, the dose is reduced after 1 month. If enoxaparin is chosen, some experts suggest reducing the initial dose after 1 month though this is based on opinion only, and the initial dose can be continued. The dose of LMWH should be adjusted to change in the patient's weight or creatinine clearance.

The treatment phase of anticoagulation differs in pregnant patients. Patients with pregnancy-associated venous thromboembolism (VTE) undergo treatment-phase anticoagulation for at least 3 months, or until 6 weeks postpartum, whichever is longer.[188][189] At the conclusion of this phase in the postpartum, decisions are made according to whether the patient is planning to breastfeed. Guidelines differ on offering extended anticoagulation for VTE associated with pregnancy, as there is an intermediate risk of future unprovoked VTE.[21][180]

Once the treatment phase has been completed, all patients should be evaluated for extended-phase therapy.[18]

Primary options

Direct oral anticoagulant (DOAC)

apixaban: 10 mg orally twice daily for 7 days, followed by 5 mg twice daily

Direct oral anticoagulant (DOAC)

rivaroxaban: 15 mg orally twice daily for 21 days, followed by 20 mg once daily

Direct oral anticoagulant (DOAC)

dabigatran etexilate: 150 mg orally twice daily, starting 5-10 days after treatment with a parenteral anticoagulant

Vitamin K antagonist

warfarin: 2-5 mg orally once daily initially, adjust dose according to target INR

Low molecular weight heparin (LMWH)

enoxaparin: 1 mg/kg subcutaneously every 12 hours; or 1.5 mg/kg subcutaneously every 24 hours

Low molecular weight heparin (LMWH)

Factor Xa inhibitor

fondaparinux: <50 kg body weight: 5 mg subcutaneously once daily; 50-100 kg body weight: 7.5 mg subcutaneously once daily; >100 kg body weight: 10 mg subcutaneously once daily

Direct thrombin inhibitor

argatroban: consult specialist for guidance on dose

Plus – physical activity

Back

Plus –

physical activity

Treatment recommended for ALL patients in selected patient group

Consider – gradient stockings

Back

Consider –

gradient stockings

Treatment recommended for SOME patients in selected patient group

Not recommended for other patients.[18]

ONGOING

extended-phase therapy: provoked DVT

1st line – consider extended anticoagulation

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1st line –

consider extended anticoagulation

The goal for continuation of anticoagulant therapy into the extended phase (i.e., beyond the first 3 months and with no scheduled stop date) is secondary prevention of venous thromboembolism (VTE).

The American College of Chest Physicians (ACCP) guidelines recommend that patients with DVT provoked by a persistent risk factor are given extended-phase anticoagulation.[18] These patients should be given a direct oral anticoagulant (DOAC), unless contraindicated, in which case they should be given warfarin. Extended-phase anticoagulation is not recommended in patients with DVT who are diagnosed in the context of a major or a minor transient risk factor.[18]

The ACCP guidelines recommend using reduced-dose apixaban or rivaroxaban for patients receiving apixaban or rivaroxaban; the choice of a particular drug and dose should consider the patient's body mass index, renal function, and adherence to the dosing regimen.[18] The decision to start or continue extended therapy should be based on patient preference and the predicted risk of recurrent VTE or bleeding.[18]

The continued use of extended-phase anticoagulation should be reassessed at least annually, as well as at any time there is a significant change in the patient's health status.[18]

For provoked (minor or major transient risk factors) DVT, anticoagulation is discontinued after a course of at least 3 months. There is consensus that patients who have an index DVT that occurs in the setting of a major transient provocation have a relatively low risk of developing recurrent VTE in the next 5 years, with estimates in the range of 15%.[18] In these patients, a time-limited course of anticoagulation of at least 3 months is suggested.[18]

The presence of a hereditary thrombophilia does not alter this recommendation, and guidelines recommend against testing for thrombophilias in patients with a DVT occurring following a major transient provocation.[55][56]

The risk of recurrent VTE is modestly higher in patients who sustain DVT in the setting of a minor transient provocation. Guidelines differ on offering extended anticoagulation for VTE associated with minor transient provoking risk factors.[21][180]

Primary options

apixaban: 5 mg orally twice daily; consider 2.5 mg orally twice daily after completing at least 6 months treatment

edoxaban: ≤60 kg body weight: 30 mg orally once daily; >60 kg body weight: 60 mg orally once daily

rivaroxaban: 20 mg orally once daily; consider 10 mg orally once daily after completing at least 6 months treatment

dabigatran etexilate: 150 mg orally twice daily

Secondary options

warfarin: 2-5 mg orally once daily initially, adjust dose according to target INR

extended-phase therapy: unprovoked DVT

1st line – extended anticoagulation or aspirin

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1st line –

extended anticoagulation or aspirin

The goal for continuation of anticoagulant therapy into the extended phase (i.e., beyond the first 3 months and with no scheduled stop date) is secondary prevention of venous thromboembolism (VTE).

The American College of Chest Physicians (ACCP) guidelines recommend that patients with unprovoked DVT are given extended-phase anticoagulation.[18] These patients should be given a direct oral anticoagulant (DOAC), unless contraindicated, in which case they should be given warfarin.

For patients with a first proximal DVT that is unprovoked and who have a low or moderate bleeding risk, extended anticoagulant therapy is recommended (with no scheduled stop date and reassessment of ongoing therapy at regular intervals, such as annually). For those patients with a high bleeding risk, 3 months' treatment only is recommended. For those patients with a second unprovoked DVT who have a low or moderate bleeding risk, extended anticoagulant therapy is recommended (with no scheduled stop date) over 3 months' treatment. In patients with a high bleeding risk, 3 months' treatment only is recommended.

Many studies have attempted to identify subgroups of patients with unprovoked VTE who do not need to be treated indefinitely with oral anticoagulation. There is strong evidence that the risk of recurrent VTE is higher in the following patients: male sex; those with a diagnosis of a proximal DVT (versus isolated calf DVT); those with ultrasound evidence of residual clot; those who have an elevated D-dimer 1 month after stopping a 3- to 6-month course of oral anticoagulation; and those who had an unprovoked DVT.[18][41] Several risk assessment models have been developed for this purpose, including the DASH score, the Vienna Prediction Model, and the "Men Continue and HER-DOO2" model.[191] The latter model identifies a subset of women with low risk for recurrent VTE after an initial unprovoked event, and one prospective validation study of this model was published.[192]

The continued use of extended-phase anticoagulation should be reassessed at least annually, as well as at any time there is a significant change in the patient's health status.[18]

If the decision is to stop extended-phase anticoagulation in patients with an unprovoked proximal DVT, the ACCP guidelines recommend aspirin (unless contraindicated) to prevent recurrent DVT.[18] The benefits of using aspirin should be balanced against the risk of bleeding and inconvenience of use. Aspirin should not, however, be considered a reasonable alternative for patients who are willing to undergo extended anticoagulation therapy, as aspirin is much less effective. The use of aspirin should in any case be reassessed when patients stop anticoagulant therapy because it might have been stopped when anticoagulant therapy was started.[18]

Primary options

apixaban: 5 mg orally twice daily; consider 2.5 mg orally twice daily after completing at least 6 months treatment

edoxaban: ≤60 kg body weight: 30 mg orally once daily; >60 kg body weight: 60 mg orally once daily

rivaroxaban: 20 mg orally once daily; consider 10 mg orally once daily after completing at least 6 months treatment

dabigatran etexilate: 150 mg orally twice daily

Secondary options

warfarin: 2-5 mg orally once daily initially, adjust dose according to target INR

Tertiary options

aspirin: 81-100 mg orally once daily

extended-phase therapy: pregnant

1st line – extended anticoagulation

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1st line –

extended anticoagulation

The treatment/extended phase of anticoagulation differs in pregnant patients. Patients with pregnancy-associated venous thromboembolism (VTE) undergo treatment-phase anticoagulation for at least 3 months, or until 6 weeks postpartum, whichever is longer.[188][189] At the conclusion of this phase in the postpartum, decisions are made according to whether the patient is planning to breastfeed. Guidelines differ on offering extended anticoagulation for VTE associated with pregnancy, as there is an intermediate risk of future unprovoked VTE.[21][180]

Extended treatment with low molecular weight heparin (LMWH) monotherapy is recommended in pregnant patients.[188]

Routine measurement of peak anti-Xa activity for pregnant or postpartum patients on LMWH is not recommended except in women at extremes of body weight (i.e., <50 kg or >90 kg) or with other complicating factors (e.g., renal impairment or recurrent VTE) that put them at high risk.

Warfarin is known to cause teratogenic effects when used in pregnancy and should be avoided.

If breastfeeding is planned, then LMWH is the agent of choice. Warfarin is an alternative; it is minimally secreted in breast milk, but there is extensive clinical experience suggesting no ill effect in the breastfeeding infant.[153][190]

Primary options

enoxaparin: 1 mg/kg subcutaneously every 12 hours

dalteparin: 200 units/kg subcutaneously every 24 hours, maximum 18,000 units/dose; or 100 units/kg subcutaneously every 12 hours, maximum 18,000 units/dose

extended-phase therapy: cancer-associated

1st line – extended anticoagulation

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1st line –

extended anticoagulation

Cancer represents a persistent provocation for venous thromboembolism (VTE) until cured. Among patients who are diagnosed with DVT and have an active cancer (e.g., cancer under any form of active therapy or palliation) there is a very high risk for recurrent VTE, and indefinite anticoagulation is recommended. Guidelines have recommended using a direct oral anticoagulant (DOAC; apixaban, edoxaban, rivaroxaban), or low molecular weight heparin (LMWH) for at least the initial 6 months of therapy.[18][19][107][195][226][227][228][229][230]

A DOAC (apixaban, edoxaban, rivaroxaban) or LMWH is the preferred agent for patients with a higher risk of bleeding, especially those with gastrointestinal cancers. LMWH is preferred for patients with drug-drug interactions with apixaban, rivaroxaban, or dabigatran.[18][193][194][195] [ ]

Primary options

apixaban: 5 mg orally twice daily; consider 2.5 mg orally twice daily after completing at least 6 months treatment

edoxaban: ≤60 kg body weight: 30 mg orally once daily; >60 kg body weight: 60 mg orally once daily

rivaroxaban: 20 mg orally once daily; consider 10 mg orally once daily after completing at least 6 months treatment

enoxaparin: 1 mg/kg subcutaneously every 12 hours; or 1.5 mg/kg subcutaneously every 24 hours

extended-phase therapy: recurrent VTE

1st line – further investigation + switch to low molecular weight heparin (LMWH)

Back

1st line –

further investigation + switch to low molecular weight heparin (LMWH)

Recurrent venous thromboembolism (VTE) is unusual among patients receiving therapeutic-dose anticoagulant therapy, except in cancer (7% to 9% on-therapy recurrence with low molecular weight heparin [LMWH]).[18][22][225] In addition to definitively establishing the presence of recurrent VTE, consideration should be given to compliance with anticoagulant therapy or the presence of underlying malignancy and the presence of any medications that may diminish the anticoagulant effect of therapy.[18]

American College of Chest Physicians (ACCP) guidelines recommend a temporary switch to LMWH (for at least 1 month) for patients with recurrent VTE who are thought to be compliant with a non-LMWH anticoagulant (or within the therapeutic range if receiving vitamin K antagonist therapy).[18] An increased dose of LMWH is appropriate for patients with recurrent VTE who have been receiving LMWH.[18]

For patients who are no longer receiving anticoagulant therapy and experience a second VTE with no identifiable risk factor (i.e., unprovoked), guidelines recommend the following anticoagulant treatment durations: low or moderate bleeding risk - extended anticoagulant therapy with periodic reassessment to review risk/benefit ratio; high bleeding risk - stop anticoagulation after 3 months.[18][22]

Primary options

enoxaparin: consult specialist for guidance on dose

dalteparin: consult specialist for guidance on dose

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Deep vein thrombosis

Treatment algorithm

suspected or confirmed DVT of the leg with phlegmasia cerulea dolens

immediate parenteral anticoagulation plus supportive care

Primary options

thrombolysis or surgical thrombectomy

suspected or confirmed DVT without phlegmasia cerulea dolens and no contraindications to anticoagulation: initiation-phase therapy

anticoagulation

Primary options

Direct oral anticoagulant (DOAC)

Direct oral anticoagulant (DOAC)

Direct oral anticoagulant (DOAC)

Direct oral anticoagulant (DOAC)

Vitamin K antagonist

Low molecular weight heparin (LMWH)

Low molecular weight heparin (LMWH)

Unfractionated heparin (UFH)

Factor Xa inhibitor

Direct thrombin inhibitor

physical activity

gradient stockings

serial imaging of the deep veins and/or anticoagulation

Primary options

Direct oral anticoagulant (DOAC)

Direct oral anticoagulant (DOAC)

Direct oral anticoagulant (DOAC)

Direct oral anticoagulant (DOAC)

Vitamin K antagonist

Low molecular weight heparin (LMWH)

Low molecular weight heparin (LMWH)

Unfractionated heparin (UFH)

Factor Xa inhibitor

Direct thrombin inhibitor

physical activity

gradient stockings

suspected or confirmed DVT without phlegmasia cerulea dolens: contraindications to anticoagulation

IVC filter

physical activity

gradient stockings

serial imaging of the deep veins

physical activity

gradient stockings

treatment-phase therapy

maintenance anticoagulation

Primary options

Direct oral anticoagulant (DOAC)

Direct oral anticoagulant (DOAC)

Direct oral anticoagulant (DOAC)

Direct oral anticoagulant (DOAC)

Vitamin K antagonist

Low molecular weight heparin (LMWH)

Low molecular weight heparin (LMWH)

Factor Xa inhibitor

Direct thrombin inhibitor

physical activity

gradient stockings

extended-phase therapy: provoked DVT

consider extended anticoagulation

Primary options

Secondary options

extended-phase therapy: unprovoked DVT

extended anticoagulation or aspirin

Primary options

Secondary options

Tertiary options

extended-phase therapy: pregnant

extended anticoagulation

Primary options

extended-phase therapy: cancer-associated

extended anticoagulation

Primary options

extended-phase therapy: recurrent VTE

further investigation + switch to low molecular weight heparin (LMWH)

Primary options