Deep vein thrombosis medical therapy

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Editor(s)-In-Chief: The APEX Trial Investigators, C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [2] ; Kashish Goel, M.D.; Assistant Editor(s)-In-Chief: Justine Cadet

Deep Vein Thrombosis Microchapters

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Overview

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Pathophysiology

Causes

Differentiating Deep vein thrombosis from other Diseases

Epidemiology and Demographics

Risk Factors

Triggers

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Natural History, Complications and Prognosis

Diagnosis

Diagnostic Approach

Assessment of Clinical Probability and Risk Scores

Assessment of Probability of Subsequent VTE and Risk Scores

History and Symptoms

Physical Examination

Laboratory Findings

Ultrasound

Venography

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Treatment

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Medical Therapy

IVC Filter

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Surgery

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Upper extremity DVT

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Overview

An approach to the treatment of DVT has been described here. The primary purpose of treatment is to prevent the following:

  • Further clot extension,
  • Acute Pulmonary embolism,
  • Recurrence of thrombosis,
  • Prevention of late complications such as:

Key Guidelines for Thrombolytic Therapy : ACCP Guidelines

Extensive iliofemoral DVT
Class II Recommendations
  • Catheter directed thrombolysis. (Grade C recommendation)
    • It is preferred over open throbectomy.(Grade C recommendation)
    • Systemic thrombolytics may be useful.(Grade C recommendation)
* Mechanical thrombectomy to shorten lytic exposure.(Grade C recommendation)
* PTA/Stenting to relief underlying venous lesion.(Grade C recommendation)

Anticoagulation

Main article: Anticoagulation

Anticoagulation is "treatment of choice" for DVT. An abnormal D-dimer level at the end of treatment may signal the need for continued treatment, in patients with first unprovoked proximal deep-vein thrombosis.[1] After diagnosis, the current approach is to start both heparin and warfarin (VKA) , and to discontinue heparin after 5 days provided the international normalized ratio (INR) is ≥ 2.0 for at least 24 h.[2]

Parenteral Anticoagulants

[3]

Heparin

  • Heparin binds to antithrombin and inactivates thrombin, factors IIa, Xa, IXa, XIa and XIIa; binds to heparin cofactor II and inactivates factor IIa; and binds to factor IXa and inhibits factor X activation.
  • Unfractionated heparin is mainly used in patients with known renal insufficiency or those who need close monitoring for bleeding, as activated partial thromboplastin time can be checked every 2 hours and doses adjusted.
  • The apparent biologic half-life of heparin increases from approximately 30 min after an IV bolus of 25 units/kg, to 60 min with an IV bolus of 100 units/kg, to 150 min with a bolus of 400 units/kg.
  • Efficacy of heparin in the initial treatment of DVT or PE is highly dependent on dosage.
  • Initial dosing of IV heparin for VTE is either weight-based (80 units/kg bolus and 18 units/kg/h infusion) or administered as a bolus of 5,000 units followed by an infusion of at least 32,000 units/d, to achieve aPTT value of 1.5-2.5 of the normal value.
  • If heparin is given subcutaneously for treatment of VTE, there are at least two options: (1) an initial IV bolus of 5,000 units followed by 250 units/kg twice daily; or (2) an initial subcutaneous dose of 333 units/kg followed by 250 units/kg twice daily thereafter.
  • The dose for acute coronary syndrome is lower as compared to the treatment of DVT
  • The main side effects are heparin-induce thrombocytopenia and osteoporosis.
  • One major advantage of heparin is that the anticoagulant effects can be reversed with IV protamine sulfate.

Low molecular weight heparin

  • LMWH is administered subcutaneously and is available in various forms like Bemiparin, Dalteparin, Danaparoid, Enoxaparin, Nadroparin, or Tinzaparin.
  • The recommended doses for treatment of PE/DVT are:
    • Enoxaparin : 1 mg/Kg body weight (twice daily). Dose is 30 mg daily for VTE prophylaxis.
    • Tinzaparin : 175 U/Kg body weight (once daily).
  • The doses in case of renal insufficiency are not clear, except Enoxaparin. It is recommended that the dose of Enoxaparin should be reduced to 50% of the usual dose in patients with a creatinine clearance of <30 mL/min.

Factor Xa Inhibitor

[3]

  • Fondaparinux binds to antithrombin and inhibits factor Xa.
  • A fixed dose of 2.5 mg daily is used for thromboprophylaxis. In patients with moderate renal insufficiency (creatinine clearance of 30-50 mL/min), dose should be reduced by 50%.
  • Recommended dosages for treatment of DVT or PE are:
    • Patient weighing <50 Kg (110 lb): 5 mg (once daily).
    • Patient weighing 50 Kg (110 lb) to 110 Kg (220 lb): 7.5 mg (once daily).
    • Patient weighing >100 Kg (220 lb): 10 mg (once daily).

Direct thrombin inhibitors

[3]

  • Direct thrombin inhibitors bind to thrombin and block its activity. These include Hirudin, bivalurudin, and argatroban.
Hirudin
  • The recommended dose of IV lepirudin for heparin induced thrombocytopenia is 0.15 mg/kg/h with or without an initial bolus of 0.4 mg/kg.
  • The anticoagulant effect of lepirudin in this setting is monitored by using the aPTT, and the dose is adjusted to achieve a target aPTT ratio of 1.5 to 2.5 times control.
  • When given for thromboprophylaxis after elective hip replacement surgery, desirudin is given subcutaneously at a dose of 15 mg twice daily without monitoring.
Bivalirudin
  • Recommended dose of Bivalirudin is a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/h for the duration of the procedure.
  • Dose reduction should be considered in patients with moderate to severe renal impairment.
Argatroban
  • Argatroban is used for the treatment and prevention of heparin-induced thrombocytopenia associated thrombosis and for anticoagulation during percutaneous coronary interventions when heparin is contraindicated because of a recent history of heparin-induced thrombocytopenia.
  • Argatroban is given as a continuous IV infusion with an initial dose of 1 to 2 m g/kg/min and the dose is adjusted to maintain the aPTT ratio in the 1.5 to 2.5 range.

Warfarin

Main article: Warfarin
  • The recommended therapeutic INR during the treatment of DVT or PE with warfarin is 2.0-3.0.

Direct factor Xa inhibitor

Rivaroxaban (orally active direct factor Xa inhibitor) has been evaluated in randomized controlled trials for treatment of DVT. EINSTEIN-DVT and EINSTEIN-Extension Studies enrolled 3449 patients with DVT and showed that rivoraxaban was non-inferior to the usual approach (lovenox initially followed by warfarin) in the treatment of DVT[4]. It is not yet approved for treatment of DVT in US, but FDA will be reviewing this application soon. European Union<refhttp://www.bayer.com/en/news-detail-bayer-group.aspx?newsid=15790</ref> has approved the use of rivoraxaban for treatment of DVT, however NICE committee in UK<refhttp://www.nelm.nhs.uk/en/NeLM-Area/News/2012---March/13/NICE-issues-preliminary-recommendations-ACD-on-rivaroxaban-for-DVT-treatment-and-the-prevention-of-recurrent-DVT-and-PE-/</ref> has asked for more evidence.

ACCP Guidelines: Recommendations for initial choice of treatment in patients with acute DVT of the leg (DO NOT EDIT)

[5]

Grade 1
"1. In patients with acute DVT of the leg, we recommend early initiation of VKA (eg, same day as parenteral therapy is started) over delayed initiation, and continuation of parenteral anticoagulation for a minimum of 5 days and until the international normalized ratio (INR) is 2.0 or above for at least 24 h (Level of evidence B)"
"2. In patients with acute DVT of the leg and whose home circumstances are adequate, we recommend initial treatment at home over treatment in hospital (Level of evidence B)."
"3. In patients with acute DVT of the leg who undergo thrombosis removal, we recommend the same intensity and duration of anticoagulant therapy as in comparable patients who do not undergo thrombosis removal (Level of evidence B)."
"4. In patients with acute DVT of the leg, we recommend against the use of an inferior vena cava (IVC) filter in addition to anticoagulants (Level of evidence B)."
"5. In patients with acute proximal DVT of the leg and contraindication to anticoagulation, we recommend the use of an IVC filter (Level of evidence B)."
Grade 2
"1. In patients with acute DVT of the leg, we suggest LMWH or fondaparinux over IV UFH (Level of evidence C) and over SC UFH (Level of evidence B) for LMWH;(Level of evidence C) for fondaparinux)."
"2. In patients with acute DVT of the leg treated with LMWH, we suggest once- over twice-daily administration (Level of evidence C)."
"3. In patients with acute proximal DVT of the leg, we suggest anti coagulant therapy alone over catheter-directed thrombolysis (CDT) (Level of evidence C)."
"4. In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over systemic thrombolysis (Level of evidence C)."
"5. In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over operative venous thrombectomy (Level of evidence C)."
"6. In patients with acute proximal DVT of the leg and an IVC filter inserted as an alternative to anticoagulation, we suggest a conventional course of anticoagulant therapy if their risk of bleeding resolves (Level of evidence B)."
"7. In patients with acute DVT of the leg, we suggest early ambulation over initial bed rest (Level of evidence C)."

ACCP Guidelines: Recommendations for duration of anticoagulant therapy (DO NOT EDIT)

[5]

Grade 1
"1. In patients with acute VTE who are treated with anticoagulant therapy, we recommend long-term therapy (see section 3.1 for recommended duration of therapy) over stopping anticoagulant therapy after about 1 week of initial therapy (Level of evidence B)"
"2. In patients with a proximal DVT of the leg provoked by surgery, we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Level of evidence B)" , (ii) treatment of a longer time-limited period (eg, 6 or 12 months) (Level of evidence B) , or (iii) extended therapy (Level of evidence B regardless of bleeding risk)."
"3. In patients with a proximal DVT of the leg provoked by a nonsurgical transient risk factor, we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Level of evidence B) , (ii) treatment of a longer time-limited period (eg, 6 or 12 months) (Level of evidence B), and (iii) extended therapy if there is a high bleeding risk (Level of evidence B) ."
"4. In patients with an isolated distal DVT of the leg provoked by surgery or by a nonsurgical transient risk factor , we recommend treatment with anticoagulation for 3 months over treatment of a longer time-limited period (eg, 6 or 12 months) (Level of evidence B) or extended therapy (Level of evidence B) regardless of bleeding risk. "
"5. In patients with an unprovoked DVT of the leg (isolated distal [see remark] or proximal), we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Level of evidence B) . After 3 months of treatment, patients with unprovoked DVT of the leg should be evaluated for the risk-benefit ratio of extended therapy. "
"6. In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a high bleeding risk, we recommend 3 months of anticoagulant therapy over extended therapy (Level of evidence B). "
"7. In patients with a first VTE that is an unprovoked isolated distal DVT of the leg, we recommend 3 months of anticoagulant treatment in those with a high bleeding risk (Level of evidence B)."
"8. In patients with a second unprovoked VTE, we recommend extended anticoagulant therapy over 3 months of therapy in those who have a low bleeding risk (Level of evidence B)".
"9. In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually)."
"10. In patients with DVT of the leg and active cancer, if the risk of bleeding is not high, we recommend extended anticoagulant therapy over 3 months of therapy (Level of evidence B)".
Grade 2
"1. In patients with DVT of the leg and active cancer, if there is a high bleeding risk, we suggest extended anticoagulant therapy (Level of evidence B)."
"2. In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk, we suggest extended anticoagulant therapy over 3 months of therapy (Level of evidence B)."
"3. In patients with a second unprovoked VTE who have a high bleeding risk, we suggest 3 months of anticoagulant therapy over extended therapy (Level of evidence B)."
"4. In patients with a proximal DVT of the leg provoked by a nonsurgical transient risk factor,We suggest treatment with anticoagulation for 3 months over extended therapy if there is a low or moderate bleeding risk (Level of evidence B)."
"5.In patients with an isolated distal DVT of the leg provoked by surgery or by a nonsurgical transient risk factor , we suggest treatment with anticoagulation for 3 months over treatment of a shorter period (Level of evidence C). "
"6. In patients with a first VTE that is an unprovoked isolated distal DVT of the leg, we suggest 3 months of anticoagulant therapy over extended therapy in those with a low or moderate bleeding risk (Level of evidence B)."
"7. In patients with a second unprovoked VTE, we suggest extended anticoagulant therapy in those with a moderate bleeding risk (Level of evidence B). "

ACCP Guidelines: Recommendations for intensity of anticoagulant effect (DO NOT EDIT)

[5]

Grade 1
"1.In patients with DVT of the leg who are treated with VKA, we recommend a therapeutic INR range of 2.0 to 3.0 (target INR of 2.5) over a lower (INR <2) or higher (INR 3.0-5.0) range for all treatment durations (Level of evidence B)".

ACCP Guidelines: Recommendations for treatment of isolated distal DVT (DO NOT EDIT)

[5]

Grade 1
"1. In patients with acute isolated distal DVT of the leg who are managed with initial anticoagulation, we recommend using the same approach as for patients with acute proximal DVT (Level of evidence B). "
"2. In patients with acute isolated distal DVT of the leg who are managed with serial imaging, we recommend no anticoagulation if the thrombus does not extend (Level of evidence B) ; we recommend anticoagulation if the thrombus extends into the proximal veins (Level of evidence B). "
Grade 2
"1. In patients with acute isolated distal DVT of the leg and without severe symptoms or risk factors for extension, we suggest serial imaging of the deep veins for 2 weeks over initial anticoagulation (Level of evidence C)."
"2. In patients with acute isolated distal DVT of the leg and severe symptoms or risk factors for extension (see text), we suggest initial anticoagulation over serial imaging of the deep veins (Level of evidence C)."
"3. In patients with acute isolated distal DVT of the leg who are managed with serial imaging, we suggest anticoagulation if the thrombus extends but remains confined to the distal veins (Level of evidence C)."

ACCP Guidelines: Recommendations for treatment of asymptomatic DVT of the leg (DO NOT EDIT)

Grade 2
"1. In patients who are incidentally found to have asymptomatic DVT of the leg, we suggest the same initial and long-term anticoagulation as for comparable patients with symptomatic DVT (Level of evidence B)".

Iliofemoral DVT (IFDVT)

Iliofemoral DVT (IFDVT) mainly affects the complete or (partial thrombosis of) any part of the iliac vein or the common femoral vein, with or without involvement of other lower extremity veins or the Inferior vena cava. The clot can block blood flow and cause swelling and pain. There is a significant risk involved, when a thrombus embolizes and travels to the lungs, causing pulmonary embolism.

ACC/AHA Guidelines- Recommendations for Initial Anticoagulation for Patients With IFDVT (DO NOT EDIT)

[6]

Class I
"1. In the absence of suspected or proven heparin-induced thrombocytopenia, patients with IFDVT should receive therapeutic anticoagulation with either intravenous UFH (Level of Evidence: A), UFH by subcutaneous injection (Level of Evidence: B), an LMWH (Level of Evidence: A), or fondaparinux (Level of Evidence: A)."
"2. Patients with IFDVT who have suspected or proven heparin-induced thrombocytopenia should receive a direct thrombin inhibitor (Level of Evidence: B)"

ACC/AHA Guidelines- Recommendations for Long-Term Anticoagulation Therapy for Patients With IFDVT (DO NOT EDIT)

[6]

Class I
"1. Adult patients with IFDVT who receive oral warfarin as first-line long-term anticoagulation therapy should have warfarin overlapped with initial anticoagulation therapy for a minimum of 5 days and until the INR is ≥2.0 for at least 24 hours, and then targeted to an INR of 2.0 to 3.0 (Level of Evidence: A)."
"2. Patients with first-episode IFDVT related to a major reversible risk factor should have anticoagulation stopped after 3 months (Level of Evidence: A)"
"3. Patients with recurrent or unprovoked IFDVT should have at least 6 months of anticoagulation and be considered for indefinite anticoagulation with periodic reassessment of the risks and benefits of continued anticoagulation (Level of Evidence: A)"
"4. Cancer patients with IFDVT should receive LMWH monotherapy for at least 3 to 6 months, or as long as the cancer or its treatment (eg, chemotherapy) is ongoing (Level of Evidence: A)"
Class IIa
"1. In children with DVT, the use of LMWH monotherapy may be reasonable (Level of Evidence: C)"

Thrombolysis

Catheter-Directed Thrombolysis

  • Catheter-Directed Thrombolysis for acute DVT has been evaluated in small randomized trials and have shown that it may preserve venous valve function, reduce post-thrombotic syndrome and improve quality of life. However, evidence regarding mortality, recurrent VTE and major bleeding is lacking.
  • According to ACCP guidelines[7], catheter-directed thrombolysis should be considered only in patients who meet all of the following criteria:
    • Iliofemoral DVT
    • Symptoms < 14 days
    • Good functional status
    • Life expectancy ≥1 year
    • Low risk of bleeding

ACCP recommendations[7]:

“

1. In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over CDT (Grade 2C).

2. In patients with acute DVT of the leg who undergo thrombosis removal, we recommend the same intensity and duration of anticoagulant therapy as in similar patients who do not undergo thrombosis removal.

”

Systemic thrombolysis

  • A Cochrane meta-analysis of randomized controlled trials showed reduced incidence of post-thrombotic syndrome and increased the vein patency, but it was associated with increased risk of bleeding.[8]
  • Conditions where systemic thrombolysis may be considered are similar to those mentioned in catheter-directed thrombolysis.
  • Further, ACCP[7] recommends using catheter-directed thrombolysis over systemic thrombolysis if resources and expertise is available.
  • Major contraindications
    • Structural intracranial disease
    • Previous intracranial hemorrhage
    • Ischemic stroke within 3 mo
    • Active bleeding
    • Recent brain or spinal surgery
    • Recent head trauma with fracture or brain injury
    • Bleeding diathesis
  • Relative contraindications
    • Systolic BP >180 mm Hg
    • Diastolic BP >110 mm Hg
    • Recent bleeding (nonintracranial)
    • Recent surgery
    • Recent invasive procedure
    • Ischemic stroke more that 3 mo previously
    • Anticoagulation (eg, VKA therapy)
    • Traumatic cardiopulmonary resuscitation
    • Pericarditis or pericardial fl uid
    • Diabetic retinopathy
    • Pregnancy
    • Age >75 y
    • Low body weight (eg, <60 kg)
    • Female sex
    • Black race

ACCP recommendations[7]:

“

1. In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over systemic thrombolysis (Grade 2C).

2. In patients with acute DVT of the leg who undergo thrombosis removal, we recommend the same intensity and duration of anticoagulant therapy as in similar patients who do not undergo thrombosis removal.

”


Compression stockings

Three randomized control trial conducted in Europe[9] [10]have found, that after the diagnosis of first-episode of proximal DVT, the daily use of knee-high graduated compression stockings (ECS) for 2 years is associated with marked reductions in the frequency of Post-thrombotic syndrome (PTS).

Elastic compression stockings should be routinely applied, beginning within 1 month of diagnosis of proximal DVT and continuing for a minimum of 1 year after diagnosis".[9] The stockings in almost all trials were stronger than routine anti-embolism stockings and were used with 20-30 mm Hg or 30-40 mm Hg pressure gradient. Most trials used knee-high stockings. A cochrane meta-analysis of randomized controlled trials reported a reduced incidence of post-phlebitic syndrome.[11] The number needed to treat, that is, to prevent one case of post-thrombotic syndrome was 4 to 5 patients.[12]

ACC/AHA Guidelines- Recommendations for Use of Compression Therapy (DO NOT EDIT)

[6]

Class I
"1. Patients with iliofemoral DVT should wear 30– to 40–mm Hg knee-high graduated ECS on a daily basis for at least 2 years (Level of Evidence: B)."
Class IIa
"1. In patients with prior iliofemoral DVT and symptomatic PTS, daily use of 30– to 40–mm Hg knee-high graduated ECS is reasonable (Level of Evidence: C)."
Class IIb
1. In patients with prior iliofemoral DVT and severe edema, intermittent sequential pneumatic compression followed by daily use of 30– to 40–mm Hg knee-high graduated ECS may be considered (Level of Evidence: B).

Guidelines Resources

  • Guidelines on the management of Pulmonary embolism: Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension[6]

References

  1. ↑ Palareti G, Cosmi B, Legnani C, Tosetto A, Brusi C, Iorio A; et al. (2006). "D-dimer testing to determine the duration of anticoagulation therapy". N Engl J Med. 355 (17): 1780–9. doi:10.1056/NEJMoa054444. PMID 17065639. Review in: Evid Based Med. 2007 Apr;12(2):45 Review in: ACP J Club. 2007 Mar-Apr;146(2):29
  2. ↑ Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ (2008). "Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)". Chest. 133 (6 Suppl): 454S–545S. doi:10.1378/chest.08-0658. PMID 18574272. Retrieved 2012-01-11. Unknown parameter |month= ignored (help)
  3. ↑ 3.0 3.1 3.2 Garcia DA, Baglin TP, Weitz JI, Samama MM (2012). "Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. 141 (2 Suppl): e24S–43S. doi:10.1378/chest.11-2291. PMID 22315264. Unknown parameter |month= ignored (help)
  4. ↑ Bauersachs R, Berkowitz SD, Brenner B; et al. (2010). "Oral rivaroxaban for symptomatic venous thromboembolism". N. Engl. J. Med. 363 (26): 2499–510. doi:10.1056/NEJMoa1007903. PMID 21128814. Unknown parameter |month= ignored (help)
  5. ↑ 5.0 5.1 5.2 5.3 Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ (2012). "Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. 141 (2 Suppl): 7S–47S. doi:10.1378/chest.1412S3. PMID 22315257. Unknown parameter |month= ignored (help)
  6. ↑ 6.0 6.1 6.2 6.3 Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldenberg N, Goldhaber SZ; et al. (2011). "Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association". Circulation. 123 (16): 1788–830. doi:10.1161/CIR.0b013e318214914f. PMID 21422387.
  7. ↑ 7.0 7.1 7.2 7.3 Kearon C, Akl EA, Comerota AJ; et al. (2012). "Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. 141 (2 Suppl): e419S–94S. doi:10.1378/chest.11-2301. PMID 22315268. Unknown parameter |month= ignored (help)
  8. ↑ Watson L, Armon M. "Thrombolysis for acute deep vein thrombosis". Cochrane Database Syst Rev: CD002783. PMID 15495034.
  9. ↑ 9.0 9.1 Prandoni P, Lensing AW, Prins MH, Frulla M, Marchiori A, Bernardi E; et al. (2004). "Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial". Ann Intern Med. 141 (4): 249–56. PMID 15313740. Review in: ACP J Club. 2005 Jan-Feb;142(1):7
  10. ↑ Partsch H, Kaulich M, Mayer W (2004). "Immediate mobilisation in acute vein thrombosis reduces post-thrombotic syndrome". Int Angiol. 23 (3): 206–12. PMID 15765034.
  11. ↑ Kolbach D, Sandbrink M, Hamulyak K, Neumann H, Prins M. "Non-pharmaceutical measures for prevention of post-thrombotic syndrome". Cochrane Database Syst Rev: CD004174. doi:10.1002/14651858.CD004174.pub2. PMID 14974060.
  12. ↑ Kakkos S, Daskalopoulou S, Daskalopoulos M, Nicolaides A, Geroulakos G (2006). "Review on the value of graduated elastic compression stockings after deep vein thrombosis". Thromb Haemost. 96 (4): 441–5. PMID 17003920.

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