Anticoagulation is the "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 their 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 hours.[2]
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 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.
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
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.
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 rivaroxaban 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 has approved the use of rivaroxaban for treatment of DVT, however NICE committee in UK has asked for more evidence.
ACCP 2012 Guidelines: Recommendations for initial choice of treatment in patients with acute DVT of the leg (DO NOT EDIT)[5]
"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)."
"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 2012 Guidelines: Recommendations for duration of anticoagulant therapy (DO NOT EDIT)
"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)".
"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). "
AHA 2011 Guidelines for duration of anticoagulant therapy (DO NOT EDIT)
"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). "
"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 2012 Guidelines: Recommendations for treatment of isolated distal DVT (DO NOT EDIT)
"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). "
"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 2012 Guidelines: Recommendations for treatment of asymptomatic DVT of the leg (DO NOT EDIT)
"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)".
ACCP 2012 Guidelines: Recommendations for treatment in special situations (DO NOT EDIT)
"1. In patients with DVT of the leg and no cancer, we suggest VKA therapy over LMWH for long-term therapy (Level of evidence C) . For patients with DVT and no cancer who are not treated with VKA therapy, we suggest LMWH over dabigatran or rivaroxaban for long-term therapy (Level of evidence C)".
"2. In patients with DVT of the leg and cancer, we suggest LMWH over VKA therapy (Level of evidence B). In patients with DVT and cancer who are not treated with LMWH, we suggest VKA over dabigatran or rivaroxaban for long-term therapy (Level of evidence B).
"3. In patients with DVT of the leg who receive extended therapy, we suggest treatment with the same anticoagulant chosen for the first 3 months (Level of evidence C).
ACCP 2012 Guidelines: Recommendations for post-thrombotic syndrome (DO NOT EDIT)
"1. In patients with acute symptomatic DVT of the leg, we suggest the use of compression stockings (Level of evidence B). "
"2. In patients with PTS of the leg, we suggest a trial of compression stockings (Level of evidence C). "
"3. In patients with severe PTS of the leg that is not adequately relieved by compression stockings, we suggest a trial of an intermittent compression device (Level of evidence B). "
"4. In patients with PTS of the leg, we suggest that venoactive medications (eg, rutosides, defibrotide, and hidrosmin) not be used (Level of evidence C). "
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 2011 Guidelines- Recommendations for Initial Anticoagulation for Patients With IFDVT (DO NOT EDIT)
"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)"
"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:
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.
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 2011 Guidelines- Recommendations for Use of Compression Therapy (DO NOT EDIT)
"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)."
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]
Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)[2]
Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension (A Scientific Statement From the American Heart Association).[6]
↑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. PMID22315264. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
↑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. PMID21128814. Unknown parameter |month= ignored (help)CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
↑ 5.05.15.25.35.45.5Guyatt 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. PMID22315257. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
↑ 7.07.17.27.3Kearon 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. PMID22315268. Unknown parameter |month= ignored (help)CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
↑Watson L, Armon M. "Thrombolysis for acute deep vein thrombosis". Cochrane Database Syst Rev: CD002783. PMID 15495034.
↑Partsch H, Kaulich M, Mayer W (2004). "Immediate mobilisation in acute vein thrombosis reduces post-thrombotic syndrome". Int Angiol. 23 (3): 206–12. PMID15765034.CS1 maint: Multiple names: authors list (link)
↑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.CS1 maint: Multiple names: authors list (link)
↑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.CS1 maint: Multiple names: authors list (link)