Deep vein thrombosis medical therapy

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Resident Survival Guide

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.; Rim Halaby, M.D. [3]; Syed Hassan A. Kazmi BSc, MD [4] Assistant Editor(s)-In-Chief: Justine Cadet

Deep Vein Thrombosis Microchapters
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For the algorithms about the treatment choices, click here.

Overview

Clinical practice guidelines by the American College of Chest Physicians guide management.

Anticoagulation therapy is the mainstay of the treatment of deep vein thrombosis (DVT). The medical treatment of DVT consists of an initial parenteral anticoagulation therapy and a long term anticoagulation therapy. The primary purpose of treatment is to prevent further clot extension, acute pulmonary embolism, recurrence of thrombosis, and late complications such as post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension. The treatment of DVT with parental anticoagulation should be initiated in case of intermediate or high suspicion of suspected DVT even before the diagnostic confirmatory tests are complete. The choice of parental anticoagulation include: low molecular weight heparin (LMWH), fondaparinux, IV unfractionated heparin (UFH) and SC-UFH; however, the administration of LMWH (once daily rather than twice daily) and fondaparinux is recommended over IV-UFH and SCUFH. Parental anticoagulation therapy should be administered for at least 5 days and until the INR is equal or more than 2 for more than 24 hours. Patients who receive long term therapy with anticoagulation should be assessed regularly for the risks vs benefits of anticoagulation therapy. An abnormal D-dimer level at the end of treatment may signal the need for continued treatment in patients with their first unprovoked proximal DVT.

Parenteral Anticoagulation Therapy

Heparin

• Heparin binds to the enzyme inhibitor antithrombin III (AT). The activated AT then inactivates thrombin and other proteases involved in blood clotting, most notably factor Xa.

• The side effects of heparin include bleeding, heparin-induced thrombocytopenia and osteoporosis. In patients with suspected or confirmed heparin-induced thrombocytopenia, lepirudin or argatroban should be used.

• The anticoagulant effects of heparin can be reversed with IV protamine sulfate.

Heparin Dosage

Shown below is a table depicting the dosage of heparin for the treatment of DVT. Note that the dose of heparin used in the treatment of acute coronary syndrome is lower than that used for the treatment of PE.

Mode of administration of Heparin	Dosage
IV injection	80 U/kg as bolus, followed by 18 U/kg/h, OR 70 U/kg as bolus, followed by 15 U/kg/h for stroke or cardiac patients
SC injection	333 U/kg as bolus, followed by 250 U/kg

Adjustment of Heparin Dosage According to aPTT

aPTT should be monitored during treatment with heparin. Prolongation of apTT correlates with an elevated serum concentration of heparin and requires adjustment of the dosage. Shown below is a table depicting the variation in the dosage according the aPTT.

aPTT	Variation in the dosage
< 1.2 x control (<35 s)	Bolus: 80 U/kg Infusion rate: increase by 4 U/kg/h
1.2-1.5 x control (35-45 s)	Bolus: 40 U/kg Infusion rate: increase by 2 U/kg/h
1.5-2.3 x control (46-70 s)	Continue the same dosage
2.3-3.0 x control (71-90 s)	Infusion rate: decrease by 2 U/kg/h
> 3.0 x control (>90s)	Stop infusion for a period of 1 hour, then Infusion rate: decrease by 3 U/kg/h

Platelet Monitoring

Among patients started on heparin, if the risk of heparin induced thrombocytopenia is more than 1%, monitor platelet count every 2 to 3 days from the 4th until the 14th day of treatment or until the discontinuation of heparin.

Low Molecular Weight Heparin

• LMWH is used as a first line therapy for the initial anticoagulation therapy for DVT.

• In addition, LMWH can also be used for the long term anticoagulation treatment for DVT, but vitamin K antagonist are recommended as first line therapy. However, among cancer patients with provoked PE, LMWH is the first line therapy for the long term anticoagulation treatment. LMWH is preferred in pregnancy to avoid the known teratogenic effects of warfarin.

• LMWH is administered subcutaneously and does not require routine coagulation monitoring.

• The recommended doses for treatment of DVT are:
  • Enoxaparin : 1 mg/Kg body weight (twice daily) OR 1.5 mg/kg once daily
  • Tinzaparin : 175 U/Kg body weight (once daily)

Fondaparinux

• Fondaparinux is used as a first line therapy for the initial anticoagulation therapy for DVT. The antithrombotic activity of fondaparinux sodium is the result of antithrombin III (ATIII)-mediated selective inhibition of factor Xa. Fondaparinux does not require routine coagulation monitoring.

• Recommended doses for the treatment of DVT depend on the weight of the patient:
  • Weight <50 Kg: 5 mg (once daily)
  • Weight between 50 Kg to 100 Kg: 7.5 mg (once daily)
  • Weight >100 Kg: 10 mg (once daily)

Oral Anticoagulation Therapy

Vitamin K Antagonist

• Vitamin K antagonist is the first line therapy for long term anticoagulation treatment of DVT.

• Warfarin should not be administered in pregnancy and LMWH should be used instead.

• Warfarin should be started as soon as possible following the initiation of parenteral anticoagulation therapy, preferably at the same day. Parenteral anticoagulation therapy should be continued for at least 5 days concomitantly with warfarin and until INR is ≥ 2 for more than 24 hours.

• Warfarin is administered as follows:
  • Begin with 5 mg warfarin for 2 days followed by dosing based on the INR.
  • Target INR is 2-3.
  • Monitor INR monthly.
  • If the INR is stable but there is one value 0.5 below or above the target range, continue the same dose and repeat INR within 1-2 weeks.
• NSAIDs, COX2 selective NSAIDs and some antibiotics should be avoided when warfarin is administered.

Factor X Inhibitors

Rivaroxaban is an oral factor X inhibitors that can be used in the long term treatment of DVT.

Direct Thrombin Inhibitors

Dabigatran is an oral direct thrombin inhibitors that can be used in the long term treatment of DVT.

Thrombolysis

Thrombolysis can refer to either systemic thrombolysis or catheter directed thrombolysis. To read more about catheter directed thrombolysis, click here.

Indications

• 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.
• Anticoagulation therapy is preferred over thrombolytic therapy in acute proximal DVT of the leg as well as in upper extremity DVT.
• According to ACCP guidelines, thrombolysis may 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
• Further, ACCP recommends using catheter-directed thrombolysis over systemic thrombolysis if resources and expertise is available.

Contraindications

Shown below is a table summarizing the absolute and relative contraindications to fibrinolytic therapy among pulmonary embolism patients.

Absolute contraindications	Relative contraindications
❑ Previous hemorrhagic stroke or stroke of unknown origin ❑ Ischemic stroke within the last 6 months ❑ Central nervous system tumor or damage ❑ Major trauma, head injury, or surgery within the last 3 weeks ❑ Gastrointestinal bleed within the last month ❑ Known bleeding	❑ Transient ischemic attack within the last 6 months ❑ Oral anticoagulant therapy intake ❑ Advanced liver disease ❑ Infective endocarditis ❑ Peptic ulcer disease that is currently active ❑ Pregnancy or within 1 week post partum ❑ Punctures that are non-compressible ❑ Traumatic resuscitation ❑ Systolic blood pressure >180 mmHg refractory to treatment

Compression Stockings

• The daily use of knee-high elastic graduated compression stockings (EGCS) for 2 years following the diagnosis of first-episode of proximal DVT 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". A cochrane meta-analysis of randomized controlled trials reported a reduced incidence of post-phlebitic syndrome with compression stockings use. The number needed to treat, that is, to prevent one case of post-thrombotic syndrome was 4.

Contraindicated Medications

Deep vein thrombosis is considered an absolute contraindication to the use of the following medications:

• Conjugated estrogens/bazedoxifene
• Drospirenone and Ethinyl estradiol
• Esterified estrogens
• Medroxyprogesterone
• Norgestrel and Ethinyl estradiol
• Norelgestromin and Ethinyl Estradiol
• Progesterone
• Raloxifene

2016 American College of Chest Physicians Evidence-Based Clinical Practice Guidelines on Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis (DO NOT EDIT)

Initial Choice of Treatment in Patients with Acute DVT of the Leg (DO NOT EDIT)

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)."

Duration of Anticoagulant Therapy (DO NOT EDIT)

Grade 1

"1. In patients with acute VTE who are treated with anticoagulant therapy, we recommend long-term 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 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. Anticoagulation should be given for 3 months in patients with a first unprovoked VTE and a high risk of bleeding (Level of Evidence B), but should be extended without a scheduled stop date in patients with a low or moderate risk of bleeding (Level of Evidence B).

"7. 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). "

"8. 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)."

"9. 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)".

"10. In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually)."

"11. 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). "

Duration of Anticoagulant Therapy (DO NOT EDIT)

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 IIb

"1. In children with DVT, the use of LMWH monotherapy may be reasonable (Level of Evidence: C). "

Intensity of Anticoagulant Effect (DO NOT EDIT)

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)".

Treatment of Isolated Distal DVT (DO NOT EDIT)

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)."

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)".

Treatment of Acute Upper Extremity DVT (DO NOT EDIT)

Grade 1

"1. In patients with UEDVT who undergo thrombolysis, we recommend the same intensity and duration of anticoagulant therapy as in similar patients who do not undergo thrombolysis. (Level of evidence B) "

Grade 2

"1. In patients with acute UEDVT that involves the axillary or more proximal veins, we suggest anticoagulant therapy alone over thrombolysis. (Level of evidence C) ".

Treatment in Special Situations (DO NOT EDIT)

Grade 2

"1. In patients with VTE without an associated cancer diagnosis, all direct oral anticoagulants (dabigatran, rivaroxaban, apixaban, or edoxaban) are recommended over vitamin K antagonist (VKA) therapy (Level of Evidence: B) and VKA therapy is recommended over low molecular weight heparin (LMWH; 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).

Post-Thrombotic Syndrome (DO NOT EDIT)

Grade 2

"1. In patients with acute DVT, the guideline recommends against the use of compression stockings routinely to prevent the post-thrombotic syndrome (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). "

Subsegmental PE Without DVT

Grade 2

"'1.For patient with subsegmental PE and no DVT, the guideline suggests clinical surveillance over anticoagulation when the risk of VTE recurrence is low (Level of Evidence C). The guideline recommends the use of anticoagulation over surveillance when the risk of VTE recurrence is high (Level of Evidence C). "

Prevention of Recurrent VTE after unprovoked Proximal DVT or PE

Grade 2

"1.For patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy, the guideline suggests the use of aspirin over no aspirin to prevent recurrent VTE if there are no contraindications to aspirin therapy (Level of evidence B). "

Recurrent VTE while on Non-LMWH Anticoagulant

Grade 2

"'1.For patients with recurrent VTE while treated with a non-LMWH anticoagulant, the guideline recommends changing to LMWH therapy (Level of Evidence C). If patients suffer a recurrent VTE while on LMWH treatment, the guideline recommends increasing the LMWH dose (Level of Evidence C). "

2011 AHA Scientific Statement- Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension (DO NOT EDIT)

Anticoagulation for Patients With IFDVT (DO NOT EDIT)

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)"

Long-Term Anticoagulation Therapy for Patients With IFDVT (DO NOT EDIT)

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)"

Use of Compression Therapy (DO NOT EDIT)

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).