Almost all patients with deep venous thrombosis (DVT) are given anticoagulants and in rare cases thrombolytics. A number of anticoagulants are effective for management of deep venous thrombosis (see also Deep Venous Thrombosis).
Non-pharmacologic treatments include surgery and inferior vena cava filters.
Anticoagulants
The anticoagulants (see figure Anticoagulants and Their Sites of Action and table Oral Anticoagulants) include
Low molecular weight heparins (LMWHs)
Factor Xa
Direct thrombin
Oral factor Xa inhibitors and direct thrombin inhibitors are sometimes referred to as direct oral anticoagulants (DOACs). However, there are also parenteral agents that inhibit both factor Xa and thrombinfactor Xa (LMWH), or that inhibit only factor Xa
Anticoagulants and Their Sites of Action
LMWH = low molecular weight heparin; TF = tissue factor; UFH = unfractionated heparin. |
Anticoagulation strategies for DVT
There are several strategies for anticoagulation of patients with DVT:
factor Xa inhibitor, or a direct thrombin inhibitor)
Initial and long-term treatment with a LMWH
Initial and long-term treatment with certain oral factor Xa
Dosing regimens for treatment of DVT differ from those used for prevention of thromboembolism in patients with atrial fibrillation.
Oral Anticoagulants). Compared to warfarin1).
The main disadvantage is the higher cost compared to warfarin and the high cost of DOAC reversal agents in the case of bleeding or need for an urgent surgery or procedure.
Duration of treatment varies. Patients with transient risk factors for DVT (eg, immobilization, surgery) can usually stop taking anticoagulants after 3 to 6 months. Patients with idiopathic (or unprovoked) DVT with no known risk factors, or recurrent DVT should take anticoagulants for at least 6 months and, in selected patients, probably for life unless they are at high risk for bleeding complications. Patients with cancer-associated thrombosis should receive at least 3 months of anticoagulation. Treatment is usually longer in patients receiving ongoing cancer therapy and in patients with advanced, metastatic disease. Patients with selected hypercoagulable states (eg, antiphospholipid syndrome or protein C, protein S, or antithrombin deficiency) should also be considered for extended-duration anticoagulation.
Low molecular weight heparins (LMWHs)
A low molecular weight heparinheparin (UFH) for reducing DVT recurrence, thrombus extension, and risk of death due to PE (2). Like UFH, LMWHs catalyze the action of antithrombin (which inhibits coagulation factor proteases), leading to inactivation of coagulation factor Xa and, to a lesser degree, factor IIa. LMWHs also have some antithrombin–mediated anti-inflammatory properties, which facilitate clot organization and resolution of symptoms and inflammation.
warfarin
LMWHs and direct oral anticoagulants are first-line treatment options for patients with cancer-associated DVT (3), including in patients who have a central venous catheter and develop DVT. Warfarin is a 2nd-line alternative due to its low cost, but use requires careful monitoring.
Complications of LMWHs include bleeding, thrombocytopenia, urticaria, and, rarely, thrombosis and anaphylaxis. Inpatients and possibly outpatients should be screened for bleeding with serial complete blood counts and, where appropriate, testing for occult blood in stool.
Unfractionated heparin (UFH)
2warfarin (about 5 days).
Complications of UFH are similar to those of LMWHs, except that , which is rare and may be life-threatening, is more common with UFHs. Long-term use of UFH causes hyperkalemia, liver enzyme elevations, and osteopenia. Rarely, UFH given subcutaneously causes skin necrosis. Inpatients and possibly outpatients being given UFH should be screened for bleeding.
Factor Xa inhibitors
rivaroxaban is 15 mg orally twice a day for 3 weeks followed by 20 mg orally once a day for a total of 3 to 6 months. Apixaban dosing is 10 mg orally twice a day for 7 days followed by 5 mg orally twice a day for 3 to 6 months.
factor Xa inhibitor is typically started within 6 to 12 hours after the last dose of a twice-daily LMWH regimen and within 12 to 24 hours after a once-daily LMWH regimen.
4, 5, 6).
factor Xa inhibitor, may be used as an alternative to UFH or LMWH for the initial treatment of DVT or PE. It is given in a fixed dose of 7.5 mg subcutaneously once a day (10 mg for patients > 100 kg, 5 mg for patients < 50 kg). It has the advantage of fixed dosing and is less likely to cause thrombocytopenia.
Direct thrombin inhibitors
Parenteral direct thrombinprevention.
Vitamin K antagonists (warfarin)
Warfarin is also a second-line option for patients with cancer-associated VTE.
Warfarinwarfarin doses. Therapeutic goal is an international normalized ratio (INR) of 2.0 to 3.0. INR is monitored weekly for the first 1 to 2 months of warfarin treatment and monthly thereafter; the dose is increased or decreased by 0.5 to 3 mg to maintain the INR within this range. Patients taking warfarin should be informed of possible drug interactions, including interactions with foods and nonprescription medicinal herbs.
Rarely, warfarin causes skin necrosis in patients with inherited protein C deficiency or protein S deficiency.
Anticoagulant treatment references
1. Kearon C, Aki EA, Ornelas J, et al: CHEST Guideline and Expert Panel Report: Antithrombotic therapy for VTE disease. Chest 149:315–352, 2016. doi: https://doi.org/10.1016/j.chest.2015.11.026
2. Segal JB, Streiff MB, Hofmann LV, Thornton K, Bass EB: Management of venous thromboembolism: a systematic review for a practice guideline [published correction appears in Ann Intern Med 2007 Mar 6;146(5):396. Hoffman, Lawrence V [corrected to Hofmann, Lawrence V]]. Ann Intern Med 146(3):211–222, 2007. doi:10.7326/0003-4819-146-3-200702060-00150
3. Schrag D, Uno H, Rosovsky R, et al: Direct Oral Anticoagulants vs Low-Molecular-Weight Heparin and Recurrent VTE in Patients With Cancer: A Randomized Clinical Trial. JAMA 329(22):1924–1933, 2023. doi:10.1001/jama.2023.7843
4. Agnelli G, Becattini C, Meyer G, et al: Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 382:1599–1607, 2020. doi: 10.1056/NEJMoa1915103
5. Raskob GE, van Es N, Verhamme P, et al: Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med Dec 12, 2017. doi: 10.1056/NEJMoa1711948
6. Young AM, Marshall A, Thirlwall J, et al: Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol 36: 2017–2023, 2018. doi: 10.1200/JCO.2018.78.8034
Bleeding During Use of Anticoagulants
Bleeding is the most common complication of anticoagulants and ranges on a continuum from minor to severe, life-threatening hemorrhage.
For minor bleeding (eg, epistaxis), local measures to stop bleeding (eg, direct pressure) are often sufficient. The anticoagulant is usually not discontinued or reversed unless bleeding becomes more severe.
For severe bleeding (eg, heavy gastrointestinal bleeding), the anticoagulant is usually withheld (at least temporarily) and other measures taken. Bleeding is generally considered severe when it is:
Heavy (loss of ≥ 2 units of blood in ≤ 7 days)
In a critical location (eg, intracranial, intraocular)
In a location where hemostasis is difficult to achieve (eg, small bowel, posterior nasal cavity, lung)
Risk factors for severe bleeding include
Age ≥ 65 years
History of prior gastrointestinal bleeding or stroke
Recent myocardial infarction
Coexisting anemia (hematocrit < 30%), renal insufficiency (serum creatinine > 1.5 mg/dL [115 micromol/L]), or diabetes
Supportive care for severe bleeding includes local measures to stop bleeding (eg, direct pressure, cauterization, injection). Patients with signs and symptoms of volume loss and those with heavy ongoing bleeding may require intravenous fluid resuscitation and packed red blood cell transfusions. These measures are sufficient for many bleeding episodes.
In patients with life-threatening and/or ongoing bleeding or bleeding in a critical location, clinicians also consider giving
Reversal agents
Antifibrinolytics
However, by definition these agents are prothrombotic and the risks of continued bleeding should be balanced with the increased risk of thrombosis.
Anticoagulant reversal
With the heparins,protamine only partially neutralizes LMWH inactivation of factor Xa. The dose is 1 mg protamine for each 100 units of UFH given or for each milligram of LMWH; protamine is infused slowly over 10 to 20 minutes (maximum dose 50 mg in 10 minutes). The dose is lowered depending on the time since UFH was given. If a 2nd dose is required, it should be one half the first dose. During all infusions, patients should be observed for hypotension and a reaction similar to an anaphylactic reaction. Because UFH given IV has a half-life of 30 to 60 minutes, protamine is typically not given to patients who have received UFH > 60 to 120 minutes beforehand) or is given at a reduced dose based on the amount of heparin estimated to be remaining in plasma, based on the half-life of UFH.
anticoagulation can be reversed with vitamin K; the dose is 1 to 2.5 mg orally if INR is 5 to 9, 2.5 to 5 mg orally if INR is >prothrombin complex concentrate is unavailable. Selected patients with overanticoagulation (INR 5 to 9) who are neither actively bleeding nor at increased risk of bleeding can be managed by omitting 1 or 2 warfarin doses and monitoring INR more frequently, then giving warfarin at a lower dose.
With prothrombin complex concentrate 50 units/kg IV can be given. Hemodialysis also may help because dabigatrandabigatran was within 2 hours.
With factor Xa inhibitors, andexanet alfa is an antidote available in the United States; however, its use is restricted in part due to its high cost (1). If the patient is on a high dose of a factor Xa< 8 hours before presentation, a high dose of andexanet alfa (800 mg IV at 30 mg/minute followed by 960 mg IV at 8 mg/minute) is given. If the patient is on a low dose of a factor Xa inhibitor or took the medication > 8 hours before presentation, a lower dose of andexanet alfaandexanet alfa although this has not been studied in research trials. If andexanet alfa is unavailable, 4-factor prothrombin complex concentratefactor Xa inhibitor within a few hours of presentation (8 hours for rivaroxaban, 6 hours for apixaban, and 2 hours for edoxaban). Hemodialysis is not effective for removal of the oral factor Xa inhibitors.
Other reversal agents for direct oral anticoagulants are currently being developed (eg, ciraparantag).
Clotting factors
Clotting factors are available in the form of
Fresh frozen plasma
Individual clotting factors
Prothrombin complex concentrate (PCC) is available in several forms. Three-factor PCC contains high levels of factors II, IX, and X, and 4-factor PCC adds factor VII; both also have proteins C and S. PCCs can be unactivated, or activated, in which some of the factors have been cleaved to the active form. The 4-factor PCC is preferred as it tends to be more effective at reversing bleeding than 3-factor PCC. If 3-factor PCC is used, fresh frozen plasma (FFP) can also be given because FFP contains factor VII, which is not contained in 3-factor PCC. Typical dose is 50 units/kg IV. Because evidence of benefit is uncertain and risk of clotting is significant, PCCs should be reserved for life-threatening bleeding.
Fresh frozen plasma contains all the clotting factors but only at normal plasma levels. It is now typically used only if PCC is unavailable; there is no evidence it is effective in bleeding due to factor Xa inhibitors
Individual clotting factors such as activated recombinant factor VII are available but are not thought to be helpful for anticoagulant-related bleeding.
Antifibrinolytics and other agents
Resumption of anticoagulation after bleeding
Clinical judgment is necessary when deciding whether to permanently stop or lower the dose of anticoagulant.
If a patient has almost completed their treatment course of anticoagulant and has a severe bleeding episode, the anticoagulant can be stopped. However, if a patient has just started or is mid-way through their treatment course and has a severe bleed, the decision of whether to stop or reduce the dose of anticoagulant is not as straightforward and should be made in consultation with a multidisciplinary team and keeping in mind the patient's priorities.
Bleeding due to anticoagulants reference
1. Connolly SJ, Crowther M, Eikelboom JW, et al: Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med 380:1326–1335, 2019. doi: 10.1056/NEJMoa1814051
Thrombolytic (Fibrinolytic) Agents
heparin alone. For patients with DVT, a clinical trial showed that catheter-directed thrombolytic therapy did not reduce the incidence of post-thrombotic syndrome compared with conventional anticoagulant therapy (1). Consequently, thrombolytic agents should be considered only in highly selected patients with DVT. Patients who may benefit from thrombolytic agents include those with extensive iliofemoral DVT who are younger (< 60 years) and do not have risk factors for bleeding. Thrombolytic therapy should be given stronger consideration in patients with extensive DVT who have evolving or existing limb ischemia (eg, phlegmasia cerulea dolens).
For patients with PE, thrombolytic therapy should be considered if patients have clinically massive PE, defined as PE associated with systemic hypotension (systolic blood pressure < 90 mm Hg), cardiogenic shock, or respiratory failure. Most other patients, with submassive PE, do not appear to benefit from thrombolytic therapy. However, in selected patients with submassive PE, thrombolytic therapy may be considered if there is clinical deterioration despite conventional anticoagulant therapy. In patients with submassive PE and right ventricular dysfunction, thrombolytic therapy should not be routinely used.
For either DVT or PE, available evidence comparing local (ie, catheter-directed) with systemic administration of thrombolytic therapy has not shown a clear benefit of either modality with respect to mortality.
Bleeding, if it occurs, is most often at the site of arterial or venous puncture sites. This complication can be treated by stopping the thrombolytic agent and doing mechanical compression or surgical repair of the puncture site. Life-threatening bleeding is treated with cryoprecipitate and fresh frozen plasma in addition to stopping the thrombolytic agent.
Thrombolytic treatment reference
1. Vedantham S, Goldhaber SZ, Julien JA, et al: Pharmacomechanical catheter-directed thrombolysis for deep-vein thrombosis. N Engl J Med 377:2240–2252, 2017. doi: 10.1056/NEJMoa1615066
More Information
The following English-language resource may be useful. Please note that THE MANUAL is not responsible for the content of this resource.
Kearon C, Aki EA, Ornelas J, et al: CHEST Guideline and Expert Panel Report: Antithrombotic therapy for VTE disease. Chest 149:315–352, 2016. doi: https://doi.org/10.1016/j.chest.2015.11.026
