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).
(See also the American College of Chest Physicians recommendations on Antithrombotic Therapy for VTE Disease .)
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 thrombin (unfractionated heparin), that inhibit mainly factor Xa (LMWH), or that inhibit only factor Xa (fondaparinux). These agents can be used both for patients with DVT and those with PE.
There are several strategies for anticoagulation of patients with DVT:
Initial treatment with an injectable heparin (unfractionated or low molecular weight) followed after several days by long-term treatment with an oral drug (warfarin, a factor Xa inhibitor, or a direct thrombin inhibitor)
Initial and long-term treatment with a LMWH
Initial and long-term treatment with certain oral Xa inhibitors (rivaroxaban or apixaban)
Some but not all of the newer oral anticoagulant drugs are alternatives to warfarin as 1st-line treatment for DVT and pulmonary embolism (PE) and may also be used as monotherapy (see table Oral Anticoagulants). Compared to warfarin, these drugs have been shown to give similar protection against recurrent DVT and have similar (or with apixaban, perhaps lower) risk of serious bleeding (1).
Their advantages are that they are effective within several hours and thus do not require a period of overlapping treatment with heparin (bridging treatment), although edoxaban and dabigatran require at least 5 days of pretreatment with an injectable anticoagulant. Also, they are given as a fixed dose and thus, unlike warfarin, do not require ongoing laboratory testing.
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 if patients are receiving ongoing cancer therapy or in patients with advanced, metastatic disease. Patients with selected hypercoagulable states (eg, antiphospholipid antibody syndrome or protein C, protein S, or antithrombin deficiency) should also be considered for extended-duration anticoagulation.
Low molecular weight heparins (eg, enoxaparin, dalteparin, tinzaparin—see table Some Low Molecular Weight Heparin Options in Thromboembolic Disease) are the initial treatment of choice because they can be given on an outpatient basis. LMWHs are as effective as UFH for reducing DVT recurrence, thrombus extension, and risk of death due to PE. 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.
LMWHs are typically given subcutaneously in a standard weight-based dose (eg, enoxaparin 1.5 mg/kg subcutaneously once a day or 1 mg/kg subcutaneously every 12 hours or dalteparin 200 units/kg subcutaneously once a day). Patients with renal insufficiency may be treated with UFH or with reduced doses of LMWH. Monitoring is not reliable because LMWHs do not significantly prolong the results of global tests of coagulation. Furthermore, they have a predictable dose response, and there is no clear relationship between the anticoagulant effect of LMWH and bleeding. Treatment is continued until full anticoagulation is achieved with warfarin (typically about 5 days). Transition to the oral drugs rivaroxaban or apixaban can be done at any time with no overlap. Transition to edoxaban or dabigatran requires at least 5 days of LMWH treatment, but no overlap is needed.
LMWHs are a 1st-line treatment option for patients with cancer-associated DVT, including in patients who have a central venous catheter and develop DVT. Warfarin is a 2nd-line alternative to LMWH due to its low cost, but use requires careful monitoring.
Unfractionated heparin may be used instead of LMWH for hospitalized patients and for patients who have renal insufficiency or failure (creatinine clearance 10 to 30 mL/minute) because UFH is not cleared by the kidneys. UFH is given as a bolus and infusion (see figure Weight-based heparin dosing) to achieve full anticoagulation, (eg, activated partial thromboplastin time [aPTT] 1.5 to 2.5 times that of the reference range). For outpatients, UFH 333 units/kg initial bolus, then 250 units/kg subcutaneously every 12 hours can be substituted for IV UFH to facilitate mobility; the dose does not need adjustment based on aPTT. Treatment is continued until full anticoagulation has been achieved with warfarin.
Complications of heparins include bleeding, thrombocytopenia (less common with LMWHs), urticaria, and, rarely, thrombosis and anaphylaxis. Long-term use of UFH causes hypokalemia, liver enzyme elevations, and osteopenia. Rarely, UFH given subcutaneously causes skin necrosis. Inpatients and possibly outpatients should be screened for bleeding with serial complete blood counts and, where appropriate, testing for occult blood in stool.
Rivaroxaban and apixaban can be started as monotherapy immediately upon diagnosis or used in transition from an injectable heparin at any time without overlap. Dosing of rivaroxaban is 15 mg orally twice a day for 3 weeks followed by 20 mg orally once a day for 9 weeks. 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.
Edoxaban requires an initial 5 to 7 days of treatment with LMWH or UFH and is then given 60 mg orally once a day.
To transition from an injectable anticoagulant, the 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.
There is also evidence that apixaban, edoxaban, and rivaroxaban can be used in select patients with cancer-associated venous thromboembolism (VTE) as an alternative to monotherapy with LMWH (2–4).
Fondaparinux, a parenteral selective 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.
Betrixaban is an oral factor Xa inhibitor that is used only for prevention (not treatment) of DVT.
Dabigatran 150 mg orally twice a day is given only after an initial 5 days of treatment with LMWH. It 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 regimen.
Vitamin K antagonists, such as warfarin, remain a 1st-line treatment option for patients with VTE, with the exception of selected patients, including pregnant women, who should continue to take heparin, and patients with cancer-associated VTE, who should receive a LMWH (emerging evidence indicates that edoxaban or rivaroxaban also are alternatives).
Warfarin 5 to 10 mg can be started immediately with heparin because it takes about 5 days to achieve desired therapeutic effect. Older patients and patients with a liver disorder typically require lower warfarin 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 or protein S deficiency Factor V Resistance to Activated Protein C (APC).
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. 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
3. 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
4. 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 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:
Risk factors for severe bleeding include
Age ≥ 65
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
However, by definition these agents are prothrombotic and the risks of continued bleeding should be balanced with the increased risk of thrombosis.
Many of the anticoagulants have specific reversal agents. If these are unavailable or ineffective, clotting factors, typically in the form of 4-factor prothrombin complex concentrate or sometimes fresh frozen plasma, can be given. Some drugs can be removed by hemodialysis or have absorption blocked by activated charcoal.
With the heparins, bleeding can be stopped or slowed with protamine sulfate. It is more effective on UFH than on LMWH because 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 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 receiving 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.
Warfarin 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 > 9, and 5 to 10 mg IV (given slowly to avoid anaphylaxis) if there is active hemorrhage. If hemorrhage is severe, prothrombin complex concentrate (PCC) should be given; fresh frozen plasma may be used if PCC 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 dabigatran, a humanized monoclonal antibody idarucizumab 5g IV is an effective antidote to bleeding. If the drug is not available, 4-factor PCC 50 units/kg IV can be given. Hemodialysis also may help because dabigatran is not highly protein bound. Oral activated charcoal is an option if the last dose of dabigatran 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 inhibitor (eg, rivaroxaban > 10 mg or apixaban > 5 mg), or if the patient took the drug < 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 drug > 8 hours before presentation, a lower dose of andexanet alfa (400 mg IV at 30 mg/minute followed by 480 mg IV at 8 mg/minute) is given. Fondaparinux anticoagulation can theoretically be reversed with andexanet alfa although this has not been studied in research trials. If andexanet alfa is unavailable, 4-factor PCC may be considered. Oral activated charcoal is an option in patients who took an oral 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 on the oral factor Xa inhibitors.
Other reversal agents for direct oral anticoagulants are currently being developed (eg, ciraparantag).
Clotting factors are available in the form of
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.
Antifibrinolytic agents can also be tried, however their use has not been studied for reversal of bleeding in patients on anticoagulants. Tranexamic acid 10 to 20 mg/kg IV bolus followed by 10 mg/kg IV every 6 to 8 hours may be used. Epsilon-aminocaproic acid may be started at 2 gm IV every 6 hours.
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.
Thrombolytic drugs, which include alteplase, tenecteplase, and streptokinase, lyse clots and may be more effective than heparin alone in selected patients, but the risk of bleeding is higher than with heparin alone. For patients with DVT, a clinical trial showed that thrombolytic therapy did not reduce the incidence of postphlebitic syndrome compared with conventional anticoagulant therapy (1). Consequently, thrombolytic drugs should be considered only in highly selected patients with DVT. Patients who may benefit from thrombolytic drugs 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, local (ie , direct) administration of thrombolytic therapy with an indwelling catheter (during percutaneous thrombectomy) has not been shown to be preferable to IV administration.
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 drug 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 drug.