All patients with deep venous thrombosis (DVT) are given anticoagulants Anticoagulants Deep venous thrombosis (DVT) is clotting of blood in a deep vein of an extremity (usually calf or thigh) or the pelvis. DVT is the primary cause of pulmonary embolism. DVT results from conditions... read more and in rare cases thrombolytics Thrombolytic (fibrinolytic) drugs Deep venous thrombosis (DVT) is clotting of blood in a deep vein of an extremity (usually calf or thigh) or the pelvis. DVT is the primary cause of pulmonary embolism. DVT results from conditions... read more . A number of anticoagulants are effective for management of deep venous thrombosis (see also Deep Venous Thrombosis Deep Venous Thrombosis (DVT) Deep venous thrombosis (DVT) is clotting of blood in a deep vein of an extremity (usually calf or thigh) or the pelvis. DVT is the primary cause of pulmonary embolism. DVT results from conditions... read more ).
Non-drug treatments include surgery Surgery Deep venous thrombosis (DVT) is clotting of blood in a deep vein of an extremity (usually calf or thigh) or the pelvis. DVT is the primary cause of pulmonary embolism. DVT results from conditions... read more and inferior vena cava filters Inferior vena cava (IVC) filter Deep venous thrombosis (DVT) is clotting of blood in a deep vein of an extremity (usually calf or thigh) or the pelvis. DVT is the primary cause of pulmonary embolism. DVT results from conditions... read more .
(See also the American College of Chest Physicians recommendations on Antithrombotic Therapy for VTE Disease [ 1 Anticoagulant treatment references 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... read more ].)
The anticoagulants (see figure and table ) include
Low molecular weight heparins (LMWHs)
Unfractionated heparin (UFH)
Factor Xa inhibitors: oral (eg, rivaroxaban, apixaban, edoxaban) and parenteral (fondaparinux)
Direct thrombin inhibitors: oral (dabigatran etexilate) and parenteral (argatroban, bivalirudin, desirudin)
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.
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:
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 ). 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 Anticoagulant treatment references 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... read more ).
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 Antiphospholipid Antibody Syndrome (APS) Antiphospholipid antibody syndrome is an autoimmune disorder in which patients have autoantibodies to phospholipid-bound proteins. Venous or arterial thrombi may occur. The pathophysiology is... read more or protein C Protein C Deficiency Because activated protein C degrades coagulation factors Va and VIIIa, deficiency of protein C predisposes to venous thrombosis. (See also Overview of Thrombotic Disorders.) Protein C is a vitamin... read more , protein S Protein S Deficiency Because protein S binds and assists activated protein C in the degradation of coagulation factors Va and VIIIa, deficiency of protein S predisposes to venous thrombosis. (See also Overview of... read more , or antithrombin Antithrombin Deficiency Because antithrombin inhibits thrombin and factors Xa, IXa, and XIa, deficiency of antithrombin predisposes to venous thrombosis. (See also Overview of Thrombotic Disorders.) Antithrombin is... read more deficiency) should also be considered for extended-duration anticoagulation.
Low molecular weight heparins (LMWHs)
Low molecular weight heparins (eg, enoxaparin, dalteparin, tinzaparin—see table ) 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 (UFH)
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 ) 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 Bleeding During Use of Anticoagulants 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... read more , thrombocytopenia Heparin-induced thrombocytopenia Platelet destruction can develop because of immunologic causes (viral infection, drugs, connective tissue or lymphoproliferative disorders, blood transfusions) or nonimmunologic causes (sepsis... read more (less common with LMWHs), urticaria Urticaria Urticaria consists of migratory, well-circumscribed, erythematous, pruritic plaques on the skin. Urticaria also may be accompanied by angioedema, which results from mast cell and basophil activation... read more , and, rarely, thrombosis Overview of Thrombotic Disorders In healthy people, homeostatic balance exists between procoagulant (clotting) forces and anticoagulant and fibrinolytic forces. Numerous genetic, acquired, and environmental factors can tip... read more and anaphylaxis Anaphylaxis Anaphylaxis is an acute, potentially life-threatening, IgE-mediated allergic reaction that occurs in previously sensitized people when they are reexposed to the sensitizing antigen. Symptoms... read more . Long-term use of UFH causes hypokalemia Hypokalemia Hypokalemia is serum potassium concentration < 3.5 mEq/L (< 3.5 mmol/L) caused by a deficit in total body potassium stores or abnormal movement of potassium into cells. The most common... read more , 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.
Factor Xa inhibitors
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 Treatment references Deep venous thrombosis (DVT) is clotting of blood in a deep vein of an extremity (usually calf or thigh) or the pelvis. DVT is the primary cause of pulmonary embolism. DVT results from conditions... read more ).
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.
Direct thrombin inhibitors
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.
Parenteral direct thrombin inhibitors (argatroban, bivalirudin, desirudin) are available but do not have a role in treatment or prevention Prevention Deep venous thrombosis (DVT) is clotting of blood in a deep vein of an extremity (usually calf or thigh) or the pelvis. DVT is the primary cause of pulmonary embolism. DVT results from conditions... read more of DVT or PE. Argatroban may be useful to treat DVT in patients with heparin-induced thrombocytopenia Heparin-induced thrombocytopenia Platelet destruction can develop because of immunologic causes (viral infection, drugs, connective tissue or lymphoproliferative disorders, blood transfusions) or nonimmunologic causes (sepsis... read more .
Vitamin K antagonists (warfarins)
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.
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. 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 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
History of prior gastrointestinal bleeding Overview of Gastrointestinal Bleeding Gastrointestinal (GI) bleeding can originate anywhere from the mouth to the anus and can be overt or occult. The manifestations depend on the location and rate of bleeding. (See also Varices... read more or stroke Overview of Stroke Strokes are a heterogeneous group of disorders involving sudden, focal interruption of cerebral blood flow that causes neurologic deficit. Strokes can be Ischemic (80%), typically resulting... read more
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 Intravenous Fluid Resuscitation Almost all circulatory shock states require large-volume IV fluid replacement, as does severe intravascular volume depletion (eg, due to diarrhea or heatstroke). Intravascular volume deficiency... read more and packed red blood cell transfusions Red blood cells (RBCs) Whole blood can provide improved oxygen-carrying capacity, volume expansion, and replacement of clotting factors and was previously recommended for rapid massive blood loss. However, because... read more . 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
Clotting factors (eg, prothrombin complex concentrate, fresh frozen plasma)
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; 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.
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 5 g IV is an effective antidote to bleeding. If the drug is not available, 4-factor PCC 50 units/kg IV can be given. Hemodialysis Hemodialysis In hemodialysis, a patient’s blood is pumped into a dialyzer containing 2 fluid compartments configured as bundles of hollow fiber capillary tubes or as parallel, sandwiched sheets of semipermeable... read more 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 Thrombolytic treatment reference 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... read more ). 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
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
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.
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
Thrombolytic (Fibrinolytic) Drugs
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 Thrombolytic treatment reference 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... read more ). 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 Cardiogenic and obstructive shock Shock is a state of organ hypoperfusion with resultant cellular dysfunction and death. Mechanisms may involve decreased circulating volume, decreased cardiac output, and vasodilation, sometimes... read more , or respiratory failure Overview of Respiratory Failure Acute respiratory failure is a life-threatening impairment of oxygenation, carbon dioxide elimination, or both. Respiratory failure may occur because of impaired gas exchange, decreased ventilation... read more . 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.