Thromboembolism Treatment & Management
- Author: Vera A De Palo, MD; Chief Editor: Harris Gellman, MD more...
Anticoagulant and thrombolytic therapy options are available. Anticoagulant therapy prevents further clot deposition and allows the patient’s natural fibrinolytic mechanisms to lyse the existing clot.
Anticoagulant inpatient medications should include heparin or a low-molecular-weight heparin (LMWH), followed by the initiation of an oral coumarin derivative. The predominant coumarin derivative in clinical use in North America is warfarin sodium.
The anticoagulant properties of unfractionated heparin (UFH), LMWH, and warfarin sodium stem from their effects on the factors and cofactors of the coagulation cascade.
Patients with acute, massive pulmonary embolism (PE) causing hemodynamic instability may be treated initially with a thrombolytic agent (ie, streptokinase or tissue plasminogen activator). Tissue plasminogen activator has increasingly been used as the first-choice thrombolytic agent. Antibodies to streptokinase may be developed, limiting its use.
Surgical interventions for venous thromboembolic disorders include thrombectomy and venous interruption.
In pregnancy, establishing a clear guideline for the treatment of thromboembolic disease is difficult from an evidence-based perspective. Heparin is the anticoagulant of choice given its relative safety for the fetus.
Heparin therapy should be discontinued immediately before delivery, and then both heparin and warfarin therapy can be started postpartum.
Pregnant women with a history of previous thromboembolic disease probably should receive some prophylaxis, as the estimated range of recurrence is 0-15%.
International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism (VTE) in patients with cancer were issued in early 2013. Recommendations include the following:
For the initial treatment of established VTE, LMWH is recommended, and fondaparinux and UFH can be also used
Thrombolysis may only be considered on a case-by-case basis
Vena cava filters (VCFs) may be considered if there is a contraindication to anticoagulation or PE recurrence under optimal anticoagulation
Periodic reassessments of contraindications to anticoagulation are recommended
VCFs are not recommended for primary VTE prophylaxis in cancer patients
For the early maintenance and long-term treatment of established VTE, LMWH for a minimum of 3 months is preferred over vitamin K antagonists (VKAs). Idraparinux is not recommended. After 3-6 months, LMWH or VKA continuation should be based on individual evaluation of the benefits and risks, tolerability, patient preference and cancer activity
For the treatment of VTE recurrence in cancer patients receiving anticoagulation, there are three options: (i) switch from VKA to LMWH when treated with VKA; (ii) increase LMWH dose when treated with LMWH, and (iii) VCF insertion
For the prophylaxis of postoperative VTE in surgical cancer patients, use of LMWH or low-dose UFH is recommended
Extended prophylaxis (4 weeks) after major laparotomy may be indicated in patients with a high risk of VTE and low risk of bleeding
Use of LMWH for VTE prevention in cancer patients undergoing laparoscopic surgery may be recommended as for laparotomy
Mechanical methods are not recommended as monotherapy except when pharmacological methods are contraindicated
In hospitalized patients with cancer and reduced mobility, prophylaxis with LMWH, UFH, or fondaparinux is recommended
Prophylaxis may be considered in some children and adults with acute lymphocytic leukemia treated with L-asparaginase, depending on local policy and patient characteristics
Routine prophylaxis is not recommended in patients receiving chemotherapy
Primary pharmacologic prophylaxis of VTE may be indicated in patients with locally advanced or metastatic pancreatic or lung cancer treated with chemotherapy and having a low risk of bleeding
In patients treated with thalidomide or lenalidomide combined with steroids and/or chemotherapy, VTE prophylaxis is recommended
In May 2013, the American Society of Clinical Oncology (ASCO) released revised clinical practice guidelines on VTE prophylaxis and treatment in patients with cancer.[26, 27] A review of the literature published from December 2007 to December 2012 was completed in MEDLINE and the Cochrane Collaboration Library, and evidence was assessed to determine which recommendations required revision. Slight changes were made to existing recommendations, and two new recommendations were added that focused on the following :
The need to assess and periodically reassess the risk for VTE
The need to educate high-risk patients on how to prevent blood clots and how to recognize the warning signs of VTE
The recommendation against the routine use of thromboprophylaxis for most ambulatory patients with cancer remained unchanged.
Heparin is the first line of therapy. It is administered by bolus dosing, followed by a continuous infusion. Adequacy of therapy is determined by an activated partial thromboplastin time (aPTT) of 1.5-2 times baseline. Progression or recurrence of thromboembolism is 15 times more likely when a therapeutic aPTT is not achieved within the first 48 hours.
A weight-based nomogram has been used to determine adequate dosing, using heparin at 80 mg/kg for the bolus and 18 mg/kg/hr for the infusion. A short course of heparin is followed by a longer course of oral anticoagulant, warfarin sodium. It should be started only after effective anticoagulation has been achieved, as there can be an increase in coagulability and thrombogenesis during the first few days of oral anticoagulant administration.
The goal is to achieve an international normalized ratio (INR) of 2.0-3.0. The optimum duration of treatment depends on several factors (eg, first episode or recurrent event, other underlying risk factors). A minimum of 3 months of oral therapy has been suggested following a first episode of DVT or PE.
The results of a Cochrane Database of Systematic Reviews study found that the use of heparin in patients with cancer but with no therapeutic or prophylactic indication for it was related to a significant reduction in death at 24 months but not at 12 months. A statistically and clinically important reduction in venous thromboembolism was also noted. It had no effect on bleeding or quality of life. Future studies are needed to investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer.
No significant reduction in mortality at 6 months, 1 year, 2 years, or 5 years was found in another, similar study from the Cochrane Database of Systematic Reviews comparing the use of oral anticoagulants with either placebo or no intervention in patients with cancer who had no therapeutic or prophylactic indication for anticoagulation. In addition, the oral anticoagulant warfarin was found to increase major and minor bleeding.
In a study of patients with a first VTE who did not have cancer and who received different durations of anticoagulant treatment, the results indicated a similar risk of recurrent venous thromboembolism whether anticoagulation therapy was stopped after 3 months or a longer period of treatment was provided. The study evaluated data from seven randomized trials that included 2925 men or women. Proximal DVT and PE showed a higher risk of recurrence whenever treatment was stopped.
Results from phase II/III studies, according to a report by Merli et al, suggested that new oral anticoagulants may provide an efficacious alternative in prevention of venous thromboembolism in orthopedic surgery and have had a good overall safety profile, with no evidence of increased hepatotoxicity. Comparison with large observational registries, however, revealed differences between real-life patient populations; differences in endpoint definitions also prevented indirect comparison of agents.
The study’s authors stated that specific compliance and postmarketing safety issues (especially liver enzyme monitoring requirements) need to be clarified before these agents can be widely accepted in routine clinical practice.
Several studies have shown that LMWH, which is a fractionated heparin, is as effective as unfractionated heparin in treating DVT. Minimal requirements for outpatient therapy with LMWH regimens include stable PE or DVT, low risk for bleeding, absence of severe renal insufficiency, availability of systems of administration and monitoring of LMWH and warfarin, and surveillance and treatment of recurrent thromboembolic disease.
A Cochrane Database of Systemic Reviews study found that LMWH, in a comparison with oral anticoagulants (eg, vitamin K antagonist [VKA] or ximelagatran), reduced venous thromboembolic events but not death in patients with cancer.
Factor Xa and direct thrombin inhibitors
Apixaban, dabigatran, rivaroxaban, and edoxaban are alternatives to warfarin for prophylaxis or treatment of DVT and PE. Apixaban, edoxaban, and rivaroxaban inhibit Factor Xa, whereas dabigatran is a direct thrombin inhibitor.
Rivaroxaban is an oral factor Xa inhibitor approved by the US Food and Drug Administration (FDA) in November 2012 for the treatment of DVT or PE, and to reduce risk of recurrent DVT and PE following initial treatment.
Approval for this indication was based on studies totaling 9478 patients with DVT or PE. Participants were randomly assigned to receive rivaroxaban, a combination of enoxaparin and a vitamin K antagonist (VKA) (eg, warfarin), or a placebo. Study endpoints were designed to measure the number of patients who experienced recurrent symptoms of DVT, PE, or death after receiving treatment.
Results showed rivaroxaban was as effective as the enoxaparin and VKA combination for treating DVT and PE. Approximately 2.1% of patients treated with rivaroxaban compared with 1.8-3% treated with the enoxaparin and VKA combination experienced a recurrent DVT or PE.[34, 35] Additionally, results from extended treatment demonstrated a reduced risk of recurrent DVT and PE. Approximately 1.3% in the rivaroxaban group experienced recurrent DVT or PE compared with 7.1% in the placebo group.[36, 37]
In August 2014, apixaban was approved for treatment of DVT and PE. The approval for treatment of PE and prevention of recurrence was based on the outcome of the AMPLIFY (Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy) and AMPLIFY-EXT studies, in which apixaban therapy was compared with enoxaparin and warfarin treatment.
The AMPLIFY study showed that, in comparison with the standard anticoagulant regimen, apixaban therapy resulted in a 16% reduction in the risk of a composite endpoint that included recurrent symptomatic VTE or VTE-associated death.
Dabigatran inhibits free and clot-bound thrombin and thrombin-induced platelet aggregation. It was approved in 2010 to reduce the risk of stroke in patients with nonvalvular atrial fibrillation. In April 2014, it was approved for the treatment of DVT and PE in patients who have been treated with a parenteral anticoagulant for 5-10 days. Additionally, it was approved to reduce the risk of DVT and PE recurrence in patients who have been previously treated. Approval was based on results from 4 global phase III trials.
The RE-COVER and RE-COVER II trials included patients with DVT and PE who were treated with parenteral anticoagulant therapy for 5-10 days. Results showed dabigatran was noninferior to warfarin in reducing DVT and PE after a median of 174 days of treatment with a lower risk of bleeding compared with warfarin.[39, 40]
The RE-SONATE trial and RE-MEDY trials included patients (n=2856) with acute DVT and PE who had completed at least 3 months of anticoagulant therapy. Results from this trial showed dabigatran was noninferior to warfarin in the extended treatment of VTE and carried a lower risk of major or clinically relevant bleeding than warfarin.
Edoxaban was approved by the FDA in January 2015 for treatment of DVT and PE in patients who have been initially treated with a parenteral anticoagulant for 5-10 days. Approval was based on the Hokusai-VTE study that included 4921 patients with DVT and 3,319 patients with PE.
Among patients with PE, 938 had right ventricular dysfunction, as assessed by measurement of N-terminal pro-brain natriuretic peptide levels. The rate of recurrent VTE in this subgroup was 3.3% in the edoxaban group and 6.2% in the warfarin group. Edoxaban was noninferior to high-quality standard warfarin therapy and caused significantly less bleeding in a broad spectrum of patients with VTE, including those with severe PE.
Thrombolytic therapy dissolves recent clots promptly by activating a plasma proenzyme, plasminogen, to its active form, plasmin. Plasmin degrades fibrin to soluble peptides. Thrombolytic therapy speeds pulmonary tissue reperfusion and rapidly reverses right heart failure. It also improves pulmonary capillary blood flow and more rapidly improves hemodynamic parameters.
Tenecteplase, alteplase, and reteplase (rt-PA) are thrombolytic agents that the Food and Drug Administration (FDA) has approved for thrombolytic use in PE. In head-to-head studies by Goldhaber and colleagues between rt-PA and heparin, there was a higher incidence of recurrent PE and death in the group receiving heparin. Patients in both groups had bleeding complications requiring transfusion therapy.[43, 44]
Thrombolytic treatment may be administered in acute PE associated with hemodynamic instability in patients who do not seem prone to bleeding, based on the American College of Chest Physician’s evidenced-based guidelines, “Antithrombotic Therapy and Prevention of Thrombosis, 9th edition.”
Absolute contraindications to thrombolysis include the following:
Gastrointestinal bleeding within the last 6 months
Active or recent internal bleeding
History of hemorrhagic stroke
Intracranial or intraspinal disease
Recent cranial surgery or head trauma
Relative contraindications include the following:
Major surgery or trauma within the last 2 weeks
Biopsy within 10 days
Other invasive procedures
Procedures in a location inaccessible to external compression
Uncontrolled coagulation defects such as thrombocytopenia
Vena caval filter
The vena caval filter is designed to trap potentially lethal emboli while maintaining vena caval patency. It is indicated in cases in which there is a contraindication to anticoagulation, when there has been a complication of anticoagulation, in the event of a failure of anticoagulation, and in the case of pulmonary embolectomy.
Thrombectomy, Embolectomy, and Ligation
Thrombectomy for venous embolism is performed less frequently given the incidence of rethrombosis, unless heparin infusion is added to the therapeutic regimen.
Pulmonary embolectomy remains a therapeutic option, but mortality is extremely high. It is reserved for cases of massive PE in which an absolute contraindication to thrombolysis is present or when all other treatment modalities have failed. It is only effective when the clot is in the large central vessels.
Catheter pulmonary embolectomy is performed by inserting a cup-tipped, steerable catheter into the central venous system, with access gained through the jugular vein or through the right common femoral vein. When the cup reaches the thrombus, suction is applied and the thrombus is extracted.
Ligation of venous tributaries is an option that is rarely practiced today. Its use has been limited by a high mortality rate and the need for continuous anticoagulation. It essentially has been replaced by the percutaneous insertion of the intracaval filter.
In general, inpatient care requires the administration and continuation of intravenous (IV) or subcutaneous (SC) anticoagulants, with an oral anticoagulant (the coumarin derivative warfarin sodium) started within 72 hours of the SC anticoagulant or, when using IV heparin, once the aPTT is therapeutic (1.5-2 times baseline).
The reason that the oral administration of warfarin sodium is started after anticoagulation with SC or IV anticoagulants has been achieved is because warfarin can have an initial procoagulant effect, particularly in patients with protein C or protein S deficiencies, potentially causing fat necrosis.
For patients whose treatment has included thrombolysis for acute, massive PE causing hemodynamic instability, heparin infusion should be started once the thrombin time or aPTT is less than 2 times baseline. Treatment with an oral coumarin derivative should begin after 24-48 hours of consistent anticoagulation.
Appropriate anticoagulation with the oral medication has been accomplished when the INR is between 2.0 and 3.0.
Once the INR is consistently within the desired range, treatment can continue in the outpatient setting as long as no other concomitant conditions are present that require continued inpatient treatment.
Prolongation of the prothrombin time should be monitored in the outpatient setting by the routine measurement of the INR, with adjustments made to maintain its level between 2.0 and 3.0. In the outpatient setting, the oral anticoagulant, warfarin sodium, is continued; oral anticoagulation treatment should be continued for at least 3 months.
In patients with recurrent venous thrombosis or with a continuing risk factor, such as a hematologic factor or a malignancy, prolonged or even indefinite anticoagulation treatment should be considered.
The results of one study suggested that outpatient care may be a safe and effective alternative to inpatient care in selected, hemodynamically stable patients with PE. The study evaluated data from 344 patients with a low risk of death at 19 emergency departments internationally. Patients in the inpatient group experienced no recurrent VTE events within 90 days and no major bleeding within 14 days or at 90 days.
While a few members of the outpatient group developed recurrent VTE within 90 days (1 of 171) and major bleeding within 14 days or at 90 days (2 of 171 and 3 of 171, respectively), patients in the outpatient group experienced less mean length of stay than did those in the inpatient group (0-5 days vs 3-9 days, respectively). One inpatient and 1 outpatient died within 90 days.
Sequelae of treated DVT includes a postthrombotic syndrome (postphlebitic syndrome), which is a chronic complication of venous thromboembolism characterized by pain and swelling. Chronic deep venous insufficiency, recurrent cellulitis, venous stasis, and ulceration of the skin can develop in up to 50% of patients treated with full anticoagulation.
The results from an open-label, randomized, controlled trial suggested that additional treatment with catheter-directed thrombolysis using alteplase (recombinant tissue plasminogen activator, or rt-PA) reduces the development of postthrombotic syndrome, prompting the authors to suggest that it be considered for patients at low risk of bleeding who have high proximal DVT.
The most feared complication of the treatment of PE is severe and fatal bleeding. Major risk factors for bleeding include intensity and duration of therapy, increased age, and significant hepatic or renal dysfunction. Comparison studies of the incidence of severe and fatal bleeding complications between heparin and rt-PA have demonstrated no significant differences. When significant bleeding does occur, it may be necessary to treat with agent-specific strategies.
Heparin-induced thrombocytopenia (HIT) and thrombosis may develop in 3-4% of patients receiving heparin. It is an immune-mediated process that typically presents within 5-10 days of therapy. It can result in bleeding or thrombosis and should be suspected when the platelet count falls precipitously to less than 50% below its baseline or to less than 100,000/µL. In such cases, heparin therapy should be stopped immediately.
LMWH cross-reacts with the antibody in vitro in 90% of cases. Therefore, it should not be substituted in the acute setting. Danaparoid, a heparinoid, has less than 10% cross-reactivity with the antibody.
Recombinant hirudin is also been approved for HIT and thrombosis. Plasmapheresis and immunoglobulin G (IgG) infusion may be effective in cases with thrombosis.
Heparin-induced osteopenia has been reported following treatment with unfractionated heparin of more than 1 month's duration.
Coumarin derivatives can cause skin necrosis, due to widespread subcutaneous microthrombosis. This can occur in individuals who are protein C-deficient, either genetically or owing to large loading doses of a coumarin derivative. Areas usually affected include the breasts, abdominal wall, and lower extremities.
Recurrence of thromboembolism had been documented following discontinuation of therapy. After a 3- to 6-month course of anticoagulant therapy, the risk of recurrent thromboembolism is lower in patients who have reversible risk factors. The recurrence rate is greater in patients with previous proximal vein thrombosis, compared with calf vein thrombosis.
After a 3-month course of anticoagulant therapy, secondary thrombosis risk is 2-4% in the first year. The recurrence risk is dependent on the precipitating risk factor. Recurrence risk is low if VTE is provoked by surgery and intermediate if related to a nonsurgical risk factor. However, the recurrence risk is high if unprovoked and in the setting of the patient with a disease-related risk factor.
Two studies indicated that aspirin reduces by one third the rate of VTE recurrence and the rate of major vascular events (a composite outcome made up of stroke, myocardial infarction, and cardiovascular death, in addition to VTE).[52, 53, 54] It also reduces arterial thrombotic events.
No special dietary requirements or restrictions exist. Diet should be as tolerated.
An exception, however, applies to patients on oral warfarin therapy, who must avoid vitamin supplements that contain vitamin K and must limit foods that are high in vitamin K (eg, broccoli, cabbage, red and green lettuce, onion, peppers, spinach, oils, mayonnaise, black and green leaf teas). For the patient on oral warfarin therapy, the diet should remain steady, with no drastic changes in content, in order to facilitate accurate, regular monitoring of INR levels. Drastic changes in vitamin K–containing foods or supplements can affect the INR.
Activity in patients with thromboembolism should be limited until anticoagulation has been achieved and the patient is on oral anticoagulant medication. Patients on oral warfarin therapy should avoid activities that could cause trauma.
Thromboprophylaxis has been reported to reduce the incidence of DVT and fatal PE. Prophylaxis may be achieved with medication or with mechanical devices. Medical prophylaxis should begin either 12 hours before surgery or immediately after surgery and should be continued for 7-10 days.[55, 56, 57, 58, 59, 60, 61, 62, 63]
Unfractionated heparin, given subcutaneously, can reduce the incidence of thromboembolism. It must be administered two or three times daily, and bleeding can be a complication. LMWHs have a longer half-life and greater bioavailability than does unfractionated heparin. The requirement for monitoring is less.
Data from an international, multicenter, randomized, controlled study found that a short-term course of thromboprophylaxis with the anticoagulant enoxaparin was more effective than an extended course of another anticoagulant, apixaban, with significantly fewer major bleeding events.
Apixaban was approved by the FDA in December 2012 to reduce risk of stroke and systemic embolism associated with nonvalvular atrial fibrillation.
Danaparoid, a low-molecular-weight glycosaminoglycan, has been shown to be effective in preventing DVT and PE. It also has been used in patients whose treatment course has been complicated by heparin-induced thrombocytopenia (HIT).
Warfarin is effective for thromboprophylaxis; it causes the depletion of vitamin K–dependent factors in the coagulation cascade. Warfarin requires close monitoring, and bleeding can be a complication. Dose-adjusted therapy should be monitored, keeping the INR in the range of 2.0-3.0.
A randomized, controlled trial comparing dalteparin with aspirin for VTE prophylaxis in total hip arthroplasty patients found aspirin to be as effective and safe as dalteparin.[65, 66]
In November 2015, the FDA approved dabigatran for prophylaxis of DVT and PE after hip replacement surgery.
External pneumatic compression has been shown to temporarily prevent the reduction in fibrinolytic activity that normally follows surgical operations. Studies have found compression devices to be effective only in patients with head trauma or spinal fracture. In total hip replacement, studies have shown them to be efficacious in preventing distal DVT but not in preventing proximal DVT.
Another method of nonpharmacologic prophylaxis is early ambulation, unless the patient has an absolute contraindication. Studies have demonstrated that both symptomatic and ultrasonographically diagnosed DVT are significantly less common with early ambulation following hip arthroplasty.
A prospective cohort study including 69,950 female nurses found an association between physical inactivity and the incidence of PE in women. The data found that the risk of PE was more than twofold greater in women who spent more time sitting than it was in women who spent less time sitting. Activities that decrease the amount of time sitting may lower the risk of PE in women.
In a randomized, controlled study of 90 patients undergoing total knee arthroplasty, Izumi et al found that intraoperative transcutaneous electrical nerve stimulation (TENS) had a significant effect with regard to prevention of DVT prophylaxis, preventing both venous stasis and blood hypercoagulability.
The results of one study suggested that routine postdischarge prophylaxis should be considered for high-risk patients. The study evaluated the risk of postdischarge VTE in patients who had undergone cancer surgery. Using data from 44,656 patients who underwent surgery for 9 cancers, the results showed that VTE occurred post discharge at an overall rate of 33.4%. VTE was significantly more likely after gastrointestinal (GI), lung, prostate, and ovarian/uterine operations.
For patients undergoing major orthopedic surgery, the ACCP evidence-based guidelines recommend the use of either LMWH; fondaparinux; dabigatran, apixaban, and rivaroxaban (for total hip arthroplasty or total knee arthroplasty but not for hip fracture surgery); low-dose unfractionated heparin; adjusted-dose vitamin K antagonist; aspirin (all grade 1B evidence); or an intermittent pneumatic compression device (grade 1C evidence) for a minimum of 10-14 days rather than no antithrombotic prophylaxis.
In a survey of members of the American Association of Hip and Knee Surgeons, more than 70% of survey participants reported that their primary hospital now mandates prophylaxis for VTE. The survey looked at VTE protocols for lower-extremity total joint surgery. LMWH was considered to be the most efficacious for prophylaxis, but aspirin was considered to be the easiest to use, with the lowest risks of bleeding and wound drainage. Warfarin was the most used agent in hospital prophylaxis, and 90% of respondents targeted an INR of 1.6-2.5.
Following a review of published literature, the American College of Physicians determined that it would not support the use of measures for universal VTE prophylaxis in patients if they were performed without regard to risk. It was reported in the study that in nonsurgical patients, heparin prophylaxis has no significant effect on mortality and leads to more bleeding and bleeding events, suggesting that it is of little or no benefit overall. In addition, no improvements in clinical outcomes were found with mechanical prophylaxis, which also resulted in an increase in lower-extremity skin damage in stroke patients.
When PE is suspected, consultation with a pulmonologist may be useful to aid in the diagnosis or to guide therapy. When the intravascular filling defect is so severe that it causes cardiac dysfunction or hypotension, the patient can be best served by transfer to an intensive care setting. Consultation with an intensive care specialist or pulmonologist would be helpful in decision-making regarding thrombolysis and in following the effectiveness of treatment.
If cancer or a hematologic disorder is one of the contributing risk factors, consultation with a hematologist or oncologist may be appropriate.
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