Venous Thromboembolism (VTE)

Venous thromboembolism (VTE) encompasses two interrelated conditions that are part of the same spectrum, deep venous thrombosis (DVT) and pulmonary embolism (PE). PE is the obstruction of blood flow to one or more arteries of the lung by a thrombus lodged in a pulmonary vessel, as shown in the image below. (See Pathophysiology and Etiology.)

Venous Thromboembolism (VTE). Pulmonary embolism within the pulmonary artery.

PE and DVT can occur in the setting of disease processes, following hospitalization for serious illness, or following major surgery. In 1856, Virchow demonstrated that 90% of all clinically important PEs result from DVT occurring in the deep veins of the lower extremities, proximal to and including the popliteal veins. However, emboli also can originate from the pelvic veins, the inferior vena cava, and the upper extremities. (See Pathophysiology, Etiology, Presentation, and Workup)[1, 2, 3, 4, 5]

Thromboembolic disease is the third most common acute cardiovascular disease, after cardiac ischemic syndromes and stroke. The spectrum of disease ranges from clinically unsuspected to clinically unimportant to massive embolism causing death, and indeed DVT and PE frequently remain undiagnosed because they may not be suspected clinically. Untreated acute proximal DVT causes clinical PE in 33-50% of patients. Untreated PE often is recurrent over days to weeks and can either improve spontaneously or cause death. (See Epidemiology, Presentation, and Workup.)

In a study of Virchow's triad in "silent" DVT, Lurie et al assessed 152 patients who underwent venous stenting for proximal venous outflow obstruction and who had routine hypercoagulation profile testing performed preoperatively.[6] By history or intraoperative chronic postphlebitic changes (CPPCs), 77 patients (50.7%) were positive for remote DVT; 51 (33.6%) had intraoperative findings of CPPCs without a history of DVT; 20 (13.2%) had intraoperative CPPCs with a history of DVT; and six (3.9%) had a history of DVT without intraoperative findings. Findings of CPPCs were significantly increased among patients with a history of DVT, and intraoperative findings of CPPCs were significantly increased in patients with one or more positive hypercoagulation markers.

Guidelines

Guidelines for the diagnosis and management of VTE have been published by the American Society of Hematology, the American Society of Clinical Oncology (ASCO), the European Society of Anesthesiology (ESA), the American College of Chest Physicians (ACCP), the American Academy of Orthopaedic Surgeons (AAOS), and the International Initiative on Thrombosis and Cancer (ITAC). Go to Guidelines for more information.

AAOS guidelines

The 2011 guidelines from the American Academy of Orthopaedic Surgeons (AAOS) on preventing VTE in patients undergoing elective hip and knee arthroplasty included the following recommendations[7, 8] :

• Recommend against routine postoperative duplex ultrasonography screening
• Assess risk of previous VTE
• Assess risk for bleeding
• Suggest discontinuance of antiplatelet agents before undergoing elective hip or knee arthroplasty
• Suggest pharmacologic agents and/or mechanical compressive devices for prevention of VTE in those undergoing elective hip or knee arthroplasty who are not at elevated additional risk for VTE or bleeding
• Pharmacologic prophylaxis and mechanical compressive devices for those who have had previous VTE and are undergoing elective hip or knee arthroplasty
• Mechanical compressive devices for those who have had known bleeding disorder and/or active liver disease and are undergoing elective hip or knee arthroplasty
• Patients should undergo early mobilization following elective hip and knee arthroplasty
• Use of neuraxial anesthesia for those undergoing elective hip or knee arthroplasty to help limit blood loss
• No recommendation can be made for or against the use of inferior vena cava (IVC) filters

Other guidelines

A study by Khokhar et al indicated that there is a lack of uniformity among venous thromboprophylactic guidelines for elective knee arthroplasty. Reviewing 12 guidelines, the investigators found that although almost all of them advocated the use of LMWH and fondaparinux (a synthetic, pentasaccharide anticoagulant), recommendations for other drugs varied, as did drug dosages, duration, and recommendation grades.[9]

In an article addressing the differences between the antithrombotic guidelines of the American College of Chest Physicians (ACCP) and those of the AAOS, the authors noted that recommendation variations were based on methodology and evidence differences.[10]  With updates to these two more popular VTE guidelines, similar recommendations were offered that focus on minimizing symptomatic VTE and bleeding complications.[11]

A thrombus is a solid mass composed of platelets and fibrin with a few trapped red and white blood cells that forms within a blood vessel. Hypercoagulability or obstruction leads to the formation of a thrombus in the deep veins of the legs, pelvis, or arms.

As the clot propagates, proximal extension occurs, which may dislodge or fragment and embolize to the pulmonary arteries. This causes pulmonary artery obstruction, and the release of vasoactive agents (ie, serotonin) by platelets increases pulmonary vascular resistance. The arterial obstruction increases alveolar dead space and leads to redistribution of blood flow, thus impairing gas exchange due to the creation of low ventilation-perfusion areas within the lung.

Stimulation of irritant receptors causes alveolar hyperventilation. Reflex bronchoconstriction occurs and augments airway resistance. Lung edema decreases pulmonary compliance. The increased pulmonary vascular resistance causes an increase in right ventricular afterload, and tension rises in the right ventricular wall, which may lead to dilatation, dysfunction, and ischemia of the right ventricle. Right heart failure can occur and lead to cardiogenic shock and even death. In the presence of a patent foramen ovale or atrial septal defect, paradoxical embolism may occur, as well as right-to-left shunting of blood with severe hypoxemia.

Risk factors for thromboembolic disease can be divided into a number of categories, including patient-related factors, disease states, surgical factors, and hematologic disorders. Risk is additive.

Patient-related factors include age older than 40 years, obesity, varicose veins, the use of estrogen in pharmacologic doses (ie, oral contraceptives or hormone replacement therapy), and immobility.

Disease states such as malignancy, congestive heart failure, nephrotic syndrome, recent myocardial infarction, inflammatory bowel disease, spinal cord injury with paralysis, and pelvic, hip, or long-bone fracture confer increased risk of thromboembolic disease.

Surgical factors are related to procedure type and procedure duration. Among patients who have undergone hip surgery, 50% have a proximal DVT on the same side as the hip surgery. This is thought to be due to a twisting of the femoral vein during total hip replacement. The incidence of DVT is higher in patients who have undergone knee surgery.[9]

In a study of patients following pelvic surgery, 40-80% had calf DVT, and 10-20% had thigh vein thromboses. Fatal PE developed in 1-5% of patients. The risk for thromboembolic disease has been shown to be increased with coronary artery bypass grafting (CABG), urologic surgery, and neurosurgery.[12]

One study identified the following four risk factors as being highly predictive of VTE among hospitalized medical patients[13] :

• Previous VTE
• An order for bed rest
• Peripherally inserted central venous catheterization line
• Cancer diagnosis

This four-element risk assessment model was accurate at identifying patients at risk of developing VTE within 90 days and was more effective than the Kucher Score, a risk assessment score.[13]

Hematologic disorders that increase thromboembolic risk include the following:

Activated protein C resistance (factor V Leiden)

• Protein C or protein S deficiency
• Antithrombin III deficiency
• Lupus anticoagulant
• Polycythemia vera
• Paroxysmal nocturnal hemoglobinuria
• Dysfibrinogenemia
• Prothrombin mutation ^[14]

Risk prediction algorithm

A prospective, open cohort study developed a new clinical risk prediction algorithm (QThrombosis) to assess the risk of VTE development. Using routinely collected data from 564 general practices in England and Wales, this study found that independent predictors at 1 and 5 years included the following[15] :

• Age
• Body mass index
• Smoking status
• Hospital admission in past 6 months
• History of varicose veins
• Congestive cardiac failure
• Chronic renal disease
• Cancer
• Chronic obstructive pulmonary disease
• Inflammatory bowel disease
• Current prescriptions for antipsychotic drugs

Oral contraceptive use, tamoxifen use, and hormone replacement therapy were noted in the study as independent predictors in women. This risk assessment can help to identify patients at high risk for VTE and may help determine a course of treatment.

United States statistics

The Centers for Disease Control and Prevention (CDC) estimated that over a 3-year period (2007-2009), there was an estimated annual average of 547,596 hospitalizations in which VTE was diagnosed, for patients aged 18 years or older.[16, 17]

Over the same period, for the same age group, an estimated average of 348,558 hospitalizations in which DVT was diagnosed occurred annually, and an estimated average of 277,549 hospitalizations in which PE was diagnosed occurred annually. Among these patients, an estimated average of 78,511 hospitalizations in which both DVT and PE were diagnosed occurred annually.

International statistics

Thromboembolism has a significant impact on morbidity and mortality internationally. A multinational report of European Union countries estimated that the total number of symptomatic, nonfatal VTE events per annum was more than 465,000 cases of DVT and more than 295,000 cases of PE. The authors estimated more than 370,000 VTE-related deaths, of which 7% were diagnosed ante mortem and 34% were sudden fatal PE.[18]

Age-, sex-, and race-related demographics

Age is a risk factor for thromboembolic disease, being greater in older patients than in younger ones. The risk doubles with each decade in persons older than 40 years.

According to the CDC, the estimated annual average number (for years 2007-2009) of hospitalizations in which VTE was diagnosed was as follows for specific adult age groups[17] :

• Aged 18-39 years - 54,034
• Aged 40-59 years - 143,354
• Aged 60 years or older - 350,208

The estimated annual average rate (for years 2007-2009) of hospitalizations in which VTE was diagnosed was as follows for specific adult age groups:

• Aged 18-39 - 60/100,000 population
• Aged 40-49 - 143/100,000 population
• Aged 50-59 years - 200/100,000 population
• Aged 60-69 years - 391/100,000
• Aged 70-79 years - 727/100,000
• Aged 80 years or older - 1134/100,000

According to the CDC, the estimated average annual number (for years 2007-2009) of hospitalizations in which VTE was diagnosed was as follows for adult males and females[17] :

• Males - 250,973
• Females - 296,623

The incidence of thromboembolism is higher in African Americans than it is in whites, whereas Asians have a lower incidence than do African Americans and whites. PE occurs more frequently in males than in females.

Thromboembolic disease accounts for approximately a quarter of a million hospitalizations in the United States annually and for about 5-10% of all deaths.

About one third of PE cases are fatal. Of these, 67% are not diagnosed ante mortem, and 34% occur rapidly. A high rate of clinically unsuspected DVT and PE leads to significant diagnostic and therapeutic delays, and this accounts for substantial morbidity and mortality.

Studies demonstrate a 95% risk reduction with treatment of thromboembolic disease. There is, however, a risk of recurrence following the discontinuance of treatment that is related to the type and number of risk factors the patient has and whether they persist following completion of treatment. Some 5-7% of all recurrences are fatal.

For the success and ease of outpatient treatment, patients on oral warfarin anticoagulation should be instructed on the impact of dietary choices on treatment goals and the need for frequent monitoring. Instruction on the avoidance of reversible risk factors would be helpful in preventing disease recurrence.

The best approach to patient education is one that starts with open communication with the patient and family, reviewing not only the procedure or planned surgical intervention, but also potential complications.

For patient education information, see the Lungs Center, as well as Pulmonary Embolism, Deep Vein Thrombosis (Blood Clot in the Leg, DVT), and Blood Clots.

With pulmonary embolism (PE), the patient often experiences acute onset of shortness of breath; sometimes the patient even pinpoints the moment of distress. Complaints related to signs of deep vein thrombosis (DVT), lower-extremity swelling, and warmth to touch or tenderness may be present. Dyspnea is the most frequent symptom of PE.

With a smaller PE near the pleura, the patient may complain of pleuritic chest pain, cough, or hemoptysis. Sometimes, massive PE can present with syncope. The patient may have a sense of impending doom, with apprehension and anxiety. History may reveal the presence of one or more causes or risk factors.

Some patients have signs of DVT, lower-extremity swelling, and tenderness and warmth to touch. Clinical signs of pulmonary thromboembolism also include the following:

• Tachypnea (respiratory rate exceeding 18 breaths/min) is the most common sign of PE
• Tachycardia often is present
• The second heart sound can be accentuated
• Fever may be present
• Lung examination findings frequently are normal
• Cyanosis may be present

In the appropriate clinical setting, when shortness of breath, hypoxemia, and tachycardia are present, there should be a high clinical suspicion of PE until it is ruled out. Timely anticoagulation is important; 5-7% of recurrences are fatal.

The likelihood of PE in a patient in whom it is suspected may be assessed by the Wells clinical decision rule. The criteria are scored as follows:

• Clinical symptoms of DVT (3 points)
• Other diagnoses less likely than PE (3 points)
• Heart rate higher than 100 beats/min (1.5 points)
• Immobilization for at least 3 days or surgery in previous 4 weeks (1.5 points)
• Previous DVT/PE (1.5 points)
• Hemoptysis (1 point)
• Malignancy (1 point)

In the modified Wells criteria, PE is likely when the score is greater than 4 and unlikely when the score is less than 4. Highly sensitive D-dimer is coupled into the decision algorithm.[19]

Diagnosis of venous thromboembolism (VTE) may include laboratory tests, imaging (eg, chest radiography, computed tomography [CT], angiography, ultrasonography [US], echocardiography, and ventilation-perfusion [V/Q] scanning) and tests such as plethysmography and electrocardiography (ECG).

Guidelines for diagnosis of VTE have been published by the American Society of Hematology (ASH).[20]  (See Guidelines.)

Arterial blood gas assessment on room air demonstrates hypoxemia (arterial oxygen tension [PaO2] < 80 mm Hg) and an elevated alveolar-arterial oxygen gradient. Acid-base status may demonstrate a respiratory alkalosis.

Enzyme-linked immunoassay (ELISA) can be used to quantify the presence of D-dimer, which is a specific degradation product of cross-linked fibrin.[21] This is an important marker of the activation of fibrinolysis. It can be elevated in pneumonia, cancer, sepsis, and surgery.

A plasma D-dimer level higher than 500 ng/mL has been shown to have a sensitivity of 97% and a specificity of 45%. The value of D-dimer is in its negative predictive value. A plasma D-dimer level lower than 500 ng/mL in those with low pretest probability essentially excludes pulmonary embolism (PE).

This study is less helpful in older patients, in that the D-dimer level tends to increase with age. In a study by Righini et al, an age-adjusted D-dimer cutoff combined with a probability assessment was shown to rule out the diagnosis of pulmonary embolism (PE) in emergency department (ED) patients with suspected PE and was associated with a low likelihood of subsequent symptomatic VTE, thus increasing the proportion of patients in whom the diagnosis could be excluded.[22]

Elevated troponins are associated with an adverse prognosis in acute PE.[23] Elevated natriuretic peptides, brain natriuretic peptide (BNP), and N-terminal pro-BNP have been shown to be predictive of adverse short-term outcomes in acute PE and can be predictive of mortality.[24, 25] Measurement of both troponin and BNP are important for risk stratification in patients with PE.

Bilirubin levels may also assist in the diagnosis of VTE. In a study that included 103 patients with VTE (distal DVT, proximal DVT, or PE) and 50 control subjects, Duman et al found that in comparison with the control group, the VTE group had a lower bilirubin level (9.0 ± 2.6 μmol/L vs 7.3 ± 3 μmol/L), a higher high-sensitivity C-reactive protein (hs-CRP) concentration (0.8 [0.3-2] mg/L vs 1.1 [0.2-3] mg/L), and a higher white blood cell (WBC) count (7.4 ± 1.5 ×109/L vs 8.2 ± 2.7 × 109/L).[26]

Chest radiographic findings most often are normal. Radiographs may, however, reveal an enlarged right descending pulmonary artery, decreased pulmonary vascularity (Westermark sign), a wedge-shaped infiltrate, or an elevation of the hemidiaphragm (Hampton hump). If infarction occurs, a pleural effusion may be present.

Helical (spiral) CT allows for the imaging of pulmonary vessels by way of intravenous (IV) contrast material as the patient moves through a gantry at a constant rate and the radiography source rotates. PE is diagnosed by identifying filling defects, which are either central or adherent to the wall (see the image below).

Venous Thromboembolism (VTE). Helical CT scan of the pulmonary arteries. A filling defect in the right pulmonary artery is present, consistent with a pulmonary embolism.

The advantage of helical CT is that it is minimally invasive and allows concurrent visualization of the parenchyma, pleura, and mediastinum. When looking at the main, lobar, and segmental veins, helical CT has a sensitivity of about 93%. Its positive predictive value is approximately 95%.

The limitations of helical CT include the need for contrast and the requirement for a higher dose of radiation than is used with some other diagnostic modalities. Obliquely or horizontally oriented vessels (eg, those of the segmental branches of the right middle lobe and lingula) are poorly visualized. The scan is technically inadequate or inconclusive in approximately 1-10% of cases.

Results from Doppler US can indicate the presence of thrombus within a vein. A normal vein is free of internal echoes and can be compressed. In acute deep vein thrombosis (DVT), however, internal echoes are present and the vessel is not compressible.

Duplex scanning of the venous system uses Doppler flow assessment combined with B-mode US. The advantage of color flow Doppler US is the ability to determine motion and the direction of flow.

Echocardiography can demonstrate signs of right-side heart strain. Right ventricular dilatation, right ventricular hypokinesis, or tricuspid regurgitation may be present. Interventricular septum bulging into the left ventricle may be present, and the size of the left ventricle may be reduced. Echocardiography can also be used to identify signs of impending heart failure.

Pulmonary angiography has long been the diagnostic criterion standard. Angiography allows for the visualization of the pulmonary vasculature with contrast agents, and in the event of PE, it evidences the cutoff of a vein and a lack of flow to the affected area.

It is an invasive procedure that requires the administration of IV contrast material, and it is more expensive than other procedures.

Pulmonary angiography leads to increased morbidity in approximately 2-5% of patients; this is related to bleeding and to complications from the use of IV contrast agents. Mortality occurs in fewer than 1% of patients in whom this procedure is performed.

Contrast venography is an invasive technique that can provide direct proof of thrombus by demonstrating a filling defect with the aid of contrast medium through the deep venous system. However, it can cause iatrogenic venous thrombosis, tissue sloughing from contrast extravasation, and an allergic contrast reaction.

V/Q scanning is a common screening technique. This modality provides a probability estimate for PE by evaluation of the size and the number of defects in the perfusion of the lung compared with the areas of ventilation.

The diagnosis of PE is easily made with this modality when the probability estimate is high for PE. With a normal scan finding, the possibility of PE is excluded. However, the test results are nondiagnostic in about 66% of cases. The image below compares normal ventilation findings with a perfusion defect.

Venous Thromboembolism (VTE). Ventilation-perfusion scan. Left image: Posterior view of normal findings on ventilation scan. Right image: Posterior view of a perfusion scan that reveals a perfusion defect in the left upper quadrant. The defect in the middle of the image is due to the position of the heart.

Impedance plethysmography may detect impaired venous emptying of the leg by assessing the volume response to temporary occlusion of the venous system. Emptying is assessed by the rapidity of volume decrease. Slow emptying indicates obstruction.

Impedance plethysmography is a noninvasive method of assessment. Sensitivity and specificity have been reported to be between 92% and 95%. However, it is of limited value when DVT is asymptomatic or distal or when findings are nonocclusive.

Conditions leading to poor forward blood flow, hypotension, or vein compression can be responsible for false-positive results.

ECG is of greatest value in ruling out myocardial infarction. Sinus tachycardia often is present, and right axis deviation, right bundle-branch block, and deeply inverted T waves in V1-V3 may be found. An S1Q3T3 pattern may be seen.

Anticoagulant and thrombolytic therapy options are available for the treatment of venous thromboembolism (VTE). Anticoagulant therapy prevents further clot deposition and allows the patient’s natural fibrinolytic mechanisms to lyse the existing clot.[27]  Guidelines have been developed for optimal management of anticoagulation therapy in patients with VTE.[28, 29] (See Guidelines.)

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 (eg,  tissue plasminogen activator [t-PA]). t-PA has increasingly been used as the first-choice thrombolytic agent.

Surgical interventions for VTE include thrombectomy and venous interruption.

Special considerations

Pregnancy

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 post partum.

Pregnant women with a history of previous thromboembolic disease probably should receive some prophylaxis, as the estimated range of recurrence is 0-15%.

Cancer

International clinical practice guidelines for the treatment and prophylaxis of VTE in patients with cancer were issued in early 2013.[30] Guidelines have also been published by the American Society of Clinical Oncology (ASCO).[31]  (See Guidelines.)

The results of a Cochrane review indicated 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.[32] A statistically and clinically important reduction in VTE 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 Cochrane review 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.[33]

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 VTE 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 deep vein thrombosis (DVT) and PE showed a higher risk of recurrence whenever treatment was stopped.[34]

Results from phase II/III studies, according to a report by Merli et al, suggested that newer oral anticoagulants may provide an efficacious alternative for prevention of VTE 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.[35]

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.

Heparin

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 employed 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; 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).[36]  A minimum of 3 months of oral therapy has been suggested following a first episode of DVT or PE.

Low-molecular-weight heparin

Several studies have shown that LMWH, which is a fractionated heparin, is as effective as UFH in treating DVT. Minimal requirements for outpatient therapy with LMWH regimens include the following:

• Stable PE or DVT
• Low risk for bleeding
• Absence of severe renal insufficiency
• Availability of systems for administration and monitoring of LMWH and warfarin, as well as surveillance and treatment of recurrent thromboembolic disease

A Cochrane review found that LMWH, in a comparison with oral anticoagulants (eg, a vitamin K antagonist [VKA] or ximelagatran), reduced VTE events but not death in patients with cancer.[37]

Factor Xa and direct thrombin inhibitors

Apixaban, dabigatran, rivaroxaban, edoxaban, and betrixaban are alternatives to warfarin for prophylaxis or treatment of DVT and PE. Apixaban, edoxaban, rivaroxaban, and betrixaban all inhibit factor Xa, whereas dabigatran is a direct thrombin inhibitor.

Rivaroxaban

Rivaroxaban, an oral factor Xa inhibitor, is approved by the US Food and Drug Administration (FDA) for a variety of treatment and prophylaxis VTE indications, including the following:

• Risk reduction for stroke and systemic embolism in nonvalvular atrial fibrillation
• Treatment of DVT
• Treatment of PE
• Reduction in risk of recurrent DVT and/or PE
• Prophylaxis of DVT following hip or knee replacement surgery
• Prophylaxis of VTE in acutely ill medical patients at risk for thromboembolic complications owing to restricted mobility (and who are not at high risk of bleeding)
• Risk reduction of major cardiovascular events with coronary artery disease (CAD) or peripheral artery disease (PAD)

In November 2012, rivaroxaban was approved by the FDA for the treatment of DVT or PE and for reduction of the risk of recurrent DVT and PE following initial treatment.[38, 39, 40, 41]

In October 2017, the FDA approved rivaroxaban in a dosage of 10 mg once daily for reducing the ongoing risk of recurrent VTE after at least 6 months of initial anticoagulation therapy.[42]  In the new prescribing information, the drug may be initiated at 15 mg twice daily for the first 21 days after VTE, then reduced to 20 mg once daily from day 22 through at least day 180. After at least 180 days, the once-daily 10-mg regimen may now be prescribed for patients at continued risk for VTE.

In October 2019, rivaroxaban was approved for prophylaxis of VTE in acutely ill medical patients who are at risk for thromboembolic complications owing to restricted mobility (and who are not at high risk of bleeding). Rivaroxaban in this setting demonstrated noninferiority to enoxaparin with short-term use (10 ± 4 days) and superiority with long-term use (35 ± 4 days) compared with short-term use of enoxaparin followed by placebo.[43]

Another study failed to show a significant benefit of rivaroxaban over placebo in reducing the composite end point of symptomatic VTE or death in medically ill patients at increased risk for VTE after discharge; however, there were few events and the primary safety outcome, major bleeding, was not significantly increased with treatment.[44]

Apixaban

In August 2014, apixaban was approved by the FDA 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.[45]

Dabigatran

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.[46, 47]

The RE-SONATE trial and RE-MEDY trials included 2856 patients with acute DVT and PE who had completed at least 3 months of anticoagulant therapy. Results showed that dabigatran was noninferior to warfarin in the extended treatment of VTE and carried a lower risk of major or clinically relevant bleeding than warfarin did.[48]

Edoxaban

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 (BNP) levels.[49] 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.

In a study of edoxaban for the treatment of cancer-associated VTE, 1050 patients were randomized to receive LMWH for at least 5 days followed by oral edoxaban (60 mg daily) or subcutaneous (SC) dalteparin (200 IU/kg body weight daily). Treatment was for 6 to 12 months. Edoxaban was noninferior to SC dalteparin for the composite outcome of recurrent VTE or major bleeding. The rate of recurrent VTE was lower, but the rate of major bleeding was higher with edoxaban.[50]

Betrixaban

Betrixaban, an FXa inhibitor, was approved by the FDA in June 2017. It is indicated for prophylaxis of VTE in adults hospitalized for acute medical illness who are at risk for thromboembolic complications owing to moderate or severe restricted mobility and other risk factors that may cause VTE.

Approval of betrixaban was based on data from the phase 3 APEX studies.[51, 52] These randomized, double-blind, multinational clinical trials compared extended-duration betrixaban (35-42 days) with short-duration enoxaparin (6-14 days) for VTE in 7513 acutely medically ill hospitalized patients with VTE risk factors.

Patients in the betrixaban group took an initial dose of 160 mg orally on day 1, followed by 80 mg once daily for 35-42 days, and received a placebo injection once daily for 6-14 days. Patients in the enoxaparin group received 40 mg SC once daily for 6-4 days and took an oral placebo once daily for 35-42 days.

Efficacy was measured in 7441 patients by using a composite outcome score composed of the occurrence of asymptomatic or symptomatic proximal DVT, nonfatal PE, stroke, or VTE-related death. Betrixaban showed significant decreases in VTE events as compared with enoxaparin.

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.

The recombinant t-PAs (rt-PAs) tenecteplase, alteplase, and reteplase are thrombolytic agents that the Food and Drug Administration (FDA) has approved for thrombolytic use in PE. In head-to-head studies by Goldhaber et al 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.[53]

Indications

Thrombolytic treatment may be administered in acute PE associated with hemodynamic instability in patients who do not seem prone to bleeding, on the basis of the American College of Chest Physicians (ACCP) evidence-based guidelines regarding antithrombotic therapy and prevention of thrombosis.[36]

Contraindications

Absolute contraindications for thrombolysis include the following:

• Gastrointestinal (GI) bleeding within the past 6 months
• Active or recent internal bleeding
• History of hemorrhagic stroke
• Intracranial or intraspinal disease
• Recent cranial surgery or head trauma
• Pregnancy

Relative contraindications include the following:

• Major surgery or trauma within the past 2 weeks
• Biopsy within 10 days
• Other invasive procedures
• Procedures in a location inaccessible to external compression
• Uncontrolled coagulation defects such as thrombocytopenia
• Nonhemorrhagic stroke

Thrombectomy for venous embolism is performed less frequently, in view of the relatively high 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 for 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.

The inferior vena cava (IVC) filter is designed to trap potentially lethal emboli while maintaining vena caval patency. It has been used in cases where anticoagulation is contraindicated, where there has been a complication of anticoagulation, where anticoagulation has failed, or in the case of pulmonary embolectomy.[54]

Although IVC filters are frequently placed in adults who have experienced acute PE or VTE to prevent a subsequent event, evidence for the safety and efficacy of the practice is limited. In a study published in late 2018, Bikdeli et al found that for older adults with PE, the use of IVC filters appears to offer no mortality benefit and may in fact confer a mortality risk.[55, 56]

Ligation of venous tributaries is an option that is rarely practiced today. Its use has been limited by a high mortality and the need for continuous anticoagulation. It essentially has been replaced by the percutaneous insertion of the IVC filter.

In general, inpatient care requires the administration and continuation of intravenous (IV) or SC anticoagulants, with an oral anticoagulant (the coumarin derivative warfarin sodium) started within 72 hours of the SC anticoagulant or, if IV heparin is being given, 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 (TT) or aPTT is less than twice the baseline value. 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 (PT) 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.[57] 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.

Whereas a few members of the outpatient group developed recurrent VTE within 90 days (1/171) and major bleeding within 14 days or at 90 days (2/171 and 3/171, respectively), patients in the outpatient group experienced less mean length of stay than did those in the inpatient group (0-5 days and 3-9 days, respectively). One inpatient and one outpatient died within 90 days.[57]

Postthrombotic syndrome

The most common long-term complication of treated DVT is postthrombotic syndrome (postphlebitic syndrome), which is a chronic complication of VTE characterized by pain and swelling.[58]  Chronic deep venous insufficiency, recurrent cellulitis, venous stasis, and ulceration of the skin can develop in as many as 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 (an 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.[59]

Bleeding

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.[60]

Heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia (HIT) and thrombosis[61] 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.

Fondaparinux has been used in suspected HIT. A study by Kang et al found that fondaparinux was shown had an effectiveness and safety profile similar to those of argatroban and danaparoid.[62]

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

Heparin-induced osteopenia has been reported following UFH treatment of more than 1 month's duration.

Skin necrosis

Coumarin derivatives can cause skin necrosis as a consequence of 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.[63]

Recurrence

Recurrence of thromboembolism had been documented following discontinuance 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 higher in patients with previous proximal vein thrombosis than in those with calf vein thrombosis.

After a 3-month course of anticoagulant therapy, the risk of secondary thrombosis is 2-4% in the first year. The recurrence risk is dependent on the precipitating risk factor: Risk is low if VTE is provoked by surgery, intermediate if it is related to a nonsurgical risk factor, and high if it is unprovoked and occurs in the setting of the patient with a disease-related risk factor.[64]

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).[65, 66] 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 the INR. 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.[67, 68, 69, 70, 71, 72, 73, 74, 75]

UFH given SC 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 UFH does. 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.[76]

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 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.[77]

The EPCAT II (Extended Venous Thromboembolism Prophylaxis Comparing Rivaroxaban to Aspirin Following Total Hip and Knee Arthroplasty II) trial randomly assigned patients to receive either aspirin 81 mg/day or rivaroxaban 10 mg/day on postoperative day 6 after an initial 5 days of rivaroxaban 10 mg/day.[78] Patients who underwent knee arthroplasty continued prophylaxis for an additional 9 days, and those who underwent hip arthroplasty continued for an additional 30 days. All patients were followed for 90 days.

The trial showed aspirin to be noninferior to rivaroxaban for VTE prophylaxis after hip or knee arthroplasty.[78] Eleven (0.64%) patients in the aspirin group developed symptomatic proximal DVT or PE during follow-up, compared with 12 (0.70%) in the rivaroxaban group. The combination of major bleeding and clinically relevant nonmajor bleeding occurred in 22 (1.29%) in the aspirin group and 17 (0.99%) in the rivaroxaban group; however, the rate of major bleeding alone was higher in the aspirin group (0.47%) than in the rivaroxaban group (0.29%).

In November 2015, the FDA approved dabigatran for prophylaxis of DVT and PE after hip replacement surgery.[79]

Nonpharmacologic prophylaxis

External pneumatic compression has been shown to be capable of temporarily preventing 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.[80]

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.[81]

Multimodal prophylaxis

Multimodal VTE prophylaxis typically includes the following:

• Discontinuance of procoagulant medications
• VTE risk stratification
• Regional anesthesia
• IV bolus of UFH before femoral preparation
• Rapid mobilization
• Use of pneumatic compression devices
• Chemoprophylaxis tailored to the patient's risk of VTE

In a study that included 257 patients with a proven history of VTE (DVT, PE, or both) who underwent 277 primary elective THAs, Gonzalez Della Valle et al assessing the safety and efficacy of multimodal prophylaxis within the first 120 postoperative days and the mortality during the first year.[82] Multimodal prophylaxis was found to be safe and effective. Very few patients developed VTE (2.5%) or died of suspected or confirmed PE; thus, postoperative anticoagulation should be prudent. Mortality during the first year was mostly unrelated to either VTE or bleeding.

Postoperative risk

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 nine cancers, the results showed that VTE occurred post discharge at an overall rate of 33.4%. VTE was significantly more likely after gastrointestinal, lung, prostate, and ovarian/uterine operations.[83]

For patients undergoing major orthopedic surgery, the ACCP evidence-based guidelines recommended 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 UFH; adjusted-dose VKA; 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.[84]

Elderly surgical patients are at increased risk for VTE. In September 2017, the European Society of Anesthesiology published guidelines for VTE prophylaxis in this population (see Guidelines).[85]

Prophylactic practice

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.[86]

A randomized, double-blind phase III study comparing rivaroxaban with SC enoxaparin found that the primary outcome of composite of any DVT, nonfatal PE, or death from any cause up to day 17 after surgery occurred in 67 (6.9%) of 965 patients who received oral rivaroxaban 10 mg/day as compared with 97 (10.1%) of 959 patients who were given enoxaparin 30 mg SC every 12 hours for the prevention of VTE after total knee arthroplasty.[87]

Pooled data from four phase III studies comparing rivaroxaban (10 mg/day) with SC enoxaparin (either 40 mg once daily or 30 mg every 12 hours) for VTE after total hip or knee arthroplasty showed that the composite of symptomatic VTE and all-cause mortality was lower in the rivaroxaban group (29/6183 rivaroxaban patients [0.5%] vs 60/6200 enoxaparin patients [1.0%]). This reduction in symptomatic VTE plus all-cause mortality was consistent across all prespecified subgroups. There were no statistically significant differences in major bleeding or nonmajor clinically relevant bleeding.[88]

After reviewing the published literature, the American College of Physicians (ACP) determined that it would not support the use of measures for universal VTE prophylaxis in patients if such measures were performed without regard to risk.[89] It was reported in the study that in nonsurgical patients, heparin prophylaxis had no significant effect on mortality and led to more bleeding and bleeding events, which suggested that it was 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.

Guidelines on the management of venous thrombosis were published in February 2021 by the European Society for Vascular Surgery (ESVS) in the European Journal of Vascular & Endovascular Surgery.[90] Class I recommendations are outlined below.

When deep vein thrombosis (DVT) is suspected, clinically assess the pretest probability as part of the diagnostic workup. Use a validated diagnostic pathway.

In the setting of suspected DVT, use ultrasonography as the first modality.

Outpatient management is recommended for most DVT cases.

For DVT treated by early thrombus removal, with or without stenting, anticoagulation therapy should be at least as long as anticoagulation therapy alone would be and at the discretion of the treating physician.

Unprovoked DVT

For unprovoked DVT, the ESVS recommends clinical examination and sex-specific occult malignancy screening (vs routine extensive screening). Reassess the patient’s bleeding risk before continuing anticoagulation longer than 3 months.

For the principal treatment phase, for patients with unprovoked proximal DVT, use of a direct oral anticoagulant (DOA) is recommended over that of low molecular weight heparin (LMWH) followed by a vitamin K antagonist (VKA). In addition, of these patients who have a low or moderate bleeding risk, extend anticoagulation past 3 months and periodically reassess the bleeding risk.

For patients with a second or subsequent unprovoked DVT, extend anticoagulation therapy longer than 3 months.

Provoked DVT

For patients with a provoked proximal DVT and a major transient risk factor, use 3 months of anticoagulation treatment rather than a shorter duration. A DOA is recommended over a VKA for the principal treatment phase.

Proximal DVT

During the initial or principal treatment phase for proximal DVT, in the setting of existing contraindications to anticoagulation, insert a temporary inferior vena cava (IVF) filter.

Apply early compression within 24 hours in those with proximal DVT at 30-40 mmHg with either multilayer bandaging or compression hosiery to reduce pain, edema, and residual venous obstruction.

For patients with proximal DVT who have limited symptoms and signs (based on the Villalta score), limit the use of below knee stockings to 6 or 12 months.

Lower-Extremity DVT

For symptomatic calf DVT that requires anticoagulant treatment, 3 months of therapy is recommended over shorter durations. For those with symptomatic calf DVT not receiving anticoagulation, clinically reassess and repeat whole-leg sonography after 1 week.

For calf DVT, DOAs are recommended over LMWH followed by VKAs.

In the setting of suspected lower limb superficial vein thrombosis, obtain a whole-leg sonogram to determine the extent of the thrombus and rule out asymptomatic DVT.

For patients with lower limb superficial vein thrombosis that:

• Is ≤ 3 cm from the junction with the deep veins, use therapeutic anticoagulation.

• Is ≥ 3 cm away from the junction with the deep veins and extends ≥ 5 cm in length, treat with fondaparinux 2.5 mg once daily.

• Extends ≥ 5 cm in sonographic length and extends ≥ 3 cm from the junction with the deep veins, treat with 45 days of anticoagulation.

Upper-Extremity DVT

For patients with suspected upper-extremity DVT, use ultrasonography as the initial diagnostic modality.

For primary upper-extremity DVT, treat with 3 months of anticoagulation.

Special Populations

Management of pediatric DVT should be guided by clinicians with specific expertise in pediatric thrombosis and hemostasis.

ESVS recommends that DVT during pregnancy be managed with therapeutic doses of LMWH for at least 3 months and for at least 6 weeks postpartum.

In the setting of cancer-associated DVT, use an LMWH for initial and principal phase anticoagulation. For those with active cancer-associated DVT, switch from an LMWH to an OA after 3-6 months of therapy for extended treatment.

In the setting of DVT and high-risk thrombophilia (eg, antiphospholipid syndrome, homozygous factor V Leiden mutation, or deficiencies of protein C or S, or antithrombin), treat with full-dose extended anticoagulation, and reassess periodically. Long-term follow-up by a thrombophilia expert is recommended.

For those with DVT and chronic kidney disease treated with an LMWH, fondaparinux, or a DOA, reassess renal function periodically.

For underweight or overweight patients with DVT that requires anticoagulation, adjust the dose of unfractionated heparin (UH), LMWHs, and fondaparinux.

The American Society of Hematology (ASH) released their updated recommendations on the management of venous thromboembolism (VTE) (deep vein thrombosis [DVT] and pulmonary embolism [PE]) in October 2020.[29] Select recommendations are outlined below.

Strong Recommendations

For patients with PE and hemodynamic compromise, it is recommended that thrombolytic therapy followed by anticoagulation be used over anticoagulation alone.

For patients with DVT and/or PE who have completed primary treatment and will continue vitamin K antagonist (VKA) therapy as secondary prevention, it is recommended that an international normalized ratio (INR) range of 2.0 to 3.0 be used over a lower INR range (eg, 1.5-1.9).

For patients with a recurrent unprovoked DVT and/or PE, indefinite antithrombotic therapy is recommended over stopping anticoagulation after completion of primary treatment.

Conditional Recommendations

Initial management

For patients with DVT and/or PE, the ASH guideline panel suggests using direct oral anticoagulants (DOACs) over VKAs. No single DOAC is suggested over another.

In most patients with proximal DVT, anticoagulation therapy alone is suggested over thrombolytic therapy in addition to anticoagulation.

For patients with PE with echocardiography and/or biomarkers that are compatible with right ventricular dysfunction but without hemodynamic compromise (submassive PE), anticoagulation alone is suggested over the routine use of thrombolysis in addition to anticoagulation.

For patients with extensive DVT in whom thrombolysis is considered appropriate, the ASH guideline panel suggests using catheter-directed thrombolysis over systemic thrombolysis.

For patients with PE in whom thrombolysis is considered appropriate, systemic thrombolysis is suggested over catheter-directed thrombolysis.

For patients with proximal DVT and significant preexisting cardiopulmonary disease, as well as for patients with PE and hemodynamic compromise, use of anticoagulation alone is suggested rather than anticoagulation plus insertion of an inferior vena cava (IVC) filter.

Primary treatment

For primary treatment of patients with DVT and/or PE, whether provoked by a transient risk factor or by a chronic risk factor or unprovoked, using a shorter course of anticoagulation for primary treatment (3-6 months) is suggested over a longer course of anticoagulation for primary treatment (6-12 months).

Secondary prevention

To guide the duration of anticoagulation for patients with unprovoked DVT and/or PE, the ASH guideline panel suggests against routine use of prognostic scores, D-dimer testing, or ultrasonography to detect residual vein thrombosis.

Indefinite antithrombotic therapy is suggested over anticoagulation cessation after completion of primary treatment for the following:

• Patients with DVT and/or PE provoked by a chronic risk factor
• Patients with unprovoked DVT and/or PE

For patients with DVT and/or PE who have completed primary treatment and will continue to receive secondary prevention, use of anticoagulation is suggested over aspirin.

For patients with DVT and/or PE who have completed primary treatment and will continue with a DOAC for secondary prevention, the ASH guideline panel suggests using a standard-dose DOAC or a lower-dose DOAC.

Recurrent events

For patients with breakthrough DVT and/or PE during therapeutic VKA treatment, the ASH guideline panel suggests using low-molecular-weight heparin (LMWH) over DOAC therapy.

For patients who develop DVT and/or PE provoked by a transient risk factor and have a history of previous unprovoked VTE or VTE provoked by a chronic risk factor, indefinite antithrombotic therapy is suggested over stopping anticoagulation after completing primary treatment.

For patients who develop DVT and/or PE provoked by a transient risk factor and have a history of a previous VTE also provoked by a transient risk factor, anticoagulation cessation after completion of primary treatment is suggested over indefinite antithrombotic therapy.

Other

For patients with DVT and/or PE with stable cardiovascular disease (CVD) who initiate anticoagulation and were previously taking aspirin for cardiovascular risk modification, it is suggested that aspirin be suspended over continuing it for the duration of anticoagulation therapy.

For patients with DVT, with or without an increased risk for postthrombotic syndrome (PTS), the ASH guideline panel suggests against the routine use of compression stockings.

The guidelines on the use of inferior vena cava (IVC) filters in the treatment of patients with venous thromboembolism (VTE; ie, deep vein thrombosis [DVT] or pulmonary embolism [PE]) were published in October 2020 by the Society of Interventional Radiology (SIR), in collaboration with the American College of Cardiology (ACC), the American College of Chest Physicians (ACCP), the American College of Surgeons (ACS) Committee on Trauma, the American Heart Association (AHA), the Society for Vascular Surgery (SVS), and the Society for Vascular Medicine (SVM).[91]

In patients with acute PE who have a contraindication for anticoagulation therapy, consideration of IVC filter placement is suggested on the basis of various clinical risk factors.

In patients with acute DVT without PE who have a contraindication for anticoagulation therapy, consideration of IVC filter placement is suggested on the basis of various clinical risk factors.

In patients undergoing anticoagulation for acute VTE in whom a contraindication for anticoagulation develops, consideration of an IVC filter is suggested if there is ongoing significant clinical risk for PE.

In patients undergoing extended anticoagulation for VTE who have completed the acute phase of treatment and in whom a contraindication to anticoagulation develops, it is suggested that an IVC filter not be placed, with rare exceptions.

In patients receiving therapeutic anticoagulation for VTE who experience recurrent VTE, it is suggested that an IVC filter not be placed, with few exceptions. Reasons for anticoagulation failure should always be addressed.

In patients with acute VTE who are being treated with therapeutic anticoagulation, routine placement of an IVC filter is not recommended.

In patients with acute PE who are receiving advanced therapies, consideration of IVC filter placement is suggested only in select patients.

In patients with DVT who are receiving advanced therapies, consideration of IVC filter placement is suggested only in select patients.

In trauma patients without known acute VTE, it is recommended that routine placement of IVC filters for primary VTE prophylaxis not be performed.

In patients without known acute VTE who are undergoing major surgery, it is suggested that routine placement of IVC filters not be performed.

In patients with indwelling IVC filters who have no other indication for anticoagulation, no recommendation can be made for or against anticoagulation.

In patients with indwelling retrievable/convertible IVC filters whose risk of PE has been mitigated or who are no longer at risk for PE, it is suggested that filters be routinely removed or converted unless risk outweighs benefit.

In patients with indwelling permanent IVC filters whose risk of PE has been mitigated or who are no longer at risk for PE, it is suggested that filter removal not be routinely performed.

In patients with complications attributed to indwelling IVC filters, consideration of filter removal is suggested after weighing of filter- versus procedure-related risks and assessment of the likelihood that filter removal will alleviate the complications.

In patients who have an IVC filter, the use of a structured follow-up program is recommended to increase retrieval rates and detect complications.

In patients in whom IVC filter removal is planned, routine preprocedural imaging of the filter and the use of laboratory studies are not suggested, except in select situations.

In patients undergoing filter retrieval whose filter could not be removed with standard techniques, attempted removal with advanced techniques is suggested if appropriate and if the expertise is available, after reevaluation of risks and benefits.

In patients undergoing IVC filter placement, no recommendation can be made for or against any specific placement technique.

In August 2019, the American Society of Clinical Oncology (ASCO) released revised clinical practice guidelines on venous thromboembolism (VTE) prophylaxis and treatment in patients with cancer.[31] Recommendations included the following:

Recommendations regarding anticoagulation for VTE prophylaxis in hospitalized patients with cancer included the following:

• Hospitalized patients who have active malignancy and acute medical illness or reduced mobility should be offered pharmacologic thromboprophylaxis in the absence of bleeding or other contraindications.
• Hospitalized patients who have active malignancy without additional risk factors may be offered pharmacologic thromboprophylaxis in the absence of bleeding or other contraindications.
• Routine pharmacologic thromboprophylaxis should not be offered to patients admitted for the sole purpose of minor procedures or chemotherapy infusion, nor to patients undergoing stem-cell/bone marrow transplantation.

Recommendations regarding anticoagulation for VTE prophylaxis during systemic chemotherapy in ambulatory patients with cancer included the following:

• Routine pharmacologic thromboprophylaxis should not be offered to all outpatients with cancer.
• High-risk outpatients with cancer (Khorana score of 2 or higher prior to starting a new systemic chemotherapy regimen) may be offered thromboprophylaxis with apixaban, rivaroxaban, or low-molecular-weight heparin (LMWH), provided that there are no significant risk factors for bleeding and no drug interactions. Consideration of such therapy should be accompanied by a discussion with the patient about the relative benefits and harms, drug cost, and duration of prophylaxis in this setting.
• Patients with multiple myeloma receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone should be offered pharmacologic thromboprophylaxis with either aspirin or LMWH for lower-risk patients and LMWH for higher-risk patients.

Recommendations regarding perioperative VTE prophylaxis in patients with cancer undergoing surgery included the following:

• All patients with malignant disease undergoing major surgical intervention should be offered pharmacologic thromboprophylaxis with either unfractionated heparin (UFH) or LMWH unless contraindicated because of active bleeding, or high bleeding risk, or other contraindications.
• Prophylaxis should be commenced preoperatively.
• Mechanical methods may be added to pharmacologic thromboprophylaxis but should not be used as monotherapy for VTE prevention unless pharmacologic methods are contraindicated because of active bleeding or high bleeding risk.
• A combined regimen of pharmacologic and mechanical prophylaxis may improve efficacy, especially in the highest-risk patients.
• Pharmacologic thromboprophylaxis for patients undergoing major surgery for cancer should be continued for at least 7-10 days. Extended prophylaxis with LMWH for up to 4 weeks postoperatively is recommended for patients undergoing major open or laparoscopic abdominal or pelvic surgery for cancer who have high-risk features, such as restricted mobility, obesity, history of VTE, or additional risk factors. In lower-risk surgical settings, the decision on appropriate duration of thromboprophylaxis should be made on a case-by-case basis.

Recommendations regarding the best method for treating cancer patients with established VTE to prevent recurrence included the following:

• Initial anticoagulation may involve LMWH, UFH, fondaparinux, or rivaroxaban. For patients initiating treatment with parenteral anticoagulation, LMWH is preferred over UFH for the initial 5 to 10 days of anticoagulation for the patient with cancer with newly diagnosed VTE who does not have severe renal impairment (defined as creatinine clearance less than 30 mL/min).
• For long-term anticoagulation, LMWH, edoxaban, or rivaroxaban for at least 6 months are preferred because of improved efficacy over vitamin K antagonists (VKAs). VKAs are inferior but may be used if LMWH or direct oral anticoagulants (DOACs) are not accessible. There is an increase in major bleeding risk with DOACs, particularly observed in GI and potentially genitourinary malignancies. Caution with DOACs is also warranted in other settings with high risk for mucosal bleeding. Drug-drug interaction should be checked prior to using a DOAC.
• Anticoagulation with LMWH, DOACs, or VKAs beyond the initial 6 months should be offered to select patients with active cancer, such as those with metastatic disease or those receiving chemotherapy. Anticoagulation beyond 6 months needs to be assessed on an intermittent basis to ensure a continued favorable risk-benefit profile.
• Based on expert opinion in the absence of randomized trial data, uncertain short-term benefit, and mounting evidence of long-term harm from filters, the insertion of a vena cava filter should not be offered to patients with established or chronic thrombosis (VTE diagnosis more than 4 weeks ago), nor to patients with temporary contraindications to anticoagulant therapy (eg, surgery). There also is no role for filter insertion for primary prevention or prophylaxis of pulmonary embolism (PE) or deep vein thrombosis due to its long-term harm concerns. It may be offered to patients with absolute contraindications to anticoagulant therapy in the acute treatment setting (VTE diagnosis within the past 4 weeks) if the thrombus burden was considered life-threatening. Further research is needed.
• The insertion of a vena cava filter may be offered as an adjunct to anticoagulation in patients with progression of thrombosis (recurrent VTE or extension of existing thrombus) despite optimal anticoagulant therapy. This is based on the panel’s expert opinion given the absence of a survival improvement, a limited short-term benefit, but mounting evidence of the long-term increased risk for VTE.
• For patients with primary or metastatic CNS malignancies and established VTE, anticoagulation as described for other patients with cancer should be offered, although uncertainties remain about choice of agents and selection of patients most likely to benefit.
• Incidental PE and deep vein thrombosis should be treated in the same manner as symptomatic VTE, given their similar clinical outcomes compared with patients with cancer with symptomatic events.
• Treatment of isolated subsegmental PE or splanchnic or visceral vein thrombi diagnosed incidentally should be offered on a case-by-case basis, considering potential benefits and risks of anticoagulation.

Recommendations regarding the use of anticoagulants to improve survival in patients with cancer in the absence of established VTE included the following:

• Anticoagulant use is not recommended to improve survival in patients with cancer without VTE.

Recommendations regarding risk prediction and awareness of VTE among patients with cancer included the following:

• There is substantial variation in VTE risk between individual patients with cancer and cancer settings. Patients with cancer should be assessed for VTE risk initially and periodically thereafter, particularly at the start of systemic antineoplastic therapy or at the time of hospitalization. Individual risk factors, including biomarkers or cancer site, do not reliably identify patients with cancer at high risk for VTE. In the ambulatory setting among patients with solid tumors treated with systemic therapy, risk assessment can be conducted with a validated risk assessment tool (eg, Khorana score).
• Oncologists and members of the oncology team should educate patients regarding VTE, particularly in settings that increase risk, such as major surgery, hospitalization, and ongoing systemic antineoplastic therapy.

With regard to off-label use in guideline recommendations, apixaban, rivaroxaban, and LMWH have not been approved by the US Food and Drug Administration (FDA) for thromboprophylaxis in outpatients with cancer. Dalteparin is the only LMWH approved by the FDA for extended therapy to prevent recurrent thrombosis in patients with cancer.

In November 2018, the American Society of Hematology (ASH) released guidelines for the diagnosis of venous thromboembolism (VTE).[20] The American Academy of Family Physicians (AAFP) endorsed these guidelines in March 2019 and provided the following key recommendations from the guidelines.[92]

D-dimer testing alone should not be used to rule in or diagnose pulmonary embolism (PE), and a positive D-dimer alone should not be used to diagnose deep vein thrombosis (DVT).

Pulmonary embolism

In individuals with a low or intermediate pretest probability or prevalence, clinicians should use a D-dimer strategy to rule out PE, followed by a ventilation-perfusion (VQ) scan or computed tomography pulmonary angiography (CTPA) in patients requiring additional testing. D-dimer testing alone should not be used to rule in a PE.

In individuals with a high pretest probability or prevalence (≥50%), clinicians should start with CTPA to diagnose PE. If CTPA is not available, a VQ scan should be used with appropriate follow-up testing.

In individuals with a high pretest probability or prevalence, D-dimer testing alone should not be used to diagnose PE and should not be used as a subsequent test after CT.

In individuals with a positive D-dimer or likely pretest probability, CTPA should be performed. D-dimer testing can be used to exclude recurrent PE in individuals with an unlikely pretest probability.

In outpatients older than 50 years, use of an age-adjusted D-dimer cutoff is safe and improves the diagnostic yield. Age-adjusted cutoff = Age (years) × 10 µg/L (using D-dimer assays with a cutoff of 500 µg/L).

Lower-extremity deep vein thrombosis

In individuals with a low pretest probability or prevalence of lower-extremity (LE) DVT, clinicians should use a D-dimer strategy to rule out DVT, followed by proximal LE or whole-leg ultrasonography (US) in patients requiring additional testing.

In individuals with a low pretest probability or prevalence (≤ 10%), a positive D-dimer alone should not be used to diagnose DVT, and additional testing following negative proximal or whole-leg US should not be conducted.

In individuals with an intermediate pretest probability or prevalence (~25%), whole-leg or proximal LE US should be used. Serial proximal US testing is needed after a negative proximal ultrasonogram. No serial testing is needed after a negative whole-leg ultrasonogram.

In individuals with suspected DVT and a high pretest probability or prevalence (≥50%), whole-leg or proximal LE US should be used. Serial US should be used if the initial ultrasonogram is negative and no alternative diagnosis is identified.

Upper-extremity deep vein thrombosis

In individuals with a low prevalence/unlikely pretest probability of upper-extremity (UE) DVT, D-dimer testing should be used to exclude UE DVT, followed by duplex US if findings are positive.

In individuals with a high prevalence/likely pretest probability, either (a) D-dimer testing followed by duplex US/serial duplex US or (b) duplex US/serial duplex US alone can be used for assessing patients suspected of having a UE DVT.

A positive D-dimer alone should not be used to diagnose UE DVT.

In November 2018, the American Society of Hematology (ASH) released the following guidelines on optimal management of anticoagulation therapy for venous thromboembolism (VTE).[28]

Initial anticoagulant dose selection

In obese patients receiving low-molecular-weight heparin (LMWH) for treatment of acute VTE, it is suggested that initial LMWH dose selection be based on actual body weight rather than on a fixed maximum daily dose (ie, capped dose).

Drug-interaction management

For patients requiring administration of inhibitors or inducers of P-glycoprotein (P-gp) or strong inhibitors or inducers of cytochrome P450 (CYP) enzymes, it is suggested to use an alternative anticoagulant (eg, a vitamin K antagonist [VKA] or LMWH) rather than a direct oral anticoagulant (DOAC) to treat VTE.

Point-of-care INR testing

For patients receiving maintenance VKA therapy for VTE, home point-of-care international normalized ratio (INR) testing (patient self-testing [PST]) is suggested in preference to any other INR testing approach except patient self-management (PSM) in suitable patients (those who have demonstrated competency to perform PST and who can afford this option).

For patients receiving maintenance VKA therapy for VTE, point-of-care INR testing by the patient at home with self-adjustment of VKA dose (PSM) is suggested in preference to any other management approach, including PST in suitable patients (those who have demonstrated competency to perform PSM and who can afford this option).

Selection of timing between INR measurements (INR recall interval)

For patients receiving VKA therapy for VTE, an INR recall interval of 4 weeks or less is suggested rather than an interval longer than 4 weeks after VKA dose adjustment due to an out-of-target-range INR.

For patients receiving maintenance VKA therapy for VTE, a longer (6-12 weeks) INR recall interval is suggested rather than a shorter (4 weeks) interval during periods of stable INR control.

Laboratory monitoring of anticoagulant response

For patients with renal dysfunction (creatinine clearance, < 30 mL/min) or obesity receiving LMWH therapy for VTE, it is suggested not to use anti–factor Xa concentration monitoring to guide LMWH dose adjustment.

For patients receiving DOAC therapy for VTE, it is suggested not to measure the DOAC anticoagulant effect during management of bleeding.

Transitions between anticoagulants

For patients transitioning from DOAC to VKA, overlapping DOAC and VKA therapy until the INR is within the therapeutic range is suggested in preference to LMWH or UFH “bridging therapy.”

Use of specialized AMS

For patients receiving anticoagulation therapy for VTE, specialized anticoagulation-management service (AMS) care is suggested in preference to care provided by the patient’s usual healthcare provider.

Structured patient education

For patients receiving oral anticoagulation therapy for VTE, supplementary patient education is suggested in addition to basic education.

Efforts to improve adherence to anticoagulant regimen

For patients receiving anticoagulation therapy for VTE, it is suggested not to use a daily lottery, electronic reminders, or a combination of the two to improve medication adherence. It is also suggested not to use visual medication schedules (provided to patients at each visit, along with brief counseling) to improve medication adherence.

Invasive procedure management

For patients at low-to-moderate risk for recurrent VTE who require interruption of VKA therapy for invasive procedures, VKA interruption alone is recommended in preference to periprocedural bridging with LMWH or UHF.

For patients interrupting DOAC therapy for scheduled invasive procedures, it is suggested not to perform laboratory testing for DOAC effect before procedures.

Excessive anticoagulation and bleeding management

For patients receiving VKA therapy for VTE with INR >4.5 but < 10 and without clinically relevant bleeding, temporary cessation of VKA alone is suggested, without the addition of vitamin K.

For patients with life-threatening bleeding during VKA therapy for VTE and an elevated INR, use of four-factor prothrombin complex concentrates (PCCs) is suggested in preference to fresh frozen plasma (FFP) as an addition to cessation of VKA and IV vitamin K.

For patients with life-threatening bleeding during oral direct Xa inhibitor therapy for VTE, it is suggested to use either four-factor PCC administration as an addition to cessation of oral direct Xa inhibitor or cessation of oral direct Xa inhibitor alone.

For patients with life-threatening bleeding during oral direct Xa inhibitor therapy for VTE, it is suggested to use coagulation factor Xa (recombinant), inactivated-zhzo in addition to cessation of oral direct Xa inhibitor rather than no coagulation factor Xa (recombinant), inactivated-zhzo.

For patients with life-threatening bleeding during dabigatran therapy for VTE, it is suggested to use idarucizumab in addition to cessation of dabigatran rather than no idarucizumab.

For patients with life-threatening bleeding during LMWH or unfractionated heparin (UFH) therapy for VTE, it is suggested to use protamine in addition to LMWH/UFH cessation rather than no protamine.

Anticoagulant resumption following bleeding

For patients receiving anticoagulation therapy for VTE who survive an episode of major bleeding, resumption of oral anticoagulation therapy within 90 days is suggested in preference to discontinuance of oral anticoagulation therapy.

In September 2017, the European Society of Anesthesiology (ESA) issued the following guidelines regarding prophylaxis for VTE in elderly patients undergoing surgery[85] :

• The risk for postoperative VTE is increased in patients older than 70 years and in elderly patients presenting with comorbidities, such as cardiovascular disorders, malignancy, or renal insufficiency; therefore, risk stratification, correction of modifiable risks, and sustained perioperative thromboprophylaxis are essential in this patient population
• Timing and dosing of pharmacoprophylaxis may be adopted from the younger population
• Direct oral anticoagulants are effective and well tolerated in the elderly; statins may not replace pharmacologic thromboprophylaxis
• Early mobilization and use of nonpharmacologic means of thromboprophylaxis should be exploited
• In elderly patients, suggest identification of comorbidities increasing the risk for VTE (eg, congestive heart failure, pulmonary circulation disorder, renal failure, lymphoma, metastatic cancer, obesity, arthritis, post-menopausal estrogen therapy) and correction if present (eg, anemia, coagulopathy)
• Suggest against bilateral knee replacement in elderly and frail patients
• Suggest timing and dosing of pharmacologic VTE prophylaxis as in the younger population
• In elderly patients with renal failure, low-dose unfractionated heparin (UFH) may be used or weight-adjusted dosing of low-molecular-weight heparin (LMWH)
• In the elderly, recommend careful prescription of postoperative VTE prophylaxis and early postoperative mobilization
• Recommend multifaceted interventions for VTE prophylaxis in elderly and frail patients, including pneumatic compression devices, LMWH, and/or direct oral anticoagulants after knee or hip replacement

In 2012, the American College of Chest Physicians (ACCP) published the ninth edition of its guidelines on antithrombotic therapy and prevention of thrombosis (updated from the eighth edition published in 2009).[36] ACCP guidelines providing recommendations for the prevention of VTE in orthopedic surgery patients addressed therapy and prevention.[84] Recommendations included the following:

• In patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA), use of one of the following is recommended for a minimum of 10-14 days rather than no antithrombotic prophylaxis: LMWH, fondaparinux, apixaban, dabigatran, rivaroxaban, low-dose UFH (LDUH), adjusted-dose vitamin K antagonist (VKA), aspirin (all grade 1B), or an intermittent pneumatic compression device (IPCD) (grade 1C)
• In patients undergoing hip fracture surgery (HFS), use of one of the following is recommended rather than no antithrombotic prophylaxis for a minimum of 10 to 14 days: LMWH, fondaparinux, LDUH, adjusted-dose VKA, aspirin (all grade 1B), or an IPCD (grade 1C)
• For patients undergoing major orthopedic surgery (THA, TKA, HFS) and receiving LMWH as thromboprophylaxis, it is recommended to start either 12 hr or more preoperatively or 12 hr or more postoperatively rather than within 4 hr or less preoperatively or 4 hr or less postoperatively (grade 1B)
• In patients undergoing THA or TKA, irrespective of the concomitant use of an IPCD or length of treatment, LMWH is suggested in preference to the other agents recommended as alternatives: fondaparinux, apixaban, dabigatran, rivaroxaban, LDUH (all grade 2B), adjusted-dose VKA, or aspirin (all grade 2C)
• In patients undergoing HFS, irrespective of the concomitant use of an IPCD or length of treatment, LMWH is suggested in preference to the other agents recommended as alternatives: fondaparinux, LDUH (grade 2B), adjusted-dose VKA, or aspirin (all grade 2C)
• For patients undergoing major orthopedic surgery, it is suggested to extend thromboprophylaxis in the outpatient period for up to 35 days from the day of surgery rather than for only 10-14 days (grade 2B)
• In patients undergoing major orthopedic surgery, dual prophylaxis with an antithrombotic agent and an IPCD is suggested during the hospital stay (grade 2C)
• In patients undergoing major orthopedic surgery and increased risk of bleeding, an IPCD or no prophylaxis is suggested rather than pharmacologic treatment (grade 2C)
• In patients undergoing major orthopedic surgery and who decline or are uncooperative with injections or an IPCD, use of apixaban or dabigatran (alternatively, rivaroxaban or adjusted-dose VKA if apixaban or dabigatran are unavailable) is recommended rather than alternative forms of prophylaxis (all grade 1B)
• In patients undergoing major orthopedic surgery, it is suggested not to use inferior vena cava (IVC) filter placement for primary prevention over no thromboprophylaxis in patients with an increased bleeding risk or contraindications to both pharmacologic and mechanical thromboprophylaxis (grade 2C)
• For asymptomatic patients following major orthopedic surgery, it is recommended not to perform Doppler (or duplex) ultrasonography (DUS) screening before hospital discharge (grade 1B)
• No prophylaxis is suggested rather than pharmacologic thromboprophylaxis in patients with isolated lower-leg injuries requiring leg immobilization (grade 2C)
• For patients undergoing knee arthroscopy without a history of prior VTE, no thromboprophylaxis is suggested rather than prophylaxis (grade 2B)

An update in 2016 addressed 12 topics from the ninth edition guidelines, as well as three new topics.[93]

Guidelines from the American Academy of Orthopaedic Surgeons (AAOS) on preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty included the following recommendations[7] :

• Recommend against routine postoperative duplex ultrasonography screening
• Assess risk of previous VTE
• Assess risk for bleeding
• Suggest discontinuance of antiplatelet agents before undergoing elective hip or knee arthroplasty
• Suggest pharmacologic agents and/or mechanical compressive devices for prevention of VTE in those undergoing elective hip or knee arthroplasty who are not at elevated additional risk for VTE or bleeding
• Pharmacologic prophylaxis and mechanical compressive devices for those who have had previous VTE and are undergoing elective hip or knee arthroplasty
• Mechanical compressive devices for those who have had known bleeding disorder and/or active liver disease and are undergoing elective hip or knee arthroplasty
• Patients should undergo early mobilization following elective hip and knee arthroplasty
• Use of neuraxial anesthesia for those undergoing elective hip or knee arthroplasty to help limit blood loss
• Unable to recommend for or against the use of inferior vena cava filters

International clinical practice guidelines for the treatment and prophylaxis of VTE in patients with cancer were issued in early 2013 by the The International Initiative on Thrombosis and Cancer.[30] Recommendations included 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 pharmacologic 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

For more information, please go to Deep Venous Thrombosis (DVT), Pulmonary Embolism (PE), Deep Venous Thrombosis Risk Stratification, Inferior Vena Cava Filters, Thrombolytic Therapy, and Deep Venous Thrombosis Prophylaxis in Orthopedic Surgery.

For more Clinical Practice Guidelines, please go to Guidelines.

Anticoagulant inpatient medications should include heparin or a low-molecular-weight heparin (LMWH), followed by the initiation of an oral coumarin derivative. Heparin is administered by bolus dosing, followed by a continuous infusion. The predominant coumarin derivative in clinical use in North America is warfarin sodium.

Apixaban, dabigatran, rivaroxaban, edoxaban, and betrixaban are alternatives to warfarin for prophylaxis or treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE). Apixaban, edoxaban, rivaroxaban, and betrixaban inhibit factor Xa, whereas dabigatran is a direct thrombin inhibitor.

Class Summary

Anticoagulant medications prevent further clot deposition. They allow the natural fibrinolytic mechanisms to lyse the existing clot.

Heparin

Heparin augments the activity of antithrombin III and prevents conversion of fibrinogen to fibrin. It does not actively lyse but is able to inhibit further thrombogenesis. The drug prevents the reaccumulation of clot after spontaneous fibrinolysis.

Warfarin (Coumadin, Jantoven)

Warfarin interferes with the hepatic synthesis of vitamin K–dependent coagulation factors. It is used for prophylaxis and treatment of venous thrombosis, PE, and thromboembolic disorders. Tailor the dose to maintain an international normalized ratio (INR) in the range of 2.0-3.0.

Enoxaparin (Lovenox)

Enoxaparin prevents DVT, which may lead to PE in patients undergoing surgery who are at risk for thromboembolic complications. The average duration of treatment is 7-14 days. Enoxaparin enhances the inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, it preferentially increases the inhibition of factor Xa. Enoxaparin also has been approved for the treatment of DVT and PE.

Dalteparin (Fragmin)

Dalteparin is indicated for the prevention of DVT, which may lead to PE. It enhances the inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, dalteparin preferentially increases the inhibition of factor Xa. The average duration of treatment is 7-14 days.

Rivaroxaban (Xarelto)

Rivaroxaban is an oral factor Xa inhibitor that inhibits platelet activation by selectively blocking the active site of factor Xa without requiring a cofactor (eg, antithrombin III) for activity. It is indicated for a variety of treatment and prophylaxis VTE indications, including risk reduction of stroke and systemic embolism in nonvalvular atrial fibrillation; treatment of DVT and PE; reduction in risk of recurrent DVT and/or PE; prophylaxis of DVT following hip or knee replacement surgery; prophylaxis of VTE in acutely ill medical patients at risk for thromboembolic complications owing to restricted mobility (and who are not at high risk of bleeding); and risk reduction of major CV events with CAD or PAD.

Dabigatran (Pradaxa)

Dabigatran is a direct thrombin inhibitor. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation is inhibited. It is indicated for the treatment of DVT and PE in patients who have been treated with a parenteral anticoagulant for 5-10 days. It is also indicated to reduce the risk of DVT and PE recurrence in patients who have been previously treated.

Apixaban (Eliquis)

Apixaban is a factor Xa inhibitor indicated for treatment of DVT and PE. It is also indicated to reduce the risk of recurrence of DVT and PE in patients who have been previously treated.

Edoxaban (Savaysa)

Edoxaban is a factor Xa inhibitor indicated for treatment of DVT and PE in patients who have been initially treated with a parenteral anticoagulant for 5-10 days.

Class Summary

As stated by the American College of Chest Physicians,[36]  thrombolytic treatment is indicated for acute, massive PE with hemodynamic instability in patients who do not seem prone to bleeding. These agents dissolve 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 improves pulmonary capillary blood flow and more rapidly improves hemodynamic parameters.

Reteplase; t-PA (Retavase)

Reteplase is used in the management of PE in hemodynamically unstable patients. Its safety and efficacy with concomitant administration of heparin or aspirin during first 24 hours after symptom onset have not been investigated.

Tenecteplase (TNKase)

Tenecteplase is a modified version of alteplase made by substituting three amino acids. It has a longer half-life than alteplase and thus can be given as a single bolus infused over 5 seconds (as opposed to the 90 minutes required for alteplase). It appears to cause less non–intracranial bleeding than alteplase but carries a comparable risk of intracranial bleeding and stroke.

Base the dose on the patient's weight. Initiate treatment as soon as possible after the onset of AMI symptoms. Because tenecteplase contains no antibacterial preservatives, it must be reconstituted immediately before use.

Class Summary

Blood coagulation cascade is dependent on the activation of factor X to factor Xa via the intrinsic and extrinsic pathways.

Apixaban (Eliquis)

Indicated to reduce risk of stroke and systemic embolism associated with nonvalvular atrial fibrillation. Also indicated for postoperative prophylaxis of DVT/PE and for treatment of DVT or PE.

Rivaroxaban (Xarelto)

Indicated for prophylaxis of DVT, which may lead to PE in patients undergoing knee or hip replacement surgery. Also indicated to reduce the risk of stroke in patients with nonvalvular atrial fibrillation. Additionally, it is indicated for treatment of DVT or PE.

Edoxaban (Savaysa)

Indicated to reduce risk of stroke and systemic embolism associated with nonvalvular atrial fibrillation (NVAF).

Betrixaban (Bevyxxa)

Indicated for prophylaxis of venous thromboembolism (VTE) in adults hospitalized for acute medical illness who are at risk for thromboembolic complications owing to moderate or severe restricted mobility and other risk factors that may cause VTE.

Class Summary

Prevents thrombus development through direct, competitive inhibition of thrombin. Thrombin enables fibrinogen conversion to fibrin during the coagulation cascade.

Dabigatran (Pradaxa)

Inhibits free and clot-bound thrombin and thrombin-induced platelet aggregation. Indicated for prevention of stroke and systemic embolism associated with nonvalvular atrial fibrillation. Also indicated for prevention and treatment of DVT or PE.