Hematology

Thrombosis/embolism

Thrombosis/embolism

What every physician needs to know:

Venous thromboembolism (VTE) refers to venous thrombosis involving the deep (deep venous thrombosis or DVT) or superficial vessels (superficial venous thrombosis or thrombophlebitis) of the upper and lower extremities and central venous vessels (e.g., inferior and superior vena cava) and pulmonary emboli (pulmonary embolism [PE]) that migrate to the lungs from these locations.

A Center for Disease Control analysis of National Hospital Discharge Survey data from 2007 - 2009 estimated that 547,596 hospitalizations occurred annually among persons aged >= 18 years for VTE; 348,558 for DVT, 277,549 for PE and 78,511 for DVT and PE. These correspond to average annual rates of hospitalization for VTE of 239 per 100,000 population, 152 per 100,000 population for DVT and 121 per 100,000 for PE (Yusef H et al. MMWR 2012). These data are underestimates as they do not include patients treated as outpatients.

The risk of VTE is very low among children, intermediate among young and middle aged adults and high among older adults. The incidence of VTE appears to be ~ similar between men and women. Ethnicity strongly influences the risk of VTE. African Americans have the highest annual incidence followed closely by Caucasians while the incidence is significantly less among Latinos and Asians (see Table I)

Table I.

Demographic VTE Risk Factors

The most important risk factors for VTE are:

  • surgery

  • trauma

  • cancer

  • thrombophilia

  • immobilization

  • medical illnesses (see below)

(Medical illnesses such as stroke, myocardial infarction, congestive heart failure, respiratory failure, infections, rheumatologic disorders (e.g., systemic lupus erythematosus), and inflammatory bowel disease.) (See Table II)

Table II.

Acquired Risk Factors for Venous Thromboembolism

Surgery

Major surgery (requiring hospitalization) is associated with a 70-fold increased risk of VTE in the first 6 weeks post-operation. The increase in risk has been documented to last up to 12 months post-operation, although the highest period of risk is in the first 2 weeks after surgery. The risk of VTE varies by type of surgery and the duration of the operation. Neurosurgery and cardiothoracic surgery are associated with the greatest risks for VTE. Ambulatory surgery (outpatient surgery) increases the risk of VTE by 10-fold.

Trauma

58% of major trauma patients (Injury Severity Score > 9) developed a DVT on routine venography performed 14 - 21 days post-injury and 18% had proximal DVT. Asymptomatic PE can be detected by CT angiography in 24% of moderately and severely injured trauma patients within 1 week of injury. Fatal PE is responsible for 12% of deaths in hospitalized trauma patients.

Cancer

Active cancer increases the risk of VTE by 4- to 7-fold. Chemotherapy in a cancer patient is associated with a 2- to 6-fold increased risk.

The risk of VTE varies by cancer type with pancreatic, brain and gastric cancers having the highest risk, lung cancer and lymphoma a somewhat lower risk, and prostate and breast cancer being among the lowest thrombotic risk categories.

Metastatic disease is associated with a 1.5- to 20-fold higher risk than regional or localized disease.

Surgery, erythropoietic stimulatory agents and central venous catheters also contribute to the increased risk of VTE in cancer patients.

Thrombophilia

Inherited and acquired thrombophilia increases the risk of VTE by 2- to 20-fold depending upon the thrombophilic condition.

  • High risk inherited thrombophilic states include antithrombin (15- to 20-fold increased risk), protein C (15- to 20-fold), and protein S deficiency (15- to 20-fold).

  • Moderate risk inherited thrombophilic states include factor V Leiden (5- to 7-fold), elevated factor VIII levels (3- to 5-fold), and the prothrombin gene 20210 mutation (2- to 3-fold).

  • Low risk inherited thrombophilic states include elevated factor IX levels (1.5- to 2.5-fold), elevated factor XI levels (1.5- to 2.5-fold), and hyperhomocysteinemia (1.5- to 2.5 fold, except in cases of homocystinuria where the risk is much higher).

Antiphospholipid syndrome is an acquired thrombophilic state associated with a variable risk of thrombosis (3- to 10-fold) depending upon the associated laboratory abnormality establishing the diagnosis.

Immobilization

In the Sirius Study of VTE risk factors in medical outpatients, immobilization was associated with a 6-fold increased risk of VTE

Medical Illnesses

Medical illnesses such as stroke, myocardial infarction, congestive heart failure, respiratory failure, infections, rheumatologic conditions, and inflammatory bowel disease all increase the risk of VTE by 2- to 10-fold

Diagnosis:

The presence of a DVT is often indicated by the development of pain, swelling, and erythema in the affected extremity. A feeling of heaviness in the leg or the sensation of a leg cramp that does not go away are common complaints.

Pulmonary embolism classically results in the sudden onset of dyspnea and pleuritic chest pain, although some patients present with gradually worsening dyspnea or back pain. Syncope or pre-syncope is an ominous presentation of PE that usually indicates a large embolic burden.

Mesenteric vein thrombosis can present acutely with severe abdominal pain and vomiting due to intestinal ischemia, or chronically with signs and symptoms of portal hypertension that include variceal bleeding, ascites, and splenomegaly. Hepatic vein thrombosis presents with abdominal pain, distention, and ascites. Cerebral vein thrombosis typically presents with severe headache, nausea, vomiting, and visual impairment.

Diagnosis of venous thrombotic disorders relies upon imaging studies. Pre-test probability models such as the Wells criteria have been developed to exclude DVT and PE in conjunction with sensitive D-dimer tests (see Table III and Table IV), but duplex ultrasonography and CT angiography remain the cornerstone of deep venous thrombosis and pulmonary embolism diagnosis.

Table III.

Wells Clinical DVT Model

Table IV.

Wells Clinical Pulmonary Embolism Model

Duplex ultrasound is also useful for diagnosis of upper extremity, thoracic, and jugular vein DVT. In some instances, computed tomography (CT) venography may be necessary for diagnosis of thrombosis in intrathoracic vessels that are not amenable to compression (e.g., the subclavian vein and superior vena cava). Therefore, CT venography should be employed when diagnostic suspicion is high in the setting of a negative duplex study.

Upper extremity thrombosis is often due to the presence of central venous catheters or anatomic compression (thoracic outlet syndrome [TOS] or tumor/nodal masses). In the absence of an identifiable cause of upper extremity (axillary-subclavian vein) thrombosis, the presence of thoracic outlet syndrome should be investigated with duplex ultrasonography or CT venography performed with the arm in stress positions. Failure to identify patients with TOS can result in recurrent axillary-subclavian vein thrombosis and post-thrombotic syndrome (PTS).

Although duplex ultrasound (US) can sometimes be useful for iliac vein and inferior vena cava (IVC) thrombosis, CT angiography is more sensitive for thrombosis in these central veins. It is important to consider CT angiography when evaluating a patient with iliofemoral DVT who may have May-Thurner (iliac vein compression) syndrome. Hepatic duplex and CT angiography are useful for mesenteric vein (portal vein, superior mesenteric vein, etc.) and hepatic vein thrombosis.

CT venography and magnetic resonance venography (MR venography) are the studies of choice for cerebral vein thrombosis. All patients with cerebral vein thrombosis should also have a dedicated ophthalmologic exam to ensure that visual complications of an elevated intracranial pressure are diagnosed and treated promptly.

What features of the presentation will guide me toward possible causes and next treatment steps?

The duration of therapy and decisions on adjunctive therapies for VTE (i.e., pharmacomechanical catheter-directed thrombolysis) are influenced by:

  • the extent and location of the VTE

  • the presence or absence of situational or persistent thrombotic triggers.

Therefore, it is imperative to investigate the cause of the thrombotic event during the initial patient evaluation.

Extensive extremity DVT should prompt consideration of catheter-directed thrombolysis, as patients with extensive proximal thrombosis rarely achieve complete clot lysis and are at high risk for post-thrombotic syndrome. The benefits of thrombolysis must be weighed against the higher risk of bleeding associated with this therapy. In the CAVenT study, catheter-directed thrombolysis (CDT) was associated with iliofemoral patency at 6 months of 66% compared to 47% in patients receiving anticoagulation alone (p=0.012). PTS developed in 41% of CDT-treated patients compared to 56% of anticoagulation alone patients (p=0.047). The result of the soon to be completed ATTRACT trial should provide important supplemental data to assist in decision-making in regards to the risks and benefits of CDT.

Massive pulmonary embolism warrants systemic or ultrasound-assisted thrombolysis or catheter or surgical thrombectomy. The benefits of thrombolytic therapy in lower risk patients remain unclear. The PEITHO study, a randomized controlled trial of tenecteplase or placebo plus systemic anticoagulation in patients with intermediate risk PE, did not identify an improvement in all-cause mortality with thrombolysis (1.2% vs. 1.8% OR = 0.65, 95% CI 23 - 1.85). Furthermore, thrombolysis was associated with a 5.6-fold (6.3% vs. 1.2%, 95% CI 2.3 - 13.39) increase in major extracranial bleeding and a 12.2-fold (2.4% vs. 0.2%, 95% CI 1.57 - 93.39) increase in stroke.

Triggered episodes of VTE occur in close temporal proximity to the inciting stimulus.

  • Surgical and medical hospital-acquired VTE generally occur within 3 months of the procedure/hospitalization. The risk is highest in the first few weeks and then declines thereafter.

  • Travel-associated VTE occurs within 8 weeks of the travel. Since travel is a weak risk factor for VTE, it is important to consider other possible risk factors for VTE that may be present and influence the ongoing risk of recurrence.

  • Pregnancy: the risk of VTE rises during the antepartum period and peaks shortly after delivery with risk declining toward baseline by 6 - 12 weeks post-partum.

  • Hormone associated thrombosis occurs during exposure and risk declines within 6 - 12 weeks of discontinuation.

  • Cancer and its treatment place patients at high risk for VTE as long as detectable cancer remains or treatment continues.

Patients with triggered VTE require a limited duration of therapy (at least 3 - 6 months, after which therapy may be discontinued if the stimulus is no longer present). If the trigger is still present (hormonal therapy, poorly controlled inflammatory bowel disease, cancer) then therapy should continue until it is absent or under adequate control. I generally treat patients with pulmonary embolism at least 6 months (rather than 3 months), as patients with PE are at higher risk for recurrent PE than patients with an initial DVT. Furthermore, PE has a higher case fatality rate than DVT (12% versus 6% 30-day mortality).

Patients with unprovoked VTE should be considered for long-term anticoagulation, as they are at high risk for recurrence. Two risk stratification models, the Ottawa (Men Continue and HER DOO2) model (see Table XI) and the Vienna model, can be used to estimate the risk of recurrence in patients with idiopathic VTE, and to identify patients at sufficiently low risk that continuation of anticoagulation may have marginal benefits. It is important to note that these models require validation. There is a free web calculator for the Vienna prediction model for recurrent VTE, available at http://cemsiis.meduniwien.ac.at/en/kb/science-research/software/clinical-software/recurrent-vte/

Table XI.

The Ottawa VTE Risk Assessment Model for assessing the risk of recurrent VTE in patients with idiopathic VTE

The potential presence of an underlying malignancy should always be considered in middle-aged patients (age 50 years or older) with idiopathic VTE. In addition to a complete history and physical examination, age-appropriate cancer screening should be undertaken in these patients.

Limited screening would consist of a complete history and physical exam, as well as standard laboratory tests (complete blood count [CBC], comprehensive metabolic profile, stool hemoccult, urinalysis) and age-appropriate cancer screening (e.g., colonoscopy, mammography). Any abnormal findings on routine evaluation warrant additional investigation. Extensive screening with CT or PET-CT has not been demonstrated to improve early cancer detection in patients with unprovoked VTE.

Patients with symptomatic calf DVT should receive at least 6 weeks (preferably 12 weeks) of anticoagulation.

Patients with proximal superficial venous thrombophlebitis (greater saphenous vein in the thigh) or persistent distal superficial venous thrombophlebitis should be treated with anticoagulation rather than initial non-steroidal anti-inflammatory drugs. In patients with acute symptomatic SVT, fondaparinux 2.5 mg daily for 45 days reduced the incidence of progressive SVT, DVT or PE (0.9% versus 5.9%, RRR 85%) compared with placebo. Recurrent unprovoked superficial thrombophlebitis should prompt consideration of malignancy as an underlying cause.

Recurrent VTE in the presence of therapeutic anticoagulation (INR 2 - 3) should prompt consideration of malignancy (Trousseau’s syndrome), antiphospholipid syndrome, paroxysmal nocturnal hemoglobinuria, myeloproliferative neoplasms (particularly polycythemia vera), heparin-induced thrombocytopenia, or local vascular compression (May-Thurner syndrome, thoracic outlet syndrome).

Patients who present with left iliofemoral DVT should be investigated for May-Thurner (iliac vein compression) syndrome, as failure to re-establish in-line flow and stent the affected venous segment predisposes the patient to a high risk of locally recurrent VTE and post-thrombotic syndrome in the affected limb.

Patients who present with upper extremity VTE must be investigated for an anatomic cause (central venous catheter, thoracic outlet syndrome, vascular compression by tumor/lymph nodes), as idiopathic thrombosis is unusual in this location.

Patients who present with intra-abdominal thrombosis (mesenteric vein thrombosis, hepatic vein thrombosis) in the absence of a recent intra-abdominal surgical procedure should be investigated for a myeloproliferative neoplasm (e.g., polycythemia vera, essential thrombocythemia), intra-abdominal malignancy, a thrombophilic disorder, or paroxysmal nocturnal hemoglobinuria.

Patients with cerebral venous sinus thrombosis should be investigated for the presence of an underlying myeloproliferative neoplasm such as polycythemia vera and essential thrombocythemia. The presence of paroxysmal nocturnal hemoglobinuria should be ruled out. It is important to assess carefully patients with cerebral venous sinus thrombosis for signs and symptoms of increased intracranial pressure, and to treat this aggressively. Subtle visual deficits can progress to life-altering visual loss unless diagnosed early. Therefore, we routinely test visual acuity in these patients and have them formally seen by neuro-ophthalmology at diagnosis.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

All patients with VTE should have routine laboratory testing (CBC with platelet count and differential, comprehensive metabolic profile, prothrombin time [PT], activated partial thromboplastin time [aPTT]) to rule out the presence of an underlying medical disorder. In young women of child-bearing age, pregnancy tests should be obtained prior to radiologic studies that may be harmful to the fetus. This information will also be critical for selection of appropriate treatment options.

Diagnosis of VTE relies heavily upon objective imaging studies. Pre-test probability models such as the Wells criteria have been developed to exclude DVT and PE in conjunction with sensitive D-dimer tests, but duplex ultrasonography and CT angiography remain the cornerstone of deep venous thrombosis and pulmonary embolism diagnosis.

Duplex is also useful for diagnosis of upper extremity, thoracic, and jugular vein DVT. In some instances, CT venography may be necessary for diagnosis of thrombosis in intrathoracic vessels which are not amenable to compression such as the subclavian vein and superior vena cava. Therefore, CT should be employed when diagnostic suspicion is high in the setting of a negative duplex study.

Upper extremity thrombosis is often due to the presence of central venous catheters or anatomic compression (thoracic outlet syndrome [TOS] or tumor/nodal masses). In the absence of an identifiable cause of upper extremity (axillary-subclavian vein) thrombosis, the presence of thoracic outlet syndrome should be investigated with duplex ultrasonography or venography performed with the arm in stress positions. Failure to identify patients with TOS can result in recurrent axillary-subclavian vein thrombosis.

Although duplex ultrasound (US) can sometimes be useful for iliac vein and IVC thrombosis, CT venography is more sensitive for thrombosis in these central veins. It is particularly important to consider CT venography when evaluating a patient with iliofemoral DVT who may have May-Thurner (iliac vein compression) syndrome. Hepatic duplex and CT venography are useful for mesenteric vein (portal vein, superior mesenteric vein, etc.) and hepatic vein thrombosis.

CT venography and magnetic resonance venography are the studies of choice for cerebral vein thrombosis. All patients with cerebral vein thrombosis should also have a dedicated ophthalmologic exam to ensure that visual complications of elevated intracranial pressure are diagnosed and treated promptly.

What conditions can underlie thrombosis/embolism:

VTE is often triggered by abnormalities in one or more of Virchow’s Triad:

  • stasis,

  • hypercoagulability of the blood,

  • vessel wall abnormalities.

Therefore, the presence of potential disorders that may influence one or more elements of Virchow’s Triad should be considered in the evaluation and management of every patient with VTE. Elimination of any removable risk factor will reduce the risk of recurrence after an initial course of anticoagulation is completed. The presence of ongoing risk factors warrants consideration of long-term therapy.

Stasis: recent immobility-travel (within 8 weeks), hospitalization (within 12 weeks), surgery (within 12 weeks or, possibly, longer), stroke (within 12 weeks), presence of anatomic vascular compression- thoracic outlet syndrome, effort thrombosis, May-Thurner syndrome, tumor or nodal masses obstructing flow, central venous catheter disrupting blood flow, pregnancy.

Hypercoagulability: cancer, surgery - inpatient>outpatient, major trauma, pregnancy, exogenous hormonal agents, chemotherapy, erythropoietic stimulatory agents, thrombophilia, inflammation associated with infections, rheumatologic diseases, inflammatory bowel disease.

Vessel wall damage: surgery - inpatient>outpatient, major trauma, central venous catheters, chemotherapy.

When do you need to get more aggressive tests:

Since the setting in which a thrombotic event occurs is the best guide to the appropriate duration of therapy, the need for thrombophilia testing is considerably less now than a few years ago. In general, if thrombophilia testing is not going to change therapy there is no compelling reason to perform it.

The most common reason for thrombophilia testing in my experience is the desire of patients or their physicians to identify the etiology of a thrombotic event. However, I try to dissuade patients from pursuing thrombophilia testing unless it will significantly influence their treatment. Testing asymptomatic family members should be discouraged.

Idiopathic venous thromboembolism

Patients with idiopathic VTE are best treated with long-term therapy. Therefore, the only reason to perform thrombophilia testing in this instance would be to determine if a patient who wishes to discontinue therapy should be advised against this option due to a high risk for recurrence.

Tests that could be ordered in this situation would include testing for the antiphospholipid syndrome including anticardiolipin antibodies, anti-beta-2 glycoprotein-I antibodies, and lupus anticoagulant/inhibitor testing including an aPTT using a low phospholipid reagent (i.e., Actin FSL, etc.) and a dilute Russell’s Viper venom time with Confirm procedure (and other tests for a lupus inhibitor).

In young patients (age < 40 years) with a positive family history of VTE (in a first degree relative), inherited thrombophilia could be considered (although it has not been proven to improve outcomes)- factor V Leiden evaluation (APC Resistance assay with reflex factor V Leiden DNA testing if activated protein C [APC] resistance assay is positive), prothrombin gene mutation, protein C, protein S and antithrombin activity levels. Patients with antithrombin, protein C and protein S deficiency are thought to be at increased risk for recurrence, as are patients with homozygous factor V Leiden or the prothrombin gene mutation or compound heterozygotes for these defects.

Alternatively, there are data supporting use of clinical prediction rules such as the Ottawa (Men Continue and HER DOO2) or Vienna Risk Criteria that incorporate patient and clinical characteristics and D-dimer levels on or off therapy in order to determine recurrence risk. While these risk scores need to be validated, they would seem to be the best strategy to use when deciding upon therapeutic duration in patients with unprovoked VTE.

Young women with venous thromboembolism who may become pregnant

Thrombophilia testing may be of benefit in young women with VTE who may become pregnant in the future, as the presence of thrombophilia may warrant more aggressive thromboprophylaxis during pregnancy – especially in women with a triggered episode of VTE.

Heparin-induced thrombocytopenia testing

Testing for heparin-induced thrombocytopenia (HIT) should be employed only if the diagnosis is suggested by the clinical situation (e.g., thrombocytopenia or thrombosis during heparin therapy). Pre-test probability models (i.e., the 4T’s score and the HIT expert probability [HEP] score) should be used to determine the probability of HIT before sending confirmatory laboratory testing

Testing for other clinical entities

Testing for clinical entities such as paroxysmal nocturnal hemoglobinuria and myeloproliferative neoplasms (e.g., JAK2 testing) should be done in patients with clinical features supporting diagnostic suspicion (thrombosis in mesenteric or hepatic veins, cerebral venous system, and supportive laboratory data for the diagnosis)

Tumor markers

I do not recommend use of tumor markers for screening patients with VTE for underlying malignancies because they are expensive and have not been demonstrated to improve survival in patients with malignancy-associated VTE.

What imaging studies (if any) will be helpful?

The diagnosis of VTE continues to rely upon confirmatory radiologic imaging studies despite the availability of pre-test probability models such as the Wells criteria and D-dimer testing. In large part this is due to the varying positive test thresholds for different D-dimer assays, local validation of positive test thresholds, and the medical-legal practice environment in the United States.

Duplex ultrasound is very sensitive (95%) and specific for the presence of proximal extremity DVT or superficial venous thrombosis. Sensitivity and specificity decline in the distal extremity veins (approximately 75% sensitive and specific in the calf deep veins). Duplex ultrasound is also useful for the diagnosis of portal and hepatic vein thrombosis. In locations where compression cannot be used in the examination (subclavian and iliac veins, inferior and superior vena cava), CT venography should be employed if diagnostic suspicion is high in the event of a negative duplex study. CT venography is also sensitive for diagnosis of intra-abdominal venous thrombosis.

CT venography/CT angiography (CTV/CTA) are sensitive and specific for diagnosis of venous thrombosis in all locations, albeit more invasive than duplex ultrasound. CTA is the diagnostic study of choice for PE. CTV is an excellent diagnostic study for cerebral venous sinus thrombosis, although MR venography is preferred by some physicians.

MR venography is useful for diagnosis of venous thrombosis. It is used preferentially for cerebral venous sinus thrombosis and pelvic vein thrombosis in some centers. Thus far, it does not appear to be as sensitive for PE as CT angiography. MR direct clot imaging is a new technique that has been demonstrated in some studies to be able to differentiate between new and chronic venous thrombosis.

Ventilation/perfusion scans (V/Q scans) are used for diagnosis of PE in patients with renal insufficiency in whom intravenous (IV) contrast may be deleterious. Some providers also use V/Q scans for diagnosis of PE in pregnant women, although it is associated with a higher fetal radiation dose than CTA with abdominal shielding.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Options for acute therapy of VTE include:

  • Weight-adjusted unfractionated heparin (UFH) (e.g., 80 units/kg bolus and 16 - 18 units/kg/hr continuous IV infusion),

  • Low molecular weight heparin (LMWH) such as: enoxaparin (1 mg/kg sc q12h or 1.5 mg/kg sc q24h), dalteparin (100 units/kg sc q12h or 200 units/kg q24h), tinzaparin (175 units/kg sc q24h),

  • Fondaparinux (5 mg daily for weight 50 kg or less, 7.5 mg daily for 50-100 kg, or 10 mg daily for more than 100 kg).

  • Apixaban (10 mg by mouth BID X 7 days and then 5 mg by mouth BID)

  • Dabigatran 150 mg by mouth BID (must be preceded by at least 5 - 10 days of therapy with a parenteral agent (e.g., UFH, LMWH or fondaparinux)

  • Edoxaban 60 mg by mouth once daily or 30 mg once daily (e.g., in the case of patients with creatinine clearance of 30 - 50 ml per minute or a body weight below 60 kg), (must be preceded by at least 5 - 10 days of therapy with a parenteral agent (e.g., UFH, LMWH or fondaparinux)

  • Rivaroxaban (15 mg by mouth BID X 3 weeks followed by 20 mg once daily)

UFH is preferable for patients judged to be at high risk for bleeding (completely reversible with protamine) and patients with very poor renal function (creatinine clearance < 20 ml/min).

Apixaban, dabigatran, edoxaban, fondaparinux, LMWH,and rivaroxaban are preferable for most other patients, as they do not require monitoring and, therefore, facilitate outpatient therapy. In addition, LMWH and fondaparinux are associated with a much lower incidence of heparin-induced thrombocytopenia than UFH. The direct oral anticoagulants (DOAC) apixaban, dabigatran, edoxaban, and rivaroxaban have not been associated with HIT and offer the added advantage of oral administration.

Apixaban, dabigatran, edoxaban, fondaparinux, and rivaroxaban should not be used in patients with a creatinine clearance less than 30 ml/min. LMWH should be used cautiously in patients with a creatinine clearance of 20 - 30 ml/min for whom the appropriate dose of enoxaparin is 1 mg/kg once daily. Dalteparin is less dependent upon renal clearance. Renally-adjusted dose recommendations have not been made.

Avoid use of apixaban and rivaroxaban in patients with moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic impairment or hepatic disease associated with coagulopathy. Avoid use of apixaban or rivaroxaban with strong inhibitors or inducers of p-glycoprotein or CYP 3A4. Avoid use of dabigatran or edoxaban with strong inhibitors or inducers of p-glycoprotein. Patients with significant liver disease (AST or ALT > 2X ULN or total bilirubin > 1.5 X ULN were excluded from participation in all the DOAC clinical trials.

Two randomized placebo-controlled trials of aspirin (100 mg once daily) in the long term treatment of idiopathic VTE after an initial course of conventional anticoagulation demonstrated that aspirin reduced the relative risk of recurrent VTE by 32% (13.8% vs. 19.1%, HR = 0.68, 95% CI 0.51 - 0.90). The risk of major and clinically-relevant non-major bleeding was not significantly increased (2.9% vs. 2.0%, HR = 1.47, 95% CI 0.70 - 3.08) However, it should be noted the risk of recurrence with aspirin in these studies is much higher than in recent extended duration treatment studies with DOACs. In the AMPLIFY-EXT study, apixaban 2.5 mg and apixaban 5 mg twice daily reduced the relative risk of recurrent VTE by 80% compared with placebo. Major and clinically significant non-major bleeding was 2.7% in placebo recipients and 3.2% in apixaban 2.5 mg BID treated patients (RR = 1.20, 95% CI: 0.69 - 2.10). Dabigatran 150 mg BID significantly reduced the risk of recurrent VTE or unexplained death compared to placebo (0.4% vs. 5.6%, HR = 0.08, 95% CI 0.02 - 0.25). Major or clinically relevant non-major bleeding was 3 fold higher with dabigatran (5.3% vs. 1.8%, HR = 2.92, 95% CI: 1.52 - 5.60). Rivaroxaban 20 mg daily was associated with an 82% relative risk reduction of recurrent VTE compared with placebo (1.3% vs. 7.1%, HR = 0.18, 95% CI: 0.09 - 0.39). Major or clinically relevant non-major bleeding was 5 fold more common than placebo (6.0% vs. 1.2%, HR = 5.19, 95% CI: 2.3 - 11.7). These trials indicate that DOACs, particularly apixaban 2.5 mg BID, are attractive alternatives to aspirin and warfarin for long-term treatment of VTE.

Warfarin is started at a dose predicted to be the patient’s maintenance dose (2.5 - 7.5 mg for most patients). Loading doses should be avoided. The duration of therapy is dictated by the setting of the VTE – unprovoked = long-term therapy, triggered VTE = limited duration therapy (see Table V, Table VI, Table VII, Table VIII, and Table IX).

Table V.

Therapeutic options for initial treatment of VTE

Table VI.

The Johns Hopkins Anticoagulation Management Service Approach to Warfarin Dose Adjustment (Designed by Peggy Kraus, PharmD CACP)

Table VII.

Warfarin management guideline

Table VIII.

Guidelines for management of excessive anticoagulation with warfarin

Table IX.

Duration of Therapy for Venous thromboembolism

Catheter-directed thrombolytic therapy (CDT) with fibrinolytic agents such as alteplase or reteplase results in more rapid and complete clot lysis than conventional anticoagulation with 2 to 3-fold more bleeding complications. CDT appears to preserve vein valve function better than anticoagulation and reduce the incidence of post-thrombotic syndrome.

CDT should be considered in any patient with extensive, acute, proximal DVT who is at low risk for bleeding complications. CDT is especially important in patients with iliofemoral DVT who have May-Thurner (iliac vein compression) syndrome. Clot lysis and venous stenting are essential to prevent recurrent thrombosis that results from venous compression.

Clot lysis may also be considered in patients with suspected thoracic outlet syndrome associated with acute axillary-subclavian vein thrombosis. However, definitive surgical correction of the anatomic abnormality that leads to vessel compression is necessary to prevent recurrence. Use of venous stents alone in this disorder has been associated with an unacceptably high rate of recurrent thrombosis.

Catheter-directed thrombolysis has also been applied to the treatment of mesenteric vein and cerebral venous thrombosis in appropriate candidates. Although systemic thrombolysis is no longer used for treatment of DVT, it is still useful in the treatment of patients with massive pulmonary embolism. The standard regimen is alteplase 100 mg administered over 2 hours. UFH is restarted without a bolus once the aPTT has declined below the upper limit of the therapeutic range after the completion of the alteplase infusion. Preliminary studies indicate that low-dose rtPA (0.6 mg/kg, maximum 50 mg over 2 hours) is similar to standard-dose rtPA in terms of recurrent PE and mortality but associated with a lower risk of major bleeding. Further investigation is necessary before adopting lower-dose rtPA as the standard regimen of systemic thrombolysis for PE. In light of the results of the PEITHO study, systemic thrombolysis should not be routinely used for patients with sub-massive PE.

Catheter-based mechanical thrombectomy devices should be considered as an adjunctive measure to reduce clot burden and shorten the duration of thrombolysis in any patient considered for CDT therapy for DVT. Mechanical or surgical thrombectomies are also useful for treatment of massive pulmonary embolism in the event of failure of clot lysis to achieve appropriate clot burden reduction or in patients who are not candidates for thrombolysis. The ultrasound-assisted thrombolysis catheter (EKOS catheter) appears to be an effective device for rapid dissolution of massive pulmonary embolism that may represent a useful and possibly safer alternative to systemic thrombolysis for high-risk PE patients.

Vena cava filters should be reserved for patients who are not candidates for anticoagulation since filters increase the relative risk of recurrent DVT by 50% and are not associated with reduced mortality. Retrievable vena cava filters should be used preferentially because they can be removed if contraindications to anticoagulation resolve.

What other therapies are helpful for reducing complications?

Catheter-directed thrombolysis should be considered in any patient with extensive DVT, as it results in more complete and rapid clot lysis and may reduce the incidence of post-thrombotic syndrome.

Catheter-directed thrombolysis and stenting are essential to the treatment of May-Thurner (iliac vein compression) syndrome. Failure to relieve venous compression with lysis and stenting will place the patient at high risk for recurrent thrombosis.

Referral to a vascular surgeon is important for patients with thoracic outlet syndrome, as surgical removal of the anatomic abnormality (cervical rib, scalene muscle venous compression) is thought to be important to prevent recurrent axillosubclavian vein thrombosis.

Until recently, knee-high graduated compression stockings (GCS, 30 - 40 mmHg) were recommended to patients with DVT to reduce the incidence of post-thrombotic syndrome (PTS). However, the SOX trial, the first randomized placebo controlled trial of GCS for prevention of PTS, found a similar incidence of PTS in patients with active and placebo GCS (14.2% versus 12.7%, p = 0.58) after 24 months follow-up. However, some investigators have pointed out that adherence to stocking therapy was suboptimal (86% and 55% reported wearing their stockings 3 or more days per week at 1 month and 24 months follow up, respectively). Nevertheless, GCS are no longer recommended for prevention of PTS. Since sub-therapeutic anticoagulation has been strongly associated with PTS (OR 2.7), PTS prevention efforts should focus on optimizing anticoagulation.

In patients with a permanent vena cava filter, anticoagulation should be employed if possible since filters are associated with a 1.5-fold increase in the incidence of DVT and a 13% cumulative incidence of inferior vena cava thrombosis at 8 years. Since 38% of the filter group in the PREPIC study were treated with anticoagulation, it is reasonable to assume the cumulative incidence of IVC thrombosis would have been closer to 20% if no patients continued anticoagulation. Filter retrieval is also an option since new techniques for retrieval of permanent filters have been developed.

What should you tell the patient and the family about prognosis?

The risk of recurrent VTE is dictated principally by the presence or absence of risk factors for thrombosis.

Patients with unprovoked VTE are generally considered to be at ongoing risk for recurrent VTE once anticoagulation is discontinued. Long-term therapy is also appropriate for patients with active cancer, cancer patients under treatment, or within six months of active disease or treatment.

The risk of recurrence in a patient with unprovoked VTE is approximately 30-50% at 10 years after discontinuation of anticoagulation. A recent meta-analysis of randomized controlled trials and observational studies of patients with VTE found that patients with idiopathic VTE had an annual incidence of recurrent VTE of 7.4% per year.

In contrast, the risk of recurrent VTE was only 0.7% per year in patients with surgical triggers and 4.2% per year with non-surgical triggers. Because the risk of major bleeding in participants of randomized controlled trials of anticoagulation was only 1 - 2% per year and major bleeding and recurrent thrombosis are associated with a similar case fatality rate (11.3% during the first 3 months of therapy), continued anticoagulation is associated with net medical benefit in most patients with an idiopathic VTE as well as those with non-surgical triggers which are still present.

In contrast, one study of hospitalized patients who met one, two or more exclusion criteria for randomized controlled trials of anticoagulation had a 3-fold, 4-fold and 15-fold higher risk of major bleeding compared with clinical trial participants. Therefore, the risks of bleeding and thrombosis should be considered when deciding upon long-term anticoagulation in patients with VTE.

Clinical tools to estimate the risk of major bleeding on anticoagulation include the HASBLED score and the tool developed by Clive Kearon for the ACCP Guideline (Table XII and Table XIII). Unfortunately, studies of bleeding risk assessment tools have found them to be poorly predictive of major and clinically relevant bleeding in patients with VTE. Therefore, it is premature to use them for clinical decision-making.

Table XII.

HASBLED Bleeding Risk Assessment Model

Table XIII.

Kearon ACCP Bleeding Risk Factors Model

The risk of recurrent VTE in patients with unprovoked VTE can be estimated using the Ottawa (Men Continue and HER DOO2) and Vienna risk prediction models. The advantage of the Ottawa model is that it uses a D dimer measured during therapy so anticoagulation does not need to be discontinued to estimate the risk of recurrence. The disadvantage of the Ottawa model is that it can only be used for women as a low risk group of men was not identified. In addition, it has not been validated in a separate patient population although a validation study has recently been completed. The Vienna model can be used to estimate recurrence risk in men and women. Its shortcoming is that the D dimer value for the model is measured 3 weeks after discontinuation of anticoagulation potentially exposing patients to risk of recurrence.

When counseling patients and their family about the risk of recurrence it is important to emphasize that recurrent events are rare during initial therapy. The risk of a fatal PE is 0.4% during initial therapy for DVT and 1.5% during initial therapy for PE.

However, the risk of recurrence is substantial if anticoagulation is not employed for acute VTE. The risk of recurrence is 40% during the first month after a thrombotic event and 10% during months 2 and 3 post-thrombosis. Therefore, a vena cava filter should be placed in the event that a patient cannot be treated for acute, proximal, lower extremity DVT.

After discontinuation of anticoagulation, if a patient suffers a recurrent thrombotic event it tends to mirror the original thrombotic event. DVT patients who suffer a recurrence develop a DVT 80% of the time while PE patients tend to have a recurrent PE 80% of the time.

Post-thrombotic syndrome occurs in as many as 50% of patients within 2 years of DVT diagnosis. The risk of PTS is increased (OR 2.7) by sub-therapeutic anticoagulation. Therefore, it is essential to optimize anticoagulation during acute treatment of DVT. Catheter-directed thrombolysis also appears to reduce the relative risk of PTS by 25% compared to anticoagulation alone for proximal iliofemoral DVT. In contrast, GCS do not appear to be effective in PTS prevention. DOACs may result in a lower risk of PTS than warfarin since they are not subject to dietary interactions and have many fewer drug-drug interactions.

“What if” scenarios.

Patient with venous thromboembolism undergoing surgery

How should you manage a patient with a previous history of VTE who is undergoing surgery? Patients with a previous history of VTE undergoing surgery should be considered for extended duration DVT prophylaxis (up to 1 month for major surgery and 10-14 days for ambulatory surgery) in order to prevent recurrent VTE. (expert opinion)

Pregnant patient with history of venous thromboembolism

How should you manage a woman with a history of VTE who is now pregnant?

Women with a previous history of unprovoked, pregnancy-associated or hormone-associated VTE should receive antepartum and postpartum anticoagulant (prophylactic [e.g., enoxaparin 40 mg daily] or intermediate dose [enoxaparin 40 mg q12h]) prophylaxis to prevent recurrent VTE.

Women with a history of surgery or trauma-associated VTE should have antepartum surveillance and post-partum thromboprophylaxis (prophylactic or intermediate dose).

Post-partum prophylaxis should be continued for at least 6 weeks postpartum.

Patients who develop VTE during pregnancy should be treated with therapeutic dose LMWH adjusted to body weight for the duration of the pregnancy and post-partum period. It remains unclear whether LMWH should be adjusted by anti-Xa LMWH levels. Some obstetricians prefer to switch to subcutaneous UFH (250 units/kg q12h adjusted by anti-Xa levels or aPTT 4 hours after the dose) at 36 weeks of pregnancy and induce labor to improve the predictability of anticoagulation in the peripartum period. UFH has the advantage of 100% protamine reversibility compared with 60-80% reversibility for LMWH.

Subcutaneous UFH/LMWH heparin should be discontinued 48 hours prior to planned delivery to ensure its clearance from the plasma. Otherwise, protamine may be necessary for reversal. Anti-Xa levels or aPTT should be used to investigate the residual presence of heparin in the mother prior to delivery. Epidural analgesia should be avoided in the presence of residual heparin. Postpartum prophylactic dose LMWH may be started 12 - 24 hours post-delivery once hemostasis is assured. Therapeutic dose LMWH should not be started until 48 - 72 hours post-delivery. Transition to therapeutic warfarin can be initiated simultaneously. Warfarin can be used safely during breastfeeding.

Contraception and venous thromboembolism

What can be used for contraception in women with a history of VTE? Hormonal therapy should be avoided, if possible, in women with a history of VTE. The safest options for contraception are a copper wire intrauterine device (IUD) and barrier methods, although the former is preferred due to its superior efficacy.

If hormonal therapy is necessary, the Mirena® (low-dose progestin) IUD is preferred because it has not been associated with an increased risk of VTE. In contrast, depot medroxyprogesterone acetate has been recently identified as being associated with an increased risk of VTE, albeit less than estrogen-containing oral contraceptives.

Travel-associated venous thromboembolism

How should patients with a history of travel-associated VTE be managed on future travel for 4 hours or longer? Patients with a history of travel-associated VTE should receive travel prophylaxis to reduce the risk of recurrent VTE. Enoxaparin 1 mg/kg injected prior to the flight and knee-high graduated compression stockings (20 - 30 mmHg) have both been demonstrated to provide travel-associated prophylaxis. Aspirin has not been shown to be effective. I favor anticoagulant prophylaxis.

Recurrent venous thromboembolism

What conditions should be considered in patients with recurrent VTE? Important conditions to consider for recurrent VTE, despite therapeutic anticoagulation, include cancer (Trousseau’s syndrome), heparin- induced thrombocytopenia, antiphospholipid syndrome, and anatomic abnormalities contributing to extreme stasis (see Table X).

Table X.

Management of recurrent VTE

Pathophysiology

Venous thromboembolism can result from derangements in vessel wall integrity, hypercoagulability of the blood, or disruptions in blood flow that result in stasis. These three components have been termed "Virchow’s Triad" in honor of Rudolf Virchow, the 19th century German pathologist who made many seminal contributions to the understanding of the pathophysiology of VTE.

Vessel walls are lined with non-thrombogenic endothelial cells that are devoid of tissue factor and express several anti-thrombotic proteins (including tissue factor pathway inhibitor, thrombomodulin, tissue plasminogen activator, and prostacyclin). Disruption of the endothelium exposes subendothelial tissue factor that can trigger activation of the extrinsic arm of the coagulation cascade and collagen that promotes the adherence of von Willebrand factor and platelets.

Hypercoagulability of the blood underlies the excess risk of thrombosis experienced by patients who have inherited factor V Leiden, the prothrombin gene mutation, and the antithrombotic protein deficiency states of antithrombin, protein C, and protein S.

Stasis contributes to VTE risk by allowing activated forms of coagulation factors to accumulate and reach a concentration sufficient to promote blood clot formation. Most episodes of VTE involve disturbances in one or more components of "Virchow’s Triad".

Post-thrombotic syndrome results from venous hypertension that occurs as a consequence of obstructed blood flow due to residual thrombus, as well as damaged venous valves. Inflammation of vessel walls and venous valves also contributes to the pathogenesis of PTS.

What other clinical manifestations may help me to diagnose thrombosis/embolism?

Deep venous thrombosis can present with extremity pain, swelling, heaviness, and erythema. The pain is often described as being similar to a muscle cramp that does not resolve. Prominent venous collaterals on the extremity, chest, or abdomen can be seen in patients with chronic vascular occlusion/stenosis.

Pulmonary embolism can present with pleuritic chest or back pain, dyspnea, progressive dyspnea with exertion, fatigue, syncope, or sudden death.

Acute mesenteric venous thrombosis can present with severe abdominal pain and signs of peritonitis, nausea and vomiting. Subacute thrombosis presents with intermittent attacks of severe abdominal pain. Patients with chronic mesenteric thrombosis can present with a vague history of abdominal pain, abdominal swelling and signs/symptoms of portal hypertension (i.e., esophageal varices), and cavernous transformation of the portal vein.

Hepatic vein thrombosis presents with acute abdominal pain and swelling with signs of ascites on physical exam.

May-Thurner syndrome (iliac vein compression syndrome) presents with signs and symptoms of proximal left leg DVT with evidence of involvement of the iliac vein on imaging. Early diagnosis of this entity is essential to ensure prompt and complete clot lysis and stenting of the vascular stricture.

IVC thrombosis is commonly associated with the presence of IVC filters, vascular webs in the IVC and renal tumors with renal vein and IVC involvement. The clinical consequence is often bilateral lower extremity swelling, as well as swelling of the lower abdomen and pelvic/groin structures. "Doughy" body wall edema may occur up to the level of the umbilicus or higher. Chronic occlusion of the IVC results in the appearance of venous collaterals in the flanks in the abdominal wall, in addition to swelling below the level of the occlusion.

Thoracic outlet syndrome should be suspected when a patient presents with unexplained proximal upper extremity DVT (i.e., absence of a central venous catheter or known local tumor or nodal vascular compression). On exam, some patients will develop paresthesias or reductions of arterial pulse strength with extremity elevation. Duplex studies of the venous and arterial circulation with the arm at baseline and in stress positions are diagnostic. Prompt clot lysis and surgical correction are necessary to prevent recurrent thrombosis.

Cerebral venous sinus thrombosis presents with sudden onset of severe persistent headaches, mental status changes (confusion, lowered level of consciousness), nausea and vomiting, and visual changes (including blindness). Prompt evaluation by CT or MRI, anticoagulation with or without thrombolysis, and neuro-opthalmological exam are important for optimal outcome.

What other additional laboratory studies may be ordered?

In patients with unprovoked VTE, D-dimer studies can be used in conjunction with the Ottawa (Men Continue and HER DOO2) and Vienna Clinical Prediction rules to determine the risk of recurrent VTE after discontinuation of anticoagulation.

What’s the evidence?

Yusuf, HR, Tsai, J, Atrash, HK. "Venous thromboembolism in adult hospitalizations - United States, 2007 - 2009". MMWR. vol. 61. 2012. pp. 401-404.

(The most recent data on the healthcare burden of VTE in the United States.)

Kearon, C, Akl, EA, Ornelas, J. "Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report". Chest. vol. 149. 2016 Feb. pp. 315-52.

(The 10th ACCP Guideline on management of venous thromboembolism.)

Iorio, A, Kearon, C, Filippucci, E. "Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review". Arch Intern Med. vol. 170. 2010. pp. 1710-1716.

(An excellent comprehensive systematic review of the risk of recurrent VTE associated with idiopathic non-surgical and surgical-triggered episodes of VTE.)

Rodger, MA, Kahn, SR, Wells, PS. "Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy". CMAJ. vol. 179. 2008. pp. 417-426.

(The original clinical study used to develop the Ottawa Risk Assessment Model for quantifying the risk of recurrent VTE in patients with idiopathic VTE.)

Eichinger, S, Heinze, G, Jandeck, LM, Kyrle, PA. "Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model". Circulation. vol. 121. 2010. pp. 1630-1636.

(The original study that developed the Vienna Risk Model for patients with idiopathic VTE.)

Enden, T, Haig, Y, Kløw, NE. "Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial". Lancet. vol. 379. 2012. pp. 31-38.

(The first randomized controlled trial of catheter-directed thrombolysis in the treatment of iliofemoral DVT. It demonstrated that DCT was associated with a reduction in post-thrombotic syndrome.)

Meyer, G, Vicaut, E, Danays, T. "Fibrinolysis for patients with intermediate-risk pulmonary embolism". N Engl J Med. vol. 370. 2014. pp. 1402-1411.

(The PEITHO study demonstrated that tenecteplase plus anticoagulation was not associated with a reduction in all cause mortality but was associated with an increase in stroke compared with placebo plus anticoagulation.)

Carrier, M, Lazo-Langner, A, Shivakumar, S, Tagalakis, V, Zarychanski, R, Solymoss, S, Routhier, N, Douketis, J, Danovitch, K, Lee, AY, Le Gal, G, Wells, PS, Corsi, DJ, Ramsay, T, Coyle, D, Chagnon, I, Kassam, Z, Tao, H, Rodger, MA. "SOME Investigators. Screening for Occult Cancer in Unprovoked Venous Thromboembolism". N Engl J Med. vol. 373. 2015 Aug 20. pp. 697-1932..

(The SOME trial demonstrated that routine screening CT of the abdomen and pelvis was not associated with clinically meaningful benefits in patients with unprovoked VTE.)

Decousus, H, Prandoni, P, Mismetti, P. "Fondaparinux for the treatment of superficial-vein thrombosis in the legs". N Engl J Med. vol. 363. 2010. pp. 1222-1232.

(This large double-blind randomized controlled trial demonstrated that low dose fondaparinux was superior to placebo for treatment of superficial venous thrombophlebitis establishing anticoagulation as the preferred approach to therapy.)

Agnelli, G, Buller, HR, Cohen, A. "Oral apixaban for the treatment of acute venous thromboembolism". N Engl J Med. vol. 369. 2013. pp. 799-808.

(This double-blind randomized controlled trial demonstrated that apixaban was as effective as enoxaparin/warfarin in the treatment of acute VTE. It establishes apixaban as single-drug option for acute VTE without the need for parenteral therapy.)

Agnelli, G, Buller, HR, Cohen, A. "Apixaban for extended treatment of venous thromboembolism". N Engl J Med. vol. 368. 2013. pp. 699-708.

(This double-blind RCT demonstrated that Apixaban 2.5 mg BID and 5 mg BID were more effective than placebo in the extended treatment of VTE. Apixaban 2.5 mg BID was as safe as placebo in the study.)

Bauersachs, R, Berkowitz, SD, Brenner, B. "Oral rivaroxaban for symptomatic venous thromboembolism". N Engl J Med. vol. 363. 2010. pp. 2499-2510.

(This open-label randomized controlled trial demonstrated that oral rivaroxaban was equivalent to enoxaparin/warfarin in the treatment of acute VTE. The extended treatment portion of the study demonstrated that rivaroxaban was superior to placebo in the long term treatment of VTE. These data demonstrate that rivaroxaban is a one drug strategy for acute and long term treatment of VTE.)

Schulman, S, Kearon, C, Kakkar, AK. "Dabigatran versus warfarin in the treatment of acute venous thromboembolism". N Engl J Med. vol. 361. 2009. pp. 2342-2352.

(Schulman and colleagues demonstrated that dabigatran was as effective as warfarin in the treatment of acute VTE. In contrast to the apixaban and rivaroxaban studies, all patients in the dabigatran study received parenteral treatment for 5-10 days prior to oral therapy.)

Schulman, S, Kearon, C, Kakkar, AK. "Extended use of dabigatran, warfarin, or placebo in venous thromboembolism". N Engl J Med. vol. 368. 2013. pp. 709-718.

(In two double-blind randomized clinical trials, dabigatran was compared to warfarin and placebo for extended therapy of VTE. Dabigatran was as effective as warfarin but associated with a lower risk of bleeding. Dabigatran was more effective than placebo for prevention of VTE but associated with 3 fold more bleeding complications.)

Simes, J, Becattini, C, Agnelli, G. "Aspirin for the Prevention of Recurrent Venous Thromboembolism: The INSPIRE Collaboration". Circulation. vol. 130. 2014. pp. 1062-1071.

(This meta-analysis of two recent large randomized clinical trials of aspirin for long term treatment of idiopathic VTE demonstrated that aspirin reduces the relative risk of recurrent VTE by 32% without increasing the risk of major bleeding.)

Büller, HR, Décousus, H. "Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism". N Engl J Med. vol. 369. 2013. pp. 1406-1415.

(In this large double-blind randomized controlled trial, edoxaban was demonstrated to be as effective as warfarin in the treatment of VTE. Similar to dabigatran, all patients on the study received at least 5-10 days of initial parenteral anticoagulation.)

Kahn, SR, Shapiro, S, Wells, PS. "Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial". Lancet. vol. 383. 2014. pp. 880-888.

(This innovative practice-changing double-blind randomized clinical trial refuted the long held belief that graduated compression stockings reduce the incidence of post-thrombotic syndrome.)

Holbrook, A, Schulman, S, Witt, DM. "Evidence-Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. vol. 141. 2012. pp. e152S-e184S.

(The latest version of the American College of Chest Physicians evidence-based guidelines on the management of vitamin K antagonist therapy.)

Bates, SM, Greer, IA, Middeldorp, S, Veenstra, DL, Prabulos, AM, Vandvik, PO. "American College of Chest Physician. Venous thromboembolism, antithrombotic therapy and pregnancy. Antithrombotic therapy and prevention of thrombosis, 9th edition. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest.. vol. 141. 2012. pp. e691S-736S..

(The most recent ACCP guideline on VTE during pregnancy and its management.)
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