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Last Updated: 6/13/2014  

Deep Venous Thrombosis

Prevention
  • Use low-dose subcutaneous unfractionated heparin, LMWH, or fondaparinux for primary prophylaxis for DVT in high-risk medical patients and surgical patients not at highest risk for venous thromboembolism.

  • Use warfarin or LMWH for primary prophylaxis for DVT in patients having hip or knee replacement, neurosurgery, or major abdominal or pelvic surgery, and patients over age 40 having general surgery for malignancy.

  • In patients undergoing hip or knee replacements, consider oral rivaroxaban as an alternative for primary prophylaxis.

  • Use mechanical compression with graduated compression stockings for primary prophylaxis against postoperative DVT.

Diagnosis
  • Categorize patients as high-, intermediate-, or low-risk, according to the Wells clinical score.

  • Perform D-dimer testing to exclude DVT in patients with a low clinical risk score.

  • Select venous ultrasonography in patients with an intermediate or high clinical risk score or a positive D-dimer result.

Therapy
  • Use LMWH as a first-line therapy for DVT in hospitalized patients and outpatients.

  • Use long-term warfarin in patients with acute VTE, beginning on the day parenteral therapy is initiated.

  • Treat patients with DVT with warfarin for at least 3 to 6 months; consider longer treatment in patients with idiopathic DVT.

  • Recommend graduated compression stockings to patients with DVT to reduce risk for postthrombotic syndrome.

  • Use LMWH for secondary prevention of VTE in patients with underlying cancer.

Consider low-dose subcutaneous unfractionated heparin, LMWH, or fondaparinux for primary prophylaxis for DVT in high-risk medical patients and in all surgical patients except those at highest risk for DVT. 
  • In hospitalized medical patients, the decision to initiate prophylaxis should be individualized based on risk for VTE and bleeding.

  • Except for patients having procedures associated with the highest risk for DVT (e.g., hip or knee replacement and neurosurgery):

    • If using unfractionated heparin, administer 5000 U preoperatively and then every 8 to 12 hours postoperatively

    • Determine whether to dose heparin every 8 or 12 hours by weighing thrombotic risk against bleeding risk

    • Note that prophylaxis is contraindicated in patients with heparin-induced thrombocytopenia or active bleeding

    • Use LMWH or fondaparinux as alternatives to unfractionated heparin

    • High-risk medical patients include those expected to be in bed for 3 days or more with another risk factor (history of VTE, cancer, high-risk medication, recent pregnancy, sepsis, acute neurologic disease, chronic inflammatory disease)

  • See table Risk Factors for Thromboembolism and Bleeding.

Evidence
  • Guidelines from NICE in the UK (1) and the American College of Chest Physicians (2) recommend prophylaxis as described above.

  • A 2012 guideline from the American College of Chest Physicians recommended heparin, LMWH, or fondaparinux for prophylaxis for thromboembolic disease (3).

  • A 2013 systematic review of routine prophylaxis compared to placebo for VTE in hospitalized frail elderly patients included three randomized trials. In patients over age 75, prophylaxis reduced VTE events (OR, 0.33 [CI, 0.13 to 0.84]), but many of the events were asymptomatic. There were no differences in mortality or bleeding between groups (4; 5).

  • A meta-analysis of 33 randomized, controlled trials with 33,813 patients having general surgery found that pharmacologic prophylaxis was associated with the following rates of minor complications: injection-site bruising (6.9%), wound hematoma (5.7%), drain-site bleeding (2.0%), and hematuria (1.6%). Major bleeding complications, such as GI tract (0.2%) or retroperitoneal (<0.1%) bleeding, were infrequent (6).

  • A meta-analysis of 12 studies comparing twice-daily to thrice-daily administration of subcutaneous unfractionated heparin in 7978 patients showed that, after adjustment for baseline risk, there was no difference in the overall rate (per 1000 patient-days) of VTE (5.4 for twice daily vs. 3.5 for thrice daily, P=0.87). Thrice-daily heparin showed a trend toward a decrease in PE (1.5 for twice daily vs. 0.5 for thrice daily, P=0.09) and in proximal DVT and PE (2.3 for twice daily vs. 0.9 for thrice daily, P=0.05). The risk for major bleeding was significantly increased with thrice-daily heparin (0.35 for twice daily vs. 0.96 for thrice daily, P<0.001) (7).

  • A meta-analysis of nine studies (n=19,958) of anticoagulant prophylaxis compared with no treatment, in at-risk medical patients showed that during anticoagulant prophylaxis, patients had significant reductions in any PE (RR, 0.43 [CI, 0.26 to 0.71]; absolute risk reduction, 0.29%; NNT for benefit, 345) and fatal PE (RR, 0.38 [CI, 0.21 to 0.69]; absolute risk reduction, 0.25%; NNT for benefit, 400), a nonsignificant reduction in symptomatic DVT (RR, 0.47 [CI, 0.22 to 1.00]), and a nonsignificant increase in major bleeding (RR, 1.32 [CI, 0.73 to 2.37]). Anticoagulant prophylaxis had no effect on all-cause mortality (RR, 0.97 [CI, 0.79 to 1.19]) (8).

  • A meta-analysis of randomized trials in hospitalized medical patients showed that compared with placebo, LMWH reduced the risk for DVT and PE (RR, 0.56 [CI, 0.45 to 0.70]; RR, 0.37 [CI, 0.21 to 0.64], respectively) (9).

  • A meta-analysis of randomized trials in hospitalized medical patients showed no difference between heparin and LMWH for mortality (RR, 0.91 [CI, 0.73 to 1.13]), PE (RR, 0.70 [CI, 0.44 to 1.11]), or major bleeding (RR, 0.89 [CI, 0.70 to 1.15]) (10).

  • A meta-analysis of the use of heparin in general medical patients (excluding stroke and myocardial infarction) showed a risk reduction in DVT (RR, 0.40 [CI, 0.31 to 0.53]; P<0.00001) and PE (RR, 0.58 [CI, 0.43 to 0.80]; P=0.0007) but also an increase in major hemorrhage (RR, 2.18 [CI, 1.28 to 3.72]; P=0.004) and minor hemorrhage (RR, 1.74 [CI, 1.26 to 2.41]; P=0.0008) compared with placebo or no treatment (11).

  • A meta-analysis of 12 randomized trials of prophylactic LMWH for patients having neurosurgical procedures showed LMWH to be effective in reducing the rate of DVT (RR, 0.60 [CI, 0.44 to 0.81]) (12).

  • A meta-analysis of 14 randomized trials comparing LMWH with unfractionated heparin in perioperative patients with cancer showed no differences in mortality (RR, 0.89 [CI, 0.61 to 1.28]) or in clinically suspected DVT (RR, 0.73 [CI, 0.23 to 2.28]) (13).

  • In a randomized study of over 4000 postoperative patients, low-dose unfractionated heparin reduced the risk for fatal PE from 0.7% to 0.1% (14). A review (15) and a meta-analysis (16) have confirmed this finding.

Rationale
  • Prophylaxis with unfractionated heparin or LMWH reduces the risk for PE and DVT.

  • Bleeding complications requiring a change in care are uncommon following postoperative pharmacologic DVT prophylaxis.

  • Twice-daily heparin dosing causes fewer major bleeding episodes, whereas thrice-daily dosing appears to offer somewhat better efficacy in preventing clinically relevant thrombotic events.

  • Compared with unfractionated heparin, LMWH is associated with a lower risk for DVT and injection-site hematoma, but no difference in the risk for bleeding or thrombocytopenia.

Comments
  • The following factors appear to be independently associated with an increased risk for postoperative VTE: female gender, higher American Society of Anesthesiologists class, ventilator dependence, preoperative dyspnea, disseminated cancer, chemotherapy within 30 days, >4 U packed erythrocyte transfusion in the 72 hours before surgery, preoperative laboratory values (albumin <3.5 mg/dL, bilirubin >1.0 mg/dL, sodium >145 mmol/L, and hematocrit >38%), and operative characteristics (type of surgical procedure, emergency operation, work relative value units, and infected/contaminated wounds) (17).

Consider warfarin or LMWH for primary prophylaxis for DVT in patients having hip or knee replacement, neurosurgery, or major abdominal or pelvic surgery; patients aged over 40 having general surgery for malignancy; and patients with an inhibitor deficiency state. In patients undergoing hip or knee replacements, consider oral rivaroxaban as well for primary prophylaxis. 
  • In patients having hip or knee replacement, neurosurgery, or major abdominal or pelvic surgery, administer LMWH or warfarin to reach a target INR of 1.8 to 3:

    • Enoxaparin: 40 mg subcutaneously once daily

    • Dalteparin: 2500 U daily for abdominal surgery; 5000 U daily for high-risk patients

    • Danaparoid: 750 U subcutaneously every 12 hours

    • Ardeparin: 50 U/kg subcutaneously every 12 hours

  • In patients undergoing elective knee replacement, prophylaxis with LMWH may be initiated 12 to 48 hours postoperatively.

  • In patients undergoing hip or knee replacement, consider primary prophylaxis with rivaroxaban, 10 mg/d.

  • In patients undergoing hip or knee replacement, continue prophylaxis for 10 to 35 days after surgery.

Evidence
  • A 2008 guideline from the American College of Chest Physicians (2) recommended prophylaxis for at least 10 days in patients with knee replacement and for 35 days in patients with hip replacement.

  • Randomized trials and meta-analysis show superior efficacy of LMWH over unfractionated heparin (18).

  • The incidence of adverse effects is low and not significantly different between warfarin and LMWH (19; 20).

  • In a comparison of enoxaparin and unfractionated heparin (7500 U subcutaneously every 12 hours), the rate of DVT was 19% for enoxaparin and 23% for unfractionated heparin (P <0.2). Enoxaparin was associated with a lower frequency of bleeding complications (5.1% vs. 9.3%, P<0.05) (21; 22).

  • A meta-analysis showed that short-duration prophylaxis (within 3 months of the procedure) after total hip or knee replacement is effective in preventing symptomatic outcomes of VTE (23). The 3-month incidence of nonfatal VTE was 3.2% (CI, 2.0% to 4.4%), and the 3-month incidence of fatal PE was 0.10% (CI, 0.02% to 0.20%).

  • A systematic review showed no convincing evidence that starting LMWH preoperatively in elective hip replacement is associated with a lower incidence of VTE than starting postoperatively (24). Perioperative regimens of LMWH may lower the risk for postoperative thrombosis in elective hip replacement, but the positive effect is offset by an increase in major postoperative bleeding.

  • Two randomized trials (n=4541 and n=2509) comparing oral rivaroxaban, 10 mg/d, with subcutaneous enoxaparin, 40 mg/d, in patients having hip arthroplasty (25; 26) and two randomized trials (N=2531 and N=3148) comparing oral rivaroxaban, 10 mg/d, with subcutaneous enoxaparin, 30 mg/d or 40 mg/d, in patients having knee arthroplasty (27; 28) showed significant reductions in the composite primary end point of DVT, nonfatal PE, and all-cause mortality or major VTE in patients receiving rivaroxaban. There were no significant differences in the rate of bleeding between the arms of all four trials.

  • Meta-analysis of 14 trials of 27,360 patients having hip or knee replacement showed no difference in major VTE between direct thrombin inhibitors and LMWH (OR, 0.91 [CI, 0.69 to 1.19]). More total bleeding events were seen with direct thrombin inhibitors (ximelagatran and dabigatran but not desirudin) in patients having hip replacement (OR, 1.40 [CI, 1.06 to 1.85]) compared with LMWH. All-cause mortality was higher in the direct thrombin-inhibitor group when the reported follow-up events were included (OR, 2.06 [CI, 1.10 to 3.87]) (29).

Rationale
  • LMWH is more effective than and as safe as low-dose unfractionated heparin for prophylaxis for high-risk surgical patients.

  • Warfarin is a suitable substitute, particularly in orthopedic patients.

  • Trials suggest that oral rivaroxaban is more effective than LMWH in reducing VTE and has the same risk for bleeding.

Comments
  • LMWH is simpler to use than warfarin because it does not require laboratory monitoring. Preparations of LMWH differ in their biochemical and pharmacological properties; the clinical importance of these differences is unclear.

  • After major abdominal or pelvic surgery, prolonged thromboprophylaxis with LMWH significantly reduces the risk for thromboembolism compared with thromboprophylaxis during hospital admittance only, without increasing bleeding complications. A meta-analysis of four randomized trials showed that prolonged thromboprophylaxis reduced the risk for overall (OR, 0.41 [CI, 0.26 to 0.63]) and symptomatic (OR, 0.22 [CI, 0.06 to 0.80]) thromboembolism, without increasing the risk for bleeding (OR, 1.11 [CI, 0.62 to 1.97]) (30).

Consider thromboprophylaxis with LMWH for patients receiving lower-limb immobilization. 
  • Consider thromboprophylaxis with LMWH for patients receiving lower-limb immobilization, taking into account other risk factors for thromboembolism and anticipated duration and extent of immobilization.

  • Consider giving patients in a plaster cast receiving lower-limb immobilization daily subcutaneous injections of LMWH to reduce the risk for thromboembolism.

Evidence
  • A meta-analysis of six randomized trials with 1490 patients showed that daily subcutaneous injections of LMWH reduced the risk for symptomatic or asymptomatic thromboembolism (OR, 0.49 [CI, 0.34 to 0.72]). Symptomatic VTE was recorded in 2 of 658 (0.3%) patients receiving LMWH and 16 of 645 (2.5%) in the control group (OR, 0.16 [CI, 0.05 to 0.56]) (31).

Rationale
  • Lower-limb immobilization is associated with an increased risk for VTE that can be reduced by LMWH.

Comments
  • Current evidence has not shown a clear overall benefit to patients, and the cost-effectiveness of treatment is not established. Most current guidelines do not recommend thromboprophylaxis for patients with lower-limb immobilization, so treatment decisions should be made on a case-by-case basis taking other risk factors into account.

Use mechanical compression with graduated compression stockings for primary prophylaxis against postoperative DVT, but not for patients with stroke. 
  • In the absence of a clear contraindication (such as severe peripheral arterial disease), use mechanical compression with graduated compression stockings.

  • Do not use graduated compression stockings for DVT prophylaxis in patients with stroke.

Evidence
  • A meta-analysis has shown that mechanical compression methods reduce the risk for DVT in postoperative patients by about two thirds when used as monotherapy and by about half when added to a pharmacologic method. These benefits are similar irrespective of the particular method used (graduated compression stockings, intermittent pneumatic compression, or foot pumps) and are similar in each of the surgical groups studied (32).

  • A meta-analysis of 18 trials of graduated compression stockings showed that the rate of DVT identified by testing on follow-up was 13% compared with 26% with no treatment (OR, 0.35 [CI, 0.26 to 0.47]). Graduated compression stockings were also effective when used alongside another method (4% vs. 16%; OR, 0.25 [CI, 0.17 to 0.36]) (33).

  • A randomized trial in 2518 patients admitted to the hospital within 1 week of acute stroke showed that graduated compression stockings were associated with a nonsignificant 0.5% absolute reduction in the risk for symptomatic or asymptomatic DVT (10.5% vs. 10.0% [CI, -1.9% to 2.9%]) and an increase in the risk for skin breaks, ulcers, blisters, or skin necrosis (5% vs. 1%; OR, 4.18 [CI, 2.40 to 7.27]) (34).

Rationale
  • Mechanical compression reduces venous stasis caused by immobilization during the postoperative period.

Consider below-knee compression stockings for individuals at high risk for DVT going on long-haul flights, and suggest frequent ambulation during the flight. Consider LMWH before departure for very high-risk patients. 
  • Consider below-knee compression stockings producing 14 to 17 mm Hg pressure starting 2 to 3 hours before flight for individuals at low to medium risk for DVT.

  • For patients at very high risk for DVT, consider a single dose of LMWH subcutaneously 2 to 4 hours before the flight in addition to compression stockings.

Evidence
  • A 2012 clinical practice guideline from the American College of Chest Physicians recommended frequent ambulation for patients on long-haul flights and below the knee compression stockings for high-risk patients. The guideline does not recommend LMWH for high-risk patients (3).

  • The LONFLIT3 study was a randomized, controlled trial of aspirin vs. LMWH in high-risk subjects going on long-haul flights. There were no DVTs in the LMWH group (n=82), however there were 4.8% DVTs in the control group (n=82), and 3.6% DVTs in the aspirin group (n=84) (35).

  • A meta-analysis of 10 randomized trials showed that wearing compression stockings reduced the risk for symptomless DVT (OR, 0.10 [CI, 0.04 to 0.25]; P<0.001). The effect of compression stockings on symptomatic DVT, PE, and death is not known because no such events occurred in the trials (36).

Rationale
  • Long-haul flights increase the risk for DVT, and compression stockings and LMWH are used for prophylaxis and treatment of DVT.

Recognize that prophylaxis for DVT in high-risk patients is more effective than screening high-risk, asymptomatic patients. 
  • Initiate primary prophylaxis for patients at high risk for DVT without screening with venography or ultrasonography; patients with ongoing risk for DVT should continue prophylaxis with warfarin or LMWH.

  • Consider ultrasonographic imaging to evaluate for DVT in high-risk patients for whom anticoagulation is contraindicated because of a high risk for bleeding.

  • Place an inferior vena cava filter in a patient at high risk for or with active bleeding if accurate, objective testing confirms the presence of DVT.

Evidence
  • Ultrasonographic imaging has low sensitivity for detecting asymptomatic DVT in high-risk postoperative patients (37; 38).

  • In postoperative asymptomatic patients, no screening methods for DVT have been shown to reduce the incidence of subsequent venous thrombosis (19).

Rationale
  • Noninvasive diagnostic tests, such as impedance plethysmography or ultrasonography, are not routinely recommended because these tests are insensitive and expensive and are not associated with improved clinical outcome.

Evaluate patients with edema, pain (particularly in the calf), and leg cyanosis for possible DVT. 
  • Obtain a detailed history of symptoms and risk factors, and perform a physical examination.

  • Specifically identify any current malignancy, past history of DVT, recent immobilization, or surgery and measure any difference in calf diameter.

    • A history of malignancy is slightly predictive of DVT, with positive LR of 2.71

    • Recent prolonged (>3 day) immobilization or recent prolonged air travel (>7 hours) are slightly predictive of DVT, with positive LR of 1.98

    • A history of DVT is slightly predictive of DVT with positive LR of 2.25

  • Examine peripheral pulses and look for cyanosis, edema, warmth, tenderness, dilated peripheral veins and Homan's sign. Blue discoloration associated with DVT is called phlegmasia cerulea dolens.

    • Difference in calf diameter is slightly predictive of DVT with positive LR of 1.80, and absence of asymmetric swelling is slightly predictive of the absence of DVT, with negative LR of 0.57.

Evidence
  • In a meta-analysis of cohort studies of patients with known malignancy, a past history of DVT, recent immobilization or surgery, and difference in calf diameter increase the likelihood of DVT slightly, whereas absence of a difference in calf diameter reduces the likelihood of DVT slightly (39). Other clinical features do not appear to be helpful in diagnosis. The Wells prediction rule performed better than individual clinical findings.

Rationale
  • The presence or absence of certain clinical features may increase or decrease the likelihood of DVT and guide subsequent diagnostic testing.

Comments
  • DVT diagnosis should not be based on clinical assessment alone.

Categorize patients as high-, intermediate-, or low-risk, according to the Wells clinical score. 
Evidence
  • Wells score has been shown to stratify risk in patients with proximal DVT in more than 20 studies, according to a meta-analysis (39).

Rationale
  • Clinical scoring allows patients to be selected for appropriate diagnostic testing.

  • Patients at high risk require definitive testing with ultrasonography or venography.

  • d-dimer may be adequate to rule out DVT in patients at low or intermediate risk.

Comments
  • The accuracy of Wells score varies substantially between studies.

  • The Wells score does not accurately risk-stratify distal DVT (39), has not been validated in certain groups (such as IV drug abusers).

  • A validation study of 1295 patients in 110 primary-care practices suggested that the Wells score performs less well in excluding DVT in primary care than secondary care (40). However, when combined with d-dimer, a validation study of 1002 patients in 300 primary care practices showed equivalent performance to a new primary care rule. A venous thromboembolic event occurred during follow-up in 7 patients with a low score and negative d-dimer finding, both with the Wells rule (7 of 447; 1.6% [CI, 0.7% to 3.3%]) and the primary care rule (7 of 495; 1.4% [CI, 0.6% to 3%]) (41).

  • A two-category version of the Wells score (high and low risk) has been proposed based on a clinical trial in which only 0.4% of the patients clinically judged unlikely to have DVT (low-risk) who had a negative d-dimer test had thromboembolic events. The authors concluded that ultrasonography could be omitted in such patients (42).

Perform d-dimer testing to exclude DVT in patients with a low clinical risk score, and understand the performance characteristics of available d-dimer assays. 
  • Measure d-dimer levels as the initial diagnostic test in patients with a low or intermediate probability of DVT.

  • Perform definitive testing for DVT with lower-extremity ultrasonography if d-dimer results are positive.

  • See table Laboratory and Other Studies for DVT.

Evidence
  • A systematic review showed that the ELISA and quantitative rapid ELISA d-dimer assays have sensitivity of 96% and low specificity for proximal DVT (43).

  • A 2007 guideline from the American Academy of Family Physicians and the American College of Physicians for the diagnosis of VTE in primary care recommended using d-dimer to rule out VTE in patients with low pre-test probability of disease, and using ultrasound in patients with intermediate or high pre-test probability of disease (44).

  • A meta-analysis of 97 studies reporting on 198 assays found that d-dimer specificity varies with pretest clinical probability of DVT. d-dimer specificity is dependent on clinical probability of DVT: Specificity is lower among patients with a high clinical probability (45).

  • The combination of low clinical probability and negative d-dimer effectively excludes DVT, according to a systematic review of 12 studies. The Simple RED d-dimer test when negative excluded DVT in patients with low clinical probability, whereas more sensitive assays did so in those with low or moderate probability (46).

  • A systematic review of 23 studies (n=13,959) of two qualitative point-of-care d-dimer tests (SimpliRED d-dimer [n=12] and Clearview Simplify d-dimer [n=7]) and two quantitative point-of-care d-dimer tests (Cardiac d-dimer [n=4] and Triage d-dimer [n=2]) showed that overall sensitivity ranged from 0.85 [CI, 0.78 to 0.90] to 0.96 [CI, 0.91 to 0.98] and overall specificity from 0.48 [CI., 0.33 to 0.62] to 0.74 [CI, 0.69 to 0.78]. The results were significantly affected by the pretest clinical probability of VTE, with the lowest post-test probability of VTE in low-risk patients (47).

Rationale
  • d-dimer has good sensitivity but poor specificity for proximal DVT.

  • d-dimer has better test characteristics and is more useful in patients with a lower clinical probability of DVT.

Comments
  • ELISA assays have higher sensitivity and lower specificity. Whole blood agglutination assays have lower sensitivity and higher specificity (43).

  • d-dimer sensitivity may be lower in pregnant patients, anticoagulated patients, and those with a prolonged history (45).

  • d-dimer specificity may be lower in patients with malignancy, pregnant patients, anticoagulated patients, and those with a past history of DVT (45).

  • Point-of-care d-dimer testing may be used in primary care to exclude DVT in patients with a low or intermediate clinical risk.

Select venous ultrasonography in patients with an intermediate or high clinical risk score or a positive d-dimer result (or all patients if d-dimer is unavailable or unreliable). 
  • Select venous ultrasonography in patients with an intermediate or high clinical score or a positive d-dimer result, or if d-dimer is unavailable or if the assay is unreliable.

  • Duplex Doppler ultrasound has sensitivity of 92% and specificity of 94% for the diagnosis of DVT.

  • See table Laboratory and Other Studies for DVT.

Evidence
  • According to a systematic review and meta-analysis of 100 cohort studies, venous ultrasonography has a high sensitivity and specificity for detecting proximal venous thrombosis but is less sensitive for the detection of calf-vein than proximal DVT (48).

  • Ultrasonography yields fewer false-positive results than impedance plethysmography (49).

  • A randomized trial of 2465 patients with suspected first episode of symptomatic DVT compared two-point ultrasonography of the proximal veins to whole-leg ultrasonography. Symptomatic VTE occurred in 7 of 801 patients (incidence, 0.9% [CI, 0.3% to 1.8%]), with negative results in the two-point strategy group and in 9 of 763 patients (incidence, 1.2% [CI, 0.5% to 2.2%]) with negative results in the whole-leg strategy group (50).

Rationale
  • Ultrasonography is highly sensitive and specific for detection of proximal (popliteal or above) DVT.

  • About 1% to 2% of patients with a normal initial ultrasonography have calf-vein thrombosis that is destined to extend into the proximal veins, generally within 5 to 8 days.

Comments
  • Duplex ultrasonography using compression ultrasonography and color-flow Doppler has higher sensitivity for detecting distal DVT but slightly lower specificity than ultrasonography using compression ultrasonography alone (48).

Consider plethysmography as an alternative to venous ultrasonography if venous ultrasonography is not available. 
  • Obtain impedance or strain-gauge plethysmography as a noninvasive study for DVT if venous ultrasonographic testing is not available, although sensitivity is lower at 75% with specificity of 90%.

  • If the initial test result is normal, obtain serial testing.

  • Recognize that in patients with peripheral arterial disease, congestive heart failure, or venous outflow obstruction due to pelvic mass or pregnancy, plethysmography may yield false-positive results.

  • See table Laboratory and Other Studies for DVT.

Evidence
  • A meta-analysis of prospective cohort studies considering both accuracy of testing compared with contrast venography and management in the safety of withholding anticoagulation in patients with normal results showed that the sensitivity for detecting proximal DVT with impedance plethysmography was 92% and for distal DVT was 42%, and the specificity was 92% (51).

  • A meta-analysis showed that impedance plethysmography has a sensitivity of 88% for proximal DVT and 28% for distal DVT, and a specificity of 90%, and that strain-gauge plethysmography has a sensitivity of 90% for proximal DVT and 56% for distal DVT, and a specificity of 81% (52).

  • In a trial of 107 patients with isolated calf muscle vein thrombosis, 54 were randomly assigned to LMWH and compression therapy and 53 to compression therapy alone. Progression to DVT occurred in 2 patients in each group with no PE or death (53).

Rationale
  • Impedance plethysmography measures the impedance of venous blood flow using electrodes applied to the leg.

  • Plethysmography has a limited role in diagnosis. Ultrasonography has superior sensitivity and specificity, whereas d-dimer provides a cheaper and more sensitive way of excluding DVT in low-risk patients.

  • Routine examination for isolated calf-vein thrombosis is not necessary because these are not reliably detected and treatment with anticoagulation does not appear to alter the risk for progression to proximal DVT or PE in low-risk patients.

  • Strain-gauge plethysmography measures changes in venous outflow and capacitance using a strain-gauge.

Comments
  • Plethysmography has a limited role in diagnosis. Ultrasonography has superior sensitivity and specificity, whereas d-dimer provides a cheaper and more sensitive way of excluding DVT in low-risk patients.

Consider MRV if the diagnosis is equivocal after ultrasonography or plethysmography. 
Evidence
  • A study of 85 patients comparing MRV with contrast venography found that MRV had a sensitivity of 100% and a specificity of 96% (54).

  • Direct MRI of clots appears capable of showing venographically diagnosed DVT. This MRI technique is noninvasive, quick, and repeatable and allows a survey of the whole lower-limb venous system (55).

Rationale
  • MRV allows direct imaging of thrombus.

Comments
  • Although the diagnostic accuracy of MRV compared with contrast venography is high, there are few outcome studies in which management decisions were based on the results of MRV.

Recognize that the differential diagnosis of DVT is extensive. 
Evidence
  • Several studies evaluated the clinical assessment of patients with suspected DVT and found that individual symptoms and signs are nonspecific and may relate to a variety of nonthrombotic disorders (56; 57; 58).

Rationale
  • Conditions, such as venous reflux and orthopedic problems, may mimic or accompany DVT.

Comments
  • Clinical suspicion confirmed with venous imaging allows for diagnosis of DVT.

Consider referring patients with persistent leg edema of unknown cause to a vascular medicine specialist. 
  • Obtain evaluation by a vascular specialist for patients with equivocal ultrasonographic or IPG results or with edema of unknown cause.

  • Recognize the expertise of the specialist in applying validated clinical models to estimate the probability of DVT vs. nonthrombotic causes of leg pain and to assess the need for invasive testing.

Evidence
  • Venous ultrasonography is much less reliable for the diagnosis of asymptomatic, isolated calf, and recurrent DVT than for the diagnosis of a first episode of proximal DVT in symptomatic patients, as noted in a review on this topic. Clinical evaluation of the probability of DVT or PE, preferably using a validated clinical model, complements venous ultrasonographic findings and helps identify patients who have DVT or who would benefit from additional (often invasive) diagnostic testing, such as venography (38).

Rationale
  • More accurate determination of pre-test probability for DVT may avert unnecessary invasive testing and increase the likelihood of arriving at a correct diagnosis.

Consult a specialist for patients with idiopathic DVT who require evaluation for a hypercoagulable state. 
  • Consider screening patients with a first episode of idiopathic DVT for thrombophilia, especially those aged under 50 and those with a family history of VTE, recurrent VTE, thrombosis in an unusual site, or life-threatening VTE.

  • See table Common Thrombophilias.

Evidence
  • A multicenter trial compared 6 months of oral anticoagulant therapy with anticoagulant therapy continued indefinitely in patients who had a second episode of VTE. Prophylactic oral anticoagulation that was continued for an indefinite period after a second episode of VTE was associated with a much lower rate of recurrence during 4 years of follow-up than was treatment for 6 months. However, there was a trend toward a higher risk for major hemorrhage when anticoagulation was continued indefinitely (59).

  • The two most common genetic polymorphisms that predispose to a first episode of VTE are factor V Leiden and prothrombin G20210A. However, the effect of these polymorphisms on the risk for recurrent VTE is unclear. A meta-analysis was done to obtain the best estimates of the relative risk for recurrent VTE associated with these genetic polymorphisms. Heterozygous factor V Leiden and prothrombin G20210A are each associated with a significantly increased risk for recurrent VTE after a first event, but the magnitude of the increase in risk is modest and by itself is unlikely to merit extended-duration anticoagulation. These data call into question the cost-effectiveness of routine testing for these common inherited thrombophilic polymorphisms among patients with a first episode of VTE (60).

  • A meta-analysis of 11 studies that evaluated the risk for recurrent VTE associated with the two most common genetic markers of hypercoagulability reported relative risks of 1.39 (CI, 1.15 to 1.67) for factor V Leiden and 1.20 (CI, 0.89 to 1.61) for prothrombin G20210A mutation (61).

Rationale
  • Markers of thrombophilia may be associated with a higher risk for recurrent DVT, and their presence could affect decisions about long-term treatment with anticoagulation.

Comments
  • Screening for thrombophilia is controversial for patients with a first episode of idiopathic DVT.

Refer patients requiring alternative drugs to a specialist with expertise in anticoagulation. 
  • Consult a specialist with expertise in using alternative drugs, such as hirudin, in patients with heparin-induced thrombocytopenia or in patients for whom treatment with warfarin is unsuccessful.

  • Consider obtaining specific advice on the use of ecarin clotting time to monitor anticoagulation in patients taking direct thrombin inhibitors.

Evidence
  • Hirudin is a safe and effective alternative for treatment of DVT in patients with HIT (62).

Rationale
  • Patients with heparin-induced thrombocytopenia and DVT tolerate alternative drugs, such as direct thrombin inhibitors.

  • Heparin can be given subcutaneously to patients unable to tolerate coumadin.

Recognize that VTE during pregnancy requires special monitoring and treatment. 
  • Recognize that the initial treatment of acute DVT is the same as that for nonpregnant patients, except warfarin is not given because of its teratogenic potential.

  • Continue unfractionated or LMWH therapy throughout pregnancy.

  • Consider switching to subcutaneous unfractionated heparin due to reports in nonpregnant patients describing a higher incidence of epidural hematoma with LMWH near the time of epidural catheter placement or removal.

  • Discontinue unfractionated heparin before delivery; unfractionated heparin is typically stopped at induction of labor.

  • Consider protamine sulfate for reversal of a markedly prolonged PTT at the time of spontaneous delivery or cesarean section.

  • Consider switching to danaparoid, a heparinoid with limited cross-reactivity with heparin, if heparin-induced thrombocytopenia develops.

  • Treat with warfarin for 4 to 6 weeks after delivery.

  • See module Thrombosis in Pregnancy

Evidence
  • A review of 486 pregnant patients treated with LMWH found that the number of adverse pregnancy outcomes was similar to that in the general population (63).

  • Two reviews address the use of antithrombotic agents in pregnancy (64; 65).

  • Two reports describe epidural hematoma with LMWH therapy associated with epidural catheter removal (66; 67).

Rationale
  • Because pregnant patients should not receive warfarin, heparin is required throughout pregnancy.

Treat most patients with DVT as outpatients with LMWH unless they have signs and symptoms of pulmonary embolus or other risk factors for adverse outcomes. 
  • Hospitalize most patients with suspected PE.

  • Treat patients with DVT as outpatients, but consider hospitalization if one of more of the following risk factors for adverse outcome are present:

    • Bilateral DVT

    • Renal insufficiency

    • Body weight <70 kg

    • Recent immobility

    • Chronic heart failure

    • Cancer

  • See module Pulmonary Embolism.

Evidence
  • A systematic review of 13 studies comparing patients with VTE who are treated with LMWH administered at home with those treated with unfractionated heparin in the hospital found no difference in outcomes (68).

  • A study evaluating the cost-effectiveness of outpatient treatment for DVT found that treatment of acute proximal DVT at home with LMWH is less costly than hospital-based treatment with unfractionated heparin (69).

  • A registry study of outpatients treated for acute DVT showed that, on multivariate analysis, bilateral DVT, renal insufficiency, body weight <70 kg, recent immobility, chronic heart failure, and cancer were associated with an increased risk for adverse events. In the derivation sample, patients with up to two risk factors had a 1.2% incidence of adverse events (23 in 1935 patients) compared with the 6.8% incidence in those with three or more risk factors. These values were 1.0% and 4.7%, respectively, in the validation sample (70).

Rationale
  • Outpatient treatment has similar outcomes to inpatient treatment for DVT.

  • Outpatient treatment is cost-effective.

  • Risk factors for adverse outcome may be used to predict those patients requiring hospitalization.

Comments
  • Insurance coverage for outpatient treatment varies.

Use LMWH as a first-line therapy for DVT in hospitalized patients. 
  • Treat acute DVT with one of the following LMWH preparations:

    • Enoxaparin: 1 mg/kg subcutaneously every 12 hours, or 1.5 mg/kg subcutaneously every 24 hours

    • Tinzaparin: 175 IU/kg subcutaneously once daily

  • Consider fondaparinux for initial treatment of DVT.

  • Use unfractionated heparin in patients with renal insufficiency.

  • See table Drug Treatment for DVT.

Evidence
  • A 2012 guideline from the American College of Chest Physicians recommended once-daily LMWH or fondaparinux for initial treatment of DVT (3).

  • Seventeen systematic reviews of trials comparing LMWH to unfractionated IV heparin have been published between 1994 and 2003, of which 11 have pooled data. None showed unfractionated heparin to be superior to LMWH in preventing recurrent DVT. Patients treated with LMWH had fewer episodes of major bleeding than those treated with unfractionated heparin. All but 1 of 10 reviews showed that LMWH significantly reduced mortality during the 3 to 6 months of follow-up compared with unfractionated heparin (68).

  • Subcutaneous unfractionated heparin has been compared with LMWH in 15 randomized, controlled trials with a total of 3054 participants. A Cochrane meta-analysis showed that, compared with LMWH, unfractionated heparin was associated with no significant differences in recurrent DVT (OR, 1.68 [CI, 0.92 to 3.04]), PE (OR, 1.18 [CI, 0.54 to 2.56]), or major bleeding (OR, 0.66 [CI, 0.33 to 1.32]) over 3-month follow-up. Subcutaneous unfractionated heparin appears to be as safe as LMWH but cannot be considered non-inferior to LMWH in terms of recurrent DVT and PE (71).

Rationale
  • LMWH is superior to unfractionated heparin for the initial treatment of DVT, particularly for reducing mortality and reducing the risk for major bleeding during initial therapy.

Consider outpatient therapy using subcutaneous LMWH to treat acute DVT. 
  • Treat acute DVT with one of the following LMWH preparations:

    • Enoxaparin: 1 mg/kg subcutaneously every 12 hours, or 1.5 mg/kg subcutaneously every 24 hours

    • Tinzaparin: 175 IU/kg subcutaneously once daily

  • Ensure that patients are carefully selected and support services are in place.

  • Understand that brief inpatient admission may be necessary for initial stabilization.

Evidence
  • A 2012 guideline from the American College of Chest Physicians recommended once-daily LMWH or fondaparinux for initial treatment of DVT, and recommended initial treatment at home for patients with appropriate home situations (3).

  • A 2007 systematic review of 13 studies comparing patients with VTE treated with LMWH administered at home to those treated with unfractionated heparin in the hospital found no difference in outcomes. Most of the studies allowed a brief inpatient admission for stabilization before outpatient treatment, and most studies excluded patients with previous VTE, thrombophilic conditions, or significant comorbidity; pregnant patients; and patients unlikely to adhere to outpatient therapy. Nine of 10 studies reporting treatment costs suggested cost savings with outpatient therapy when compared with inpatient therapy (68).

Rationale
  • Outpatient treatment appears to be as safe as inpatient treatment, is more convenient for patients, and may be cheaper for health services.

  • Outpatient treatment is only appropriate for selected patients with limited comorbidities and requires support services to be in place.

Comments
  • A meta-analysis of five studies has shown that once-daily treatment with LMWH is as effective and safe as twice-daily treatment (72). However, evaluation of confidence intervals around the point estimates suggests that the risk for recurrent VTE may be higher in patients on once-daily treatment.

  • A randomized trial suggested that fixed-dose subcutaneous unfractionated heparin is as effective and safe as LMWH in patients with acute VTE and may be suitable for outpatients treatment (73).

  • A meta-analysis showed that the efficacy and safety of enoxaparin vs. unfractionated heparin for preventing VTE is not affected by the presence of symptomatic PE. After 3 months, the relative risk for recurrent VTE, major bleeding, and death was the same in patients with DVT whether or not they had concurrent symptomatic PE (74).

Use long-term warfarin in patients with acute VTE unless it is contraindicated, beginning on the day parenteral therapy is initiated. Treat patients with DVT with warfarin for at least 3 to 6 months, depending on the clinical situation. 
  • Begin warfarin (initial dose 5 to 10 mg) on the same day other therapy is initiated and determine duration of therapy based on patient risk factors.

  • Continue heparin or LMWH concomitantly with warfarin until the therapeutic potential of warfarin is achieved for 2 consecutive days.

  • Aim for an INR of 2 to 3.

  • Consider long-term LMWH as an alternative to oral anticoagulation in patients for whom warfarin is ineffective or intolerable or in patients with active cancer.

  • Consider self-management of oral anticoagulation with supervision in selected patients receiving long-term warfarin.

  • Treat patients with transient risk factors for 3 months; treat patients with idiopathic DVT for 3 months, then individualize further therapy.

  • Consider using d-dimer to individualize therapy after 3 months of warfarin. Patients with an elevated d-dimer benefit from continued anticoagulation; patients with a normal d-dimer are at low risk for recurrence.

  • See table Drug Treatment for DVT.

  • See table Recommendations for the Duration of Anticoagulant Therapy for Patients with DVT.

Evidence
  • A 2012 guideline from the American College of Chest Physicians recommended that patients with DVT provoked by surgery or another risk factor receive warfarin for 3 months and that patients with unprovoked DVT may be treated for at least 3 months and then reevaluated. The guideline recommended limiting the therapy to 3 months in patients with unprovoked DVT and high risk for bleeding, but recommended treating patients with low bleeding risk for longer (3).

  • A 2012 Cochrane review of warfarin or LMWH for long-term treatment of VTE included 15 randomized, controlled trials with 3197 participants. Overall, there was less bleeding (OR, 0.5 [CI, 0.31 to 0.79]) with LMWH compared to warfarin and a trend toward a lower risk of recurrent VTE (75).

  • Ten randomized trials have compared the safety and efficacy of LMWH vs. oral anticoagulation for treatment of VTE (68). All the trials either showed no difference in rates of recurrent VTE or bleeding, or favored LMWH.

  • A multicenter, randomized, open-label clinical trial compared LMWH to vitamin-K antagonist therapy for 3 months. Eighteen of 369 patients receiving tinzaparin (4.9%) had recurrent VTE at 3 months compared with 21 of 368 (5.7%) receiving usual care (absolute difference, -0.8% [CI, -4.1% to 2.4%]). Hemorrhagic complications occurred less frequently in the LMWH group largely because of less minor bleeding: 48 of 369 patients (13.0%) vs. 73 of 368 patients (19.8%) receiving usual-care anticoagulation (absolute difference, -6.8%; P=0.011; RR, 0.66) (76).

  • Two meta-analyses of trials evaluating the duration of anticoagulation for VTE have shown that patients who receive long-term anticoagulation are protected from recurrent VTE for as long as they are receiving therapy (77; 78). However, the absolute risk for recurrent VTE declines over time, whereas the risk for major bleeding remains. Thus, the efficacy of anticoagulation administration decreases over time since the index event (78).

  • A meta-analysis of seven trials, including 1888 patients who had completed at least 3 months of anticoagulation for a first episode of unprovoked VTE, showed that a negative d-dimer result was associated with a 3.5% annual risk for recurrent disease, whereas a positive d-dimer result was associated with an 8.9% annual risk for recurrence (79).

  • A randomized trial showed patients with an elevated d-dimer after 3 months of anticoagulation benefit from continued treatment. Patients with elevated d-dimers were randomized to receive continued anticoagulation or to discontinue; the primary endpoint was a composite of recurrent VTE and bleeding. After 18 months of follow-up, 15% of patients who stopped anticoagulation had events compared with 2.9% of patients who continued, resulting in an NNH of 12 (CI, 4 to 153) associated with stopping treatment. Patients with normal d-dimers discontinued treatment and had similar event rates to patients with high d-dimers who continued treatment (80; 81).

  • Administering a large loading dose of warfarin may result in excess anticoagulation and in a transient hypercoagulable state during the first 24 to 36 hours that is due to a decline in protein-C levels. A randomized trial of 49 patients given either 5 or 10 mg of warfarin showed no significant difference in reduction in the time course of factor II levels, but the 5-mg dose was less likely to produce excess anticoagulation. The lower dose was also associated with less decline in factor VII and protein-C levels (82).

  • In a study of 53 patients, 66% of patients receiving a 5-mg dose and 24% receiving a 10-mg dose of warfarin achieved a therapeutic INR that remained under 3.0 (83).

  • A systematic review and meta-analysis of 14 trials with a total of 3049 participants showed that self-monitoring of anticoagulation was associated with fewer thromboembolic events, fewer serious bleeds, and lower mortality than standard anticoagulation. However, self-monitoring is not feasible for all patients and requires identification and education of suitable candidates (84).

Rationale
  • Treatment with warfarin reduces the risk for recurrent DVT and pulmonary embolus.

  • Long-term LMWH is a safe and effective alternative for patients in whom oral anticoagulation is not appropriate.

  • Patients without an identifiable risk factor are more likely to have a recurrent venous thrombosis and should be treated for a minimum of 6 months with oral anticoagulation.

  • Patients with idiopathic DVT may benefit from 2 years or more of oral anticoagulation and that d-dimer may be used to guide decision-making.

Comments
  • The duration of anticoagulation for patients with no known risk factors for recurrence remains controversial. A randomized trial comparing 3 to 6 months of anticoagulation showed no significant difference in thrombotic events and an increased rate of major hemorrhage in patients receiving 6 months of anticoagulation (85). However, the trial failed to achieve target recruitment and was thus not adequately powered to demonstrate equivalence.

  • The anticoagulant potential of warfarin takes days to reach. Warfarin may initially create a paradoxical procoagulant state before full anticoagulation, hence the need to continue treatment with heparin until warfarin achieves its therapeutic potential.

  • The magnitude of drug interaction with warfarin is highly variable.

  • Long-term treatment with LMWH is associated with a lower risk of bleeding than treatment with warfarin but its cost and the inconvenience of injecting the medication make it a secondary choice.

  • A meta-analysis of 15 studies (9 randomized, controlled trials and 6 prospective, observational studies) showed that men seem to have a 50% higher risk than women for recurrent VTE after stopping anticoagulant treatment (86).

Consider recommending graduated compression stockings to reduce edema and possibly the risk for postthrombotic syndrome. 
  • Recommend compression stockings in patients with bothersome edema.

  • Consider recommending compression stockings to reduce the risk for postthrombotic syndrome, for patients for whom they are well tolerated.

    • Advise that compression stockings be used within 1 month of diagnosis of proximal DVT and continued for a minimum of 1 year.

    • Size graduated compression stocking to fit the patient's calf and to achieve a pressure of 20 to 30 mm Hg or 30 to 40 mm Hg.

    • Remind patients that compression stockings lose elasticity after 6 months of repeated use and may need to be replaced.

Evidence
  • A 2004 Cochrane review of nonpharmacologic measures for the prevention of postthrombotic syndrome after DVT included three randomized trials of compression stockings (using pressures of 20 to 30 mm Hg or 30 to 40 mm Hg). Overall, the compression stocking group had a lower rate of postthrombotic syndrome (OR, 0.31 [CI, 0.20 to 0.48]) and severe postthrombotic syndrome (OR, 0.39 [CI, 0.20 to 0.76]) (87).

  • A randomized trial compared elastic compression stockings (pressure, 30 to 40 mm Hg) to placebo stockings (pressure <5 mm Hg) in 806 patients with symptomatic proximal DVT. The rate of postthrombotic syndrome at 6 months or later was 14.2% in the active stocking group and 12.7% in the placebo stocking group (P=0.58), with similar severity in both groups (88).

  • A randomized trial compared below-the-knee compression stockings to no stockings in 180 patients hospitalized with a first DVT. The incidence of postthrombotic syndrome was lower in the stocking group at 6 months (21.1% vs. 40.0%), 1 year (22.2% vs. 46.7%), and 2 years (24.5% vs. 49.1%) (89).

Rationale
  • None.

Consider intravenous or catheter-directed thrombolysis in patients with iliofemoral DVT. 
  • Consider an intravenous or catheter-directed thrombolytic drug such as tissue plasminogen activator for patients with iliofemoral DVT.

  • Consider contraindications to thrombolysis carefully.

  • See table Drug Treatment for DVT.

Evidence
  • A 2004 Cochrane review identified 12 randomized, controlled trials with over 700 patients comparing thrombolysis vs. anticoagulation for acute DVT. Thrombolysis was associated with reduced postthrombotic syndrome (RR, 0.66 [CI, 0.47 to 0.94]), increased bleeding complications (RR, 1.73 [CI, 1.04 to 2.88]), and non-significant changes in leg ulceration (RR, 0.53 [CI, 0.12 to 2.43]), and venous function at late follow-up (RR, 2.33 [CI, 0.32 to 17.27]) (90). Note that the review was updated online in 2010 with the same included trials.

  • A randomized trial of 209 patients with first iliofemoral DVT showed that catheter-directed thrombolysis with alteplase was associated with reduced postthrombotic syndrome at 24 months (absolute risk reduction, 14.4% [CI, 0.2 to 27.9]; NNT, 7 [CI, 4 to 502]; P=0.047), but there were 20 bleeding complications related to catheter-directed thrombolysis (three major, five clinically relevant) compared to none in the control group (91).

Rationale
  • Thrombolysis with secondary venous patency probably reduces the risk for postthrombotic syndrome but is associated with an increased risk for bleeding.

  • Severe postthrombotic syndrome is probably more common in patients with iliofemoral-vein thrombosis.

Comments
  • An ongoing trial of catheter-directed thrombolysis in 692 patients with symptomatic proximal DVT will provide further evidence (92).

Consider hirudin for patients with heparin-induced thrombocytopenia. 
  • Avoid using all heparins and warfarin if HIT is suspected.

  • Use a direct thrombin inhibitor, such as lepirudin, to treat DVT in patients with HIT.

  • Monitor recombinant hirudin anticoagulation with ecarin clotting time assay.

  • See table Drug Treatment for DVT.

Evidence
  • Neither argatroban nor lepirudin has been evaluated in randomized studies of patients with HIT due to the lack of an appropriate, ethical comparator treatment. However, both agents have been shown to improve outcomes in nonrandomized studies (93; 94).

  • An analysis of three prospective, multicenter trials in patients with HIT compared 91 patients treated with lepirudin with 47 nonrandomized control patients. Treatment with lepirudin was associated with a reduction in a combined end point of limb amputation, thromboembolic complications, or death (19.8% vs. 29.9%, P=0.03), primarily because of a reduction in new thromboembolic complications (4.4% vs. 14.9%, P=0.02), and was associated with no significant difference in major bleeding episodes (14.3% vs. 8.5%, P=0.54) (93).

  • Another nonrandomized trial compared 418 patients treated with argatroban to 185 historical control patients. Treatment significantly reduced a combined end point of death, amputation, or new thrombosis (28.0% vs. 38.8%, P=0.04) (94).

  • Most authorities recommend a minimum of a 4-day overlap of recombinant hirudin with coumadin in HIT patients in order to reduce the risk for recurrent thrombosis and warfarin-induced limb gangrene (95).

  • Thrombolytic therapy can be accomplished safely in patients with a history of HIT receiving hirudin, but anticoagulant monitoring may be challenging (96).

  • The ecarin clotting time is a useful assay for monitoring recombinant hirudin anticoagulation (97).

Rationale
  • The direct thrombin inhibitors argatroban (a synthetic molecule derived from l-arginine) and lepirudin (a recombinant protein derived from leech hirudin) are not associated with HIT and, thus, can be safely used in patients with both DVT and HIT.

Use LMWH for secondary prevention of VTE in patients with underlying cancer. 
  • In patients with cancer and VTE, administer LMWH:

    • Enoxaparin, 1.5 mg/kg·d

Evidence
  • A meta-analysis of six randomized trials comparing LMWH with warfarin in patients with cancer and symptomatic, confirmed VTE showed no statistically significant survival benefit (hazard ratio, 0.96 [CI, 0.81 to 1.14]) but a statistically significant reduction in VTE (hazard ratio, 0.47 [CI, 0.32 to 0.71]). There was no statistically significant difference between LMWH and warfarin in bleeding outcomes (RR, 0.91 [CI, 0.64 to 1.31]) or thrombocytopenia (RR, 1.02 [CI, 0.60 to 1.74]) (98).

Rationale
  • For secondary prophylaxis of VTE in patients with cancer, LMWH reduces venous thromboembolic events, but not death, compared with warfarin.

Comments
  • Warfarin is associated with a high bleeding rate in patients with VTE and cancer (99).

Consider daily low-dose aspirin or other therapies for patients who have completed primary therapy for DVT. 
  • Consider aspirin, 81 mg/d, for patients who have completed primary therapy for DVT and have no contraindication to aspirin therapy.

  • Consider warfarin or LMWH for long-term therapy in select high-risk patients.

Evidence
  • A 2013 systematic review and network meta-analysis of oral anticoagulants and antiplatelet agents for the secondary prevention of venous thromboembolism included 11,999 patients in the efficacy analysis and 12,167 in the safety analysis, from 12 studies. Compared to placebo, standard adjusted dose vitamin K antagonists (OR, 0.07 [CI, 0.03 to 0.15]), low intensity vitamin K antagonists (OR, 0.28 [CI, 0.13 to 0.57]), dabigatran (OR, 0.09 [CI, 0.04 to 0.21]), apixaban, 5 mg bid (OR, 0.18 [CI, 0.08 to 0.38]), apixaban, 2.5 mg bid (OR, 0.17 [CI, 0.08 to 0.36]), and rivaroxaban (OR, 0.17 [CI, 0.06 to 0.4]) decreased the incidence of recurrent thromboembolism. Low-dose aspirin did not decrease the risk of recurrent thromboembolism (OR, 0.65 [CI, 0.39 to 1.03]). Standard adjusted dose vitamin K antagonists (OR, 5.24 [CI, 1.78 to 18.25]), low-intensity vitamin K antagonists (OR, 4.77 [CI, 1.38 to 19.49]), and rivaroxaban (OR, 20.79 [CI, 1.31 to 14,000) increased the risk for major bleeding (100).

  • A 2012 randomized, controlled trial compared aspirin, 100 mg/d, to placebo in 402 patients who had completed 6 to 18 months of oral anticoagulation for a first DVT. After 2 years of follow-up, the rate of recurrent VTE was lower in the aspirin group with NNT of 12. Adverse events including bleeding did not differ between the groups (101).

  • A 2012 randomized, controlled trial compared aspirin, 100 mg/d, to placebo in 822 patients who had completed therapy for a first episode of unprovoked VTE. After 37 months follow-up, there was a nonsignificant trend toward reduced recurrent VTE in the aspirin group (6.5% in the placebo group vs. 4.8% in the aspirin group, P=0.09). There was a reduction in the secondary composite endpoint of VTE, MI, stroke, or cardiovascular death with aspirin (5.2%) compared with placebo (8%) with HR, 0.66 (CI, 0.48 to 0.92). There was no difference in the risk of bleeding in the groups (102).

Rationale
  • Even after treatment patients with history of VTE remain at increased risk.

Comments
  • The optimal long-term therapy for secondary prevention of VTE is not clear.

Inform patients about the mechanism of action of warfarin and caution them about diet and drug interactions. 
Evidence
  • Changes in dietary vitamin-K intake can cause the INR to fluctuate (103).

  • Warfarin is metabolized by the cytochrome CYP2C (P450IIC) isoenzyme that is induced by anticonvulsants and other drugs. Coadministration of these drugs enhances warfarin clearance and thus increases the dose required for adequate anticoagulation (104).

  • Numerous other drugs inhibit warfarin metabolism (105).

Rationale
  • Control of vitamin-K intake reduces large fluctuations in INR.

  • Alerting the physician responsible for INR adjustment to medication changes will allow him or her to monitor for potential drug interactions.

Comments
  • The magnitude of drug interaction is highly variable.

Monitor ongoing anticoagulation for the duration of therapy in patients with DVT. Treat all patients with DVT for at least 3 months; consider longer treatment in patients with idiopathic DVT. 
  • Monitor INR every 4 weeks for the duration of warfarin therapy, once the level of anticoagulation is stable.

  • Consider patient self-testing or self-management of INR in appropriate patients.

  • Discontinue warfarin at full therapeutic doses after 3 to 6 months in patients with a first episode of proximal DVT, but consider long-term, low-dose warfarin (INR, 1.5 to 2) to prevent DVT recurrence.

  • Evaluate patients for postthrombotic syndrome.

Evidence
  • Treatment for 4 or 6 weeks resulted in recurrence rates higher than seen with either 12 or 26 weeks of therapy (106; 107; 108).

  • Patients without an identifiable risk factor are more likely to have hypercoagulability disorder and should generally be treated for 6 months (109).

  • A systematic review of self-testing and self-monitoring of oral anticoagulation in patients with DVT and other indications found that self-managed patients had lower rates of major thrombotic events (NNT, 61 [CI, 47 to 104])and all-cause mortality (NNT, 36 [CI, 25 to 73])(109; 110).

  • A randomized, controlled trial found that long-term, low-intensity warfarin is associated with a reduction in recurrent VTE of 76% to 81% as compared with placebo. If a composite end point of major hemorrhage, death, or thromboembolism is considered, then there is still a 48% reduction in risk. There was no significant difference between the placebo and warfarin groups with regard to major hemorrhage (111).

Rationale
  • A 3- to 6-month course of warfarin therapy for proximal DVT is associated with a lower rate of recurrence than are shorter courses of treatment.

  • Long-term (2 to 4 years), low-intensity warfarin (INR, 1.5 to 2) is associated with a lower rate of recurrence than shorter courses of treatment.

Monitor and treat patients for postthrombotic syndrome with compression stockings or intermittent compression. 
  • Ask patients about edema, extremity ulcers, and lower extremity pain, and look for swelling, telangectasias, or eczema on physical exam.

  • If the patient develops postthrombotic syndrome, instruct the patient to wear stockings and elevate feet when possible; consider recurrent DVT in differential diagnosis.

  • Note that outpatient pneumatic compression is usually reserved for patients who do not respond to foot elevation and stockings.

  • See figure Postphlebitic Syndrome Manifesting as Chronic Venous Stasis.

Evidence
  • A 2003 Cochrane review of compression therapy for postthrombotic syndrome included one crossover trial which compared lower to higher pressure intermittent compression, and one trial which compared elastic stockings (30 to 40 mm Hg) to placebo stocking (one size too large). The first study found that higher pressures improved symptoms and the second found no benefit from elastic stockings (112).

  • A randomized crossover trial compared therapeutic intermittent compression (50 mm Hg) to placebo compression (15 mm Hg) in 15 patients with severe postthrombotic syndrome. Symptom scores were significantly better with compression than with placebo compression (113).

  • A cohort study of 528 patients with a first episode of DVT who were treated with graduated compression stockings reported cumulative incidences of postthrombotic syndrome of 24.5%, 29.6%, and 29.8% at 2, 5, and 8 years, respectively (114).

  • A 2010 narrative review on postthrombotic syndrome noted that compression and leg elevation are the cornerstones of therapy (115).

Rationale
  • Postthrombotic syndrome is characterized by symptoms of recurrent pain and swelling and signs of stasis skin changes and ulceration.

Table Grahic Jump Location
 Laboratory and Other Studies for Suspected DVT

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TestSensitivity (%)Specificity (%)Likelihood Ratio PositiveLikelihood Ratio NegativeNotes
d-dimer (ELISA)All DVT: 94 Proximal: 98 Distal: 8645Usually used in combination with ultrasonography or clinical scoring. The laboratory results should be available within 2 hours of blood draw for adequate clinical utility
d-dimer (latex)All DVT: 89 Proximal: 94 Distal: 7955Usually used in combination with ultrasonography or clinical scoring. The laboratory results should be available within 2 hours of blood draw for adequate clinical utility
d-dimer (whole blood)All DVT: 87 Proximal: 84 Distal: 6468Usually used in combination with ultrasonography or clinical scoring. The laboratory results should be available within 2 hours of blood draw for adequate clinical utility
Duplex Doppler ultrasonographyAll DVT: 92 Proximal: 96 Distal: 7194Proximal: 19Proximal: 0.05Combines Doppler audio measurements of blood flow with visual ultrasonographic imaging
Compression ultrasonographyAll DVT: 90 Proximal: 94 Distal: 5798The compressibility of the proximal veins is assessed with the ultrasonographic probe
Impedance plethysmographyAll DVT: 75 Proximal: 88 Distal: 2890Proximal: 16Proximal: 0.09Impedance plethysmography measures the electrical resistance (impedance) in blood from changes in volume and flow rate in the leg with a pneumatic thigh cuff. This noninvasive test cannot distinguish acute DVT from other conditions that affect venous outflow, such as right-sided heart failure, peripheral arterial disease, or an external mass compressing the vein
Strain-gauge plethysmographyAll DVT: 83 Proximal: 90 Distal: 5681Uses a strain gauge around the calf to measure changes in venous outflow and capacitance after release of the tourniquet
Venography100100This test can be of limited value if there is poor contrast filling of the deep veins; however, it is the historical criterion standard for DVT
MRVAll DVT: 92 Proximal: 94 Distal: 6295MRV is more expensive than ultrasonographic imaging. Patients with such metal devices as pacemakers may not be able to have MRV imaging

DVT = deep venous thrombosis; ELISA = enzyme-linked immunosorbent assay; MRV = magnetic resonance venography.

Table Grahic Jump Location
 Differential Diagnosis of DVT

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DiseaseCharacteristics
DVTLower extremity edema, risk factors
Venous insufficiency (venous reflux)Usually due to venous hypertension from such causes as venous reflux or obesity
Obtain ultrasonographic evaluation of venous reflux
Superficial thrombophlebitisFirm, tender, varicose vein
Superficial thrombosis is rarely associated with DVT
Muscle strain, tear, or traumaPain occurring with range of motion more characteristic of orthopedic problem due to trauma. Usually history of leg injury.
Order appropriate radiologic studies to evaluate for orthopedic problem such as bone fracture
Leg swelling in a paralyzed limbHistory of paraplegia
Patients with a paralyzed limb may develop edema without DVT
Baker's cystFrequent pain localized to popliteal region of leg
Seen on ultrasonography
CellulitisSkin erythema and warmth
Consider antibiotic treatment
LymphedemaToe edema is more characteristic of lymphedema than of venous edema.
Lymphedema can occur in one or both legs

DVT = deep venous thrombosis.

Table Grahic Jump Location
 Drug Treatment for DVT

Swipe to view table

Drug or Drug ClassDosingSide EffectsPrecautionsClinical Use
FirstLineIconblackboxiconLow-molecular-weight heparinsThrombocytopenia, elevated hepatic enzymes, injection site reactions, allergic reactionsblackboxicon Spinal or epidural hematomas with neuraxial anesthesia or spinal puncture. Avoid with: history of HIT, pork allergyFor primary prophylaxis in eligible patients. Monitor thrombocytopenia
blackboxiconEnoxaparin (Lovenox)Prophylaxis: 30 mg SC q12hr or 40 mg SC qd. Treatment: 1 mg/kg SC q12hr or 1.5 mg/kg SC qdAnemia, fever, edema, nauseaFirst-line for acute DVT in hospitalized patients. Consider as outpatient therapy to treat acute DVT
blackboxiconTinzaparin (Innohep)Treatment: 175 IU/kg SC qdCaution with sulfite sensitivityFirst-line for acute DVT in hospitalized patients. Not FDA approved for prophylaxis
blackboxiconDalteparin (Fragmin)Prophylaxis: 2500-5000 IU SC qd. Extended treatment of VTE in cancer patients: 200 IU/kg SC qd for 1 month, then 150 IU/kg qd months 2-6
FirstLineIconblackboxiconFactor Xa inhibitorsThrombocytopenia, elevated hepatic enzymesblackboxicon Spinal or epidural hematomas with neuraxial anesthesia or spinal puncture. Avoid with severe CKD. Caution with: geriatric patients, hepatic disease or moderate CKD
blackboxiconFondaparinux (Arixtra)Prophylaxis: 2.5 mg SC qd. Treatment: 5 mg, 7.5 mg or 10 mg (based on weight) SC qdDermatologic reactions, anemia, hypokalemia, edema, hypotension, GI and CNS side effectsCaution with weight <50 kg. Do not use for prophylaxis in patients <50 kgFor primary prophylaxis, except in patients at highest risk
blackboxiconRivaroxaban (Xarelto)Prophylaxis: 10 mg PO qd for 12 days after knee replacement or 35 days after hip replacementMuscle cramps, extremity pain, hypersensitivity reactionsblackboxicon Stroke risk following discontinuation in AF patients. Avoid with moderate hepatic diseaseFor primary prophylaxis with hip or knee replacement. Limited long-term efficacy or safety data
FirstLineIcon Unfractionated heparinProphylaxis: 5000 IU SC preoperatively, then 5000 IU SC q8-12hr. Treatment: 80 IU/kg IV bolus, then 18 IU/kg/hr IV continuous infusion. Adjust per aPTTThrombocytopenia, elevated hepatic enzymesAvoid with: history of HIT, bovine or pork allergyConsider low-dose SC heparin for primary prophylaxis, except in patients at highest risk. Use for treatment in patients with CKD. Monitor thrombocytopenia
FirstLineIconblackboxiconWarfarinInitially, 5 mg PO qd. Adjust dose according to INR. Target INR 2-3. Continue heparin or LMWH until INR achieved for 2 days. If lepirudin used instead of heparin, overlap with warfarin for 4-5 daysSystemic cholesterol microembolization, uncommon skin necrosisblackboxicon Major or fatal bleeding. Avoid in pregnancy. Caution with: ITP, HIT, hepatic disease, protein C or S deficiencyConsider for primary prophylaxis in eligible patients. Used for long-term therapy (3-6 months) Monitor INR regularly
Direct thrombin inhibitorsFor prophylaxis in patients with HIT
Argatroban (Acova)Prophylaxis or treatment: 2 mcg/kg·min IV continuous infusion, up to 15 to 25 mg/hr IV continuous infusion. Target aPTT 1.5-3GI side effects, cardiovascular adverse events, infection, hypotension, allergic reactionsReduce dose with hepatic disease
Bivalirudin (Angiomax)Prophylaxis with orthopedic surgery: 1 mg/kg SC q8hrThrombocytopenia, GI side effects, cardiovascular adverse events, hypotension, urinary retention, CNS side effects, serious allergic and hypersensitivity reactionsReduce dose with severe CKDNot FDA approved for DVT
Dabigatran (Pradaxa)Prophylaxis: 220 mg or 150 mg PO qd, starting with a half-dose 1—4 hours after surgery. Continue 6-10 days for knee replacement and 28—35 days for hip replacementCaution with: CKD, P-glycoprotein inhibitionAdministered orally. The ecarin clotting time (ECT) is a better test than aPTT. Not FDA approved for DVT
blackboxiconDesirudin (Iprivask)Prophylaxis: 15 mg SC q12hr for 9-12 days after hip replacementSerious allergic reactionsblackboxicon Spinal or epidural hematomas with neuraxial anesthesia or spinal puncture. For CrCl 31-60, use 5 mg SC q12hr, for CrCl<31, use 1.7 mg SC q12hr, and monitor aPTT and SCr daily
Lepirudin (Refludan)Prophylaxis: Per ACCP: 0.1 mg/kg·hr IV. Per manufacturer: Initial dose of 0.4 mg/kg (up to 110 kg) slow IV infusion, followed by 0.15 mg/kg·hr IV for 2-10 days. Target aPTT 1.5-2.5. If warfarin is started, include a 4-5 day overlapSerious allergic and hypersensitivity reactionsReduce dose with CKD
ThrombolyticsHypotensionAvoid in patients with severe hypertension. Caution with: severe hepatic disease, CKDConsider intravenous or catheter-directed thrombolysis in patients with severe iliofemoral DVT
Alteplase, tPA (Activase)2-hr infusion of 4 mcg/kg·min, followed by a maintenance infusion of 1 mcg/kg·min for 33 hrNot FDA approved for DVT
Streptokinase (Streptase)250,000 IU loading dose IV, followed by 100,000 IU/hr IV infusion. Continue infusion for 72 hrAllergic reactions (fever, shivering), tolerance or hypersensitivity with repeat use
Antiplatelet agent
Aspirin81-100 mg/dGI side effects, hypersensitivity reactions, minor bleedingAvoid with severe hepatic disease or severe CKD. Caution with asthma, GI diseaseFor secondary prevention of VTE after completion of primary treatment

FirstLineIcon = first-line agent; blackboxicon = black box warning; ACCP = American College of Chest Physicians; AF=atrial fibrillation; aPTT = activated partial thromboplastin time; bid = twice daily; CKD = chronic kidney disease; CNS = central nervous system; CrCl = creatinine clearance; DVT = deep venous thrombosis; FDA = Food and Drug Administration; GI = gastrointestinal; HIT = heparin-induced thrombocytopenia; hr = hour; IM = intramuscular; INR = international normalized ratio; ITP = idiopathic thrombocytopenic purpura; IV = intravenous; PO = oral; q12hr = every 12 hours; q8hr = every 8 hours; qd = once daily; qid = four times daily; SC = subcutaneous; SCr = serum creatinine; tid = three times daily; VTE = venous thromboembolism

ACP Smart Medicine provides key prescribing information for practitioners but is not intended to be a source of comprehensive drug information.

Table Grahic Jump Location
 Modified Wells Clinical Score

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Clinical CharacteristicScore
Active cancer (treatment ongoing, within 6 months, or palliative)1
Paralysis, paresis, or recent plaster immobilization of the lower extremities1
Recently bedridden >3 days or major surgery within 12 weeks requiring general or regional anaesthesia1
Localized tenderness along the distribution of the deep venous system1
Entire leg swollen1
Calf swelling 3 cm larger than asymptomatic side (measured 10 cm below the tibial tuberosity)1
Pitting edema confined to the symptomatic leg1
Collateral superficial veins (nonvaricose)1
Previously documented DVT1
Alternative diagnosis at least as likely as DVT-2
ScoreProbabilityLikelihood ratio for DVT
>2High5.2
1 or 2Intermediate-
<1Low0.25

Reprinted from 116.

Table Grahic Jump Location
 Recommendations for the Duration of Anticoagulant Therapy for Patients with DVT*

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Characteristics of Patient†Risk of Recurrence in the Year After Discontinuation (%)Duration of Therapy
Major transient risk factor33 months‡
Minor risk factor; no thrombophilia<10 if risk factor avoided
>10 if risk factor persistent
6 months‡
CellTxtL::Until factor resolves
Idiopathic event; no thrombophilia or low-risk thrombophilia<106 months‡§
Idiopathic event; high-risk thrombophilia>10Indefinite
More than one idiopathic event>10Indefinite
Cancer; other ongoing risk factor>10Indefinite

* Data are from 117, 118, and 119.

† Examples of major transient risk factors are major surgery, a major medical illness, and leg casting. Examples of minor transient risk factors are the use of an oral contraceptive and hormone-replacement therapy. Examples of low-risk thrombophilias are heterozygosity for the factor V Leiden and G20210A prothrombin-gene mutations. Examples of high-risk thrombophilia are antithrombin, protein C, and protein S deficiencies; homozygosity for the factor V Leiden or prothrombin-gene mutation or heterozygosity for both; and the presence of antiphospholipid antibodies.

‡ Tailoring the duration of anticoagulation on the basis of ultrasonographic findings of residual thrombus at 3 months can reduce the rate of recurrent VTE compared to fixed-duration anticoagulation (120).

§ Therapy may be prolonged if the patient prefers to prolong it, if the risk of bleeding is low, or if d-dimer level is elevated 1 month after discontinuation of treatment (80). In patients with a first unprovoked venous thromboembolism, men have a 2.2-fold higher risk of recurrent venous thromboembolism than do women (121).

Reprinted from 122. Copyright ©2004 Massachusetts Medical Society. All rights reserved.

Table Grahic Jump Location
 Selected Drug Interactions with Warfarin

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Agents That Decrease Warfarin AbsorptionDrugs That Inhibit Warfarin MetabolismDrugs That Enhance Warfarin ClearanceDrugs That Potentiate Warfarin Action
CholestyramineAmiodaronePhenytoinAcetaminophen
ColestipolDisulfiramRifampin
FluconazoleGlutethimide
Cimetidine (but not other H2 blockers)Griseofulvin
Omeprazole
Phenylbutazone
Oxyphenbutazone
Sulfinpyrazone
Sulfonamide antibiotics
Propafenone
Quinolone antibiotics
Tamoxifen
Disopyramide
Miconazole
Clofibrate
Quinolone antibiotics (varied response depending on agent)
Table Grahic Jump Location
 Food Interactions with Warfarin

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FoodInteraction
Proteolytic enzymes (papain), fried or boiled onionsIncrease fibrinolytic activity
Large amounts of vitamin A, E, K, CAlter prothrombin time
Green and herbal teasAlter prothrombin time
Table Grahic Jump Location
 Vitamin K Content of Selected Foods

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FoodVitamin K Content (mcg/100 g)
Kale726
Turnip greens650
Collards440
Spinach413
Brussels sprouts250
Soy bean oil198
Broccoli147
Cabbage110
Lettuce75
Olive oil56
Butter30
Margarine30
Table Grahic Jump Location
 Common Thrombophilias

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Mechanism of DiseasePopulation PrevalenceClinical ManifestationsTest
Antiphospholipid antibodiesBinding of antiphospholipid antibodies to damaged endotheliumUnknownIncreased risk of VTE, arterial thrombosis, and recurrent pregnancy lossELISA for anticardiolipin antibodies
Antithrombin III deficiencyNaturally occurring inhibitor of coagulation. Hereditary or acquired deficiency0.02% among whitesIncreased risk of VTE. VTE at unusual sites. Resistance to heparinAntithrombin III levels
Protein S deficiencyCofactor for protein C. Hereditary or acquired deficiency0.7% among whitesIncreased risk of VTEProtein S levels
Protein C deficiencyNaturally occurring anticoagulant. Hereditary or acquired deficiency0.2%-0.4% among whitesIncreased risk of VTE. Warfarin-induced skin necrosis and hypercoagulable stateProtein C levels
Factor V LeidenMutation of factor V rendering it resistant to degradation5% among whites, very uncommon in Africans and Southeast AsiansIncreased risk of VTE, especially during pregnancy. Cerebral vein thrombosisPCR for factor V Leiden, activated protein C resistance
Prothrombin 20210AMutation of prothrombin leading to increased plasma levels2% among whites, very uncommon in non-white populationsIncreased risk of VTE. Cerebral vein thrombosisDNA analysis
HyperhomocysteinemiaVarious mechanisms. Mostly due to deficiencies of folate or vitamins B12 and B6UnknownIncreased risk of VTE and arterial thrombosisFasting plasma homocysteine

DNA = deoxyribonucleic acid; ELISA = enzyme-linked immunosorbent assay; PCR = polymerase chain reaction; VTE = venous thromboembolism.

Reprinted with permission from 123.

Table Grahic Jump Location
 Risk Factors for Venous Thromboembolism and Bleeding

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Risk factors for venous thromboembolism
Inherited disorders:
Factor V Leiden mutation
Prothrombin gene mutation
Protein S or C deficiency
Antithrombin deficiency
Acquired risk factors:
Surgery
Cancer
Immobilization
Trauma
Presence of a central venous catheter
Pregnancy
Congestive heart failure
Chronic renal failure
Antiphospholipid antibody syndrome
Obesity
Smoking
Older age
History of thromboembolism
Drugs (oral contraceptives, hormone replacement therapy, tamoxifen)
Risk factors for bleeding with anticoagulant therapy
Older age
Female sex
Diabetes
Hypertension
Presence of cancer
Acute or chronic alcoholism
Liver disease
Severe chronic kidney disease
Peptic ulcer disease
Anemia
Poor treatment adherence
Prior stroke or intracerebral hemorrhage
Presence of bleeding lesions
Bleeding disorder
Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, antiplatelet agents, antibiotics, statins, fibrates, and steroids

Adapted from 10.

  • Postphlebitic Syndrome Manifesting as Chronic Venous Stasis Stasis dermatitis affects the skin on the lower legs, particularly around the medial malleoli. Findings that support the diagnosis of chronic venous insufficiency and stasis dermatitis include hyperpigmentation due to hemosiderin deposition, visible varicose veins, and edema. Patients may develop chronic venous ulceration.
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APTT

activated partial thromboplastin time

CBC

complete blood count

CI

confidence interval

DNA

deoxyribonucleic acid

DVT

deep venous thrombosis

ECG

electrocardiography

ELISA

enzyme-linked immunosorbent assay

FDA

Food and Drug Administration

GI

gastrointestinal

HIT

heparin-induced thrombocytopenia

INR

international normalized ratio

IPG

impedance plethysmography

iv

intravenous

LMWH

low-molecular-weight heparin

MI

myocardial infarction

MRI

magnetic resonance imaging

MRV

magnetic resonance venography

NNH

number needed to harm

NNT

number needed to treat

OR

odds ratio

PCR

polymerase chain reaction

PE

pulmonary embolism

PTT

partial thromboplastin time

RR

relative risk

sc

subcutaneous

SERM

selective estrogen replacement modulator

V/Q

ventilation/perfusion (lung scan)

VTE

venous thromboembolism


Guidelines

Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians

Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension: A Scientific Statement From the American Heart Association.

Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians

Management of venous thromboembolism: a systematic review for a practice guideline

Recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer

Venous thromboembolism prophylaxis in hospitalized patients: a clinical practice guideline from the American College of Physicians

Systematic Reviews

Anticoagulants versus non-steroidal anti-inflammatories or placebo for treatment of venous thromboembolism (Cochrane Review)

Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery (Cochrane Review)

Antiplatelet and anticoagulation for patients with prosthetic heart valves (Cochrane Review)

Combined intermittent pneumatic leg compression and pharmacological prophylaxis for prevention of venous thromboembolism in high-risk patients (Cochrane Review)

Combined use of rapid D-dimer testing and estimation of clinical probability in the diagnosis of deep vein thrombosis: systematic review

Compression therapy for treating stage I and II (Widmer) post-thrombotic syndrome (Cochrane Review)

Duration of anticoagulation following venous thromboembolism: a meta-analysis

Efficacy and safety outcomes of oral anticoagulants and antiplatelet drugs in the secondary prevention of venous thromboembolism: systematic review and network meta-analysis

Elastic compression stockings for prevention of deep vein thrombosis (Cochrane Review)

Heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures (Cochrane Review)

Heparins and mechanical methods for thromboprophylaxis in colorectal surgery (Cochrane Review)

Home versus in-patient treatment for deep vein thrombosis (Cochrane Review)

Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis

Indirect comparison meta-analysis of aspirin therapy after coronary surgery

Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients

Meta-analysis: low-molecular-weight heparin and bleeding in patients with severe renal insufficiency

Meta-analysis: the value of clinical assessment in the diagnosis of deep venous thrombosis

Meta-analysis: travel and risk for venous thromboembolism

Non-pharmaceutical measures for prevention of post-thrombotic syndrome

Once versus twice daily LMWH for the initial treatment of venous thromboembolism (Cochrane Review)

Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients: a meta-analysis of randomized controlled trials

Postmenopausal estrogen replacement and risk for venous thromboembolism: a systematic review and meta-analysis for the U.S. Preventive Services Task Force

Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis

Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review

Reduction of out-of-hospital symptomatic venous thromboembolism by extended thromboprophylaxis with low-molecular-weight heparin following elective hip arthroplasty: a systematic review

Risk of deep vein thrombosis following a single negative whole-leg compression ultrasound: a systematic review and meta-analysis.

Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review.

Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review

Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis

Sensitivity and specificity of ultrasonography in the diagnosis of upper extremity deep vein thrombosis: a systematic review

Silent pulmonary embolism in patients with deep venous thrombosis: a systematic review.

Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism

Systematic review: d-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism

Systematic review: the Trousseau syndrome revisited: should we screen extensively for cancer in patients with venous thromboembolism?

Thrombosis prophylaxis in patient populations with a central venous catheter: a systematic review

DOI: 10.7326/d202
The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.
Disclosures:
Emile R. Mohler, III, MD, FACP receives consultancy fees/honoraria from Takeda, Merck, GSK, and Boehringer Ingelheimer; has a pending grant from NHLBI for an infrared device to simultaneously measure skeletal blood, muscle blood flow, and oxygenation in patients with PAD; has a current NHLBI grant on microcirculation in claudication and exercise rehabilitation; owns/co-founded Flox Medical; and holds a patent on VOIS device. Steve Goodacre, MD has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations.
Deborah Korenstein, MD, FACP, Editor in Chief, ACP Smart Medicine, has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. Richard B. Lynn, MD, FACP, Editor, ACP Smart Medicine, has no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients.
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