- Development of blood clot within the deep veins, usually accompanied by inflammation of the vessel wall.
- The major clinical consequences are embolization, usually to the lung, and postphlebitic syndrome.
- System(s) affected: Cardiovascular
- The age- and gender-adjusted incidence of VTE is 100 times higher in the hospital than in the community (1).
- 1/3 of VTE cases die within 30 days, 1/5 will have sudden death due to PE. The 28-day DVT fatality rate is 9%.
- In the US, VTE occurs for the 1st time in 100 persons per 100,000 per year.
- Approximately 2/3 of the new VTE cases are DVT alone.
- Higher incidence among Caucasians and African Americans relative to Hispanics and Asians
- Complicates approximately 1 in 1,000 pregnancies.
Variable; dependent on medical condition or procedure:
- 22–52% of the patients with PE have DVT.
- 25% of patients with superficial venous thrombosis (2)
- Present in 11% of patients with acquired brain injury entering to neurorehabilitation
- Acquired: Age, previous thrombosis, iImmobilization, major surgery, orthopedic surgery, malignancy, oral contraceptives, hormonal replacement therapy, antiphospholipid syndrome, polycythemia vera, paroxysmal nocturnal hemoglobinuria, prolonged travel, pregnancy/puerperium
- Inherited: Antithrombin deficiency, protein C deficiency, protein S deficiency, factor V Leiden R506Q, prothrombin G20210A, dysfibrinogenemia
- Mixed/unknown: Hyperhomocysteinemia, high levels of factor VIII, activated protein C resistance not factor V Leiden, high levels of factor IX, high levels of thrombin activatable fibrinolysis inhibitor (TAFI), high levels of factor XI
- Factor V Leiden is found in 5% of the population and in 20% of all VTE events. It is the most common thrombophilia. Homozygosity is found in 1 per 5,000 persons. It increases the risk of VTE 3- to 8-fold in heterozygous carriers and 50- to 80-fold in homozygous.
- PT20210A is found in 3% of Caucasians. Increases the risk of thrombosis about 3-fold.
- Mechanical thromboprophylaxis is recommended in patients with high bleeding risk and as an adjunct to anticoagulant based thromboprophylaxis. Mechanical measures include early ambulation, graduated compression stockings, venous foot pump, intermittent pneumatic compression.
- Level of risk
- With minor surgery in mobile patient or fully mobile medical patients, risk of VTE <10%; early ambulation recommended
- With medical patients on bed rest, general, and gynecologic or urologic surgeries, risk of VTE 10–40%; prophylactic LMWH, low-dose UFH or Fondaparinux recommended
- Hip or knee arthroplasty, major trauma, spinal cord injury, or hip fracture surgery, risk of VTE is 40–80%; LMWH, Fondaparinux, or oral vitamin K antagonist [INR 2–3] recommended
Factors involved may include venous stasis, endothelial injury, and abnormalities of coagulation.
- Active cancer within 6 months +1
- Paralysis or immobilization of lower extremity +1; Recent bedridden >3 days or major surgery within 4 weeks +1
- Tenderness/cord along vein +1
- Entire leg swollen +1
- Calf circumference >3 cm vs other leg +1
- Alternative diagnosis likely -2
- High probability +3
- Moderate probability +3
- Low probability 0
- Establish pretest probability based on Wells criteria.
- Classify as “Provoked” or “Idiopathic.” Determine the presence of risk factors including family history.
- Clinical assessment of bleeding risk: bleeding with previous history of anticoagulation, history of liver disease, recent interventions, history of gastrointestinal bleed.
Physical exam is only 30% accurate for DVT. Resistance to dorsiflexion of the foot (Homan sign) is unreliable. Palpable tender cords are helpful if present but are often not present. Erythema over area of thrombosis (often not present). Fever is occasionally present. Swelling of collateral veins. Massive edema with cyanosis is a medical emergency (phlegmasia cerulea dolens, rare). Pain on medial tibia percussion (Lisker sign). Pain on compression of calf against tibia in the anteroposterior plane (Bancroft or Moses sign). Thoracic outlet maneuvers in Upper extremity DVT. Attention to signs of possible malignancy.
Diagnostic Tests & Interpretation
- D-dimer (sensitive but not specific; has a high NPV); most protocols are used to rule out DVT in low pretest probability cases: If D-dimer negative, DVT is ruled out with low pretest probability cases. Do not order D-dimer if pretest probability is moderate or high.
- CBC, platelet count, activated partial thromboplastin time (aPTT), prothrombin time (PT)/international normalized ratio (INR)
- In young patients with idiopathic or recurrent VTE consider:
- Factor V Leiden, G20210A prothrombin, serum homocysteine, factor VIII level, and lupus anticoagulant
- Protein C and S levels, antithrombin activity, anticardiolipin antibodies.
- Testing for genetic polymorphisms CYP2C9 and VK0RC1 (www.warfarindosing.org for current recommendations)
- Thrombosis lowers antithrombin III; workup for deficiency performed after therapy completed. Secondary antithrombin deficiency is more common than primary.
- Compression ultrasound (US): Noninvasive; sensitive and specific for popliteal, femoral thrombi, but has poor ability to detect calf vein thrombi
- Contrast venography: Gold standard, is technically difficult, risk of morbidity
- Impedance plethysmography: As accurate as duplex ultrasound, less operator dependency, but poor at detecting calf vein thrombi; not widely available
- Magnetic resonance venography: As accurate as contrast venography; may be useful for patients with contraindications to IV contrast
- 125I-fibrinogen scan: Detects only active clot formation; very good at detecting ongoing calf thrombi; takes 4 hours for results
Cellulitis, fracture, ruptured synovial cyst (Baker cyst), lymphedema, muscle strain/tear, extrinsic compression of vein (for example, by tumor or enlarged lymph nodes), compartment syndrome, localized allergic reaction, filariasis (in developing countries)
- All DVTs should receive treatment. Consider starting therapy even before confirmation in patients with high pre-test probability.
- 2008 American College of Chest Physicians Guidelines recommend low molecular weight heparin [LMWH], unfractionated heparin [UFH] (either IV, or fixed-dose or adjusted-dose subcutaneous heparin), or fondaparinux and warfarin for at least 5 days until the INR is 2–3 for 24 hours (3)[A].
- Unfractionated heparin (UFH):
- IV drip: Initial dose of 80 units/kg or 5,000 Units followed by continuous infusion of 18 units/kg/hour. Target an APTT ratio >1.5. The APTT prolongation shall correspond to a 0.3 to 0.7 anti Xa level.
- SC UFH: Monitored: 17,500 units or 250 units/kg b.i.d. with APTT adjustment to an equivalent to 0.3–0.7 anti Xa. Alternatively, fixed dose: 333 units/kg followed by b.i.d. dose 250 units/kg.
- Enoxaparin (Lovenox): 1 mg/kg/dose subcutaneously every 12 hours or 1.5 mg/kg/dose per day
- Dalteparin (Fragmin): 200 IU/kg subcutaneously every 24 hours
- Fondaparinux (Arixtra): 5 mg (body weight <50 kg), 7.5 mg (body weight = 50–100 kg), or 10 mg (body weight >100 kg) subcutaneously once daily.
- Maintenance therapy:
- Warfarin (Coumadin): 5 mg/d for 3 days, then adjust to a target INR of 2–3.
- Adverse effects:
- Heparin or LMWH: Bleeding, edema, injection site irritation, skin eruptions, hematoma, thrombocytopenia
- Fondaparinux: Bleeding, injection site irritation, rash, fever, anemia
- Warfarin: Bleeding, skin necrosis, teratogenicity
- Heparin or LMWH: Bleeding, heparin hypersensitivity, heparin-induced thrombocytopenia (HIT), ITP, infants/neonates
- Fondaparinux: Bleeding, endocarditis, renal failure, thrombocytopenia
- Warfarin: Current bleeding, alcoholism, preeclampsia, pregnancy, surgery, high fall risk
If warfarin is contraindicated, heparin can be given by intermittent subcutaneous self-injection.
- Warfarin (Coumadin) is a teratogen; treat with full-dose heparin initially, followed by subcutaneous heparin starting at 15,000 units every 12 hours.
- Warfarin is safe with breast-feeding.
- LMWH, dalteparin, and fondaparinux are pregnancy category B.
- Discharge with compression stockings 30–40 mm Hg. Stress use to prevent post-phlebitic syndrome. Continue compression therapy for 2 years.
- Intermittent pneumatic compression may be tried in patients with significant edema.
- In selected patients with proximal DVT (Iliofemoral DVT, <2 weeks of symptoms, good functional status, >1 year of life expectancy), catheter directed thrombolysis or open thrombectomy may be considered.
- When anticoagulants have failed or are contraindicated, filtering devices are recommended.
Admission for: Respiratory distress, proximal VTE, candidates for thrombolysis, active bleeding, renal failure, phlegmasia cerulea dolens, history of heparin-induced thrombocytopenia
Medically stable and properly anticoagulated; overlap of anticoagulation and warfarin monitoring may be done as an outpatient
- Gradual resumption of normal activity, with avoidance of prolonged immobility.
- Duration of warfarin treatment after DVT:
- 3 months for treatment of a DVT secondary to a reversible risk factor
- Patients with unprovoked DVT shall be considered for prolonged secondary prophylaxis:
- In patients who have completed 3 months of anticoagulation after an unprovoked VTE, a positive D Dimer 1 month after discontinuation of therapy correlates with the risk of VTE recurrence (4).
- Tailoring the anticoagulation duration base on recanalization ultrasound evidence, may reduce the rate of recurrent VTE (5).
- Consider prolonged secondary prophylaxis (1 year or indefinitely): Recurrent DVT; PE; active cancer (LMWH preferred over warfarin); life-threatening event (large pulmonary embolism, limb-threatening DVT); cerebral or visceral vein thrombosis; antithrombin deficiency with event; homozygous for factor V Leiden; combined clotting disorders (e.g., combined heterozygous factor V Leiden and PT20210A); antiphospholipid syndrome
- Monitor platelet count while on heparin.
- Monitoring with LMWH and fondaparinux: Periodic platelet count. An anti-factor Xa activity level may help guide titration of therapy.
- Investigate significant bleeding (e.g., hematuria or GI hemorrhage) because anticoagulant therapy may unmask a preexisting lesion (e.g., cancer, peptic ulcer disease, or arteriovenous malformation).
Patients taking warfarin must be aware that foods high in vitamin K can affect INR.
- Patients should wear compression stockings post-DVT; these can be cumbersome and uncomfortable; however, they can reduce the risk of DVT recurrence and post-phlebitic syndrome.
- Dietary habits should be discussed when warfarin is initiated to ensure that intake of vitamin K-rich foods are identified.
- 20% of untreated proximal (e.g., above the calf) DVTs progress to pulmonary emboli, and 10–20% of those are fatal; with anticoagulant therapy, mortality is decreased 5–10-fold.
- DVT confined to the infrapopliteal veins has a small risk of embolization, but can propagate into the proximal system. Best treatment uncertain, but most recommend 6–12 weeks of anticoagulation.
- Pulmonary embolism (fatal in 10–20%)
- Arterial embolism (paradoxical embolization) with AV shunting
- Chronic venous insufficiency
- Postphlebitic syndrome (pain and swelling in affected limb without new clot formation)
- Treatment-induced hemorrhage
- Soft tissue ischemia associated with massive clot and high venous pressures: phlegmasia cerulea dolens (rare, but a surgical emergency)
1. Heit JA, Melton LJ, Lohse CM, et al. Incidence of venous thromboembolism in hospitalized patients vs community residents. Mayo Clin. Proc. 2001;76:1102–10.
2. Decousus H, Quéré I, Presles E, et al. Superficial venous thrombosis and venous thromboembolism: a large, prospective epidemiologic study. Ann Intern Med. 2010;152:218–24.
3. Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:454S–545S.
4. Palareti G, Cosmi B, Legnani C, et al. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med. 2006;355:1780–9.
5. Prandoni P, Prins MH, Lensing AW, et al. Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial. Ann Intern Med. 2009;150:577–85.
See Also (Topic, Algorithm, Electronic Media Element)
Antithrombin Deficiency; Factor V Leiden; Protein C Deficiency; Protein S Deficiency; Prothrombin 20210 (Mutation); Pulmonary Embolism
- 453.40 Acute venous embolism and thrombosis of unspecified deep vessels of lower extremity
- 453.41 Acute venous embolism and thrombosis of deep vessels of proximal lower extremity
- 453.42 Acute venous embolism and thrombosis of deep vessels of distal lower extremity
- 453.9 Embolism and thrombosis of unspecified site
- 128053003 Deep venous thrombosis (disorder)
- 40198004 Thrombophlebitis of deep veins of lower extremity (disorder)
- 16750002 deep thrombophlebitis (disorder)
- 266267005 deep vein phlebitis and thrombophlebitis of the leg (disorder)
- Many cases are asymptomatic and are diagnosed after embolization.
- 25% of the patients with superficial thrombophlebitis will have DVT at presentation.
- Heparin and warfarin should overlap for a minimum of 5 days or longer to achieve target INR.
- Consider thoracic outlet syndrome in upper extremity DVT.
- Do a cancer-oriented review of systems and age- and gender-appropriate cancer screening in: Recurrent VTE, Not catheter associated Upper extremity DVT, bilateral lower extremity DVT, intra-abdominal DVT.