Deep vein thrombosis

Deep vein thrombosis (DVT) is the formation of a blood clot within the deep veins, most commonly those of the lower extremities. The main risk factors for DVT are vascular endothelial damage (e.g., surgery or trauma), venous stasis (e.g., immobility), and hypercoagulability (e.g., thrombophilia), collectively referred to as the Virchow triad. Symptoms include edema, warmth, and dull pain of the affected extremity. Patients may also present with features of pulmonary embolism (PE), a severe complication of DVT. The Wells criteria for DVT are used to determine the pretest probability (PTP) of DVT. The initial test of choice for DVT is D-dimer in patients with a low PTP and venous ultrasound (US) in patients with moderate or high PTP. A negative D-dimer assay (i.e., levels < 500 ng/mL) allows DVT to be ruled out, while a positive D-dimer (levels ≥ 500 ng/mL) is nonspecific and requires a venous ultrasound to confirm the diagnosis. Noncompressibility of the affected vein is the most important sonographic feature of DVT. Primary treatment with long-term anticoagulation for 3–6 months is recommended in all patients with DVT, with the exception of isolated asymptomatic distal DVT, for which expectant management with serial ultrasound may be considered, as the risk of postthrombotic sequelae is low. Secondary prevention (i.e., anticoagulation extended indefinitely after completion of primary treatment) is also recommended for select patients, depending on the extent and etiology of the DVT and on the patient's bleeding risk. Catheter-directed thrombolysis or thrombectomy may be considered for limb-threatening ischemia, acute iliofemoral DVT, and patients with contraindications to anticoagulation. Primary prevention of VTE is recommended in patients at risk of DVT or PE (e.g., seriously ill medical patients, most surgical patients, and long-distance travelers with additional risk factors for VTE) and includes mechanical and pharmacological measures.

• Deep vein thrombosis (DVT): the formation of one or more blood clots in a deep vein, typically of the lower extremities ^[1][2][3]
  • Proximal DVT: DVT of the lower extremity affecting the femoral vein, profunda femoris vein, and/or the popliteal vein (up to the calf vein trifurcation) ^[4]
  • Distal DVT: DVT of the lower extremity that is confined to the veins beyond the calf vein trifurcation (i.e., below the knee joint)
  • Provoked DVT: DVT in an individual with ≥ 1 risk factor for VTE
  • Unprovoked DVT (idiopathic DVT): DVT in an individual without risk factors for VTE
• Venous thromboembolism (VTE): an umbrella term that encompasses DVT and pulmonary embolism (PE)
  • Recurrent VTE: DVT and/or PE that recurs in a patient after the completion of the first 2 weeks of antithrombotic therapy. ^[5]

Any factor that causes hypercoagulability, endothelial damage, and/or venous stasis can cause DVT (see “Virchow triad”).

Remember DVT risk factors using the mnemonic “THROMBOSIS”: Travel, Hypercoagulable/HRT, Recreational drugs, Old (> 60), Malignancy, Blood disorders, Obesity/Obstetrics, Surgery/Smoking, Immobilization, Sickness (CHF/MI, IBD, nephrotic syndrome, vasculitis)!

References:^[10][11]

The Virchow triad

The Virchow triad refers to the three main pathophysiological components of thrombus formation.

1. Hypercoagulability: increased platelet adhesion, thrombophilia (e.g., factor V Leiden mutation), use of oral contraceptives, pregnancy
2. Endothelial damage: Inflammatory or traumatic vessel injuries can lead to activation of clotting factors through contact with exposed subendothelial collagen.
3. Venous stasis: varicosis, external pressure on the extremity, immobilization (e.g., hospitalization, bed rest, long flights or bus rides), local application of heat

To remember the three pathophysiological components of thrombus formation, think: “HE'S Virchow”: H-Hypercoagulability, E-Endothelial damage, S-Stasis.

References:^[10][12][13]

• May be asymptomatic
• Localized unilateral symptoms
  • Typically affects deep veins of the legs, thighs, or pelvis
    • More common in the left lower extremity
    • May-Thurner syndrome: compression of the left iliac vein between the right iliac artery and a lumbar vertebral spur (occurs in > 20% of adults) ^[14][15]
  • Swelling, feeling of tightness or heaviness
  • Warmth, erythema, and possibly livid discoloration
  • Progressive tenderness, dull pain
    • Homans sign: calf pain on dorsal flexion of the foot
    • Meyer sign: Compression of the calf causes pain.
    • Payr sign: pain when pressure is applied over the medial part of the sole of the foot
  • Distention of superficial veins
  • Distal pulses are normal.
• General symptoms: fever ^[16]
• Possible signs of pulmonary embolism: dyspnea, chest pain, dizziness, weakness

References:^[10][17]

• The Wells score for DVT, also known as the Wells criteria, is used to calculate the pretest probability of DVT of the lower extremities. ^[18][19]
• A different version of the score is used to determine the probability of PE (see “Wells criteria for PE”).

Approach to lower extremity DVT ^[4][21][22]

This approach is valid for evaluating a first-episode or recurrent lower extremity DVT, based on the pretest probability (PTP): See “Wells criteria for DVT.” ^[21]

Initial evaluation of DVT

Based on the patient's pretest probability, the initial test to evaluate for DVT may be either D-dimer or compression ultrasound.

D-dimer ^[21][22]

• Indication: preferred initial test for nonpregnant patients with a low PTP of DVT (Wells score = 0)
• Interpretation
  • Cutoff for normal range is typically 500 ng/mL
  • Some centers use age-adjusted D-dimer cutoffs (See also “Diagnostics” in “Pulmonary embolism”) ^[24][25][26]
• Accuracy
  • High sensitivity (∼ 96%)
  • Low specificity (∼ 36%) ^[4]
  • Not reliable for ruling out DVT in patients with intermediate or high PTP

In patients with a low pretest probability of DVT, a negative D-dimer (< 500 ng/mL) rules out DVT. ^[21]

A positive D-dimer alone does not confirm DVT. ^[21]

Lower extremity venous ultrasound ^{[4][21][22][27]}

• Indications
  • Preferred initial test for patients with moderate or high PTP of lower extremity DVT (Wells score ≥ 1)
  • Preferred initial test for pregnant or postsurgical patients even if the PTP of DVT is low
  • Next diagnostic step in patients with a low PTP of lower extremity DVT but a positive D-dimer
• Procedures ^[22]
  • Compression ultrasound: The vein is identified and external pressure is directly applied over it with the probe.
    • Proximal leg: allows for evaluation of the femoral and popliteal veins up to the trifurcation
    • Whole leg: allows for evaluation of the proximal leg PLUS distal calf veins (beyond the trifurcation)
  • Venous duplex ultrasound: can be added to compression ultrasound
    • Involves the addition of color Doppler
    • Allows for better evaluation of noncompressible deep veins ^[28]
• Supportive findings ^[28]
  • Noncompressibility of the obstructed vein
  • Intraluminal hyperechoic mass
  • Distention of the affected vein
  • On Doppler imaging
    • Absent venous flow (complete obstruction) or abnormal venous flow (partial obstruction)
    • Inadequate augmentation of venous flow on distal calf compression or Valsalva maneuver
  • Of recurrent DVT: thrombosis in a new venous segment or a > 4 mm increase in noncompressibility of the obstructed vein
• Accuracy: : operator-dependent; high sensitivity and specificity (∼ 95%) for proximal DVT; lower sensitivity and specificity (∼ 65%) for distal DVT ^[27]

Compression ultrasound of the whole leg with color Doppler (i.e., duplex scanning) is the most accurate test for diagnosing DVT. ^[22]

Additional evaluation

Routine laboratory studies

These are recommended to assess organ function and bleeding risk prior to anticoagulation.

• CBC
• BMP
• Liver chemistries
• Coagulation studies
  • Assess the patient's baseline coagulation status
  • Screen for subtherapeutic INR in patients on VKA therapy with suspected recurrent DVT

Venography, CT venography, or MR venography ^[4][27]

• Indications
  • Inconclusive findings on compression US
  • Inability to perform compression US due to, e.g., obesity, significant lower limb edema, immobilization cast
• Finding: intraluminal filling defect

Screening for an underlying cause

Patients with the following may require additional evaluation: unprovoked DVT, unexplained recurrent VTE, and/or a history suggestive of a hypercoagulable state or occult malignancy. ^[2]

• Thrombophilia screening ^[2]
  • Thrombosis in patients < 45 years
  • Unusual thrombus localization
  • Positive family history
  • Recurrent or multiple thromboses
  • Recurrent pregnancy loss
  • See “Diagnostics” in “Hypercoagulable states.”
• Screening for occult malignancy ^[2][29][30]
  • Indications: unprovoked VTE (esp. patients > 50 years), recurrent VTE, unusual thrombus location
  • Investigations: routine age-appropriate cancer screening recommended ^[29][30]
    • In addition to routine laboratory studies: consider e.g., urinalysis, FOBT, serum calcium levels
    • Consider CXR, colonoscopy, mammogram, digital rectal exam, Pap smear

• Superficial thrombophlebitis
• Muscle or soft tissue injury (i.e., posttraumatic swelling or hematoma)
• Lymphedema
• Venous insufficiency
• Ruptured popliteal cyst
• Cellulitis
• Compartment syndrome

The differential diagnoses listed here are not exhaustive.

Definition

• Inflammation and thrombosis of a superficial vein
• Variants
  • Thrombophlebitis migrans (Trousseau syndrome)
  • Superficial thrombophlebitis of the breast (Mondor disease)

Risk factors

• Risk factors for VTE
• Varicose veins ^[31]
• Venous cannulation, IV drug administration
• Behçet disease
• Thromboangiitis obliterans ^[32]

Risk factors for concomitant DVT ^[33][34]

• Age ≥ 75 years
• Past history of VTE
• Superficial thrombophlebitis affecting nonvaricose veins or veins above the knee ^[34][35]
• Recent immobilization, surgery, or trauma
• Pregnancy, recent childbirth, use of estrogen therapy
• Obesity, autoimmune disease, thrombophilia, CHF, or active cancer

Clinical features

• Pain, tenderness, induration, and erythema overlying a superficial vein, often with a palpable cord (the thrombosed vein)
• Most commonly affects the superficial veins of the leg
• Concomitant DVT and/or PE present in ∼ 25% of patients (see “Clinical features of DVT” and “Clinical features of PE”) ^[33][35][36]

Diagnostics

Superficial thrombophlebitis is typically a clinical diagnosis. The primary differential diagnoses are localized skin or soft tissue inflammation (e.g., cellulitis, vasculitis) ^[33][37]

• Compression ultrasound with/without Doppler
  • Indication: presence of any risk factor for concomitant DVT or if the clinical diagnosis is unclear
  • Findings: thickened, edematous, noncompressible superficial vein with/without an intraluminal thrombus, with/without extension into a deep vein
• Evaluation for the underlying cause: same as that for DVT (see “Diagnostics" above)

Treatment ^[34][38]

All patients should be evaluated and treated for concomitant pulmonary embolism or DVT.

• Symptomatic care: indicated for all patients ^[34]
  • Oral and/or topical analgesics: See “Pain management.”
  • Compression therapy with graduated compression stockings
• Anticoagulation: to consider based on thrombus length (e.g., ≥ 5 cm), location (i.e., proximity to the deep venous system), and risk factors for DVT
  • Not required in the following circumstances: (i.e., provide symptomatic care only)
    • Superficial thrombophlebitis caused by venous cannulation
    • Thrombus length < 5 cm without risk factors for concomitant DVT
  • Prophylactic regimen (for 45 days)
    • Indications
      • Thrombus length ≥ 5 cm located > 3 cm away from the SFJ
      • Thrombus length < 5 cm with any risk factors for concomitant DVT
    • Options
      • Rivaroxaban ^[39]
      • Fondaparinux ^[40]
      • LMWH, such as enoxaparin : preferred in pregnant patients
  • Therapeutic regimen (for at least 3 months)
    • Indication: any length thrombus located < 3 cm from the SFJ
    • Options: See “Long-term anticoagulation” in “Treatment.”

Complications

• DVT
• Pulmonary embolism
• Infection (septic thrombophlebitis)

Approach ^[7][23]

• Evaluate and treat concomitant pulmonary embolism.
• Assess bleeding risk on anticoagulation for VTE.
• Initiate anticoagulation therapy based on the extent and etiology of DVT: See “Therapeutic approach to DVT.”
  • Expectant management: serial venous ultrasound without anticoagulation
  • Primary treatment: anticoagulation for 3–6 months in patients not being managed expectantly
  • Secondary prevention; (of recurrent DVT): extended anticoagulation ; after completion of primary treatment; should be individualized (e.g., patients with chronic risk factors)
• Treat the underlying cause, if feasible.

Primary treatment (anticoagulation) ^[7][23][41]

Primary treatment is the duration of anticoagulation required to treat an acute DVT (typically 3–6 months). Most patients receive long-term treatment with oral anticoagulants, which often require bridging therapy with initial parenteral anticoagulation.

Initial parenteral anticoagulation (for the first 5–10 days)

• Indications
  • Bridging therapy for VKAs: parenteral anticoagulation overlaps with oral anticoagulation until therapeutic INR is maintained.
  • Parenteral lead-in therapy for dabigatran and edoxaban: These DOACs are started after completion of lead-in parenteral therapy without overlapping.
• Options:
  • Low molecular weight heparin (LMWH); (e.g., enoxaparin; ) : preferred in pregnant women and patients with normal renal function, liver disease, or active cancer ^[34][42]
  • Fondaparinux (factor Xa inhibitor) : preferred in patients with a history of heparin-induced thrombocytopenia
  • Unfractionated heparin (UFH) bolus plus infusion; : preferred in patients with renal failure, inadequate subcutaneous absorption (i.e., morbid obesity), and those at a high risk of bleeding ^[41][43]

Treatment with heparin (especially UFH) can cause heparin-induced thrombocytopenia. For early detection, perform regular CBCs.

Long-term anticoagulation (for 3–6 months)

• Indication: all patients with DVT who cannot be managed expectantly and have no contraindications to anticoagulation. (See “Therapeutic approach to DVT”)
• Direct oral anticoagulants (DOACs): first-line therapy in nonpregnant patients (preferred over VKAs) ^[44][45]
  • Regular monitoring of coagulation parameters is not required.
  • Associated with a lower risk of major bleeding
  • Options (any of the following)
    • Direct factor Xa inhibitors: rivaroxaban , apixaban , or edoxaban
    • Direct thrombin inhibitors: dabigatran
  • Dabigatran and edoxaban require parenteral lead-in therapy while rivaroxaban and apixaban can be started immediately ^[44]
• Vitamin K antagonists (VKAs): warfarin
  • Requires bridging therapy
    • Initiate simultaneously with initial parenteral anticoagulation
    • Continue parenteral anticoagulation with warfarin for at least 5 days and until therapeutic INR has been maintained for 48 hours ^[45][46]
  • Second-line therapy in nonpregnant patients
  • Requires dose adjustment to maintain a target INR of 2–3
• LMWH: preferred in pregnant women; and in patients with active cancer; , e.g., enoxaparin ^[44]

Initial parenteral anticoagulation (with LMWH, fondaparinux, or UFH) should be initiated at the same time as warfarin and before dabigatran and edoxaban. Initial parenteral anticoagulation is not required for patients receiving rivaroxaban or apixaban. ^[7][23]

Secondary prevention (extended anticoagulation of indefinite duration) ^[7][23][41]

The decision to extend anticoagulation indefinitely after primary treatment is typically made after balancing the risk of recurrent DVT (e.g., for patients with chronic risk factors) with the bleeding risk on anticoagulation for VTE.

• Indications: See “Therapeutic approach to DVT.”
• Options ^[23]
  • First episode of DVT: Continue the same anticoagulant used for long-term anticoagulation (e.g., warfarin, or DOACs).
  • Recurrent DVT while appropriately anticoagulated
    • On an oral anticoagulant: Switch to LMWH; either temporarily or for the remaining duration of therapy (e.g., enoxaparin ).
    • On LMWH: Increase LMWH dose by 25–33%
  • Patients wishing to discontinue anticoagulation : Consider aspirin (unless there are contraindications)
• Monitoring: Reassess bleeding risk periodically (e.g., annually).

Extended anticoagulation is usually not required in patients with a provoked DVT due to a transient or reversible risk factor (e.g., surgery, intravascular catheter). ^[23][41]

Advanced therapy

These are not routinely indicated.

• Catheter-directed thrombolysis (CDT) ^[7][23]
  • Indications
    • Limb-threatening ischemia (phlegmasia cerulea dolens)
    • Consider in acute (< 14 days) iliofemoral DVT in patients with low risk of bleeding and life expectancy ≥ 1 year ^[23][47]
  • Agents: streptokinase, urokinase, rtPA ^[47]
• Thrombectomy
  • Indications: same as for CDT; consider as an alternative to CDT in patients with absolute contraindications to thrombolysis ^[47]
• Inferior vena cava filter (Greenfield filter)
  • Indications ^[23][48]
    • DVT with a high risk of PE (e.g., proximal DVT) in patients with contraindications for anticoagulation, absolute contraindications to thrombolysis, and contraindications to thrombectomy (e.g., patients with active bleeding, recent major surgery, recent intracranial hemorrhage) ^[49]
    • Consider in anticoagulated patients with severe PE to prevent subsequent PE. ^[23][48]

Supportive care ^[23]

• Encourage early ambulation; minimize bedrest. ^[50][51][52]
• Graduated compression stockings
  • Consider only for symptomatic relief (i.e., reduction of edema and pain)
  • No longer routinely recommended to prevent postthrombotic syndrome. ^[23][41]
• Analgesics for pain relief: See “Pain management”; avoid NSAIDs if the patient is receiving anticoagulation or thrombolytics. ^[53]
• Delay any elective surgery for at least 3 months after initiation of anticoagulation therapy. ^[41]

Risk factors for bleeding in patients with VTE ^[23]

• Patient characteristics
  • Age > 65 years
  • Decreased functional capacity and comorbidity
  • Frequent falls
• Past medical history
  • Prior history of bleeding
  • Prior history of stroke
  • Recent surgery
• Chronic conditions
  • Cancer
  • Renal failure
  • Liver failure
  • Diabetes
  • Alcohol use disorder
• Medication history
  • Poor anticoagulant control
  • Antiplatelet therapy
  • NSAID use
• Laboratory abnormalities
  • Low platelets
  • Anemia

Risk assessment

VTE prophylaxis refers to the primary prevention of DVT or PE in at-risk individuals and includes general preventive measures, mechanical VTE prophylaxis, and pharmacological VTE prophylaxis. VTE prophylaxis should be chosen based on the presence of risk factors for VTE and estimated risk of bleeding on anticoagulation therapy. ^[54]

• General preventive measures
  • Regular exercise
  • Early postoperative mobilization
  • Physiotherapy
  • Avoid certain medications (e.g., OCPs) in patients with thrombophilias (e.g., factor V Leiden).
• Pharmacological VTE prophylaxis (antithrombotics): LMWH, low-dose UFH, and DOACs are recommended.
• Mechanical VTE prophylaxis
  • Graduated compression stockings: preferred in long-distance travelers
  • Intermittent pneumatic compression stockings: preferred in seriously ill medical patients and in surgical patients
• Duration of prophylaxis in hospitalized patients ^[54]
  • Mechanical VTE prophylaxis: until the patient is mobile
  • Pharmacological VTE prophylaxis
    • Seriously ill medical patients: at least 7 days; extend to span the duration of hospitalization
    • Surgical patients: consider extended therapy for > 3 weeks ^[55]

Prophylaxis is usually indicated in seriously ill patients who are hospitalized, patients undergoing major surgery, patients with major trauma, and long-distance travelers with additional risk factors for VTE.

In surgical patients, the first dose of the antithrombotic should be administered within 12 hours of completing the surgery. ^[55]

LMWH or low-dose UFH is recommended for postoperative anticoagulation in patients who have undergone major surgery.

Phlegmasia cerulea dolens

• Definition: : a severe form of phlebothrombosis characterized by obstruction of all veins of one extremity, with subsequent restriction of arterial flow; ; associated with high mortality
• Symptoms
  • Severe swelling, edema, and pain
  • Coldness, cyanosis, and pulselessness
• Treatment
  • Emergency surgery: venous thrombectomy, fasciotomy
  • Fibrinolysis if surgery fails
  • Amputation as last resort
• Complications: shock, gangrene, acute renal failure (due to rhabdomyolysis)

Paget-Schroetter disease (upper extremity DVT)

• Definition: acute thrombosis of a brachial, axial, or subclavian vein
• Etiology
  • Effort-induced thrombosis: triggered by repetitive strenuous activity of the upper extremities (e.g., weight-lifting, operation of a jackhammer)
  • Thoracic outlet syndrome
• Treatment: anticoagulation, fibrinolysis, surgery (e.g., first rib resection) for thoracic outlet syndrome ^[62]

References:^[62][63]

• Pulmonary embolism: Pulmonary emboli most commonly originate in the proximal deep veins of the lower extremities (e.g., iliac, femoral, or popliteal veins).
• Postthrombotic syndrome (chronic venous insufficiency)
• Venous gangrene (rare complication) ^[64]

We list the most important complications. The selection is not exhaustive.

• Determine the pretest probability (PTP) of DVT (see “Wells score”).
• Choose diagnostic algorithm according to PTP:
  • Low PTP: D-dimer followed by lower extremity venous ultrasound.
  • Intermediate/high PTP: Start with lower extremity venous ultrasound.
  • Consider CT/MR venography if inconclusive.
• Obtain baseline laboratory studies: e.g., CBC, BMP, liver chemistries, coagulation studies
• If no obvious trigger: Screen for underlying cause (e.g., thrombophilia, malignancy).
• Assess for features of pulmonary embolism and initiate treatment for PE if needed: See “Acute management checklist for PE.”
• Assess bleeding risk: See "Estimated risk of major bleeding on anticoagulation therapy in patients with VTE."
• Initiate anticoagulation therapy based on extent of DVT (see “Therapeutic approach to DVT”).
• Treat the underlying cause, if feasible.

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