Deep vein thrombosis (Phlebothrombosis)

Deep vein thrombosis (DVT) is the formation of a blood clot in a deep vein of the legs, thigh, or pelvis. Thrombosis is most often seen in individuals with a history of immobilization, obesity, malignancy, or hereditary thrombophilia. Vascular endothelial damage, venous stasis, and hypercoagulability, collectively referred to as the Virchow triad, are the main factors contributing to the development of DVT. Symptoms usually occur unilaterally and include swelling, tenderness, and redness or discoloration. Pulmonary embolism (PE), a severe complication of DVT, should be suspected in patients with dizziness, dyspnea, and fever. The diagnostic test of choice for DVT is compression ultrasound. In most cases, a negative D-dimer test allows thrombosis or PE to be ruled out, but a positive test is nonspecific. Initial acute treatment of DVT consists of anticoagulation with heparin and, if the thrombus is large or unresponsive to anticoagulation, may also include thrombolysis or thrombectomy. Secondary prophylaxis is achieved with oral warfarin or direct factor Xa inhibitors and supportive measures such as regular exercise and compression stockings.

Risk factors for deep vein thrombosis

• History of DVT or PE (30x increased risk) ^[1]
• Immobilization: e.g., post-surgery, long-distance flights, trauma (20x increased risk)
• Age > 60 years
• Malignancy
• Hereditary thrombophilia (especially factor V Leiden)
• Pregnancy, estrogen use (oral contraceptives)
• Obesity
• Smoking
• IV drug use
• Nephrotic syndrome
• Insufficient thrombosis prophylaxis, noncompliance with prophylaxis

To remember the risk factors of deep vein thrombosis, think “THROMBOSIS”: Travel, Hypercoagulable/HRT, Recreational drugs, Old (> 60), Malignancy, Blood disorders, Obesity/Obstetrics, Surgery/Smoking, Immobilization, Sickness (CHF/MI, IBD, nephrotic syndrome, vasculitis)!

References:^[2][3]

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-Hypercoaguability, E-Endothelial damage, S-Stasis.

References:^[2][4][5]

• 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) ^[6][7]
  • Swelling, feeling of tightness or heaviness
  • Warmth, erythema, and possibly livid discoloration
  • Progressive tenderness, dull pain
    • Homan 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 ^[8]
• Possible signs of pulmonary embolism: dyspnea, chest pain, dizziness, weakness

References:^[2][9]

The diagnostic approach for suspected DVT is determined by the Wells score. Compression ultrasonography and D-dimer levels are the main diagnostic tests.

Wells criteria for deep vein thrombosis

The Wells score for DVT identifies the probability of DVT. A different version of the score may be used to determine the probability of PE (see Wells criteria for PE).

Criteria		Score
Medical history	Active cancer	+1
	Previously documented DVT	+1
Immobilization	Paralysis or recent (cast) immobilization of lower extremity	+1
	Recently bedridden (≥ 3 days) or Major surgery (< 12 weeks)	+1
Clinical symptoms	Tenderness localized along the deep venous system	+1
	Swelling of the entire leg	+1
	Calf swelling ≥ 3 cm compared to asymptomatic calf	+1
	Unilateral pitting edema in symptomatic leg	+1
	Presence of collateral (non-varicose) superficial veins	+1
Differential diagnosis	Alternative diagnosis at least as likely as DVT	-2
Interpretation 2 risk group < 2: DVT unlikely (low risk) ≥ 2: DVT likely (high risk) OR 3 risk group 0: low risk 1–2: moderate risk of DVT ≥ 3: high risk of DVT

Compression ultrasonography with Doppler (test of choice)

• Description
  • A combination of ultrasonography (to visualize the vein) and Doppler (to assess blood flow abnormalities) in which the examiner applies gentle pressure to normally compressible veins using an ultrasound probe
  • High sensitivity and specificity in the popliteal and femoral veins, but very operator dependent
• Indications: clinical suspicion of a DVT or pulmonary embolism
• Findings: noncompressibility of the obstructed vein, visible hyperechoic mass, absent or abnormal flow in Doppler imaging

D-dimer testing

• High sensitivity (∼ 95%), low specificity (∼ 50%)
• Useful for ruling out DVT (normal D-dimer levels rule out DVT)
• Elevated D-dimers alone are not proof of DVT.

Further diagnostic tests

• Venography: (angiography)
  • Most accurate assessment of calf veins and valvular competency
  • Indications: obesity, severe edema, equivocal results in previous tests
• CT scan: : suspected pulmonary embolism or underlying malignancy
• Thrombophilia screening (coagulation studies)
  • Indications: young patients, unusual thrombus localization, positive family history
  • At earliest, tests should be performed 2 weeks after discontinuing anticoagulation.
• General tumor screening
  • Indications: idiopathic thrombosis (esp. patients > 50 years)
  • Tests: CBC, renal function tests, liver function tests, urinalysis; , and chest x-ray
  • Ensure that patient is up-to-date on all age-appropriate cancer screening (e.g., colonoscopy, mammogram, digital rectal exam)

References:^{[12][13][14][15][16][17][18]}

Superficial thrombophlebitis

• Definition: Inflammation and thrombosis of a superficial vein, most commonly in the leg. It may co-exist with DVT, and it rarely causes PE.
• Risk factors: same as for DVT (see risk factors for deep vein thrombosis above), but also
  • Varicose veins
  • Venous cannulation, IV drug administration
  • Behçet disease
  • Thromboangiitis obliterans ^[19]
• Variants
  • Thrombophlebitis migrans (Trousseau syndrome)
  • Superficial thrombophlebitis of the breast (Mondor disease)
• Clinical features: pain, tenderness, induration, and erythema overlying a superficial vein, often with a palpable cord (the thrombosed vein)
• Diagnostics
  • Typically a clinical diagnosis
  • Duplex ultrasound
    • Indicated if the clinical diagnosis is not clear
    • Findings: A thickened, edematous, noncompressible vessel with or without an intraluminal thrombus
  • Tests to diagnose the underlying cause: See “Further diagnostic tests” under “Diagnostics” above.
• Treatment
  • Symptomatic: NSAIDs, compression, elevation of the affected limb
  • Anticoagulation (e.g., LMWH, fondaparinux) if larger segments of the vein (≥ 5cm) are affected
  • DVT treatment if the thrombus is close to the junction with the deep venous system (see “Treatment” below)
• Complications
  • Extension into the deep veins → DVT
  • Infection (septic thrombophlebitis)
  • Distal embolization (PE)

Other differential diagnoses of DVT

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

References:^{[20][15][21][22]}

The differential diagnoses listed here are not exhaustive.

Anticoagulation

• Acute therapy
  • Heparin bolus plus constant heparin infusion for 4–5 days
    • Unfractionated heparin or low molecular weight heparin (see also parenteral anticoagulation)
    • Alternatively: fondaparinux (factor Xa inhibitor)
  • Target: Achieve and maintain an aPTT of 1.5x–2.5x the mean of the control value or upper normal limit.
  • Simultaneous initiation of warfarin once aPTT is therapeutic
• Secondary prophylaxis
  • Warfarin with target therapeutic INR of 2.0–3.0
    • Duration of treatment
      • First thrombosis: usually 3–6 months
      • For confirmed thrombophilia and recurrent thrombosis: indefinite
  • OR direct oral factor Xa inhibitor (i.e., rivaroxaban, apixaban)
    • Regular monitoring of coagulation parameters not required → improved patient compliance
    • Duration of treatment: at least 3 months

Additional therapy

• Thrombolysis
  • Goal: faster resolution of thrombi
  • Indications
    • Slow response to anticoagulation
    • Pulmonary embolism with hemodynamic instability
    • Can be considered for acute proximal DVT of the leg
  • Agents: streptokinase, urokinase, tissue plasminogen activator
  • Catheter-directed thrombolysis: The thrombolytic agent is administered directly at the site of obstruction via a venous catheter.
• Thrombectomy
  • Intravenous thrombus removal via a catheter
  • Indications
    • Insufficient response to anticoagulation and thrombolysis
    • Extensive thrombus
    • Phlegmasia cerulea dolens
  • Low-dose heparin is required prior to the procedure.
• Inferior vena cava filter : (Greenfield filter): indicated in patients with DVT at high risk of developing pulmonary embolism who have contraindications to anticoagulation, thrombolysis, and thrombectomy (e.g., active bleeding, recent major surgery, recent intracranial hemorrhage)
• Compression therapy with bandages or compression stockings
• Early mobilization as early as tolerated, minimize bedrest.

References:^{[12][23][24][2][4][25][26][27]}

• Pulmonary embolism
• Postthrombotic syndrome (chronic venous insufficiency)

References:^[2]

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