Deep vein thrombosis (Phlebothrombosis)

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.

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

Risk factors for venous thromboembolism [6][7]
Transient risk factors	Chronic risk factors
Surgical factors Surgery under general anesthesia Cesarean delivery Immobilization Acute illness requiring complete bed rest Lower extremity injury with restricted mobility for ≥ 3 days Long-distance travel Estrogen-related factors Pregnancy Use of OCPs or HRT Intravascular devices, such as: Indwelling venous catheter Implanted pacemaker or cardiac defibrillator leads Patient factors Obesity Smoking IV drug use Nonadherence to VTE prophylaxis	Patient factors Age > 60 years Personal or family history of DVT or PE [8] Prothrombotic chronic illnesses Active cancer Nephrotic syndrome [9] Autoimmune disorders APLA syndrome Inflammatory bowel disease Hereditary thrombophilia Factor V Leiden Antithrombin III deficiency, protein C deficiency, and protein S deficiency Prothrombin mutation

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-Hypercoaguability, 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”).

Modified Wells criteria for deep vein thrombosis [18][19][20]
Criteria		Score
Medical history	Active cancer	+ 1
	Previously documented DVT	+ 1
Immobilization	Paralysis, paresis, or recent (cast) immobilization of lower extremity	+ 1
	Recently bedridden for ≥ 3 days OR underwent major surgery within the past 12 weeks under general/local anesthesia	+ 1
Clinical features	Tenderness localized along the deep venous system	+ 1
	Swelling of the entire leg	+ 1
	Calf swelling ≥ 3 cm compared to the contralateral leg	+ 1
	Pitting edema confined to the symptomatic leg	+ 1
	Distended collateral superficial veins (nonvaricose)	+ 1
Differential diagnosis	Alternative diagnosis as likely as or more likely than DVT	- 2
Interpretation (pretest probability for DVT) [21] 0: low 1–2: intermediate ≥ 3: high

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

Diagnostic approach for suspected lower-extremity DVT [21][4][22]
Test result		Pretest probability
		Low	Intermediate	High
Initial D-dimer	Negative (< 500 ng/mL)	DVT ruled out	Initial D-dimer is not diagnostically helpful in this risk group. [23]
	Positive (≥ 500 ng/mL)	Possible DVT; proceed to venous US
Venous ultrasound (US) [22]	Negative	DVT ruled out		Repeat venous US within a week if no alternate diagnosis [4]
	Positive	DVT confirmed; screen for an underlying cause if no risk factors for DVT are identified on initial evaluation.
	Inconclusive	Consider venography, CT venography, or MR venography.

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 ^{[21][27][4][22]}

• 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 ^[27][4]

• 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.

Approach ^[23][7]

• 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.

Therapeutic approach to DVT [23][22][7]
Options	Indications
Expectant management (i.e., serial venous ultrasound over 2 weeks)	Isolated distal DVT without severe symptoms or risk factors for clot extension (see “Expectant management” for details) [23]
Primary treatment only (i.e., anticoagulation for 3–6 months)	Isolated distal DVT with severe symptoms and/or risk factors for clot extension Any of the following in a patient with high bleeding risk: Proximal DVT (provoked or unprovoked) Recurrent DVT (provoked or unprovoked) DVT provoked by a transient risk factor
Primary treatment PLUS secondary prevention (i.e., anticoagulation for 3–6 months PLUS extended anticoagulation of indefinite duration)	Any of the following in a patient with low or moderate bleeding risk: Unprovoked proximal DVT Unprovoked recurrent DVT DVT provoked by chronic risk factors (e.g., active cancer, thrombophilia)
Advanced therapy (e.g., catheter-directed thrombolysis, thrombectomy, IVC filter)	Consider in the following situations: Acute iliofemoral DVT Limb-threatening ischemia DVT in a patient with contraindications to anticoagulation

Expectant management ^[23][22][7]

• Indication: asymptomatic or only mildly symptomatic isolated distal DVT without risk factors for clot extension
• Relative contraindications
  • Severe symptoms
  • Risk factors for clot extension
    • Markedly elevated D-dimer levels
    • Thrombosis > 5 cm in length and/or > 0.7 cm in diameter
    • Thrombosis of multiple distal veins
    • Thrombosis in close proximity to the proximal leg veins
    • Past history of VTE
• Measures
  • Serial venous US for 2 weeks after symptom onset to identify clot extension
  • If evidence of clot extension is:
    • Absent: No further management is required.
    • Confined to distal veins: Consider anticoagulation.
    • Involves proximal veins: Initiate anticoagulation.

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

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) ^[23][41][7]

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) ^[23][7]
  • 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]

Disposition ^[23][41][7]

• Outpatient therapy is preferred for patients with uncomplicated DVT.
• Hospital admission during the acute phase is recommended for patients with:
  • Suspected limb ischemia
  • High bleeding risk
  • Inability or unwillingness to self-administer parenteral anticoagulant therapy
  • Significant comorbidities
  • Limited social supports
  • Pain requiring IV analgesia

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]

Approach to VTE prophylaxis [54][55][56]
	Indications	Choice of prophylaxis [57][58]
Low-risk patients	Chronically ill medical or nursing home patients Medical outpatients with minor risk factors for VTE Minor general surgery Long-distance (> 4 hours) travelers without risk factors for DVT	Pharmacological or mechanical VTE prophylaxis is not routinely required. Encourage general preventative measures.
At-risk outpatients	Long-distance (> 4 hours) travelers with an additional risk factor for DVT [54]	First-line: mechanical prophylaxis preferred; consider LMWH, e.g., enoxaparin as an alternative Second-line: full-dose ASA [59]
	Patients with active cancer PLUS additional VTE risk factors without high bleeding risk	First-line: LMWH, e.g., enoxaparin , or low-dose UFH
Medical inpatients	Seriously ill or critically ill patients without high bleeding risk [60]	First-line: LMWH, e.g., enoxaparin ; consider fondaparinux for non-critically ill patients Second-line: low-dose UFH Third-line: mechanical VTE prophylaxis
	Seriously ill or critically ill medical patients with high bleeding risk	Preferred: mechanical VTE prophylaxis only, until bleeding risk subsides
Surgical patients	Hip arthroplasty Knee arthroplasty )	First-line: low-dose ASA or apixaban [23][61] Second-line: LMWH Third-line: low-dose UFH Fourth-line: mechanical VTE prophylaxis
	Major neurosurgical procedures with risk factors for DVT and low bleeding risk	First-line: LMWH, e.g., enoxaparin Second-line: low-dose UFH Third-line: mechanical VTE prophylaxis
	Major surgeries (non-neurosurgical) The following procedures in patients with risk factors for DVT: Laparoscopic cholecystectomy Urological surgery Major trauma in a patient with low to moderate bleeding risk	First-line: LMWH, e.g., enoxaparin , or low-dose UFH Second-line: mechanical VTE prophylaxis
	The following procedures in patients without risk factors for DVT: Major neurosurgical procedure Laparoscopic cholecystectomy Urological surgery Major trauma in patients with high bleeding risk	Preferred: mechanical VTE prophylaxis only

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.

• Pulmonary embolism: Pulmonary emboli most commonly originate in the proximal deep veins of the lower extremities.
• Postthrombotic syndrome (chronic venous insufficiency)

References:^[10]

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