Deep venous thrombosis

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Deep-vein thrombosis, also known as deep-venous thrombosis (DVT), is the formation of a blood clot ("thrombus") in a deep vein. It commonly affects the leg veins, such as the femoral vein or the popliteal vein or the deep veins of the pelvis. Occasionally the veins of the arm are affected (known as Paget-Schrötter disease). Embolism and thrombosis is the more general class of pathologies of this kind.

Thrombi may develop first in the calf veins (calf vein thrombosis), "growing" in the direction of flow of the vein. DVTs are distinguished as being above or below the trifucation of the popliteal vein. Very extensive DVTs can extend into the iliac veins or the inferior vena cava. The risk of pulmonary embolism is higher in the presence of more extensive clots.

Epidemiology

DVTs occur in about 1 per 1000 persons per year. About 1-5% will die from the complications (i.e. pulmonary embolism).

DVT is much less common in the pediatric population. About 1 in 100,000 people under the age of 18 experiences deep vein thrombosis, possibly due to a child's high rate of heartbeats per minute, relatively active lifestyle when compared with adults, and fewer comorbodities (e.g. malignancy).

Medical inpatients at risk of DVT can be identified with clinical prediction rules.[1][2]

Predicting which medical inpatients will develop DVT.[1][2]
  heading
RAM[1] prior VTE
order for bed rest
PICC insertion
cancer
Kucher score[2]

Cancer 3 points
Prior VTE 3
Hypercoagulability 3
Major surgery 2
Bed rest 1
Age >70 years 1
Obesity (BMI >30) 1
Estrogens 1

Cause/etiology

Virchow's triad

Many factors are involved in the formation of a thrombus (clot). Virchow's triad is a group of 3 factors known to affect clot formation: rate of flow, the consistency (thickness) of the blood, and qualities of the vessel wall. Among the risk factors are advanced age, obesity, infection, immobilization, female sex, use of oral contraceptives, tobacco usage and air travel ("economy class syndrome", a combination of immobility and relative dehydration) are some of the better-known causes.[3] Thrombophilia (tendency to develop thrombosis) often expresses itself with recurrent thromboses.

Underlying malignancy

DVT may be due to underlying malignancy, especially if the DVT is associated with older age, idiopathic DVT, bilateral thrombosis, or anemia.[4] These patients have a worse prognosis.

Genetics

A twin study found a genetic contribution to venous thromboembolism among men but not women.[5] Among men, the concordance rates for mono- and dizygotic twin pairs were 0.22 and 0.08.

Various single-nucleotide polymorphisms (SNPs) have been associated with DVT.[6]

Signs and symptoms

There may be no symptoms referrable to the location of the DVT, but the classical symptoms of DVT include pain, swelling and redness of the leg and dilatation of the surface veins. In up to 25% of all hospitalized patients, there may be some form of DVT, which often remains clinically inapparent (unless pulmonary embolism develops).

There are several techniques during physical examination to increase the detection of DVT, such as measuring the circumference of the affected and the contralateral limb at a fixed point (to objectivate edema), and palpating the venous tract, which is often tender. Physical examination is unreliable for excluding the diagnosis of deep vein thrombosis.

A careful history has to be taken considering risk factors (see below), including the use of estrogen-containing methods of hormonal contraception, recent long-haul flying, and a history of miscarriage (which is a feature of several disorders that can also cause thrombosis). A family history can reveal a hereditary factor in the development of DVT.

It is vital that the possibility of pulmonary embolism be included in the history, as this may warrant further investigation (see pulmonary embolism).

Complications As a complication, post-thrombotic syndrome can develop. Post-phlebitic syndrome occurs in 10% of patients with deep vein thrombosis (DVT). It presents with leg oedema, pain, nocturnal cramping, venous claudication, skin pigmentation, dermatitis and ulceration (usually on the medial aspect of the lower leg). In phlegmasia alba dolens, the leg is pale and cool with a diminished arterial pulse due to spasm. It usually results from acute occlusion of the iliac and femoral veins due to DVT. In phlegmasia cerulea dolens, there is an acute and nearly total venous occlusion of the entire extremity outflow, including the iliac and femoral veins. The leg is usually painful, cyanosed and oedematous. Venous gangrene may supervene.

Diagnosis

Homan's sign is used in clinical practice to diagnose DVT.

The gold standard is intravenous venography, which involves injecting a peripheral vein of the affected limb with a contrast agent and taking X-rays, to reveal whether the venous supply has been obstructed. Because of its invasiveness, this test is rarely performed.

Impedance plethysmography and Doppler ultrasonography are non-invasive alternatives.

Probability scoring for lower extremity DVT

Wells rule

The best studied clinical prediction rule is the Wells rule; however, use of the Wells rule is complicated by the rule having been modified over time. For example, in a recent review, the version of the Wells rule used in the articles was not clear although studies were published over a range of years.[7] This has resulted in guidelines recommending use of outdated versions of the Wells rule.[8] The rule was introduced in 1995.[9]

2003[10]-2006[11] Wells 10 point rule:
  1. Active cancer (treatment within last 6 months or palliative) -- 1 point
  2. Calf swelling >3cm compared to other calf (measured 10cm below tibial tuberosity) -- 1 point
  3. Collateral superficial veins (non-varicose) -- 1 point
  4. Pitting edema (confined to symptomatic leg) -- 1 point
  5. Swelling of entire leg - 1 point
  6. Localized pain along distribution of deep venous system -- 1 point
  7. Paralysis, paresis, or recent cast immobilization of lower extremities -- 1 point
  8. Recently bedridden > 3 days, or major surgery requiring regional or general anesthetic in past 12 weeks -- 1 point
  9. Previously documented DVT -- 1 point
  10. Alternative diagnosis at least as likely -- Subtract 2 points

Interpretation:

Score of 2 or higher - deep vein thrombosis is likely. Consider imaging the leg veins.
Score of less than 2 - deep vein thrombosis is unlikely. Consider blood test such as d-dimer test to further rule out deep vein thrombosis.

2003 Wells 10 point rule:In 2003, Wells published a 10 point rule that adds a point for history of previous DVT (yellow box).[10] In 2006, Wells reviewed the available clinical prediction rules for DVT and did not further modify the 2003 rule.[11]

Based on his 2003 study, Wells recommends that DVT is excluded only when the 10-point score is < 2 and the D-dimer is negative.[11] Independent studies validate the Wells 10 point rule.[12][13][7] However, the d-dimer assays vary; for rapid quantitative immunoturbidimetric assays, a cutoff of 1.0 <g/mL is used.[12]

Earlier version: 1995 Original Wells 12 point rule:[9]
Major points

  • Active cancer (treatment ongoing or within previous 6 months or palliative)
  • Paralysis, paresis. or recent plaster irnmobilisation of the lower extremities
  • Recently bedridden >3 days and/or major surgery within 4 weeks
  • Localised tenderness along tl’e distribution of the deep venous system
  • Thigh and calf swollen (should be measured)
  • Calf swelling 3cm >symptornless side (measured 10cm below tibial tuberosity
  • Strong family history of (NT (2 first degree relatives with history of CVI)

Minor points

  • History of recent trauma C 60 days) to the symptomatic leg
  • Pitting oedema; symptomatic leg only
  • Dilated superficial veins (non-varicose) in symptomatic leg only
  • Hospitisation within previous 6 months
  • Erythema

Earlier version: 1997 Wells 9 point rule:[14]

  1. Active cancer (treatment ongoing or within previous 6 months or palliative) - 1 point
  2. Paralysis, paresis, or recent plaster immobilisation of the lower extremities - 1 point
  3. Recently bedridden for more than 3 days or major surgery, within 4 weeks - 1 point
  4. Localised tenderness along the distribution of the deep venous system - 1 point
  5. Entire leg swollen - 1 point
  6. Calf swelling by more than 3 cm when compared with the asymptomatic leg (measured 10 cm below tibial tuberosity) - 1 point
  7. Pitting oedema (greater in the symptomatic leg) - 1 point
  8. Collateral superficial veins (non-varicose) - 1 point
  9. Alternative diagnosis as likely or greater than that of deep-vein thrombosis - subtract 2 points
Interpretation: low (score 0), medium (score of 1 or 2), or high (score 3)

In 2005 a large study found that the 1997 Wells score failed to adequately exclude DVT in primary care patients.[15] Unfortunately, the 2005 study was completed in March, 2003, 6 months prior to publication of the 2003 revision by Wells to his rule in which he added a 10th variable.

AMUSE Primary Care Rule

Because of concerns about the failed study in 2005 of the older, 9-point 1997 Wells rule (not that the current Wells rule has 10 points)[15], the Amsterdam Maastricht Utrecht Study on thromboEmbolism (AMUSE) Investigators developed a rule with 7 clinical variable plus the D-dimer.[16][17] Patients with a score of 3 or less are considered normal; patients with a score of 4 should receive ultrasonography.

  • Use of hormonal contraceptives
  • Active cancer in past 6 mo
  • Surgery in previous month
  • Absence of leg trauma
  • Distention of collateral leg veins
  • Difference in calf circumference ≥ 3 cm (2 points)
  • Abnormal d-dimer assay (6 points)

Patients with score ≥ 4 should receive ultrasonography of the leg.

The AMUSE investigators report that their rule and the Wells 10 variable rule perform similarly.[13] This rule has not been externally validated by independent research groups.

Probability scoring for upper extremity DVT

The Constans Clinical Decision Score may help. Its components are:[18]

  • Venous material present (Centeral venous catheter or pacemaker thread) (1 point)
  • Localized pain (1 point)
  • Unilateral edema (1 point)
  • Other diagnosis at least as plausible (-1 point)

A score of 1 or less, along with negative d-dimer, excluded DVT. Thus, the d-dimer should be checked on every patient suspected of upper extremity DVT.

Imaging the leg veins

Ultrasonography

Compression B-mode ultrasonography[19] scanning of the leg veins, combined with Duplex Doppler ultrasonography[20] (to determine blood flow), can reveal a thrombus.

Distinguishing acute versus chronic thrombosis with Duplex Doppler ultrasonography has been examined in one study of 103 examination in 101 patients:[21]

In this study "no results were false-positive for acute DVT due to the changes of chronic DVT."

Whole leg ultrasonography
Risk outcomes following a single negative whole-leg compression ultrasonography according to a systematic review.[22]
Wells score Death (%) from embolism and thrombosis (95% CI)
All patients 0.7%
Low risk 0.3% (0 to 0.7%)
Intermediate risk 0.8% (0 to 1.8%)
High risk 2.5% (0 to 7.1%)

Either whole leg Doppler ultrasonography or serial 2-point ultrasonography plus D-dimer are equivalent strategies according to a randomized controlled trial[23] that was included in the meta-analysis.

An uncontrolled cohort study found that anticoagulation can be safely withheld in patients with normal whole leg Doppler ultrasonography.[24]

Venography

Venography can determine acute versus chronic thrombosis:[21]

  • Acute thrombosis is suggested by any of:
    • "constant filling defect or thrombus was identified"
    • "persistent nonfilling of a venous segment despite adequate technique"
    • " abrupt termination of the opaque column of contrast material in a venous segment"
  • Chronic thrombosis is suggested by any of:
    • "irregular walls suggestive of retracted adherent thrombus"
    • "a lumen smaller than expected"
    • "numerous well-developed adjacent collateral veins"
    • "Valvular incompetence in the deep veins was considered further evidence of chronic DVT but was not required for the diagnosis."

Blood tests

In a low-probability situation, current practice is to commence investigations by testing for D-dimer levels. A low D dimer level should prompt other possible diagnoses (such as a ruptured Baker's cyst, if this has not been considered as part of the history).

  • D-dimer levels. This cross-linked fibrin degradation product is an indication that thrombosis is occurring, and that the blood clot is being dissolved by plasmin. Interpretation may be increased by using age adjusted levels:[25]
    • "In patients younger than 50 years, PE was excluded in those with a D-dimer value lower than 500 µg/L.{"
    • "In patients 50 years or older, the D-dimer test result was considered negative in those with a D-dimer value lower than their age multiplied by 10."

Other blood tests usually performed at this point are:

Differential diagnosis

Rupture of the tendon of the plantaris muscle may mimic deep venous thrombosis.[26]

Prophylaxis (Prevention)

General Medical Inpatients

Clinical practice guidelines state:

  • American College of Physicians (ACP) in 2011:[27][28]
    • "ACP recommends assessment of the risk for thromboembolism and bleeding in medical (including stroke) patients prior to initiation of prophylaxis of venous thromboembolism (Grade: strong recommendation, moderate-quality evidence)."
    • "ACP recommends pharmacologic prophylaxis with heparin or a related drug for venous thromboembolism in medical (including stroke) patients unless the assessed risk for bleeding outweighs the likely benefits (Grade: strong recommendation, moderate-quality evidence)."
    • "ACP recommends against the use of mechanical prophylaxis with graduated compression stockings for prevention of venous thromboembolism (Grade: strong recommendation, moderate-quality evidence)."
    • "ACP does not support the application of performance measures in medical (including stroke) patients that promotes universal venous thromboembolism prophylaxis regardless of risk."
  • American College of Chest Physicians (ACCP) in 2011:[29]
  • "For acutely ill hospitalized medical patients at increased risk of thrombosis, we recommend anticoagulant thromboprophylaxis with low-molecular-weight heparin (LMWH), low-dose unfractionated heparin (LDUH) bid, LDUH tid, or fondaparinux (Grade 1B) and suggest against extending the duration of thromboprophylaxis beyond the period of patient immobilization or acute hospital stay (Grade 2B).
  • "For acutely ill hospitalized medical patients at low risk of thrombosis, we recommend against the use of pharmacologic prophylaxis or mechanical prophylaxis (Grade 1B)."
  • "For acutely ill hospitalized medical patients at increased risk of thrombosis who are bleeding or are at high risk for major bleeding, we suggest mechanical thromboprophylaxis with graduated compression stockings (GCS) (Grade 2C) or intermittent pneumatic compression (IPC) (Grade 2C)."
  • "For critically ill patients, we suggest using LMWH or LDUH thromboprophylaxis (Grade 2C). For critically ill patients who are bleeding or are at high risk for major bleeding, we suggest mechanical thromboprophylaxis with GCS and/or IPC at least until the bleeding risk decreases (Grade 2C)."
  • "In outpatients with cancer who have no additional risk factors for VTE we suggest against routine prophylaxis with LMWH or LDUH (Grade 2B) and recommend against the prophylactic use of vitamin K antagonists (Grade 1B)."

Extending anticoagulation for an addition 28 days may benefit patients who are "women, patients older than 75 years, and those with level 1 mobility. Level I mobility is being bed rest or sedentary without bathroom privileges."[30]

Compression devices that are mobile may be effective.[31]

Rosuvastatin, a hydroxymethylglutaryl-coenzyme A reductase inhibitor (statin), may reduce embolism and thrombosis according to the Jupiter randomized controlled trial.[32]

Studies on implementing guidelines are available.[2][33]

Oncology patients

According to a clinical practice guideline by the American Society of Clinical Oncology, "all hospitalized cancer patients should be considered for VTE prophylaxis with anticoagulants in the absence of bleeding or other contraindications."[34]

For oncology patients who have had a thrombus, consider lifelong prophylaxis with enoxaparin 1.5 mg/kg per day.[35]

Surgery Patients

The risk of DVT after surgery may persist up to 12 weeks.[36]

Hip or knee surgery

Clinical practice guidelines by the American College of Chest Physicians[37] and the American Academy of Orthopaedic Surgeons[38] address prevention. Unfortunately, these guidelines have substantial conflict.[39]

Low molecular weight heparins may provide better anticoagulation for prophylaxis of deep venous thrombosis among orthopedic patients than direct thrombin inhibitors because the latter may increase complications.[40] However, if anticoagulation is started before surgery, direct thrombin inhibitors may be more effective.

Extending anticoagulation (25-35 days) with low molecular weight heparin, such as enoxaparin 30 to 40 mg subcutaneously once daily can reduce symptomatic DVT in one of every 45 patients treated and can reduce any (symptomatic or assymptomatic) DVT in one of every 8 patients treated.[41] As these studies were short term, it is likely that some patients with asymptomatic DVT progress to chronic venous insufficiency.

Even knee arthroscopic meniscectomy may benefit from low molecular weight heparin.[42]

Factor Xa inhibitors

Spinal surgery

Clinical practice guidelines by the American College of Chest Physicians address this topic.[47]

Travelers

Travel may[48] or may not[49] lead to DVT according to meta-analyses.

Trials suggests that wearing compression socks while traveling also reduces the incidence of thrombosis in people on long haul flights. A randomized study in 2001 compared two sets of long haul airline passengers, one set wore travel compression hosiery the others did not. The passengers were all scanned and blood tested to check for the incidence of DVT. The results showed that asymptomatic DVT occurred in 10% of the passengers who did not wear compression socks. The group wearing compression had no DVTs. The authors concluded that wearing elastic compression hosiery reduces the incidence of DVT in long haul airline passengers.[50].

Therapy

Treatment options have been reviewed.[51]

Regarding the duration of anticoagulation, see embolism and thrombosis: treatment.
  • Elastic compression stockings have been strongly encouraged.[55][57] The stockings in almost all trials were stronger than routine anti-embolism stockings and created either 20-30 mm Hg or 30-40 mm Hg. Most trials used knee-high stockings. A meta-analysis of randomized controlled trials by the Cochrane Collaboration showed reduced incidence of post-phlebitic syndrome.[58] The number needed to treat is quite potent at 4 to 5 patients need to prevent one case of post-phlebitic syndrome.[59] However, a more recent trial found that prophylactic use of compression stockings after deep venous thrombosis may not prevent venous insufficiency.[60]Compression stocking can cause local complications.[61]
  • Inferior vena cava filter also referred to as a Greenfield filter, reduces pulmonary embolism[62] and is an option for patients with an absolute contraindication to anticoagulant treatment (e.g., cerebral hemorrhage) or those rare patients who have objectively documented recurrent PEs while on anticoagulation. However these filters are themselves potential foci of thrombosis,[63] IVC filters are viewed as a temporizing measure for preventing life-threatening pulmonary embolism.
  • Hospitalization should be considered in patients with more than two of the following risk factors as these patients may have more risk of complications during treatment[64]:
    • bilateral DVT, renal insufficiency, body weight <70 kg, recent immobility, chronic heart failure, and cancer

Oncology patients

A clinical practice guideline published in 2004 by the American College of Chest Physicians states:[65]

"for patients with DVT and cancer, we recommend LMWH for the first 3 to 6 months of long-term anticoagulant therapy (Grade 1A). For these patients, we recommend anticoagulant therapy indefinitely or until the cancer is resolved".

A clinical practice guideline published in 2007 by the American Society of Clinical Oncology states:[34]

"1) low molecular weight heparin LMWH is the preferred approach for the initial 5 to 10 days of anticoagulant treatment of the cancer patient with established VTE, 2) LMWH given for at least 6 months is also the preferred approach for long-term anticoagulant therapy. Vitamin K antagonists with a targeted INR of 2 to 3 are acceptable for long-term therapy when LMWH is not available. 3) After 6 months, indefinite anticoagulant therapy should be considered for selected patients with active cancer, such as those with metastatic disease and those receiving chemotherapy. This recommendation is based on Panel consensus in the absence of clinical trials data."

Determining when to stop treatment

D-Dimer

An abnormal D-dimer level at the end of treatment might signal the need for continued anticoagulation with warfarin among patients with embolism and thrombosis such as a first unprovoked pulmonary embolism.[66] If the D-dimer is abnormal, anticoaguation should be continued, if the D-dimer is normal, the duration of treatment is uncertain.[67] In an observation study that collected the D-dimer before stopping anticoagulation, the D-dimer was not as predictive.[68]

Ultrasonography

Ultrasonography, using the following protocol may[69] or may not[70] help determine when to stop anticoaguation[69]:

"If veins had not recanalized, we invited patients to have further ultrasonography after 3 and 9 months in patients with secondary DVT and after 3, 9, 15, and 21 months in those with unprovoked DVT. Anticoagulation was discontinued when the veins had recanalized, along with further ultrasonography"

Prognosis

Reducing the risk of recurrence after an unprovoked deep venous thrombosis.[71] [72] [66] [73] [74]
  Treatment or test Risk if treated or test result is favorable Risk if not treated or test result is unfavorable Comments
Randomized controlled trial[71] Aspirin 100 mg daily for 2 years 6% per year 11.2% per year 0.5% major bleeding
Randomized controlled trial[72] Rivaroxaban for 6-12 months 1% over 6-12 months 7% over 6-12 months 0.7% major bleeding
Systematic review of a diagnostic test[66][74] Normal d-dimer 4% per year 9% per year
Systematic review of a diagnostic test[73] Recanalization of veins (no residual vein obstruction or RVO) Insignificant difference

Postthrombotic syndrome

Postthrombotic syndrome along with postphlebitic syndrome are forms of venous insufficiency. Postthrombotic syndrome is a "condition caused by one or more episodes of deep vein thrombosis, usually the blot clots are lodged in the legs. Clinical features include edema; pain; aching; heaviness; and muscle cramp in the leg. When severe leg swelling leads to skin breakdown, it is called venous stasis ulcer."[75][76]

The incidence of postthrombotic syndrome is 76.1 per 100,000 person-years.[77] Regarding the etiology of the postthrombotic syndrome, about 40% are from prior DVT[78] although only 25% of patients report a prior diagnosis of DVT[77]. This suggests nearly half of the prior DVTs were undiagnosed.

Natural history of a diagnosed DVT

The natural history of a diagnosed DVT is as follows. After two years, the probability of postthrombotic syndrome is:[79]

  • No postthrombotic syndrome 60%
  • Mild postthrombotic syndrome 26%
  • Moderate postthrombotic syndrome 11%
  • Severe postthrombotic syndrome 3%

Risk factors include:

  • Prior ipsilateral DVT
  • Obesity
  • Female gender
  • Older age

After 5 to 10 years: One cohort reported 28% incidence (using a definition that required more significant symptoms)at five years.[80]

Among patients 6 to 8 years after a DVT, two studies provide risks:

  • "42% reported pain, swelling, or discoloration."[81]
  • A second study found 70% risk at 8 years.[63]

After 10 to 20 years: Although after 20 years, only 26.8% of patients will have sought medical care and be diagnosed with late complications of DVT[82], when patients are actively studied 10-20 years after their initial thrombosis, 80% have some signs of postthrombotic syndrome.[83]

Recurrent DVT

Risk factors for recurrence if anticoagulation is stopped are:[84]

  • post-thrombotic symptoms such as "hyperpigmentation, edema or redness of either leg"
  • D-dimer > or = 250 microg/L while taking warfarin> Other studies suggest the D-dimer should be checked after stopping warfarin.
  • body mass index > or = 30 kg/m(2)
  • age > or = 65 years
  • male gender

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