Deep vein thrombosis: Difference between revisions

Deep vein thrombosis
Deep vein thrombosis
Other names	Deep venous thrombosis;
	DVT in the right leg with swelling and redness
Specialty	Various
Symptoms	Pain, swelling, redness, or warmth of the affected area
Complications	Pulmonary embolism, post-thrombotic syndrome
Risk factors	Recent surgery, older age, cancer, history of VTE, family history, trauma, lack of movement, obesity, hormonal birth control, pregnancy and the period following birth, antiphospholipid syndrome, certain genetic conditions
Diagnostic method	Ultrasound
Differential diagnosis	Ruptured Baker's cyst, cellulitis, hematoma, varicose veins
Prevention	Frequent walking, calf exercises, aspirin, anticoagulants (blood thinners), intermittent pneumatic compression, graduated compression stockings
Treatment	Anticoagulation, graduated compression stockings
Medication	Low-molecular-weight heparin, warfarin, direct oral anticoagulant
Frequency	1–2 out of 1,000 people per year

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Deep vein thrombosis (DVT) is the formation of a blood clot in a deep vein, most commonly in the legs or pelvis.^[6]^[a] Symptoms can include pain, swelling, redness, or warmth of the affected area, but some DVTs have no symptoms.^[1] Complications can include pulmonary embolism, as a result of detachment of a clot, which travels to the lungs, and post-thrombotic syndrome.^[1]^[2] Together, DVT and pulmonary embolism are known as venous thromboembolism (VTE).^[1]

The mechanism of clot formation typically involves some combination of decreased blood flow rate, increased tendency to clot, and injury to the blood vessel wall.^[1] Risk factors include recent surgery, older age, cancer, history of VTE, family history, trauma, lack of movement, obesity, hormonal birth control, pregnancy and the period following birth, antiphospholipid syndrome, and certain genetic conditions.^[1]^[2] Genetic factors include non-O blood type, deficiencies of antithrombin, protein C, and protein S and the mutations of factor V Leiden and prothrombin G20210A.^[2] As of 2019, a total of 33 locations on human DNA have been identified that contribute to VTE risk.^[7]

Individuals suspected of having DVT can be assessed using a clinical prediction rule such as the Wells score.^[2]^[3] A D-dimer test can also be used to assist with excluding the diagnosis or to signal a need for further testing.^[1] Diagnosis is most commonly confirmed by ultrasound of the suspected veins.^[1] An estimated 4–10% of DVTs affect the arms.^[8]

Anticoagulation (blood thinners) is the standard treatment.^[1] Typical medications include low-molecular-weight heparin, a direct oral anticoagulant, or warfarin.^[2] Preventive efforts following surgery can include early and frequent walking, calf exercises, aspirin, anticoagulants, graduated compression stockings, or intermittent pneumatic compression.^[4] The rate of DVTs increases from childhood to old age; in adulthood, about one in 1000 adults are affected per year.^[9] About 5% of people are affected by a VTE at some point in time.^[3]

Signs and symptoms

Signs and symptoms of DVT, while highly variable, include pain or tenderness, swelling, warmth, dilation of surface veins, redness or discoloration, and cyanosis with fever.^[10] Although, some with DVT have no symptoms.^[11] Signs and symptoms alone are not sufficiently sensitive or specific to make a diagnosis, but when considered in conjunction with pre-test probability, can help determine the likelihood of DVT.^[11] In most suspected cases, DVT is ruled out after evaluation,^[12] and symptoms are more often due to other causes, such as cellulitis, ruptured Baker's cyst, musculoskeletal injury and hematoma, lymphedema, and chronic venous insufficiency.^[11]^[13] Other differential diagnoses include tumors, venous or arterial aneurysms, and connective tissue disorders.^[14]

Causes

The disease term venous thromboembolism (VTE) includes the development of either DVT or pulmonary embolism (PE).^[15]^[16] The three factors of Virchow's triad—venous stasis, hypercoagulability, and changes in the endothelial blood vessel lining (such as physical damage or endothelial activation)—contribute to VTE and are used to explain its formation.^[17]^[18] Other related causes include activation of immune system components, the state of microparticles in the blood, the concentration of oxygen, and possible platelet activation.^[19] Various risk factors contribute to VTE, though many at high risk never develop it.^[20]

Acquired risk factors include the strong risk factor of older age,^[10] which alters blood composition to favor clotting.^[21] Previous VTE, particularly unprovoked VTE, is a strong risk factor.^[22] Major surgery and trauma increase risk because of tissue factor from outside the vascular system entering the blood.^[17] Minor leg injuries,^[23] lower limb amputation,^[24] hip fracture, and long bone fractures are also risks.^[6] In orthopedic surgery, venous stasis can be temporarily provoked by a cessation of blood flow as part of the procedure.^[19] Inactivity and immobilization contribute to venous stasis, as with orthopedic casts,^[25] paralysis, sitting, long-haul travel, bed rest, hospitalization,^[17] and in survivors of acute stroke.^[26] Conditions that involve compromised blood flow in the veins are May–Thurner syndrome, where a vein of the pelvis is compressed, and venous thoracic outlet syndrome, which includes Paget–Schroetter syndrome, where compression occurs near the base of the neck.^[27]^[28]^[29]

Cancer can grow in and around veins, causing venous stasis, and can also stimulate increased levels of tissue factor.^[30] Cancers of the bone, ovary, brain, pancreas, and lymphomas are especially associated with increased VTE risk.^[24] Chemotherapy treatment also increases risk.^[18] Obesity increases the potential of blood to clot, as does pregnancy. In the postpartum, placental tearing releases substances that favor clotting. Oral contraceptives^[b] and hormonal replacement therapy increase the risk through a variety of mechanisms, including altered blood coagulation protein levels and reduced fibrinolysis.^[19]

Family history of VTE is a risk factor for a first VTE.^[32] Genetic factors that increase the risk of VTE include deficiencies of three proteins that normally prevent blood from clotting—protein C, protein S, and antithrombin. Deficiencies in antithrombin, protein C, and protein S^[c] are rare but strong, or moderately strong, risk factors.^[17]^[19] These three deficiencies increase the risk of VTE by about 10 times.^[23] Factor V Leiden, which makes factor V resistant to inactivation by activated protein C,^[32] mildly increases VTE risk^[d] by about three times.^[7]^[32] Having a non-O blood type roughly doubles VTE risk.^[19] Non-O blood type is common globally, making it an important risk factor.^[34] Individuals without O blood type have higher blood levels of von Willebrand factor and factor VIII than those with O blood type, increasing the likelihood of clotting.^[34] The genetic variant prothrombin G20210A, which increases prothrombin levels,^[17] increases risk by about 2.5 times.^[7] Additionally, approximately 5% of people have been identified with a background genetic risk comparable to the factor V Leiden and prothrombin G20210A mutations.^[7]

Inflammatory diseases^[19]^[35] such as Behçet's syndrome,^[36] and some autoimmune diseases,^[37] such as primary antiphospholipid syndrome^[38] and systemic lupus erythematosus (SLE),^[39] increase risk. SLE itself is frequently associated with antiphospholipid syndrome.^[40] Other associated conditions include heparin-induced thrombocytopenia,^[41] thrombotic storm,^[42] catastrophic antiphospholipid syndrome,^[43] paroxysmal nocturnal hemoglobinuria,^[44] nephrotic syndrome,^[20] infection,^[20]^[35] HIV,^[20] polycythemia vera,^[25] intravenous drug use,^[45]^[46] and smoking.^[e] Blood alterations including dysfibrinogenemia,^[25] low free protein S,^[20] activated protein C resistance,^[20] hyperhomocysteinemia,^[17] high fibrinogen levels,^[17], high factor IX levels,^[17] and high factor XI levels^[17] are associated with increased risk.

Some risk factors influence the location of DVT within the body. In isolated distal DVT, the profile of risk factors appears distinct from proximal DVT. Transient factors, such as surgery and immobilization, appear to dominate, whereas thrombophilias^[f] and age do not seem to increase risk.^[49] Common risk factors for having an upper extremity DVT include having an existing foreign body (such as a central venous catheter, a pacemaker, or a triple-lumen PICC line), cancer, and recent surgery.^[8]

Pathophysiology

DVT often develops in the calf veins and "grows" in the direction of venous flow, towards the heart.^[50] When DVT does not grow, it can be cleared naturally and dissolved into the blood (fibrinolysis).^[51] Veins in the leg or pelvis are most commonly affected,^[6] including the popliteal vein (behind the knee), femoral vein (of the thigh), and iliac veins of the pelvis. Extensive lower-extremity DVT can even reach into the or the inferior vena cava (in the abdomen).^[52] Upper extremity DVT most commonly affects the subclavian, axillary, and jugular veins.^[8]

The causes of arterial thrombosis, such as with heart attacks, are more clearly understood than those of venous thrombosis.^[53] With arterial thrombosis, blood vessel wall damage is required, as it initiates coagulation,^[53] but clotting in the veins mostly occurs without any such damage.^[17] The beginning of venous thrombosis is thought to be caused by tissue factor, which leads to conversion of prothrombin to thrombin, followed by fibrin deposition.^[18] Red blood cells and fibrin are the main components of venous thrombi,^[17] and the fibrin appears to attach to the blood vessel wall lining (endothelium), a surface that normally acts to prevent clotting.^[53] Platelets and white blood cells are also components. Platelets are not as prominent in venous clots as they are in arterial ones, but they can play a role.^[19] Inflammation is associated with VTE,^[g] and white blood cells play a role in the formation and resolution of venous clots.^[51]

Often, DVT begins in the valves of veins.^[51] The blood flow pattern in the valves can cause low oxygen concentrations in the blood (hypoxemia) of a valve sinus. Hypoxemia, which is worsened by venous stasis, activates pathways—ones that include hypoxia-inducible factor-1 and early-growth-response protein 1. Hypoxemia also results in the production of reactive oxygen species, which can activate these pathways, as well as nuclear factor-κB, which regulates hypoxia-inducible factor-1 transcription.^[18] Hypoxia-inducible factor-1 and early-growth-response protein 1 contribute to monocyte association with endothelial proteins, such as P-selectin, prompting monocytes to release tissue factor-filled microvesicles, which presumably begin clotting after binding to the endothelial surface.^[18]

Diagnosis

DVT diagnosis requires the use of imaging devices such as ultrasound. Clinical assessments, which predict DVT likelihood, can help determine if a D-dimer test is useful. In those not highly likely to have DVT, a normal D-dimer result^[h] can rule out a diagnosis.

Classification

Provoked DVTs occur in association with acquired risk factors, such as surgery, oral contraceptives, trauma, immobility, obesity, or cancer; cases without acquired states are called unprovoked or idiopathic.^[55] Acute DVT is characterized by pain and swelling^[56] and is usually occlusive,^[57] which means that it obstructs blood flow, whereas non-occlusive DVT is less symptomatic.^[58] The label "chronic" has been applied to symptomatic DVT that persists longer than 10 to 14 days.^[59] DVT that has no symptoms, but is found only by screening, is labeled asymptomatic or incidental.^[60]^[61] An initial episode of DVT is called incident and any subsequent DVT is termed recurrent.^[62]^[63] Bilateral DVT refers to clots in both legs while unilateral means that only a single leg is affected.^[64]

DVT in the legs is proximal when above the knee and distal (or calf) when below the knee.^[65]^[66] DVT below the popliteal vein, a proximal vein behind the knee, is classified as distal^[57] and has limited clinical significance compared to proximal DVT.^[67] Iliofemoral DVT involves at a minimum the common iliac vein (see image below).^[11] Upper extremity DVT occurs in the arms or the base of the neck. Phlegmasia alba dolens and phlegmasia cerulea dolens occur when a DVT is very large and causes significant obstruction of the veins (complete or near-complete occlusion). In the former, the affected leg is white and painful as the congestion is so severe that the arterial blood supply is reduced. In the latter, the arterial supply is reduced to the point that there is a blue tinge and venous gangrene can develop, generally with severe pain.^[68]^[58]

The iliac veins (in the pelvis) include the external iliac vein, the internal iliac vein, and the common iliac vein

Probability

Swelling in the leg from fluid (edema) can result in "pitting" after pressure is applied. (This person did not have DVT.)

In those with suspected DVT, a clinical assessment of probability can be useful to determine which tests to perform.^[69]^[70] The most studied clinical prediction rule is the Wells score.^[12]^[71]

Wells score or criteria: (possible score −2 to 9)

Active cancer (treatment within last 6 months or palliative): +1 point
Calf swelling ≥ 3 cm compared to asymptomatic calf (measured 10 cm below tibial tuberosity): +1 point
Swollen unilateral superficial veins (non-varicose, in symptomatic leg): +1 point
Unilateral pitting edema (in symptomatic leg): +1 point
Previous documented DVT: +1 point
Swelling of entire leg: +1 point
Localized tenderness along the deep venous system: +1 point
Paralysis, paresis, or recent cast immobilization of lower extremities: +1 point
Recently bedridden ≥ 3 days, or major surgery requiring regional or general anesthetic in the past 12 weeks: +1 point
Alternative diagnosis at least as likely: −2 points^[10]

Those with Wells scores of two or more have a 28% chance of having DVT, those with a lower score have 6% probability. Alternatively, Wells scores can be categorized as high if greater than two, moderate if one or two, and low if less than one, with likelihoods of 53%, 17%, and 5%, respectively.^[12]^[13]

D-dimer

D-dimers are a fibrin degradation product, and an elevated level can result from plasmin dissolving a clot—or other conditions.^[54] Hospitalized patients often have elevated levels for multiple reasons.^[12]^[72] When individuals are at a high-probability of having DVT, diagnostic imaging is preferred to a D-dimer test.^[70]^[73] For those with a low or moderate probability of DVT, a D-dimer level can be obtained, which excludes a diagnosis if results are normal.^[54] An elevated level requires further investigation with diagnostic imaging to confirm or exclude the diagnosis.^[74]^[75]

For a suspected first leg DVT in a low-probability situation, the American College of Chest Physicians recommends testing either D-dimer levels with moderate or high sensitivity or compression ultrasound of the proximal veins. These options are suggested over whole-leg ultrasound, and D-dimer testing is the suggested preference overall.^[74] The UK National Institute for Health and Care Excellence (NICE) recommends D-dimer testing prior to proximal vein ultrasound.^[70]

For a suspected first leg DVT in a moderate-probability scenario, a high-sensitivity D-dimer is suggested as a recommended option over ultrasound imaging, with both whole-leg and compression ultrasound possible.^[75] The NICE guideline uses a two-point Wells score and does not refer to a moderate probability group.^[70]

Imaging

Imaging tests of the veins are used in the diagnosis of DVT, most commonly either proximal compression ultrasound or whole-leg ultrasound. Each technique has drawbacks: a single proximal scan might miss a distal DVT, while whole-leg scanning can lead to distal DVT overtreatment.^[12] Doppler ultrasound,^[76] CT scan venography, MRI venography, or MRI of the thrombus are also possibilities.^[12]^[74]

Ultrasonography for suspected deep vein thrombosis has a sensitivity of 97% in detecting DVTs of the proximal legs.^[77]

The gold standard for judging imaging methods is contrast 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 cost, invasiveness, availability, and other limitations, this test is rarely performed.^[12] In one study, it found a DVT in an additional 20% of patients with pulmonary embolism where an ultrasonography was negative.^[78]

An ultrasound with a blood clot visible in the left common femoral vein. (The common femoral vein is distal to the external iliac vein.)
Doppler ultrasonography showing absence of flow and hyperechogenic content in a clotted femoral vein (labeled subsartorial) distal to the branching point of the deep femoral vein. (Subsartorial is a proposed name for a section of the femoral vein.)^[79]
An abdominal CT scan demonstrating an iliofemoral DVT, with the clot in the right common iliac vein of the pelvis

Prevention

For the prevention of blood clots in the general population, the Centers for Disease Control and Prevention recommends an active lifestyle including leg exercises and walking when sitting for hours at a time as well as maintaining a healthy body weight.^[80] Walking and leg exercises reduce venous stasis because leg muscle contractions compress the veins and pump blood up towards the heart.^[81] Excess body weight is another risk factor that can be modified, and as such, interventions and lifestyle modifications that help someone lose weight work to reduce DVT risk.^[32] Depending upon the risk for DVT, different preventive measures can be recommended. In immobile individuals, physical compression methods improve blood flow.

Anticoagulation, which increases the risk of bleeding, is sometimes used in high-risk scenarios. The risk of major bleeding with long-term anticoagulation is about 3% per year,^[23] and the point where annual VTE risk is thought to warrant long-term anticoagulation is estimated to be between 3 and 9%.^[82] Usually, only when individuals exceed a 9% annual VTE risk is long-term anticoagulation a common consideration.^[82] For example, antithrombin deficiency, a strong or moderately strong risk factor, carries an annual risk of VTE of only 0.8–1.5%;^[23] as such, asymptomatic individuals with thrombophilia do not warrant long-term anticoagulation.^[83]

Statins have been investigated as a potential primary prevention measure to reduce VTE occurrence. The JUPITER trial, which used rosuvastatin, has provided some tentative evidence of effectiveness.^[84]^[7] Out of all the statins that have been studied, rosuvastatin appears to be the only one with the potential to reduce VTE risk.^[85]

Hospital (non-surgical) patients

Low-molecular weight heparin is usually given by subcutaneous injections with a needle under the skin of these colored areas

A 2014 Cochrane review found that using heparin in medical patients did not change the risk of death or pulmonary embolism.^[86] While its use decreased people's risks of DVTs, it also increased people's risks of major bleeding.^[86] The review thus recommended the need to balance risks and benefits.^[86]

The 2012 ACCP guidelines for nonsurgical patients^[87]^[i] recommend anticoagulation for the acutely ill in cases of elevated risk when neither bleeding nor a high risk of bleeding exists.^[88] Mechanical prophylaxis is suggested when risks for bleeding and thrombosis are elevated.^[89] For the critically ill, either pharmacological or mechanical prophylaxis is suggested depending upon the risk.^[90] Heparin can also be used in outpatients with cancer who have solid tumors and additional risk factors for VTE—listed as "previous venous thrombosis, immobilization, hormonal therapy, angiogenesis inhibitors, thalidomide, and lenalidomide"—and a low risk of bleeding.^[91]

After surgery

Major orthopedic surgery—total hip replacement, total knee replacement, or hip fracture surgery—has a high risk of causing VTE.^[92] If prophylaxis is not used after these surgeries, symptomatic VTE has about a 4% chance of developing within 35 days.^[93] Options for VTE prevention in people following nonorthopedic surgery include early walking, mechanical prophylaxis (intermittent pneumatic compression or graduated compression stockings), and drugs (low-molecular-weight heparin and low-dose-unfractionated heparin) depending upon the risk of VTE, risk of major bleeding, and person's preferences.^[94] Following major orthopedic surgery, the ACCP recommends treatment with drugs that reduce the risk of clots (such as fondaparinux and aspirin) with low-molecular-weight heparin (LMWH) suggested as a preference.^[93] Intermittent pneumatic compression is also an option.^[93]^[95] Graduated compression stockings are effective after both general and orthopedic surgery.^[5]

Pregnancy

The risk of VTE is increased in pregnancy by about five times^[23]^[96] because of a more hypercoagulable state, a likely adaptation against fatal postpartum hemorrhage.^[97] Additionally, pregnant women with genetic risk factors are subject to a roughly three to 30 times increased risk for VTE.^[98] Preventive treatments for pregnancy-related VTE in hypercoagulable women were suggested by the ACCP in 2012. Homozygous carriers of factor V Leiden or prothrombin G20210A with a family history of VTE were suggested for antepartum LMWH and either LMWH or a vitamin K antagonist (VKA) for the six weeks following childbirth. Those with another thrombophilia and a family history but no previous VTE were suggested for watchful waiting during pregnancy and LMWH or—for those without protein C or S deficiency—a VKA. Homozygous carriers of factor V Leiden or prothrombin G20210A with no personal or family history of VTE were suggested for watchful waiting during pregnancy and LMWH or a VKA for six weeks after childbirth. Those with another thrombophilia but no family or personal history of VTE were suggested for watchful waiting only.^[99] Warfarin, a common VKA, can cause harm to the fetus and is not used for VTE prevention during pregnancy.^[98]^[100]

Travelers

Suggestions for at-risk long-haul travelers^[j] include calf exercises, frequent walking, and aisle seating in airplanes to ease walking.^[101]^[102] Graduated compression stockings have sharply reduced the levels of asymptomatic DVT in airline passengers, but the effect on symptomatic DVT, PE, or mortality is unknown, as none of the individuals studied developed these outcomes.^[103] However, graduated compression stockings are not suggested for long-haul travelers (>4 hours) without risk factors for VTE. Likewise, neither aspirin nor anticoagulants are suggested in the general population undertaking long-haul travel.^[104] Those with significant VTE risk factors^[k] undertaking long-haul travel are suggested to use either graduated compression stockings or LMWH for VTE prevention. If neither of these two methods are feasible, then aspirin is suggested.^[104]

Treatment

Anticoagulation

Structural representations of the backbone of heparins (left), which vary in the size of their chain, and the synthetic pentasaccaride (five-sugar) fondaparinux (right)

Treatment for DVT is warranted when the clots are either proximal, distal and symptomatic, or upper extremity and symptomatic.^[105] Anticoagulation, which prevents further coagulation, but does not act directly on existing clots, is the standard treatment for DVT.^[106]^[l] Balancing risk vs. benefit is important in determining the duration of anticoagulation, and three months is generally the standard length of treatment.^[70] In those with an annual risk of VTE in excess of 9%, as after an unprovoked episode, extended anticoagulation is a possibility.^[82] Those who finish VKA treatment after idiopathic VTE with an elevated D-dimer level show an increased risk of recurrent VTE (about 9% vs about 4% for normal results), and this result might be used in clinical decision-making.^[108] Thrombophilia test results rarely play a role in the length of treatment.^[38] Two forms of direct oral anticoagulants (DOACs) have been developed: oral direct thrombin inhibitors and oral factor Xa inhibitors, which can be an effective and safe alternative to warfarin for acute DVT.^[109]

For acute cases in the leg, the ACCP recommended a parenteral anticoagulant (such as LMWH, fondaparinux, or unfractionated heparin) for at least five days^[m] and a VKA, the oral anticoagulant, the same day. LMWH and fondaparinux are suggested over unfractionated heparin, but both are retained in those with compromised kidney function, unlike unfractionated heparin.^[111]^[112] The VKA is generally taken for a minimum of three months^[113] to maintain an international normalized ratio of 2.0–3.0, with 2.5 as the target.^[114]^[115] The benefit of taking a VKA declines as the duration of treatment extends,^[116] and the risk of bleeding increases with age.^[15]

The ACCP recommended treatment for three months in those with proximal DVT provoked by surgery.^[117] A three-month course is also recommended for those with proximal DVT provoked by a transient risk factor, and three months is suggested over lengthened treatment when bleeding risk is low to moderate.^[118] Unprovoked DVT patients should have at least three months of anticoagulation and be considered for extended treatment.^[119] Those whose first VTE is an unprovoked proximal DVT are suggested for anticoagulation longer than three months unless there is a high risk of bleeding.^[120] In that case, three months is sufficient.^[121] Those with a second unprovoked VTE are recommended for extended treatment when bleeding risk is low, suggested for extended treatment when bleeding risk is moderate,^[122] and suggested for three months of anticoagulation in high-risk scenarios.^[123]

Stockings, walking, and repeat imaging

The ACCP recommended initial home treatment instead of hospital treatment for those with acute leg DVT. This applies as long as individuals feel ready for it, and those with severe leg symptoms or comorbidities would not qualify. An appropriate home environment is expected: one that can provide a quick return to the hospital if necessary, support from family or friends, and phone access.^[124] Walking is suggested for those without severe pain or edema.^[125] Graduated compression stockings—which apply higher pressure at the ankles and a lower pressure around the knees^[111] might be used for symptomatic management of acute DVT symptoms, but they are not recommended for reducing the risk of post-thrombotic syndrome,^[126] as the potential benefit of using them for this goal "may be uncertain".^[10] Nor are compression stockings likely to reduce VTE recurrence.^[127]

Instead of anticoagulation, a follow-up imaging test (typically ultrasound) about one-week post-diagnosis is an option for those with an acute isolated distal DVT without a high risk for extension; if the clot does not grow, the ACCP does not recommend anticoagulation.^[111]^[128] This technique can benefit those at a high risk for bleeding. Patients can choose anticoagulation over serial imaging, however, to avoid the inconvenience of another scan if concerns about the risk of bleeding are insignificant.^[128] When applied to symptomatic patients with a negative initial ultrasound result, serial testing is inefficient and not cost effective.^[57]

Interventions

Thrombolysis is the injection of an enzyme into the veins to dissolve blood clots, and while this treatment has been proven effective against the life-threatening emergency clots of stroke and heart attacks, randomized controlled trials^[129]^[130]^[131] have not established a net benefit in those with acute proximal DVT.^[10]^[132] Drawbacks of catheter-directed thrombolysis (the preferred method of administering the clot-busting enzyme^[10]) include a risk of bleeding, complexity,^[n] and the cost of the procedure.^[126] Thus, anticoagulation is the preferred treatment for DVT.^[126] However, this preference does not apply to those with DVT so severe that there is "impending venous gangrene".^[126] As of 2016, those thought to be the best candidates for catheter-directed thrombosis have iliofemoral DVT, symptoms for less than 14 days, good functional status (ability to perform one's activities of daily living), life expectancy of at least 1 year, and a low risk of bleeding.^[70]^[126] Phlegmasia cerulea dolens (bottom left image) might be treated with catheter-directed thrombolysis.^[11] Of note, however, is that a variety of contraindications to thrombolysis exist.^[126] Identifying who might benefit from thrombolysis is a goal of future research.^[132]

Phlegmasia cerulea dolens (literally: painful blue edema) is a particularly severe form of acute, proximal, and occlusive DVT. It is life-threatening and limb-threatening.^[133]
A venogram before catheter-directed thrombolysis against Paget–Schroetter syndrome, a rare and severe arm DVT shown here in a judo practitioner, with highly restricted blood flow shown in the vein
After treatment with catheter-directed thrombolysis, blood flow in the axillary and subclavian vein were significantly improved. Afterwards, a first rib resection provided thoracic outlet decompression to reduce the risk of recurrent DVT and the risk of sequelae from thoracic outlet compression.^[134]

Inferior vena cava filters (IVC filters) are not recommended for those using the standard treatment for acute DVT, anticoagulation.^[126] NICE recommends IVC filters in settings where someone with an acute proximal DVT or PE cannot receive anticoagulation, and that the filter is removed when anticoagulation can be safely started.^[70] They are used on the presumption that they reduce PE, although their effectiveness and safety profile are not well established.^[135] In general, they are only recommended in some high-risk scenarios.^[135] The ACCP recommended them for those with a contraindication to anticoagulant treatment but not in addition to anticoagulation, unless an individual with an IVC filter but without a risk for bleeding develops acute proximal DVT. In this case, both anticoagulation and an IVC filter were suggested.^[136] While IVC filters themselves are associated with a long-term risk of DVT,^[135] they are not reason enough to maintain extended anticoagulation.^[137] In 2017, an expert panel with the American College of Cardiology stated that the judicious use of IVC filters was critical.^[138]

A mechanical thrombectomy device can remove venous clots, although the ACCP considers it an option only when the following conditions apply: "iliofemoral DVT, symptoms for < 7 days (criterion used in the single randomized trial), good functional status, life expectancy of ≥ 1 year, and both resources and expertise are available."^[111] Anticoagulation alone is suggested over thrombectomy.^[139]

Prognosis

PE is the most serious complication of proximal DVT, and the risk of PE is higher when clots are present in the thigh and pelvis.^[135] Distal DVT is hardly if ever associated with PE.^[12] Around 56% of those with proximal DVT have PE as well, although a chest CT is not needed simply because of the presence of a DVT.^[140] If proximal DVT is left untreated, in the following 3 months approximately half of people will experience symptomatic PE.^[6] Untreated lower extremity DVT has a 3% PE-related mortality rate, while deaths associated with upper extremity DVT are extremely rare.^[141]

Another frequent complication of proximal DVT is post-thrombotic syndrome,^[142] which is caused by a reduction in the return of venous blood to the heart.^[24] Some symptoms of post-thrombotic syndrome are pain, edema, paresthesia, and in severe cases, leg ulcers. After DVT, an estimated 20–50% of people develop the syndrome and 5–10% develop the severe form.^[142]

The presence of a remaining thrombus after a DVT occurs in a minority of people, and it increases the risk of recurrence, though to a lesser extent than an elevated D-dimer.^[24] VTE recurrence in those with prior DVT is more likely to recur as DVT than PE.^[143] Cancer^[10] and unprovoked DVT are strong risk factors for recurrence.^[22] In individuals who have an initial proximal unprovoked DVT, about 16% will have recurrent VTE in the 2 years after they complete their course of anticoagulants. If DVT and PE manifest together for an inital unprovoked DVT, the rate of recurrence in this timeframe is about 17%. VTE recurrence is less common in distal DVT than proximal DVT.^[144] In the 10 years following an inital VTE, approximately a third of people will have a recurrence.^[145] In upper extremity DVT, annual VTE recurrence is about 2–4%.^[15] After surgery, a provoked proximal DVT or PE has an annual recurrence rate of only 0.7%.^[22]

A seemingly unprovoked VTE might suggest the presence of an undiagnosed cancer,^[146] but it is not common practice to screen people with unprovoked VTE for the presence of cancer.^[22] Scanning individuals with a CT of the abdomen and pelvis in this scenario has not proven beneficial.^[147]

Epidemiology

About 1.5 out of 1000 adults a year have a first VTE in high-income countries.^[148]^[149] VTE is rare in children, with an incidence of about 1 in 100,000 a year. From childhood to old age, incidence increases by a factor of about 1000, with almost 1% of the elderly experiencing VTE yearly.^[150] About 60% of all VTEs occur in those 70 years of age or older.^[6] DVT occurs in the upper extremities in about 4–10% of cases.^[8] A minority of upper extremity DVTs are due to Paget–Schroetter syndrome, also called effort thrombosis, which occurs in 1–2 people out of 100,000 a year, usually in athletic males around 30 years of age or in those who do significant amounts of overhead manual labor.^[28]^[134]

During pregnancy and after childbirth, acute VTE occurs about 1.2 of 1000 deliveries. Despite it being relatively rare, it is a leading cause of maternal morbidity and mortality.^[151] After surgery with preventive treatment, VTE develops in about 10 of 1000 people after total or partial knee replacement, and in about 5 of 1000 after total or partial hip replacement.^[152] About 400,000 Americans develop an initial VTE each year, with 100,000 deaths or more attributable to PE.^[149] In England, an estimated 25,000 a year die from hospital-related VTE.^[153] For unclear reasons, people of Asian descent have a lower VTE risk than whites.^[9]

In North American and European populations, around 4–8% of people have a thrombophilia,^[23] most commonly factor V leiden and prothrombin G20210A. For populations in China, Japan, and Thailand, deficiences in protein S, protein C, and antithrombin predominate.^[154] Non-O blood type is present in around 50% of the general population and varies with ethnicity, and it is present in about 70% of those with VTE.^[34]^[155] Altogether, global data is incomplete.^[156] As of 2011, available data was dominated by North American and European populations.^[9]

Social

Being on blood thinners because of DVT can be life-changing for patients because it may prevent them from continuing lifestyle activities such as contact or winter sports to prevent bleeding episodes after potential injuries.^[158] Head injuries prompting brain bleeds are of particular concern. This has caused NASCAR driver Brian Vickers to forego participation in races. Professional basketball players including NBA players Chris Bosh and hall of famer Hakeem Olajuwon have dealt with recurrent blood clots,^[159] and Bosh's career was significantly hampered by DVT and PE.^[160] Tennis star Serena Williams was hospitalized in 2011 for PE thought to have originated from a DVT.^[161] Due to her knowledge of DVT and PE, in 2017, after feeling the sudden onset of a PE symptom, Serena accurately advocated for herself to have PE diagnosed and treated.^[157]

Other notable people have been affected by DVT. Former US President Richard Nixon had recurrent DVT,^[162] and so has former Secretary of State Hillary Clinton. She was first diagnosed while First Lady in 1998 and again in 2009.^[163] Dick Cheney was diagnosed with an episode while Vice President,^[164] and TV show host Regis Philbin had a DVT after hip-replacement surgery.^[165] DVT has also contributed to the deaths of famous people. For example, DVT and PE played a role in rapper Heavy D's death.^[166] NBC journalist David Bloom died while covering the Iraq War from a PE that was thought to have progressed from a missed DVT.^[167] And actor Jimmy Stewart had a DVT that progressed to a fatal PE when he was 87.^[165]

Field of medicine

Patients with a history of DVT might be managed by primary care, general internal medicine, hematology, cardiology, vascular surgery, or vascular medicine.^[168] Patients suspected of having an acute DVT are often referred to the emergency department for evaluation.^[169] Interventional radiology is the specialty that typically places and retrieves IVC filters,^[170] and vascular surgery might do catheter directed thrombosis for some severe DVTs.^[134]

History

Warfarin, a common vitamin K antagonist, was the mainstay of pharmocological treatment for about 50 years.

The earliest case of DVT was described by Sushruta in his book Sushruta Samhita around 600–900 BC.^[171] The next case was not described until 1271, in the leg of a 20-year-old male.^[171]^[172] At some point, the increased incidence of DVT in women after childbirth was noticed, and in the late 1700s, a public health recommendation was issued to encourage women to breastfeed as a means to prevent this phenomenon; the DVT was called "milk leg", as it was thought to result from milk building up in the leg.^[173]

In 1856, German physician and pathologist Rudolf Virchow published what is referred to as Virchow's triad, the three major causes of thrombosis.^[20]^[173] The triad provides the theoretical framework for the current explanation of venous thrombosis,^[20] although it was focused on the effect of a foreign body in the venous system and the conditions required for clot propagation.^[174]

Multiple pharmacological therapies for DVT were introduced in the 20th century: oral anticoagulants in the 1940s, subcutaneous injections of LDUH in 1962 and subcutaneous injections of LMWH in 1982.^[175] For around 50 years, a months-long warfarin (Coumadin) regimen was the mainstay of pharmacological treatment after several days of using a subcutaneous heparin.^[176]^[177] To avoid the blood monitoring required with warfarin and the injections required by heparin and heparin-like medicines, a new generation of anticoagulant pills that can be taken by mouth and do not require blood monitoring has sought to replace these traditional anticoagulants.^[177] In the late 2000s to early 2010s, direct oral anticoagulants—including dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis)—came to the market, making this field of medicine fast changing.^[22] The New York Times described a "furious battle" among the three makers of these drugs "for the prescription pads of doctors".^[176]

Diagnoses were commonly performed by impedance plethysmography in the 1970s and 1980s, but the use of Doppler ultrasound techniques, with their increased sensitivity and specificity, largely superseded this method.^[178]

Economics

Initial DVT costs for an average hospitalized patient in the U.S. are around $7,700–$10,800.^[179] VTE follow-up costs at three months, six months, and a year are about $5,000, $10,000, and $33,000 respectively; in Europe, the three and six-month figures are about €1,800 and €3,200.^[180] Post-thrombotic syndrome is a significant contributor to DVT follow-up costs.^[179] Annual DVT costs in the U.S. are an estimated $5 billion^[181] or in excess of $8 billion,^[182]^[183] and the average annual cost per treated individual is thought to be about $20,000.^[182] As an example, if 300,000 symptomatic DVT patients were treated at costs averaging $20,000 annually, that would cost $6 billion a year.

Research directions

A 2019 study published in Nature Genetics expanded the known genetic loci associated with VTE from 11 to 33.^[7] In their updated 2018 clinical practice guidelines, the American Society of Hematology identified 29 separate research priorities, most of which related to patients who are acutely or critically ill.^[104] Inhibition of Factor XI, P-selectin, E-selectin, and a reduction in formation of neutrophil extracellular traps are potential therapies that might treat VTE without increasing bleeding risk.^[184]

Notes

^ Thrombosis associated with the head (cerebral venous sinus thrombosis) and the abdominal organs (viscera)—such as portal vein thrombosis, renal vein thrombosis, and Budd–Chiari syndrome—are separate diseases excluded from the scope of this definition.
^ Third-generation combined oral contraceptives (COCs) have an approximate two to three times higher risk than second-generation COCs.^[24] Progestogen-only pill use is not associated with increased VTE risk.^[31]
^ Type I^[20]
^ Factor V Leiden increases the risk of DVT more than it does for PE, a phenomenon referred to as the factor V Leiden paradox.^[33]
^ "It is important to note that smoking is not an independent risk factor, although it increases the risk for cancers and other comorbidities and works synergistically with other independent risk factors."^[47]
^ The term 'thrombophilia' as used here applies to the five inherited abnormalities of antithrombin, protein C, protein S, factor V, and prothrombin, as is done elsewhere.^[23]^[48]
^ VTE might cause the observed inflammation.^[19]
^ An elevated level is greater than 250 ng/mL D-dimer units (DDU) or greater than 0.5 μg/mL fibrinogen equivalent units (FEU).^[54] A normal level is below these values.
^ Page e197S of Kahn et al.^[87] specifies that the guideline does not apply to those with "trauma and spinal cord injury" nor does it apply to those "with ischemic and hemorrhagic stroke."
^ Specified as those with "previous VTE, recent surgery or trauma, active malignancy, pregnancy, estrogen use, advanced age, limited mobility, severe obesity, or known thrombophilic disorder"
^ For example "recent surgery, history of VTE, postpartum women, active malignancy, or ≥2 risk factors, including combinations of the above with hormone replacement therapy, obesity, or pregnancy"^[104]
^ Evidence for anticoagulation comes from studies other than definitive randomized controlled trials that demonstrate efficacy and safety for anticoagulation vs. placebo or using NSAIDs.^[107]
^ The international normalized ratio should be ≥ 2.0 for 24 hours minimum,^[110] but if the ratio is > 3.0, then the parenteral anticoagulant is not needed for five days.^[111]
^ "Up to 83% of patients treated by any catheter-based therapy, need adjunctive angioplasty, and stenting".^[10]

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Cited literature

Dalen, James E. (2003). Venous thromboembolism. CRC Press. ISBN 978-0-8247-5645-1. {{cite book}}: Invalid |ref=harv (help); Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ (February 2012). "Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. 141 (2 Suppl): 7S–47S. doi:10.1378/chest.1412S3. PMC 3278060. PMID 22315257. {{cite journal}}: Invalid |ref=harv (help); Unknown parameter |displayauthors= ignored (|display-authors= suggested) (help)
Hecht ME (2010). A practical guide to hip surgery: From pre-op to recovery. Sunrise River Press. ISBN 978-1-934716-12-0. {{cite book}}: Invalid |ref=harv (help)
Rosendaal, Frits R. (2009). van Beek, Edwin J. R.; Büller, Harry R.; Oudkerk, Mathijs (eds.). Deep vein thrombosis and pulmonary embolism. John Wiley & Sons. ISBN 978-0-470-74499-4. {{cite book}}: Invalid |ref=harv (help); Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
Welch, Ellen (2010). Venous thromboembolism: A nurse's guide to prevention and management. John Wiley & Sons. ISBN 978-0-470-51189-3. {{cite book}}: Invalid |ref=harv (help); Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)

External links

Clinical prediction website – Wells score for deep vein thrombosis

[7] Thrombosis associated with the head (cerebral venous sinus thrombosis) and the abdominal organs (viscera)—such as portal vein thrombosis, renal vein thrombosis, and Budd–Chiari syndrome—are separate diseases excluded from the scope of this definition.

[33] Third-generation combined oral contraceptives (COCs) have an approximate two to three times higher risk than second-generation COCs.^[24] Progestogen-only pill use is not associated with increased VTE risk.^[31]

[35] Type I^[20]

[37] Factor V Leiden increases the risk of DVT more than it does for PE, a phenomenon referred to as the factor V Leiden paradox.^[33]

[52] "It is important to note that smoking is not an independent risk factor, although it increases the risk for cancers and other comorbidities and works synergistically with other independent risk factors."^[47]

[54] The term 'thrombophilia' as used here applies to the five inherited abnormalities of antithrombin, protein C, protein S, factor V, and prothrombin, as is done elsewhere.^[23]^[48]

[60] VTE might cause the observed inflammation.^[19]

[62] An elevated level is greater than 250 ng/mL D-dimer units (DDU) or greater than 0.5 μg/mL fibrinogen equivalent units (FEU).^[54] A normal level is below these values.

[96] Page e197S of Kahn et al.^[87] specifies that the guideline does not apply to those with "trauma and spinal cord injury" nor does it apply to those "with ischemic and hemorrhagic stroke."

[110] Specified as those with "previous VTE, recent surgery or trauma, active malignancy, pregnancy, estrogen use, advanced age, limited mobility, severe obesity, or known thrombophilic disorder"

[115] For example "recent surgery, history of VTE, postpartum women, active malignancy, or ≥2 risk factors, including combinations of the above with hormone replacement therapy, obesity, or pregnancy"^[104]

[119] Evidence for anticoagulation comes from studies other than definitive randomized controlled trials that demonstrate efficacy and safety for anticoagulation vs. placebo or using NSAIDs.^[107]

[124] The international normalized ratio should be ≥ 2.0 for 24 hours minimum,^[110] but if the ratio is > 3.0, then the parenteral anticoagulant is not needed for five days.^[111]

[146] "Up to 83% of patients treated by any catheter-based therapy, need adjunctive angioplasty, and stenting".^[10]

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@@ Line 159: / Line 159: @@
 | footer = Structural representations of the backbone of heparins (''left''), which vary in the size of their chain, and the synthetic pentasaccaride (five-sugar) [[fondaparinux]] (''right'')
 }}
-[[Anticoagulation]], which prevents further coagulation, but does not act directly on existing clots, is the standard treatment for DVT.<ref name="ADAM">{{cite web |url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001209/#adam_000156.disease.treatment |title=Deep venous thrombosis |date=19 February 2012 |encyclopedia=A.D.A.M. Medical Encyclopedia |publisher=PubMed Health |access-date=2 July 2012 |url-status=live |archive-url=https://web.archive.org/web/20120926073924/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001209/#adam_000156.disease.treatment |archive-date=26 September 2012  }}</ref>{{efn|Evidence for anticoagulation comes from studies other than definitive [[randomized controlled trial]]s that demonstrate [[efficacy]] and safety for anticoagulation vs. placebo or using [[NSAID]]s.<ref name="Cundiff">{{cite journal | vauthors = Cundiff DK, Manyemba J, Pezzullo JC | title = Anticoagulants versus non-steroidal anti-inflammatories or placebo for treatment of venous thromboembolism | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD003746 | date = January 2006 | pmid = 16437461 | doi = 10.1002/14651858.CD003746.pub2 | veditors = Cundiff DK }}</ref>}} Balancing risk vs. benefit is important in determining the duration of anticoagulation, and three months is generally the standard length of treatment.<ref name=NICECG144/> In those with an annual risk of VTE in excess of 9%, as after an unprovoked episode, extended<!--add note here--> anticoagulation is a possibility.<ref name="Keeling"/> Those who finish VKA treatment after idiopathic VTE with an elevated D-dimer level show an increased risk of recurrent VTE (about 9% vs about 4% for normal results), and this result might be used in clinical decision-making.<ref name="Douketis">{{cite journal | vauthors = Douketis J, Tosetto A, Marcucci M, Baglin T, Cushman M, Eichinger S, Palareti G, Poli D, Tait RC, Iorio A | display-authors = 6 | title = Patient-level meta-analysis: effect of measurement timing, threshold, and patient age on ability of D-dimer testing to assess recurrence risk after unprovoked venous thromboembolism | journal = Annals of Internal Medicine | volume = 153 | issue = 8 | pages = 523–31 | date = October 2010 | pmid = 20956709 | doi = 10.7326/0003-4819-153-8-201010190-00009 }}</ref> Thrombophilia test results rarely play a role in the length of treatment.<ref name="Baglin">{{cite journal | vauthors = Baglin T | title = Inherited and acquired risk factors for venous thromboembolism | journal = Seminars in Respiratory and Critical Care Medicine | volume = 33 | issue = 2 | pages = 127–37 | date = April 2012 | pmid = 22648484 | doi = 10.1055/s-0032-1311791 }}</ref> Two forms of [[direct oral anticoagulants]] (DOACs) have been developed: oral [[direct thrombin inhibitor]]s and oral [[Direct Xa inhibitor|factor Xa inhibitors]], which can be an effective and safe alternative to warfarin for acute DVT.<ref>{{cite journal | vauthors = Robertson L, Kesteven P, McCaslin JE | title = Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis | journal = The Cochrane Database of Systematic Reviews | issue = 6 | pages = CD010956 | date = June 2015 | pmid = 26123214 | doi = 10.1002/14651858.CD010956.pub2 | editor-last = Cochrane Vascular Group }}</ref>
+Treatment for DVT is warranted when the clots are either proximal, distal and symptomatic, or upper extremity and symptomatic.<ref name=2017CC>{{cite journal | vauthors = Bartholomew JR | title = Update on the management of venous thromboembolism | journal = Cleveland Clinic Journal of Medicine | volume = 84 | issue = 12 Suppl 3 | pages = 39–46 | date = December 2017 | pmid = 29257737 | doi = 10.3949/ccjm.84.s3.04 | doi-access = free}}</ref> [[Anticoagulation]], which prevents further coagulation, but does not act directly on existing clots, is the standard treatment for DVT.<ref name="ADAM">{{cite web |url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001209/#adam_000156.disease.treatment |title=Deep venous thrombosis |date=19 February 2012 |encyclopedia=A.D.A.M. Medical Encyclopedia |publisher=PubMed Health |access-date=2 July 2012 |url-status=live |archive-url=https://web.archive.org/web/20120926073924/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001209/#adam_000156.disease.treatment |archive-date=26 September 2012  }}</ref>{{efn|Evidence for anticoagulation comes from studies other than definitive [[randomized controlled trial]]s that demonstrate [[efficacy]] and safety for anticoagulation vs. placebo or using [[NSAID]]s.<ref name="Cundiff">{{cite journal | vauthors = Cundiff DK, Manyemba J, Pezzullo JC | title = Anticoagulants versus non-steroidal anti-inflammatories or placebo for treatment of venous thromboembolism | journal = The Cochrane Database of Systematic Reviews | issue = 1 | pages = CD003746 | date = January 2006 | pmid = 16437461 | doi = 10.1002/14651858.CD003746.pub2 | veditors = Cundiff DK }}</ref>}} Balancing risk vs. benefit is important in determining the duration of anticoagulation, and three months is generally the standard length of treatment.<ref name=NICECG144/> In those with an annual risk of VTE in excess of 9%, as after an unprovoked episode, extended<!--add note here--> anticoagulation is a possibility.<ref name="Keeling"/> Those who finish VKA treatment after idiopathic VTE with an elevated D-dimer level show an increased risk of recurrent VTE (about 9% vs about 4% for normal results), and this result might be used in clinical decision-making.<ref name="Douketis">{{cite journal | vauthors = Douketis J, Tosetto A, Marcucci M, Baglin T, Cushman M, Eichinger S, Palareti G, Poli D, Tait RC, Iorio A | display-authors = 6 | title = Patient-level meta-analysis: effect of measurement timing, threshold, and patient age on ability of D-dimer testing to assess recurrence risk after unprovoked venous thromboembolism | journal = Annals of Internal Medicine | volume = 153 | issue = 8 | pages = 523–31 | date = October 2010 | pmid = 20956709 | doi = 10.7326/0003-4819-153-8-201010190-00009 }}</ref> Thrombophilia test results rarely play a role in the length of treatment.<ref name="Baglin">{{cite journal | vauthors = Baglin T | title = Inherited and acquired risk factors for venous thromboembolism | journal = Seminars in Respiratory and Critical Care Medicine | volume = 33 | issue = 2 | pages = 127–37 | date = April 2012 | pmid = 22648484 | doi = 10.1055/s-0032-1311791 }}</ref> Two forms of [[direct oral anticoagulants]] (DOACs) have been developed: oral [[direct thrombin inhibitor]]s and oral [[Direct Xa inhibitor|factor Xa inhibitors]], which can be an effective and safe alternative to warfarin for acute DVT.<ref>{{cite journal | vauthors = Robertson L, Kesteven P, McCaslin JE | title = Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis | journal = The Cochrane Database of Systematic Reviews | issue = 6 | pages = CD010956 | date = June 2015 | pmid = 26123214 | doi = 10.1002/14651858.CD010956.pub2 | editor-last = Cochrane Vascular Group }}</ref>
 For acute cases in the leg, the ACCP recommended a [[parenteral]] anticoagulant (such as LMWH, fondaparinux, or unfractionated heparin) for at least five days{{efn|The international normalized ratio should be ≥ 2.0 for 24 hours minimum,<ref>[[#CITEREFGuyattAklCrowtherGutterman2012|Guyatt et al. 2012]], p. 20S: 2.4.</ref> but if the ratio is > 3.0, then the parenteral anticoagulant is not needed for five days.<ref name="Kearon2"/><!--e435S-->}} and a VKA, the oral anticoagulant, the same day. LMWH and fondaparinux are suggested over unfractionated heparin, but both are retained in those with compromised kidney function, unlike unfractionated heparin.<ref name="Kearon2"/><!--e435S--><ref>[[#CITEREFGuyattAklCrowtherGutterman2012|Guyatt et al. 2012]], p. 20S: 2.5.1.</ref> The VKA is generally taken for a minimum of three months<ref>[[#CITEREFGuyattAklCrowtherGutterman2012|Guyatt et al. 2012]], pp. 20S–21S: 3.1.</ref> to maintain an international normalized ratio of 2.0–3.0, with 2.5 as the target.<ref name="Strijkers">{{cite journal | vauthors = Strijkers RH, Cate-Hoek AJ, Bukkems SF, Wittens CH | title = Management of deep vein thrombosis and prevention of post-thrombotic syndrome | journal = BMJ | volume = 343 | pages = d5916 | date = October 2011 | pmid = 22042752 | doi = 10.1136/bmj.d5916 | url = https://semanticscholar.org/paper/f88e2ecee25752d2ed8376dff8da5d81656013da }}</ref><ref>[[#CITEREFGuyattAklCrowtherGutterman2012|Guyatt et al. 2012]], p. 22S: 3.2.</ref> The benefit of taking a VKA declines as the duration of treatment extends,<ref>{{cite journal | vauthors = Middeldorp S, Prins MH, Hutten BA | title = Duration of treatment with vitamin K antagonists in symptomatic venous thromboembolism | journal = The Cochrane Database of Systematic Reviews | issue = 8 | pages = CD001367 | date = August 2014 | pmid = 25092359 | doi = 10.1002/14651858.CD001367.pub3 }}</ref> and the risk of bleeding increases with age.<ref name="de Jong"/>

Classification	D ICD-10: I80.2 ICD-9-CM: 453.40 MeSH: D020246 DiseasesDB: 3498
External resources	MedlinePlus: 000156 eMedicine: med/2785 Patient UK: Deep vein thrombosis