Deep vein thrombosis

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"DVT" redirects here. For other uses, see DVT (disambiguation).
Deep vein thrombosis
Classification and external resources

A deep vein thrombosis in the right leg. Note the swelling and redness.
ICD-10 I80.2
ICD-9 453.40
DiseasesDB 3498
MedlinePlus 000156
eMedicine med/2785
MeSH D020246

Deep vein thrombosis (DVT) is the formation of a blood clot ("thrombus") in a deep vein. Deep vein thrombosis commonly affects the leg veins (such as the femoral vein, the popliteal vein, or the iliofemoral vein as in May-Thurner syndrome) or the deep veins of the pelvis. Occasionally the veins of the arm are affected (such as in Paget-Schrötter disease). A DVT can occur without symptoms, but in many cases the affected extremity will be painful, swollen, red, and warm, and the superficial veins may be engorged. The most serious complication of a DVT is that the clot could dislodge and travel to the lungs, which is called a pulmonary embolism (PE). DVT and PE are the two manifestations of the disease venous thromboembolism (VTE). DVT is a medical emergency, so, all limb swellings, however trivial, should be regarded as a DVT until proven otherwise. Untreated lower extremity DVT has a 3% PE-related mortality rate. Deaths associated with upper extremity DVT are extremely rare.[1] A late complication of DVT is the post-thrombotic syndrome, which can manifest itself as edema, pain or discomfort and skin problems.

According to Virchow's triad, venous thrombosis occurs due to three factors: decreased flow rate of the blood (venous stasis), damage or activation of the blood vessel wall and an increased tendency of the blood to clot (hypercoagulability). Several medical conditions can lead to DVT, such as physical trauma, cancer, infections and antiphospholipid syndrome. There are several factors which can increase a person's risk for DVT, including older age (the strongest risk factor), surgery, immobilization (as with bed-rest, orthopedic casts, or during long-haul flights), heavy smoking, obesity, certain drugs (such as oral contraceptives) and inborn tendencies to form clots known as thrombophilia (for example, in carriers of factor V Leiden). Women have an increased risk during pregnancy (due to altered blood protein levels) and in the postnatal period, partially due to substances released by the placenta.

The most commonly used tests for the diagnosis of DVT are a blood test called D-dimers and doppler ultrasound of the affected veins. Sometimes, further testing is required to find the cause of the DVT. Treatment for DVT is dominated by anticoagulation, but if not possible, an inferior vena cava filter may be used. Prevention of DVT is advised in at-risk medical and surgical inpatients with options such as early and frequent ambulation (walking), anticoagulants, graduated compression stockings or intermittent pneumatic compression (IPC).

Contents

[edit] Classification

DVTs can be lower extremity (from the lower limbs), upper extremity, abdominal or pelvic in origin.[2] DVTs in the legs are proximal (or iliofemoral)[3] when above the knee and distal when below the knee.[4] DVTs below the popliteal vein, a proximal vein behind the knee, are in distal calf veins.[5] An incident DVT is an initial episode and any subsequent DVTs are termed recurrent.[6] DVTs that have no symptoms, but are found only by screening, are termed asymptomatic.[7] Pain and swelling are symptoms of acute DVT.[8] Acute DVTs are usually occlusive,[5] meaning they obstruct blood flow, whereas nonocclusive DVTs are more asymptomatic.[9] The label of chronic has been applied to symptomatic DVTs which persist longer than 10 or 14 days.[10] A severe and uncommon form of DVT is phlegmasia cerulea dolens, which often develops on top of a life-threatening illness.[9][11] DVTs that develop in association with surgery are perioperative and can form during surgery (intraoperative) or afterwards (postoperative).[12]

A DVT is classified, together with a pulmonary embolism (PE), as a venous thromboembolism (VTE), a distinct disease state.[13]

[edit] Signs and symptoms

There may be no symptoms referable to the location of the DVT, but the classical symptoms of DVT include pain, swelling and redness of the leg and dilation 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.

In phlegmasia alba dolens, the leg is pale and cool with a diminished arterial pulse caused by spasm. It usually results from acute occlusion of the iliac and femoral veins because of 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 (blue from lack of oxygen) and edematous (filled with fluid). Venous gangrene may develop as a result.

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

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, intravenous drug use and a history of miscarriage (which is a feature of several disorders that can also cause thrombosis). In the case of long-haul flying, recent studies have shown that risk of DVT is higher in travellers who smoke, are obese, or are currently taking contraceptive pills.[14] A family history can reveal a hereditary factor in the development of DVT. Approximately 35 percent of DVT patients have at least one hereditary thrombophilia, including deficiencies in the anticoagulation factors protein C, protein S, antithrombin, or mutations in the factor V and prothrombin genes.[15]

[edit] Causes

Venous thrombi are recognized to be caused mainly by a combination of venous stasis and hypercoagulability—but to a lesser extent endothelial damage and activation.[16] The three factors of stasis, hypercoaguability, and alterations in the blood vessel wall represent Virchow's triad, and changes to the vessel wall are the least understood.[17] Various risk factors increase the likelhood of any one individual developing a thrombosis. Older age is the strongest risk factor;[17] after aging, blood composition favors clotting.[16]

[edit] Risk factors

[edit] Pathophysiology

DVTs usually develops first in the calf veins, "growing" in the direction of flow of the vein (proximally).[20] Also, there is a strong tendency for it to develop in the left leg (about 70 to 90% of the time) "possibly because of exacerbation of the compressive effects on the left iliac vein due to its being crossed by the right iliac artery."[21] Very extensive lower extremity DVTs can extend into the iliac veins or the inferior vena cava. Rarer DVTs can affect the upper extremities or the mesenteric (from the intestines) and pelvic veins.[2]

In contrast to the understanding for how arterial thromboses occur, as with heart attacks, venous thrombosis formation is not well understood.[22] With arterial thrombosis, blood vessel wall damage is required for thrombosis formation, as it initiates coagulation,[22] but the majority of venous thrombi form without any injured epithelium.[16]

Red blood cells and fibrin are the main components of venous thrombi,[16] and the thrombi appear to attach to the blood vessel wall endothelium, normally a non-thrombogenic surface, with fibrin.[22] Platelets in venous thorombi attach to downstream fibrin, while in arterial thrombi, they compose the core.[22] As a whole, platelets constitute less of venous thrombi when compared to arterial ones.[16] The beginning of the process is thought to be initiated by tissue factor effected thrombin production, which leads to fibrin deposition.[17]

The valves of veins are a recognized site of VT initiation. Due to the blood flow pattern, the base of the valve sinus is particularly deprived of oxygen (hypoxic). Stasis excacerbates hypoxia, and this state is linked to the activation of white blood cells (leukocytes) and the endothelium. Specifically, the two pathways of hypoxia-inducible factor-1 (HIF-1) and early growth response 1 (EGR-1) are activated by hypoxia, and they contribute to monocyte and endothelial activation. Hypoxia also causes reactive oxygen species (ROS) production that can activate HIF-1, EGR-1, and nuclear factor-κB (NF-κB), which regulates HIF-1 transcription.[17]

HIF-1 and EGR-1 pathways lead to monocyte association with endothelial proteins, such as P-selectin, prompting monocytes to release tissue factor filled microvesicles, which presumably initiate fibrin deposition (via thrombin) after binding the endothelial surface.[17]

[edit] Diagnosis

Abdominal computed tomographic scan showing a common iliac vein thrombosis. The arrow indicates the filling defect in the vein visualised using radiocontrast.

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.

[edit] Physical examination

Homans sign: Dorsiflexion of foot elicits pain in posterior calf. Pratt's sign: Squeezing of posterior calf elicits pain. However, these medical signs do not perform well and are not included in clinical prediction rules that combine best findings in order to diagnose DVT.[23]

[edit] Probability scoring

In 2006, Scarvelis and Wells overviewed a set of clinical prediction rules for DVT,[5] on the heels of a widely adopted set of clinical criteria for pulmonary embolism.[24][25]

Wells score or criteria: (Possible score -2 to 9)

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

[edit] Blood tests

An ultrasound image demonstrating a blood clot in the left common femoral vein.

[edit] D-dimer

In a low-probability situation, current practice is to commence investigations by testing for 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. A low D-dimer level should prompt other possible diagnoses (such as a ruptured Baker's cyst, if the patient is at sufficiently low clinical probability of DVT).[26][27]

[edit] Other blood tests

Other blood tests usually performed at this point are[citation needed]:

[edit] Imaging

Impedance plethysmography, Doppler ultrasonography, compression ultrasound scanning of the leg veins, combined with duplex measurements (to determine blood flow), can reveal a blood clot and its extent (i.e. whether it is below or above the knee). Duplex ultrasonography, due to its high sensitivity, specificity and reproducibility, has replaced venography as the most widely used test in the evaluation of the disease. This test involves both a B mode image and Doppler flow analysis. It is most sensitive and specific for detecting proximal thrombi (in the popliteal and femoral veins), but substantially less so for distal thrombi (in the calf veins).[28]

[edit] Prevention

Walking is an effective preventative measure.[29] Walking activates the body's muscle "pumps", increasing venous velocity and preventing low blood flow. Anticoagulants and mechanical measures may also be used. In 2012, the American College of Chest Physicians (ACCP) released their 9th edition of clinical guidelines, which included recommendations on VTE prevention.[30] The recommendations were given strengths with "grades", depending upon the evidence for them.

Grade Description of 2012 ACCP grade[a]
1A Strong recommendation, high-quality evidence
1B Strong recommendation, moderate-quality evidence
1C Strong recommendation, low- or very-low-quality evidence
2A Weak recommendation, high-quality evidence
2B Weak recommendation, moderate-quality evidence
2C Weak recommendation, low- or very-low-quality evidence[31]

[edit] Surgery patients

Surgery patients are at an increased risk of forming a DVT. In patients who have undergone non-orthopedic surgery, early ambulation (walking), mechanical prophlaxis (intermittent pneumatic compression [IPC] or graduated compression stockings [GCS]), and drugs (low-molecular-weight heparin [LMWH], low-dose-unfractionated heparin [LDUH]) are potential treatments recommended for patients depending upon their risk of VTE, risk of major bleeding, and preferences.[32] In major orthapedic surgery patients—those undergoing total hip arthroplasty, total knee arthroplasty, and hip fracture surgery—additional drug options, such as fondaparinux and aspirin, are recommended (1B), though LMWH is preferred (2B or 2C).[33] IPC is an option (1C).[33]

[edit] Pregnancy

See also: Hypercoagulability in pregnancy

The risk of VTE is increased in pregnancy by about 4-fold[21] due to a more hypercoaguable state, a likely adaptation against fatal postpartum hemorrhage.[34] Additionally, pregnant women with genetic suceptibility to blood coagulation are subject to a further and approximate 3- to 30-fold increased risk for VTE, depending upon the risk factor(s).[35]

The 2012 ACCP clinical guidelines suggested that specific groups of at-risk pregnant women receive targeted (INR of 2 to 3) preventative measures. Homozygous carriers of factor V Leiden or prothrombin G20210A with a family history of VTE were recommended to receive antepartum LMWH and either LMWH or vitamin K antagonists for the 6 weeks following childbirth (2B); those with another thrombophlia and a family history but no previous VTE were recommended to be subject to clinical vigilance during pregancy and LMWH or (for those without protein C or S deficiency) vitamin K antagonists (2C); homozygous carriers with no personal or family history of VTE were recommended to be subject to clinical vigilance during pregancy and LMWH or vitamin K antagonists for 6 weeks after childbirth (2B); and those with another thrombophilia but no family or personal history of VTE were suggested to receive clinical vigilance (2C).[35]

Warfarin, a common vitamin K antagtonist, is known to have teratogenic effects on the fetus if administered in early pregnancy[36][37] and is not advised in pregnant women.

[edit] Travellers

In the 2012 ACCP clinical guidelines, grade 2C recommendations were offered. For at risk long-haul travelers—those with "previous VTE, recent surgery or trauma, active malignancy, pregnancy, estrogen use, advanced age, limited mobility, severe obesity, or known thrombophilic disorder"—recommendations for prevention included frequent walking, calf exercizes, and aisle seating in airplanes to facilitate walking.[30][38] The use of "properly fitted, below-knee GCS providing 15 to 30 mm Hg of pressure at the ankle during travel" was recommended though use of aspirin or anticoagulants were not.[30]

Compression stockings have sharply reduced the levels of asymptomatic DVT in airline passenters, but the effect on symptomatic VTE is unknown as no individuals studied developed symptomatic VTE.[39]

[edit] Primary

One randomized controlled trial (RCT) using a statin, the JUPITER trial which used rosuvastatin, demonstrated a reduction in DVT occurence with primary prevention. Additional RCTs to demonstrate efficacy with statins are advised.[40]

[edit] Medical inpatients

Clinical practice guidelines state:

  • American College of Physicians (ACP) in 2011:[13][41]
    • "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."
  • The summary of the 2012 ACCP guidelines state:
    • "For acutely ill hospitalized medical patients at increased risk of thrombosis, we recommend anticoagulant thromboprophylaxis with [LMWH], [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 [GCS] (Grade 2C) or [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)."[30]

[edit] Treatment

[edit] Anticoagulation

Anticoagulation is the usual treatment for DVT. In general, patients are initiated on a brief course (i.e., less than a week) of heparin treatment while they start on a 3- to 6-month course of warfarin (or related vitamin K inhibitors). Low molecular weight heparin (LMWH) is preferred,[42] though unfractionated heparin is given in patients who have a contraindication to LMWH (e.g., renal failure or imminent need for invasive procedure). In patients who have had recurrent DVTs, anticoagulation is generally life-long. The Cochrane Collaboration has meta-analyzed the risk and benefits of prolonged anti-coagulation.[43] Once the thrombosis is treated with RBC-thinning agents, the affected area has a fair chance of returning to its normal proportions. However, thinning agents do not lessen the chance of embolism to the pulmonary or coronary arteries. Thus, while the area affected with deep venous thrombosis (i.e. the legs) may cease coagulation, pulmonary embolism is still as possible. In a 2008 Cochrane review, it was found that anticoagulation used in combination with leg compression is a more effective therapy than anticoagulation alone.[44]

An abnormal D-dimer level at the end of treatment might signal the need for continued treatment among patients with a first unprovoked proximal deep-vein thrombosis.[45]

Despite the fact that no one disputes this,[vague] based on a meta analysis done by the Cochrane Collaboration where they found only one randomized trial of anti coagulation vs placebo in the treatment of VTE in which there was no significant difference between the two.[46]

Current[dated info] recommendations for initial treatment of acute DVT include initiation of a vitamin K antagonist (VKA) together with LMWH or UFH on the first treatment day.[47] Heparin may be discontinued when the international normalized ratio (INR) is stable and greater than 2.0. For the duration and intensity of treatment for acute DVT of the leg, the recommendations include the following:

  • for patients with a first episode of DVT secondary to a transient (reversible) risk factor, long-term treatment with a VKA for 3 months.
  • for patients with a first episode of idiopathic DVT, treatment with a VKA for at least 6 to 12 months. The dose of VKA is adjusted to maintain INR in the range of 2.0 to 3.0.
  • for the prevention of the post-thrombotic syndrome, the use of an elastic compression stocking is recommended.

[edit] Thrombolysis

Thrombolysis can be systemic or, depending upon medical capabilities, catheter-directed, but anticoagulation alone is preferred (2C) in the 2012 ACCP clinical guidelines. Although, those "who are most likely to benefit" from thrombolysis—"who attach a high value to prevention of postthrombotic syndrome (PTS), and a lower value to the initial complexity, cost, and risk of bleeding"—"are likely to choose [it] over anticoagulation alone."[48]

[edit] Thrombectomy

A mechanical thrombectomy device can remove a thrombus. However, the 2012 ACCP clinical guidelines recommend only considering it as a treatment option 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."[48] In general, anticoagulation alone is preferred (2C).[48]

[edit] Serial imaging

Repeated imaging of a DVT is a management technique when applied to acute isolated distal DVT; if the thrombosis does not extend, no anticoagulation is recommended.[48]

[edit] Compression stockings

Elastic compression stockings should be routinely applied "beginning within 1 month of diagnosis of proximal DVT and continuing for a minimum of 1 year after diagnosis".[42] Starting within one week may be more effective.[49] They reduce the risk of postthrombotic syndrome.[50] The stockings in almost all trials were stronger than routine anti-embolism stockings and exerted a pressure of 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-thrombotic syndrome.[51] The number needed to treat is relatively high, at 4 to 5 patients needing to have been treated to prevent one case of post-thrombotic syndrome.[52]

[edit] Compression systems

Intermittent pneumatic compression (IPC) can be of benefit to patients deemed to be at risk of deep vein thrombosis. IPC is an accepted treatment method for preventing blood clots or deep venous thromboses (DVTs) and complications of venous stasis in persons after trauma, orthopaedic surgery, neurosurgery, or in disabled persons who are unable to walk or mobilise effectively.

Intermittent pneumatic compression (IPC) uses an air pump to inflate and deflate an airtight bag wrapped around the leg. This technique is also used to stop blood clots developing during surgery. However, the review of trials found conflicting evidence about whether or not IPC is better than compression bandages and hosiery. Intermittent pneumatic compression (IPC) is better for healing leg ulcers than no compression but it is uncertain if it improves healing when bandages or hosiery are already used [53]

[edit] Inferior vena cava filter

Inferior vena cava filters (IVC filters) reduce pulmonary embolism[54] and are recommended for patients with an contraindiciation to anticoagulant treatment, but not those on anticoagulants.[48] IVC filters are themselves potential of thrombosis,[55] and are viewed as a temporizing measure for preventing life-threatening pulmonary embolism.[56]

[edit] Home vs. hospital

Home treatment is recommended for the initial treatment of those with acute leg DVT (1B) who feel "well enough to be treated at home (eg, [those without] severe leg symptoms or comorbidity)" as long as there is an adequate home environment, which is described as "well-maintained living conditions, strong support from family or friends, phone access, and ability to quickly return to the hospital if there is deterioration."[48]

[edit] Prognosis

Main article: Post-thrombotic syndrome

In the one to two year period after the initial development of symptoms of deep vein thrombosis (DVT), post-thrombotic syndrome occurs in between as few as a fifth, and as many as half of cases. A "severe" post-thrombotic syndrome likewise varies in frequency between a twentieth and a tenth of individuals diagnosed with DVT. This malady is sometimes characterized by varicose ulceration.[57]

The risk of pulmonary embolism is higher in the presence of more extensive clots.

[edit] Epidemiology

DVTs occur in about 1 per 1000 adults per year.[58] It is estimated that approximately 350,000 to 600,000 Americans each year suffer from DVT and pulmonary embolism and at least 100,000 deaths may be directly or indirectly related to these diseases.[59]

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, blood protein levels that do not favor coagulation, and fewer comorbidities (e.g. malignancy).

In pregnant women, it has an incidence of 0.5 to 7 per 1,000 pregnancies, and is the second most common cause of maternal death in developed countries after bleeding.[60]

VTE develops after knee- and hip-surgery patients who receive preventative measures at rates of about 1 per 100 after total or partial knee arthroplasty and about 1 per 200 after total or partial hip arthroplasty.[61]

[edit] History

In 1851, German physician Rudolf Virchow published a paper[62] which formed the basis of what is referred to today as Virchow's triad. It contained a triad of factors to explain why venous thrombi form. Virchow also noted that more deep venous thrombosis occurred in the left leg than in the right and proposed compression of the left common iliac vein by the overlying right common iliac artery as the underlying cause (see May-Thurner syndrome).

[edit] Research directions

As of 2011, three large RCTs "on the effectiveness and safety of catheter directed thrombolysis (the Norwegian CaVent trial, the North American ATTRACT trial, and the Dutch CAVA trial)" were underway.[63]

[edit] Notes

  1. ^ For more detailed text descriptions of the grades, including benefits vs. the risks and burdens, the methodologic strength of supporting evidence, and implications, see Table 4 of Guyatt et al., p. 62S

[edit] References

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