Deep venous thrombosis

Deep-vein thrombosis, also known as deep-venous thrombosis (DTV), 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).

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. 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. These patients have a worse prognosis.

Genetics
A twin study found a genetic contribution to venous thromboembolism among men but not women. 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.

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.

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. This has resulted in guidelines recommending use of outdated versions of the Wells rule. The rule was introduced in 1995.

1995 Original Wells 12 point rule: Major points Minor 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)
 * 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

1997 Wells 9 point rule:


 * 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. 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.

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

Based one his 2003 study, Wells recommends that DVT is excluded only when the 10-point score is < 2 and the D-dimer is negative.

AMUSE rule
Because of concerns about the failed study in 2005 of the older, 9-point 1997 Wells rule (note that the current Wells rule has 10 points), the Amsterdam Maastricht Utrecht Study on thromboEmbolism (AMUSE) Investigators developed a rule with 7 clinical variable plus the D-dimer. 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.

This rule has not been externally validated by independent research groups.

Ultrasonography
Compression B-mode ultrasonography scanning of the leg veins, combined with Duplex Doppler ultrasonography (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:
 * Acute DVT in 31 examinations. Duplex Doppler ultrasonography
 * Chronic DVT in 10 patients. Duplex Doppler ultrasonography identified 6 of the 10. Two of the missed cases were in the calf.
 * Combined acute and chronic DVT in 2 patients. Duplex Doppler ultrasonography identified the acute changes in both patients, but did not identify the chronic changes.

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

Whole leg ultrasonography
Either whole leg Doppler ultrasonography or serial 2-point ultrasonography plus D-dimer are equivalent strategies according to a randomized controlled trial.

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

Venography
Venography can determine acute versus chronic thrombosis:
 * 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. 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 this has not been considered as part of the history).

Other blood tests usually performed at this point are:
 * complete blood count
 * Primary coagulation studies: PT, APTT, Fibrinogen
 * liver enzymes
 * renal function and electrolytes

Differential diagnosis
Rupture of the tendon of the plantaris muscle may mimic deep venous thrombosis.

Prophylaxis (Prevention)
Clinical practice guidelines by the American College of Chest Physicians (ACCP) provide recommendations on DVT prophylaxis in hospitalized patients.

New clinical practice guidelines by the American College of Chest Physicians (ACCP) were published in 2008.

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

General Medical Inpatients
Regarding general medical inpatients the 2008 guidelines state:
 * "For acutely ill medical patients admitted to hospital with congestive heart failure or severe respiratory disease, or who are confined to bed and have one or more additional risk factors, including active cancer, previous VTE, sepsis, acute neurologic disease, or inflammatory bowel disease, we recommend thromboprophylaxis with LMWH (Grade 1A), LDUH (Grade 1A), or fondaparinux (Grade 1A)."

Enoxaparin or unfractionated heparin may be used. LMWH may be more effective than UFH. If UFH heparin is used, 5000 U 3 times daily may be more effective

Since publication of the ACCP guidelines, an additional randomized controlled trial and meta-analysis including the trial have been published. The meta-analysis concluded " Anticoagulant prophylaxis is effective in preventing symptomatic venous thromboembolism during anticoagulant prophylaxis in at-risk hospitalized medical patients. Additional research is needed to determine the risk for venous thromboembolism in these patients after prophylaxis has been stopped." With regards to which patients are at risk, most studies in the meta-analysis were of patients with New York Heart Association Functional Classification (NYHA) III-IV heart failure. Regarding patients at lesser risk of DVT, the trial above and an earlier trial are relevant yet inconclusive.

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."

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

Hip or knee surgery
Clinical practice guidelines by the American College of Chest Physicians and the American Academy of Orthopaedic Surgeons address prevention.

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. As these studies were short term, it is likely that some patients with assymptomatic DVT progress to chronic venous insufficiency.

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


 * Factor Xa inhibitors
 * Fondaparinux for one week can prevent embolism and thrombosis during perioperative care according to randomized controlled trials of hip fracture surgery.
 * Rivaroxaban can prevent embolism and thrombosis during perioperative care according to randomized controlled trials of two weeks of therapy after knee arthoplasty or 5 weeks of therapy after hip arthroplasty (absolute risk reduction 1.7%).

Travelers
Travel may or may not 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. .

Therapy
Treatment options have been reviewed.
 * Thrombolysis is generally reserved for extensive clot, e.g. an iliofemoral thrombosis. Although a meta-analysis of randomized controlled trials by the Cochrane Collaboration shows improved outcomes with thrombolysis, there may be an increase in serious bleeding complications.


 * 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, though unfractionated heparin is given in patients who have a contraindication to LMWH (e.g., renal failure or imminent need for invasive procedure). Rivaroxaban may provide oral treatment.


 * Regarding the duration of anticoagulation, see embolism and thrombosis: treatment.


 * Elastic compression stockings should be routinely applied. 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. The number needed to treat is quite potent at 4 to 5 patients need to prevent one case of post-phlebitic syndrome. Compression stocking can cause local complications.


 * Inferior vena cava filter reduces pulmonary embolism and is an option for patients with an absolute contraindiciation to anticoagulant treatment (e.g., cerebral hemorrhage) or those rare patients who have objectively documented recurrent PEs while on anticoagulation, an inferior vena cava filter (also referred to as a Greenfield filter) may prevent pulmonary embolisation of the leg clot. However these filters are themselves potential foci of thrombosis, 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 :
 * 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:
 * "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:
 * "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."

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. If the D-dimer is abnormal, anticoaguation should be continued, if the D-dimer is normal, the duration of treatment is uncertain. In an observation study that collected the D-dimer before stopping anticoagulation, the D-dimer was not as predictive.

Ultrasonography
Ultrasonography, using the following protocal may or may not help determine when to stop anticoaguation :
 * "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"

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."

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

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

Among patients 6 to 8 years after a DVT, "42% reported pain, swelling, or discoloration."

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, when patients are actively studied 10-20 years after their initial thrombosis, 80% have some signs of postthrombotic syndrome.

Recurrent DVT
Risk factors for recurrence if anticoagulation is stopped are:
 * 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