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Deep vein thrombosis
With no room for error, treatment is a balancing act between bleeding and clotting
by Vicky Tagalakis, MD
Vol.14, No.09, September 2006

What is deep vein thrombosis?
Deep vein thrombosis (DVT) represents thrombus formation within the deep venous system, and although this can occur in any vein, most clinical events arise in the deep vessels of the legs. DVT usually starts in the calf veins, from where it can extend into the proximal veins, and subsequently embolize to the lungs. DVT is a frequent occurrence in the general population, with an estimated annual incidence rate of 0.1-0.2%.

What are the signs and symptoms?
The development of symptoms primarily depends on the location and extent of the thrombus. Although many DVTs begin in the calf veins, symptoms are uncommon until there's extension into the proximal veins. In general, the most frequent presenting symptoms of DVT include pain, swelling and redness of the affected limb. On examination, findings may include warmth, edema, tenderness, and a palpable cord, which represents a thrombosed vein.

Differential diagnoses include a ruptured Baker's cyst, cellulitis, chronic venous insufficiency, and knee tendon or ligament tears. Keep in mind that about half of patients with DVT have no symptoms or signs of DVT and may instead present with symptoms of pulmonary embolism (PE), such as shortness of breath and chest pain.

What are the risk factors?
Risk factors for DVT are commonly classified as inherited or acquired, with the latter further classified as transient or persistent (see Table 1). The inherited factors are collectively termed "inherited thrombophilia" and represent a genetic tendency for thrombus formation that usually presents in young adults and is often recurrent. The most frequent thrombophilias are factor V Leiden mutation, prothrombin gene mutation, elevated factor VIII levels and hyperhomocysteinemia, which collectively occur in about 10-20% of the general population (see Table 2).

A DVT risk factor can be identified in about 70-80% of patients diagnosed with DVT. Moreover, more than one risk factor can be attributed to a given patient. For example, hospitalized individuals with DVT have an average of 1.5 risk factors, with 26% of patients having at least three risk factors. In addition, 50% of DVT episodes in patients with inherited thrombophilia are associated with an acquired risk factor, such as surgery, cancer or pregnancy. Also, the "potency" of DVT risk factors isn't equal (see Table 1). When they occur together, they may act synergistically to increase the risk of DVT. For example, among oral contraceptive users, the presence of a factor V Leiden gene mutation increases the risk of DVT by 30-fold, compared to 4-8-fold with either risk factor alone.

In about 20-30% of patients with DVT, a risk factor can't be identified. Several cohort studies suggest that 2-10% of individuals with idiopathic DVT will develop cancer within 1-3 years after a DVT diagnosis. Recent trials, however, suggest that although intensive screening for malignancy in patients who present with idiopathic DVT can lead to detection of occult cancers, it remains unproven whether discovery of these cancers improves morbidity or survival.

Who's at risk for DVT?
Though DVT occurs in the community, approximately 60% of all venous thromboembolism (VTE) cases occur in hospitalized or recently discharged patients. Important risk factors associated with hospitalization include immobilization, exposure to surgical procedures and interventions, and a high prevalence of medical conditions related to thrombosis that often require hospital admission, such as malignancy, congestive heart failure, lower extremity fracture, trauma and stroke.

Effective and safe primary DVT prophylactic measures are available for hospitalized patients, depending on their risk category. For example, surgical patients are categorized as low risk, moderate risk, high risk and highest risk (see Table 3). Low-risk surgical patients don't generally require prophylaxis, whereas those considered high risk (i.e. patients undergoing major orthopedic surgery) need thrombo-prophylaxis (details can be found in the report, on the "Prevention of Venous Thromboembolism" for the Seventh American College of Chest Physician Consensus Conference [ACCP] on Antithrombotic Therapy). Thromboprophylaxis is recommended in any acutely ill individual who has been admitted to hospital with a severe illness, such as congestive heart failure or severe respiratory disease, or who is confined to bed and has one or more additional risk factors, such as cancer, previous VTE or stroke.

How do we deal with complications?
The major complications of DVT include recurrent thrombosis, post-thrombotic syndrome (PTS) and fatal PE. Recurrent thrombosis is a common complication after a first-time DVT following adequate anticoagulation therapy, and depends largely on the nature of the precipitating risk factor of the initial DVT. Patients with a first DVT associated with a major transient risk factor (i.e. recent surgery), have a low risk of recurrence (about 3%) in the first year after stopping anticoagulant therapy. On the other hand, patients with a persistent risk factor, such as malignancy, or those with an idiopathic or "unprovoked" VTE (i.e. no risk factor identified), have a higher rate of recurrence — about 10% in the first year and 30% over the subsequent five years. Calf-vein DVT, as compared to proximal DVT (above-knee), not only is associated with a lower risk of proximal vein extension and embolization to the lungs, but is also less likely to recur. As a result, patients diagnosed with calf-vein DVT don't generally receive anticoagulation.

PTS is the most common complication of DVT and is characterized by chronic pain, swelling, heaviness and other signs in the affected limb. In severe cases, venous ulcers may develop. The frequency of PTS after symptomatic DVT ranges between 20-50%, while severe PTS occurs in 5-10% of patients after DVT. In most cases, PTS develops within 1-2 years post-DVT. The only clearly identified risk factor for PTS is recurrent ipsilateral DVT, which raises the risk of PTS as much as six-fold.

Mortality rates associated with DVT complicated by PE are significant. In the U.S., it's estimated that 50,000-100,000 people die of PE annually. While the one-month fatality rate following a diagnosis of DVT with PE ranges between 9-15%, and is largely attributable to fatal PE, the 2-3-year rates are estimated to be 32% for PE and 25% for DVT. Most of these late deaths are due to comorbid conditions, such as malignancy or cardiopulmonary disease.

What's involved in the diagnosis?
An objective diagnosis of DVT is important for optimal and safe management of a patient diagnosed with DVT. Although anticoagulant therapy lowers the risk of DVT recurrence — and perhaps the development of PTS — it also increases the risk of major bleeding. Moreover, only 25-35% of patients with suspected DVT actually have the disease. As such, diagnostic modalities must accurately diagnose a DVT when present, and safely exclude DVT when absent so that symptomatic patients without DVT aren't inappropriately anticoagulated.

Three imaging modalities are available to detect the presence of a clot within a vein — contrast venography, impedance plethysmography and compression ultrasonography. Though contrast venography is considered the gold standard for diagnosing DVT, it isn't recommended as an initial test because it's invasive and associated with discomfort. The most widely used and preferred modality is compression ultrasonography with venous imaging. It's non-invasive, easy to perform, and has been proven to be highly sensitive (> 95%) and specific (> 95%) to diagnose symptomatic and asymptomatic proximal vein DVT. There are, however, some limitations. For one, it's limited in patients with a cast or other leg immobilization devices. Secondly, it can't detect thrombi in the iliac vessels. Finally, because imaging for calf vein DVT is relatively inaccurate and often inadequate, serial testing of proximal veins is necessary when the first test is negative because approximately 2% of patients with an initially negative ultrasound develop a positive study seven days later.

However, incorporating both a clinical prediction rule for DVT (e.g. Wells score, see Table 4) and serum d-dimer testing into the diagnostic approach adds to the accuracy of the non-invasive imaging tests for the diagnosis of proximal DVT in outpatients, and in some circumstances, eliminates the need for diagnostic imaging. The Wells score has been assessed and validated in many studies of outpatients with suspected DVT, and can accurately categorize patients with a low, moderate or high probability of having a DVT. Validation of the Wells score in hospitalized patients, though, is lacking. d-dimers, which are fibrin degradation products, occur in nearly all patients with DVT at levels greater than 500 ng/mL. d-dimers alone, however, are insufficient to diagnose DVT and shouldn't be used as a screening test because high serum levels can also be present in hospitalized patients, individuals with malignancy, those who've undergone recent surgery, and in pregnant women.

As a result, outpatients presenting with suspected DVT should be initially assessed using a clinical prediction rule in combination with d-dimer testing. For example, a low clinical pre-test probability estimate for the diagnosis of DVT, and a low or normal d-dimer level exclude a diagnosis of DVT without the need for a non-invasive imaging test. Among patients with a high or moderate pre-test clinical probability estimate, a normal d-dimer result doesn't rule out a DVT, and as such, all these individuals require diagnostic imaging. A normal above-knee ultrasound result, though, safely eliminates the need for serial ultrasound testing in these patients, whereas serial testing is necessary in those with a moderate or high probability score, a positive d-dimer assay, and a normal initial above-knee ultrasound.

Finally, newer imaging techniques to diagnose DVT have been developed. These include magnetic resonance venography and computed tomography. The latter has been studied the most in PE protocols that include imaging of subdiaphragmatic veins at the same sitting. Though both modalities seem highly accurate to diagnose DVT, further studies are needed to establish their role in the clinical setting.

What are the basics of treatment?
The cornerstone of DVT treatment is short-term anti-coagulation (i.e. heparin) for at least five days. This is overlapped with, and followed by, long-term anticoagulation in the form of an oral vitamin K antagonist (i.e. warfarin) for at least 3-6 months to avoid a recurrence, limit acute limb swelling, and prevent embolization and PTS. Until recently, initial therapy consisted of unfractionated heparin (UFH), which required hospital admission for continuous intravenous administration and frequent blood coagulation monitoring. The advent of low molecular weight heparins (LMWHs) has revolutionized the initial treatment of DVT and offers several treatment advantages compared to UFH. They include a more predictable anticoagulant response, once or twice daily subcutaneous injection, weight-adjusted dosing and no lab monitoring. Several studies have shown that outpatient LMWH is as safe and effective as inpatient UFH, and even though LMWH drugs cost more, avoiding hospitalization or decreasing its length leads to cost savings. The Seventh ACCP Consensus Conference on Antithrombotic Therapy now recommends that LMWHs be preferred over UFH for the treatment of acute DVT.

Inherited thrombophilia Prevalence in population (%) RR of first venous thrombo-embolism*

* compared with healthy control population.

When faced with a diagnosis of acute proximal DVT, the clinician must first decide whether there are any contraindications to anticoagulation, and whether the patient is suitable for outpatient therapy with LMWH. Contraindications to, or complications of, anticoagulation in patients with proximal DVT include active bleeding or an elevated risk of bleeding, such as severe thrombocytopenia or history of gastrointestinal bleeding within 1-3 months. In these cases, insertion of an intravenous filter may be warranted and anticoagulation is recommended as soon as possible afterward because the filter alone isn't an effective treatment for DVT.

If no contraindications to anticoagulation exist, the physician must then decide if the individual is suitable for outpatient LMWH therapy. This implies that the patient understands the implications of the disease and the rationale behind treatment. As such, review the correct use and potential adverse effects of LMWH with the patient and identify any signs and symptoms of complications, such as bleeding. In addition, ensure proper and close follow-up. If the patient is incapable of self-treatment, and there are no home health nursing services available or outpatient medical services, then hospitalization is necessary to administer heparin therapy. Certain patient conditions, however, may preclude the use of LMWH (i.e. a history of heparin-induced thrombocytopenia) or require caution and vigilant monitoring for complications. For example, altered pharmacokinetics (i.e. patients with renal dysfunction, underlying liver disorders and obesity) may result in insufficient or excessive anticoagulation, increasing the risk of therapeutic failure or bleeding. Moreover, there may be circumstances where close observation in hospital may be required because of a high risk of embolization, such as iliofemoral DVT or patient instability, such as DVT complicated with massive PE.

What about long-term treatment?
Long-term anticoagulation with warfarin can be started with heparin at the time of DVT diagnosis, and thereafter, heparin can be discontinued when the target INR of 2.5 (2.0-3.0) is reached. Low-intensity warfarin (INR 1.5-1.9) and high-intensity warfarin (INR 3.1-4.0) haven't been shown to be more effective or safer than standard intensity therapy. Laboratory monitoring of the INR and dose adjustment of warfarin is frequently required as a result of the wide variability in individual anticoagulant responses, in addition to the influence of drug interactions (particularly antibiotics) and foods rich in vitamin K (i.e. liver, broccoli, Brussels sprouts, spinach, and other green leafy vegetables) on the anticoagulant effect. Consequently, when patients are first started on warfarin, they should be advised to inform their physicians of all new prescription and over-the-counter medications, to avoid certain foods, and to limit changes in their diet. In addition, women of child-bearing age should be advised of the risk of birth-defects with warfarin, use an effective form of contraception, and inform their physician immediately if pregnant.

How long should anticoagulation last?
The length of treatment isn't standard and depends on the risk of a DVT recurrence following cessation of long-term anticoagulation. As a result, the clinician must perform a thorough clinical assessment to determine DVT risk factors and assess the possibility of major bleed—ing with extended anticoagulation. This is generally estimated to be 2% per year in the absence of other risk factors for bleeding, such as active peptic ulcer disease and liver dysfunction.

For example, patients with a first-episode DVT secondary to a major transient risk factor (i.e. surgery) have a low risk of recurrence after three months of anticoagulation (about 3% in the first year after stopping anticoagulation and 10% over five years), and as such, treatment lasting longer than three months isn't justified. For patients with idiopathic DVT, stopping anticoagulant therapy after six months is associated with a subsequent risk of recurrent VTE of approximately 10% in the first year and about 30% over five years. Consequently, anticoagulation of at least 6-12 months — and perhaps indefinitely — is recommended in most of these patients. Individuals with a continuing risk factor, such as cancer, also have a high risk of recurrence within a year of stopping anticoagulation, therefore, anticoagulant therapy is recommended for at least 6-12 months, and likely indefinitely or until the cancer is cured. Regarding cancer patients, recent evidence favours the use of LMWH as opposed to warfarin for long-term anticoagulation because of decreased rates of DVT recurrence and major bleeding. The Seventh ACCP provides useful and complete guidelines on the length of antithrombotic therapy according to patient risk factors.

Is there anything new on the treatment scene?
Though LMWH and vitamin K antagonists are effective antithrombotic agents, there are important limitations. For example, LMWH must be administered subcutaneously, which restricts its use in the long-term treatment of DVT, and vitamin K antagonists have a narrow therapeutic window and require frequent blood monitoring to minimize the risk of bleeding and thrombosis. As a result, there has been intense interest to develop newer antithrombotic agents that can be easily administered, require no coagulation monitoring, and have a low side-effect profile. A novel parenteral antithrombotic is fondaparinux, a direct thrombin inhibitor, which has been licensed for the prevention of venous thrombosis after major orthopedic surgery and for initial treatment of venous thrombosis. It's administered subcutaneously once daily and produces a reliable anticoagulant response that requires no blood monitoring. Unlike LMWH, it's not associated with heparin-induced thrombocytopenia. On the downside, there's no specific antidote in the case of uncontrolled bleeding.

Ximelagatran, the first oral direct thrombin inhibitor, has been shown to be as effective as warfarin without increased bleeding in the long-term treatment of patients with venous thrombosis, and requires no routine coagulation monitoring. In addition, unlike the vitamin K antagonists, it has a rapid onset of action that obviates the need for a parenteral anticoagulant when initiating therapy, and it doesn't have any drug or food interactions. Though there is no antidote, its very short half-life of 3-4 hours makes it unlikely that this would be a significant clinical issue. However, ximelagatran is associated with unexplained elevation of liver enzymes in about 6-16% of patients, the long-term significance of which is uncertain. Lack of this information has prevented licensing of this drug in North America.

Although several new agents have been developed and evaluated, their role in treatment and prophylaxis of venous thrombosis remains to be delineated, and side-effect profiles must be better understood. It's clear that not only must these newer agents show equivalence or superiority to established medications, but their advantages have to be substantial to offset any added costs.

Vicky Tagalakis, MD, FRCPC, MSc is an internist at the Sir Mortimer B. Davis Jewish General Hospital and Associate Professor of Medicine at McGill University. She is involved in clinical research related to venous thromboembolism and in the treatment of patients with venous thrombosis.

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TABLE 1. Risk factors for venous thromboembolism

ACQUIRED FACTORS
Strong risk (odds ratio > 10)

TABLE 3. Risk of venous thromboembolism in surgical patients without prophylaxis

Adapted from the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. Chest 2004;126 (Supplement 3).

Clinical characteristic Score

*Adapted from Wells PS, Anderson DR, Rodger M et al. NEJM 2003;349:1227-35.

Suggested readings and references:

  1. The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence-Based Guidelines. Chest 2004;126;(Supplement 3).
  2. Lee, AY. Management of thrombosis in cancer: primary prevention and secondary prophylaxis. Br J Haematol 2005;128:291-302.
  3. Lopez JS, Kearon C, Lee AY. Deep venous thrombosis. Hematology (Am Soc Hematol Educ Program) 2004;439-56.
  4. Wells PS, Owen C, Doucette S et al. Does this patient have deep vein thrombosis? JAMA 2006;295:199-207.
  5. Weitz J, Bates M. New anticoagulants. J Thromb Haemst 2005;3:1843-53.
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