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Evaluating Idiopathic Venous Thromboembolism: What Is Necessary, What Is Not

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Evaluating Idiopathic Venous Thromboembolism: What Is Necessary, What Is Not Applied Evidence N EW R ESEARCH F INDINGS T HAT A RE C HANGING C LINICAL P RACTICE Evaluating idiopathic venous thromboembolism: What is necessary, what is not Charles F. S. Locke, MD Johns Hopkins Community Physicians, Baltimore, Md Neil C. Evans, MD Department of Veterans Affairs Medical Center, Washington, DC Practice recommendations n which direction, and how aggressively, should the investigation proceed when ■ In low-risk patients, the physician should Icommon and obvious causes of venous conduct a thorough history and physical thromboembolism—recent surgery, trauma, examination. Routine laboratory testing immobilization, or malignancy—are absent from may be useful, but further evaluation for a patient’s history? underlying malignancy is unnecessary (B). Two causes of hypercoagulability warrant ■ Test for disorders associated with consideration: occult malignancy and coagulation hypercoagulability under the following disorders resulting in thrombophilia. This review circumstances: when a thrombotic event provides guidance on diagnostic testing and occurs in a person younger than age 50; extent of the work-up, summarized in an if a patient has a family history of venous algorithm (Figure). thromboembolism; or if there are recurrent episodes of unexplained venous ■ MALIGNANCY AND VENOUS thromboembolism (C). THROMBOEMBOLISM ■ When homocysteine levels are elevated in Armand Trousseau first described the association 5 the presence of factor V Leiden or the between VTE and cancer nearly 150 years ago. prothrombin gene G20210A mutation, risk For patients with known malignancy, a search for of recurrent thrombosis appears to be other possible causes of thrombosis is seldom increased beyond the risk associated with needed (strength of recommendation [SOR]=B). any one defect alone (B). However, for individuals with idiopathic DVT or pulmonary embolism (PE), the clinician’s dilemma is in deciding how aggressively to look for occult malignancy. In a prospective study of 738 patients with objectively verified sympto- matic deep vein thrombosis (DVT), cancer was the most common underlying cause and emerged as a major predictor of recurrent thrombotic Corresponding author: Charles F.S. Locke, MD, Johns Hopkins 6 Community Physicians, 2360 W. Joppa Rd., Baltimore, MD events. Unfortunately, no laboratory test pre- 21093. E-mail: [email protected]. dicts occult cancer among patients with VTE.7 770 OCTOBER 2003 / VOL 52, NO 10 · The Journal of Family Practice EVALUATING IDIOPATHIC VENOUS THROMBOEMBOLISM Risk of malignancy in perspective Evidence of malignancy is usually discovered VTE Facts when taking a patient’s history and conducting a physical examination. Searching beyond the t is estimated that more than 250,000 history and physical exam is seldom revealing. Ipatients are hospitalized for venous throm- In 1992, Prandoni and colleagues8 published boembolism (VTE) in the United Sates each a report of a study of 262 patients with symp- year.1 The number of VTE cases annually in tomatic DVT, 250 of whom were followed for this country ranges from 600,000 to 2 years. One hundred seven patients had 2 million.2,3 The most common causes of recognized nonmalignant risk factors for DVT VTE include surgery, trauma, hospital or and were not evaluated for cancer. Of the nursing home confinement and malignant 155 patients with idiopathic venous thrombo- neoplasm.4 sis, 5 (3.3%) were discovered to have occult carcinoma. Malignancy was suggested in 4 of the 5 by history or physical examination. experts recommend ultrasound and Ca-125 In a similar study, Hettiarachchi et al9 eval- testing to investigate possible ovarian cancer, uated 400 patients with confirmed DVT and no data support use of these tests in ovarian found 70 (18%) had a diagnosis of cancer at cancer screening.12 the time of presentation. Of the remaining An evaluation of the Danish National 326 patients (4 were lost to follow-up), 189 Registry data has suggested that cancer diag- had recognized risk factors for DVT, 3 (1.6%) nosed at the time of, or within a year of, the of whom were also found to have cancer; and diagnosis of VTE is usually advanced and is 137 patients had unexplained DVT, 10 of whom associated with a poor prognosis.13 Indeed, the (7.3%) were found to have occult carcinoma. authors of the Danish study concluded that for As in the Prandoni study, most of the patients patients with VTE, “[our] pragmatic recom- subsequently discovered to have cancer (10 of mendation [is] to use only simple methods of 13, 77%) had suggestive clinical findings in screening and to look for cancer in patients the history or physical examination.9 with signs and symptoms of cancer.”13 Venous thromboembolism Recommended work-up and specific types of cancer We conclude the literature8–13 does not support Two large, retrospective epidemiologic studies an aggressive search for hidden cancer in a reviewed cases of thousands of patients in patient with idiopathic VTE (SOR=B). Routine the Danish and Swedish National Patient evaluation should include a careful history and Registries.10,11 Investigators for these studies physical examination. Because of their low found an approximately 30% increase in the cost, reliability, and ready availability, studies diagnosis of cancer among patients with VTE such as a complete blood count, basic chem- compared with the general population. istry panel, liver function tests, and urinalysis Because of their large size, both of these may be considered (SOR=B). Examples of studies were able to demonstrate a significant findings during the initial history, physical association between thrombosis and pancreat- exam, and laboratory studies that should ic, liver, and ovarian cancers. prompt further evaluation include anorexia, For liver and pancreatic cancers, consensus weight loss, cough, abdominal bloating, unex- opinion suggests that early diagnosis does not plained anemia, hyponatremia, hematuria, and change prognosis. Similarly, although some abnormal liver enzymes. OCTOBER 2003 / VOL 52, NO 10 · The Journal of Family Practice 771 EVALUATING IDIOPATHIC VENOUS THROMBOEMBOLISM AppliFIGURE Evaluating idiopathic venous thromboembolism Deep vein thrombosis or 1. Obtain complete medical history pulmonary embolism 2. Perform physical exam without evidence of underlying 3. Consider complete blood causative factors such as recent count, surgery, trauma, or known urinalysis, and basic metabolic malignancy panel (other laboratory tests, as indicated) YES Do findings suggest occult Further evaluation as malignancy? indicated NO Test for the most common coagulation disorders: 1. Activated protein C resistance (or factor V Leiden, if patient is Does any of the following taking anticoagulation drug) YES apply to the patient? NO Arrange for further 2. Prothrombin gene G20210A 1. Less than 50 years old evaluation, as clinical mutation 2. Family history of VTE judgment warrants 3. Hyperhomocysteinemia 3. Recurrent episodes of VTE 4. Anti-phospholipid antibody syndrome Test for factor V Leiden; if result is positive, and Do test results confirm YES prothrombin G20210A existence of one of these Activated protein C resistance result is positive or disorders? homocysteine elevated, consider prolonged NO anticoagulation therapy Consider prolonged Anti-phospholipid anticoagulation therapy antibody syndrome Consider testing for less with higher INR goal common coagulation disorders: 1. Protein C deficiency 2. Protein S deficiency Consider treatment with 3. Antithrombin III deficiency Hyperhomocysteinemia vitamin B12, folate Unnecessary studies. Some authorities cate the use of more elaborate screens recommend a chest radiograph in the routine for occult malignancy, such as computerized evaluation for occult malignancy,9 but its clinical tomography, magnetic resonance imaging, or utility for patients without pulmonary symptoms serologic tumor markers. has not been clearly demonstrated. Because of Caveat. In the past, nearly all patients with their expense and low test yield, we do not advo- pulmonary embolism or DVT were hospitalized 772 OCTOBER 2003 / VOL 52, NO 10 · The Journal of Family Practice EVALUATING IDIOPATHIC VENOUS THROMBOEMBOLISM to receive treatment with continuous intra- management decisions remains unclear in many venous heparin. Presumably these patients rou- cases. Finally, serologic evaluation for throm- tinely received a careful history evaluation, bophilia would be costly if conducted physical examination, and standard blood work. for all patients with VTE, and the potential With increased use of low-molecular-weight clinical benefit would be small. heparins (given subcutaneously once or twice Although large epidemiologic studies are daily), many individuals with VTE are candi- lacking to help identify patients at increased dates for treatment partially or totally on an risk of a hypercoagulable disorder, patients with outpatient basis.14,15 Be sure that individuals clinically significant inherited thrombophilia receiving outpatient treatment for idiopathic tend to have VTE at a young age.23–25 VTE receive the same attention and routine In addition, advanced age alone is often work-up as hospitalized patients. regarded as an identifiable risk factor for DVT. A recent retrospective study demonstrated the ■ COAGULATION DISORDERS risk for DVT rose rapidly during the 6th through AND VENOUS THROMBOEMBOLISM 8th decades of life.26 With advances in laboratory testing, more than We generally recommend testing for hyper- half of idiopathic VTE cases can be attributed to coagulable
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