Evaluating idiopathic venous thromboembolism: What is necessary, what is not

Locke, Charles F. S.

Applied Evidence

Evaluating idiopathic venous thromboembolism: What is necessary, what is not

J Fam Pract. 2003 October;52(10):770-776

By

Charles F. S. Locke, MD

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References

1. Goldhaber SZ. Pulmonary embolism. N Engl J Med 1998;339:93-104.

2. Deitcher SR. Overview of enoxaparin in the treatment of deep vein thrombosis. Am J Manag Care 2000;6(suppl):S1026-S1033.

3. Hirsh J, Hoak J. Management of deep vein thrombosis and pulmonary embolism. A statement for healthcare professionals. Council on Thrombosis (in consultation with the Council on Cardiovascular Radiology), American Heart Association. Circulation. 1996;93:2212-2245.

4. Heit JA, Silverstein MD, Mohr DN, et al. Risk factors for deep vein thrombosis and pulmonary embolism. Arch Int Med 2000;160:809-815.

5. Trousseau A. Phlegmasia alba dolens. In: Clinique Medicale de l’Hotel-Dieu de Paris. Vol. 3. 2nd ed. Paris: JB Bailliere; 1865;654-712.

6. Hansson PO, Sorbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med 2000;160:769-774.

7. Naschitz JE, Yeshurun D, Lev LM. Thromboembolism in cancer. Cancer 1993;71:1384-1390.

8. Prandoni P, Lensing AW, Buller HR, et al. Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N Engl J Med 1992;327:1128-1133.

9. Hettiarachchi RJ, Lok J, Prins MH, et al. Undiagnosed malignancy in patients with deep vein thrombosis: incidence, risk indicators, and diagnosis. Cancer 1998;83:180-185.

10. Baron JA, Gridley G, Weiderpass E, et al. Venous thromboembolism and cancer. Lancet 1998;351:1077-1080.

11. Sorenson HT, Mellemkjaer L, Steffensen FH, et al. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med 1998;338:1169-1173.

12. Jacobs I, Davies AP, Bridges J, et al. Prevalence screening for ovarian cancer in postmenopausal women by CA 125 measurement and ultrasonography. BMJ 1993;306:1030-1034.

13. Sorensen HT, Mellemkjaer L, Olsen JH, et al. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000;343:1846-1850.

14. Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996;334:677-681.

15. Koopman M, Prandoni P, Piovella F, et al. for the Tasman Study Group. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med 1996;334:682-687.

16. Mateo J, Oliver A, Borrell M, Sala N, Fontcuberta J. Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism—results of the Spanish Multicentric Study on Thrombophilia (EMET-Study). Thromb Haemost 1997;77:444-451.

17. Ben-Tal O, Zivelin A, Seligsohn U. The relative frequency of hereditary thrombotic disorders among 107 patients with thrombophilia in Israel. Thromb Haemost 1989;61:50-54.

18. Ridker PM, Hennekens CH, Lindpaintner K, et al. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995;332:912-917.

19. Margaglione M, Brancaccio V, Giuliani N, et al. Increased risk for venous thrombosis in carriers of the prothrombin G—>A20210 gene variant. Ann Intern Med 1998;129:89-93.

20. Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh 1965;13:516.-

21. Griffith JH, Evatt B, Zimmerman TS, et al. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981;68:1370-1373.

22. Comp PC, Nixon RR, Cooper MR, et al. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984;74:2082-2088.

23. Hillarp A, Dahlback B, Zoller B. Activated protein C resistance: from phenotype to genotype and clinical practice. Blood Rev 1995;9:201-212.

24. Zoller B, Berntsdotter A, Garcia de Frutos P, et al. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995;85:3518-3523.

25. Van Boven HH, Reitsma PH, Rosendaal FR, et al. Factor V Leiden (FV R506Q) in families with inherited antithrombin deficiency. Thromb Haemost 1996;75:417-421.

26. Heit JA, Silverstein MD, Mohr DN, et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism. Arch Intern Med 2000;160:809-815.

27. Bertina RM, Koeleman BPC, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64-67.

28. Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening. JAMA 1997;277:1305-1307.

29. Koster T, Rosendaal FR, de Ronde H, Briet E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study. Lancet 1993;342:1503-1506.

30. Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995;85:1504-1508.

31. Rosendaal FR, Doggen CJ, Zivelin A, et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998;79:706-708.

32. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3´ untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698-3703.

33. De Stefano V, Martinelli I, Mannucci PM, et al. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med 1999;341:801-806.

34. den Heijer M, Koster T, Blom HJ, et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996;334:759-762.

35. Ray JG. Meta-analysis of hyperhomocysteinemia as a risk factor for venous thromboembolic disease. Arch Intern Med 1998;158:2101-2106.

36. den Heijer M, Rosendaal FR, Blom HJ, Gerrits WB, Bos GM. Hyperhomocysteinemia and venous thrombosis: a meta-analysis. Thromb Haemost 1998;80:874-877.

37. Ridker PM, Hennekens CH, Selhub J, Miletich JP, Malinow MR, Stampfer MJ. Interrelation of hyperhomocyst(e)inemia, factor V Leiden, and risk of future venous thromboembolism. Circulation 1997;95:1777-1782.

38. Kluijtmans LA, den Heijer M, Reitsma PH, Heil SG, Blom HJ, Rosendaal FR. Thermolabile methylenetetrahydrofolate reductase and factor V Leiden in the risk of deep-vein thrombosis. Thromb Haemost 1998;79:254-258.

39. DeStefano V, Zappacosta B, Persichilli S, et al. Prevalence of mild hyperhomocysteinaemia and association with thrombophilic genotypes (factor V Leiden and prothrombin G20210A) in Italian patients with venous thromboembolic disease. Br J Haematol 1999;106:564-568.

40. Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999;340:901-907.

41. Simioni P, Prandoni P, Lensing AWA, et al. The risk of recurrent venous thromboembolism in patients with an Arg⁵⁰⁶—>Gln mutation in the gene for factor V (factor V Leiden). N Engl J Med 1997;336:399-403.

42. Ridker PM, Miletich JP, Stampfer MJ, Goldhaber SZ, Lindpaintner K, Hennekens CH. Factor V Leiden and risks of recurrent idiopathic venous thromboembolism. Circulation 1995;92:2800-2802.

43. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists’ Collaboration. BMJ 1998;316:894-898.

44. McCrae KR. Antiphospholipid antibody associated thrombosis: a consensus for treatment? Lupus 1996;5:560-570.

Practice recommendations

In low-risk patients, the physician should conduct a thorough history and physical examination. Routine laboratory testing may be useful, but further evaluation for underlying malignancy is unnecessary (B).
Test for disorders associated with hypercoagulability under the following circumstances: when a thrombotic event occurs in a person younger than age 50; if a patient has a family history of venous thromboembolism; or if there are recurrent episodes of unexplained venous thromboembolism (C).
When homocysteine levels are elevated in the presence of factor V Leiden or the prothrombin gene G20210A mutation, risk of recurrent thrombosis appears to be increased beyond the r isk associated with any one defect alone (B).

In which direction, and how aggressively, should the investigation proceed when common and obvious causes of venous thromboembolism—recent surgery, trauma, immobilization, or malignancy—are absent from a patient’s history?

Two causes of hypercoagulability warrant consideration: occult malignancy and coagulation disorders resulting in thrombophilia. This review provides guidance on diagnostic testing and extent of the work-up, summarized in an algorithm (Figure).

FIGURE
Evaluating idiopathic venous thromboembolism

Malignancy and Venous Thromboembolism

Armand Trousseau first described the association between VTE and cancer nearly 150 years ago.⁵ For patients with known malignancy, a search for other possible causes of thrombosis is seldom needed (strength of recommendation [SOR]=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 symptomatic deep vein thrombosis (DVT), cancer was the most common underlying cause and emerged as a major predictor of recurrent thrombotic events.⁶ Unfortunately, no laboratory test predicts occult cancer among patients with VTE.⁷

Risk of malignancy in per spective

Evidence of malignancy is usually discovered when taking a patient’s history and conducting a physical examination. Searching beyond the history and physical exam is seldom revealing.

In 1992, Prandoni and colleagues⁸ published a report of a study of 262 patients with symptomatic DVT, 250 of whom were followed for 2 years. One hundred seven patients had recognized nonmalignant risk factors for DVT and were not evaluated for cancer. Of the 155 patients with idiopathic venous thrombosis, 5 (3.3%) were discovered to have occult carcinoma. Malignancy was suggested in 4 of the 5 by history or physical examination.

In a similar study, Hettiarachchi et al⁹ evaluated 400 patients with confirmed DVT and found 70 (18%) had a diagnosis of cancer at the time of presentation. Of the remaining 326 patients (4 were lost to follow-up), 189 had recognized risk factors for DVT, 3 (1.6%) of whom were also found to have cancer; and 137 patients had unexplained DVT, 10 of whom (7.3%) were found to have occult carcinoma. As in the Prandoni study, most of the patients subsequently discovered to have cancer (10 of 13, 77%) had suggestive clinical findings in the history or physical examination.⁹

Venous thromboembolism and specific types of cancer

Two large, retrospective epidemiologic studies reviewed cases of thousands of patients in the Danish and Swedish National Patient Registries.^10,11 Investigators for these studies found an approximately 30% increase in the diagnosis of cancer among patients with VTE compared with the general population. Because of their large size, both of these studies were able to demonstrate a significant association between thrombosis and pancreatic, liver, and ovarian cancers.

For liver and pancreatic cancers, consensus opinion suggests that early diagnosis does not change prognosis. Similarly, although some experts recommend ultrasound and Ca-125 testing to investigate possible ovarian cancer, no data support use of these tests in ovarian cancer screening.¹²

An evaluation of the Danish National Registry data has suggested that cancer diagnosed at the time of, or within a year of, the diagnosis of VTE is usually advanced and is associated with a poor prognosis.¹³ Indeed, the authors of the Danish study concluded that for patients with VTE, “[our] pragmatic recommendation [is] to use only simple methods of screening and to look for cancer in patients with signs and symptoms of cancer.”¹³

Recommended work-up

We conclude the literature^8-13 does not support an aggressive search for hidden cancer in a patient with idiopathic VTE (SOR=B). Routine evaluation should include a careful history and physical examination. Because of their low cost, reliability, and ready availability, studies such as a complete blood count, basic chemistry panel, liver function tests, and urinalysis may be considered (SOR=B ). Examples of findings during the initial history, physical exam, and laboratory studies that should prompt further evaluation include anorexia, weight loss, cough, abdominal bloating, unexplained anemia, hyponatremia, hematuria, and abnormal liver enzymes.