216 Goldhaber Figure 2 Homocysteine metabolism and possible mechanism of atherothrombotic dis- ease. (Reprinted with permission from Ref. 30.) tients with newly diagnosed VTE, I usually screen for factor V Leiden and the prothrombin gene mutation, which are more common than other inherited throm- bophilias (29), as well as acquired hyperhomocysteinemia (Fig. 2) and anticardio- lipin antibodies. Elevated levels of homocysteine are usually easily treated with folate (30,31), and the presence of anticardiolipin antibodies suggests the possible need for prolonged and intensive anticoagulation (32,33). B. Cancer Data from the Danish National Registry of Patients were used to investigate the risk of a diagnosis of cancer following the detection of VTE not associated with Venous Thromboembolism 217 Figure 3 Cumulative probability of newly diagnosed cancer after a first VTE episode, according to whether the VTE was idiopathic or nonidiopathic. (Reprinted with permission from Ref. 35.) surgery, known cancer, or pregnancy (34). There was a 30% increased risk of a diagnosis of cancer among those with newly detected VTE. The risk was substan- tially elevated only during the first 6 months of follow-up and declined rapidly thereafter. Of those diagnosed with cancer within 1 year after the initial VTE hospitalization, 40% had distant metastases at the time of the cancer diagnosis. The association between cancer and VTE was most pronounced for cancers of the pancreas, ovary, liver (primary hepatic cancer), and brain. In the Swedish Cancer Registry, the risk of diagnosed cancer after a first episode of VTE was elevated during at least the following 2 years (35). The standardized incidence ratio for newly diagnosed cancer was 3.4 during the first year after VTE and remained between 1.3 and 2.2 for the following 5 years. Of the 854 patients with VTE, 534 had idiopathic VTE occurring in the absence of surgery, trauma, temporary immobilization, or oral contraceptive use. These were the patients in whom the association between VTE and the subsequent diagnosis of cancer was apparent (Fig. 3). IV. WOMEN’S HEALTH A. Generations of Oral Contraceptives First-generation oral contraceptives contained more than 50 µg of estrogen and were associated with an alarming increase in the frequency of VTE, especially 218 Goldhaber massive PE. Second-generation oral contraceptives contain less than 50 µg and were introduced in the United States in 1967. Eventually, in 1989, first-generation pills were withdrawn from the market. Third-generation oral contraceptives utilize the new progestogens, desoges- trel or gestodene. They cause acne and hirsutism less often and have a more favorable effect on carbohydrate metabolism and lipid profiles than second-gener- ation pills. Ironically, they are associated with a doubling or tripling of the VTE rate compared with second-generation oral contraceptives (36,37). The explana- tion for this surprising finding is that third-generation oral contraceptives lead to acquired resistance to activated protein C, thus creating an effect similar to the factor V Leiden mutation (38). Despite the high relative risk of VTE from oral contraceptives, the absolute risk is low. A New Zealand study of oral contraceptives and fatal PE estimated the absolute risk of death from PE in current users as 1 per 10.5 million woman- years. In this study, the risk of fatal PE was double among those taking third- generation pills (39). B. Oral Contraceptives and Thrombophilia Oral contraceptives and thrombophilia appear to interact synergistically to in- crease the risk of VTE. In a case-control study at Leiden University, women with the factor V Leiden mutation who used oral contraceptives were at a 35-fold greater risk of VTE than controls (40). In a subsequent analysis from the Leiden Thrombophilia Study, which included cases with factor V Leiden, protein C or S deficiency, the prothrombin gene 20210 A mutation, and antithrombin-III defi- ciency, the overall risk of developing DVT during the first 6 months of oral contraceptive use was increased 19-fold in thrombophilic women compared with controls (41). Whether women with a family history of VTE but no personal past history of VTE should be screened prior to oral contraceptive use is controversial. For women with known thrombophilia but no prior VTE, the safest policy is to use alternative forms of contraception. However, no definitive ban on using oral con- traceptives can be justified in this setting because the absolute risk of VTE re- mains very low. C. Pregnancy PE is the leading cause of maternal death in the United Kingdom. Beginning in the 1980s, the number of fatal PEs began to increase, especially following vaginal delivery. In the mid-1990s, about two-thirds of the fatal PEs classified as maternal deaths occurred postpartum, with cesarean section accounting for approximately half of these catastrophic events (42). Venous Thromboembolism 219 Two-thirds of DVT occur during pregnancy, and the remainder occur post- partum. The risk of DVT is present throughout pregnancy and increases during the third trimester. Of all antepartum DVT, about one-fifth occur during the first trimester, one-third during the second trimester, and almost one-half during the third trimester (43). After delivery, two of the most important risk factors for VTE are increased maternal age and cesarean section. Emergency cesarean section in- creases the VTE risk by about 50% compared with elective cesarean section. Thrombophilia increases the risk of VTE during pregnancy and the puerpe- rium. In a control study, the prevalence of factor V Leiden was 44% among women with a history of VTE during pregnancy or the puerperium, and the prevalence of the prothrombin gene mutation was 17%. Compared with controls, the Leiden mu- tation increased the risk of VTE ninefold, and the prothrombin gene mutation in- creased the risk by a factor of 15. The combination of the Leiden and prothrombin gene mutations virtually multiplied the risk, estimated to be 107 times greater than control. Fortunately, the absolute risk of VTE among carriers of each mutation was low: 0.2% for Leiden and 0.5% for the prothrombin gene. However, among those few women with both thrombophilic mutations, the absolute risk soared to 4.6% (44). Regardless of factor V Leiden, pregnancy itself causes hypercoagulabil- ity because it induces a relative state of activated protein C resistance. Thrombophilia has also been implicated in otherwise unexplained recurrent pregnancy loss. The factor V Leiden mutation appears to double the risk of fetal loss, possibly because of an increased frequency of placental vein thrombosis (45,46). In addition to fetal demise, genetic thrombophilia appears to be associ- ated with obstetrical complications, such as preeclampsia, abruptio placentae, fetal growth retardation, and stillbirth (47). It has been common practice to prophylax with heparin those pregnant women who suffered a prior VTE. In a prospective study of 125 pregnant women with a single prior VTE, antepartum heparin was withheld but postpartum antico- agulation was administered for 4 to 6 weeks (48). Only 3 of the 125 women (2.4%) developed antepartum VTE. Thus, VTE during pregnancy may be less common in this population than had been previously thought. D. Hormone Replacement Therapy The traditional teaching used to be that hormone replacement therapy (HRT) does not predispose to VTE. In 1996, this assumption was challenged when three separate large data sets implicated HRT as doubling, tripling, or even quadrupling the risk of VTE (49–51). As with oral contraceptives, the risk of VTE was highest during the first year of HRT. The Heart and Estrogen/progestin Replacement Study was a randomized trial of 2763 postmenopausal women who had a history of coronary heart disease but no previous VTE. They were allocated to conjugated equine estrogens, 0.625 220 Goldhaber mg, plus medroxyprogesterone acetate, 2.5 mg, versus placebo. In results that surprised the medical community, HRT did not reduce the rate of new coronary events (52). Furthermore, the rate of VTE tripled among those women receiving HRT (53). Certain subgroups were at especially high risk of increased VTE, including women with lower extremity fractures (18-fold increase), cancer (4- fold increase), postoperative state (5-fold increase), or nonsurgical hospitalization (6-fold increase). Women with factor V Leiden seem to be at especially high risk of VTE if they take HRT (54). E. Selective Estrogen Receptor Modulators An alternative to HRT is raloxifene, a selective estrogen receptor modulator that has estrogenic effects on bone, lipid metabolites, and blood clotting but an estro- gen antagonist effect on breast tissue. In a randomized controlled trial of 7705 osteoporotic postmenopausal women, raloxifene decreased the risk of breast can- cer by 75% and decreased the rate of vertebral fractures, as had been hoped, but it tripled the rate of VTE (55). Tamoxifen, another selective estrogen receptor modulator, also acts as an estrogen agonist on bone and an estrogen antagonist on breast tissue. In the British Cancer Prevention Trial of women at high risk of breast cancer, 55 months of treatment with tamoxifen 20 mg daily halved the rate of breast cancer. However, the DVT rate increased by 60%, and the PE rate tripled (56). V. CONCLUSIONS In summary, VTE has enormous clinical impact. PE has a high mortality rate despite advances in therapy, and VTE has a high recurrence rate after anticoagula- tion is discontinued. DVT is often characterized by leg discomfort and postthrom- botic venous insufficiency that adversely impacts the quality of life. Patients with VTE often feel like they have a sword dangling over them because this disease may be latent for many years and then recur. The etiologies of VTE are multifac- torial, and we have arrived at an exciting juncture where we can identify with increasing sophistication predisposing genetic, environmental, and hormonal fac- tors that contribute to the risk of this illness. REFERENCES 1. Oger E. 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Cummings SR, Eckert S, Krueger KA, Grady D, Powles TJ, Cauley JA, Norton L, Nickelsen T, Bjarnason NH, Morrow M, Lippman ME, Black D, Glusman JE, Costa A, Jordan VC. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA 1999; 281:2189–2197. 56. Fisher B, Costantino JP, Wickerham L, et al. Tamoxifen for the prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998; 90:1371–1388. 13 Integrated Diagnostic Approach to Venous Thromboembolism Henri Bounameaux University Hospital of Geneva and Geneva School of Medicine, Geneva, Switzerland Diagnosis of deep vein thrombosis (DVT) depends mainly upon three clinical tools: venous compression ultrasonography (US), assessment of prior clinical probability (PCP), and measurement of fibrin D-Dimer (DD). In suspected pul- monary embolism (PE), the same tools can be applied, in addition to ventilation/ perfusion lung scan (V/Q scan). In a few patients, venography (suspected DVT) or pulmonary angiography (suspected PE) may also be required. I. BRIEF DESCRIPTION OF THE DIAGNOSTIC TOOLS Today venous compression ultrasonography (US) is the key diagnostic tool in patients with a first episode of clinically suspected DVT. The sensitivity and specificity exceed 90% for proximal DVT (1). The corresponding values are definitely less (50% or less) for isolated distal DVT. Although these results may be superior in experienced hands, they clearly highlight the need for integrating the US result in a comprehensive approach. A crucial issue in this regard is clinical assessment, which can be made either by means of a standardized Wells score (2) or in an empirical way (3). These two means have been compared in the case of suspected DVT (4). Both the Wells score and the empirical evaluation can triage patients into a low, inter- mediate, or high clinical probability category. However, the empirical method performed slightly better in categorizing patients in the high-probability class, while the Wells score categorized more patients in the low-probability class. 225 [...]... Patients with DVT and/ or PE (n) Sensitivity (%, 95% CI) Specificity (%, 95% CI) 1311, 305 971 , 310 2393, 489 98 .7 (96 .7 99.6) 99.4 ( 97. 7–99.9) 90.2 ( 87. 2–92 .7) 39.6 (36.5–42.6) 39.6 (35.9–43.4) 68.5 (66.5 70 .6) DD, D-dimer, DVT, deep vein thrombosis; PE, pulmonary embolism; 95% CI, 95% confidence interval Venous Thromboembolism 2 27 II BACKGROUND OF DIAGNOSTIC STRATEGIES IN SUSPECTED DVT AND PE Contemporary... %) 3-month VTE risk [% (95% CI)] Cogo et al (10) RUS Bernardi et al (11) RUS ϩ DD Wells et al (2) RUS ϩ PCP Perrier et al (3) US ϩ DD ϩ PCP 170 2 24% — — 170 2 (100%) 946 28% — Instant-IA 946 (100%) 593 16% score — 593 (100%) 474 24% empirical Vidas DD 346 (73 %) 1302 (76 %) 88 (9%) 166 (28%) 0.9% 0 0 .7% (0.3–1.2) 5 .7% 0 0.4% (0–0.9) 1.8% 33 (6%) 0.6% (0.1–1.8) 0 — 2 (0.4%) 2.6% (0.2–4.9) VTE, venous thromboembolism; ... Newman TE, Ginsberg JS Noninvasive diagnosis of deep venous thrombosis Ann Intern Med 1998; 128:663– 677 Venous Thromboembolism 233 2 Wells PS, Anderson DR, Bormanis J, Guy F, Mitchell M, Gray L, Clement C, Robinson KS, Lewandowski B Value of assessment of pretest probability of deepvein thrombosis in clinical management Lancet 19 97; 350: 179 5– 179 8 3 Perrier A, Desmarais S, Miron MJ, de Moerloose P, Lepage... Heart 19 97; 77 :346–349 15 McConnell MV, Solomon SD, Rayan ME, et al Regional RV dysfunction detected by echocardiography in acute pulmonary embolism Am J Cardiol 1996; 78 :469– 473 16 Remy-Jardin M, Remy J, Wattine L, Giraud F Central pulmonary thromboembolism: diagnosis with spiral volumetric CT with single-breath hold technique—comparison with pulmonary angiography Radiology 1992; 185:381–3 87 17 May JR,... probability and a nondiagnostic lung scan (i.e., abnormal but non-high-probability pattern), provided no proximal DVT had been detected on US exam This combination was present in 175 patients of the cohort (22%), and was safe to rule out PE since the 3-month thromboembolic risk was only 1 .7% (95% CI; 0.4–4.9%) (18) Venous Thromboembolism 231 Because these strategies have a similar efficacy, the less resource-intensive... pulmonary embolism Chest 19 97; 111:218–224 29 Urokinase Pulmonary Embolism Trial: phase 1 results—a cooperative study JAMA 1 970 ; 214:2163–2 172 30 Arcasoy SM, Kreit JW Thrombolytic therapy of pulmonary embolism Chest 1999; 115:1695– 170 7 31 Jerjes-Sanchez C, Ramirez-Rivera A, Garcia M de L, et al Streptokinase and heparin versus heparin alone in massive pulmonary embolism: a randomized controlled trial... 1995; 2:2 27 229 32 Goldhaber SZ, Haire WD, Feldstein ML, et al Alteplase versus heparin in acute pulmonary embolism: randomize trial assessing right-ventricular function and pulmonary perfusion Lancet 1993; 341:5 07 511 33 Kasper W, Konstantitnides S, et al Management strategy and prognosis of pulmonary embolism registry: results of a multi-center registry J Am Coll Cardiol 19 97; 30:1165–1 173 34 Verstralte... diagnosis of venous thromboembolism in outpatients Lancet 1999; 353:190–195 4 Miron MJ, Perrier A, Bounameaux H Clinical assessment of suspected deep vein thrombosis: comparison between a score and empirical assessment J Intern Med 2000; 2 47: 249–254 5 Bounameaux H, de Moerloose P, Perrier A, Miron MJ D-dimer testing in suspected venous thromboembolism: an update Q J Med 19 97; 90:4 37 442 6 The PIOPED... Med 2000; 109:3 57 361 Fennerty T Pulmonary embolism Hospitals should develop their own strategies for diagnosis and management BMJ 1998; 3 17: 791 79 2 14 The Management of Massive Pulmonary Embolism Jeremy P Feldman University of California at San Francisco, San Francisco, California Samuel Z Goldhaber Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts Venous thromboembolism. .. in suspected venous thromboembolism: an overview Thromb Haemost 1994; 71 :1–6 12 Bounameaux H, de Moerloose P, Perrier A, Miron MJ D-Dimer testing in suspected venous thromboembolism: an update QJ Med 19 97; 90:4 37 441 13 Goldhaber SZ, Simons GR, Elliot CG Quantitative plasma d-dimer levels among patients undergoing pulmonary angiography for suspected pulmonary embolism JAMA 1993; 270 :2819–2822 14 Kasper . Med 2000; 160 :76 1 76 8. 8. Hansson PO, Sorbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med 2000; 160 :76 9 77 4. 9. Douketis. pulmonary embolism in women. JAMA 19 97; 277 :642–645. 17. Zornberg GL, Jick H. Antipsychotic drug use and risk of first-time idiopathic venous thromboembolism: a case-control study. Lancet 2000; 356:1219–1223. 18 (35.9–43.4) SimpliRED 2393, 489 90.2 ( 87. 2–92 .7) 68.5 (66.5 70 .6) DD, D-dimer, DVT, deep vein thrombosis; PE, pulmonary embolism; 95% CI, 95% confidence in- terval. Venous Thromboembolism 2 27 II. BACKGROUND OF DIAGNOSTIC