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Prevalence of Moderate Hyperhomocysteinemia in Patients with Early-Onset Venous and Arterial Occlusive Disease

Isabella Fermo, PhD; Silvana Vigano' D'Angelo, MD; Rita Paroni, PhD; Giuseppina Mazzola, PhD; Giliola Calori, MD; and Armando D'Angelo, MD
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From the Istituto Scientifico IRCCS H. S. Raffaele, Milan, Italy. Acknowledgments: The authors thank Mrs. Marilena Lomartire and Drs. Omid Safa and Patrizia Della Valle for their invaluable technical assistance. Grant Support: In part by a grant from the Italian National Research Council (CNR). Request for Reprints: Isabella Fermo, PhD, Laboratorio Centrale Analisi, Istituto Scientifico H. S. Raffaele, Via Olgettina 60, 20132 Milano, Italy. Current Author Addresses: Drs. Fermo and Paroni: Laboratorio Analisi, Istituto Scientifico H. S. Raffaele, Via Olgettina 60, 20132 Milano, Italy. Drs. Vigano' D'Angelo, Mazzola, and D'Angelo: Servizio Di Coagulazione, Istituto Scientifico H. S. Raffaele, Via Olgettina 60, 20132 Milano, Italy.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1995;123(10):747-753. doi:10.7326/0003-4819-123-10-199511150-00002
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Objective: To evaluate the prevalence of moderate hyperhomocysteinemia and inherited thrombophilia disorders (congenital defects of the natural anticoagulant or fibrinolytic mechanisms) in patients with early-onset venous or arterial thromboembolic disease.

Design: Cross-sectional 2-year evaluation of consecutive unrelated patients with a history of venous or arterial occlusive disease occurring before the age of 45 years or at unusual sites, in the absence of local predisposing factors.

Setting: Thrombosis research unit of a community hospital.

Patients: 107 patients with venous thromboembolism (mean age at event, 32.9 ± 11.9 years) and 50 patients with arterial occlusive disease (mean age at event, 31.1 ± 10 years) who did not have acquired coagulation defects, overt cancer, or acquired conditions affecting methionine metabolism.

Measurements: Total plasma homocysteine (fasting levels), antithrombin III, protein C, protein S, activated protein C resistance, plasminogen, and heparin cofactor II were measured at least 3 months after the event. In 87 patients, total plasma homocysteine levels were also measured 8 hours after an oral methionine load was administered (L-methionine, 0.1 g/kg body weight). Ninety-fifth percentiles of the distribution of these variables were established in 60 apparently healthy persons; sex-specific ranges were used for protein S and total plasma homocysteine. Relatives of patients with laboratory abnormalities were studied to confirm inheritance of the defects.

Results: Moderate hyperhomocysteinemia was detected in 13.1% (95% CI, 7.6% to 21.3%) and in 19.2% (CI, 9.0% to 31.9%) of patients with venous or arterial occlusive disease. The prevalence of hyperhomocysteinemia was almost twice as high when based on homocysteine measurements done after oral methionine load as when based on fasting levels. The remaining defects were detected only in patients with venous occlusive disease (activated protein C resistance in 11.2% of patients, protein S or C deficiency in 6.6%, and plasminogen deficiency in 0.9%), with an overall prevalence of 18.7% (CI, 12.1% to 27.6%). Inheritance of hyperhomocysteinemia and of the other defects was confirmed in 26 of the 30 families studied. Event-free survival analysis showed that the relative risk for occlusive disease in patients with moderate hyperhomocysteinemia and other defects was 1.70 times (CI, 1.19 to 2.42; P < 0.01) greater than in patients without defects. After adjustment for the presence of predisposing factors (for example, use of contraceptive drugs, pregnancy, surgery, prolonged bedrest, smoking, mild hypertension or dyslipidemia) and a family history of thrombosis, the age at first event of patients with moderate hyperhomocysteinemia was similar to that of patients with the other defects (26.4 ± 11.2 years compared with 25.2 ± 10.6 years), and the 43 patients with defects were significantly younger at first event than the 114 patients without defects (25.5 ± 11.1 years compared with 31.0 ± 12.3; P < 0.005). Patients with mild hyperhomocysteinemia had a higher rate of recurrence than those without defects (52% compared with 25%; P = 0.01); among the 56 patients who had their first event more than 1 year before observation, the recurrence rate was higher (80% [CI, 51% to 95%]) in patients with defects than in patients without defects (41% [CI, 26% to 57%] P = 0.01).

Conclusions: Moderate hyperhomocysteinemia may have pathogenic significance in premature venous and arterial occlusive disease and should be included among the (inherited) disorders of venous and arterial thrombophilia.





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