Fermo I, Vigano' D'Angelo S, Paroni R, Mazzola G, Calori G, D'Angelo A
Istituto Scientifico IRCCS H. S. Raffaele, Milan, Italy.
Ann Intern Med. 1995 Nov 15;123(10):747-53. doi: 10.7326/0003-4819-123-10-199511150-00002.
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.
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.
Thrombosis research unit of a community hospital.
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.
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.
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).
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.
评估早发性静脉或动脉血栓栓塞性疾病患者中中度高同型半胱氨酸血症及遗传性血栓形成倾向疾病（天然抗凝或纤维蛋白溶解机制的先天性缺陷）的患病率。
对连续的无亲缘关系、年龄在45岁之前或在不寻常部位发生静脉或动脉闭塞性疾病且无局部诱发因素的患者进行为期2年的横断面评估。
一家社区医院的血栓形成研究单位。
107例静脉血栓栓塞患者（事件发生时的平均年龄为32.9±11.9岁）和50例动脉闭塞性疾病患者（事件发生时的平均年龄为31.1±10岁），这些患者无获得性凝血缺陷、明显癌症或影响蛋氨酸代谢的获得性疾病。
在事件发生至少3个月后测量血浆总同型半胱氨酸（空腹水平）、抗凝血酶III、蛋白C、蛋白S、活化蛋白C抵抗、纤溶酶原和肝素辅因子II。在87例患者中，口服蛋氨酸负荷（L-蛋氨酸，0.1 g/kg体重）8小时后也测量了血浆总同型半胱氨酸水平。在60名明显健康的人中确定了这些变量分布的第95百分位数；蛋白S和血浆总同型半胱氨酸使用按性别划分的范围。对实验室异常患者的亲属进行研究以确认缺陷的遗传性。
在静脉或动脉闭塞性疾病患者中，分别有13.1%（95%CI，7.6%至21.3%）和19.2%（CI，9.0%至31.9%）检测到中度高同型半胱氨酸血症。基于口服蛋氨酸负荷后测量的同型半胱氨酸水平得出的高同型半胱氨酸血症患病率几乎是基于空腹水平得出的患病率的两倍。其余缺陷仅在静脉闭塞性疾病患者中检测到（11.2%的患者存在活化蛋白C抵抗，6.6%的患者存在蛋白S或C缺乏，0.9%的患者存在纤溶酶原缺乏），总体患病率为18.7%（CI，12.1%至27.6%）。在研究的30个家族中的26个家族中证实了高同型半胱氨酸血症和其他缺陷的遗传性。无事件生存分析表明，中度高同型半胱氨酸血症和其他缺陷患者发生闭塞性疾病的相对风险比无缺陷患者高1.70倍（CI，1.19至2.42；P<0.01）。在调整了诱发因素（如使用避孕药、怀孕、手术、长期卧床休息、吸烟、轻度高血压或血脂异常）和血栓形成家族史后，中度高同型半胱氨酸血症患者首次事件发生的年龄与其他缺陷患者相似（分别为26.4±11.2岁和25.2±10.6岁），43例有缺陷的患者首次事件发生时的年龄明显低于114例无缺陷的患者（分别为25.5±11.1岁和31.0±12.3岁；P<0.005）。轻度高同型半胱氨酸血症患者的复发率高于无缺陷患者（52%对25%；P = 0.01）；在观察前1年以上发生首次事件的56例患者中，有缺陷患者的复发率高于无缺陷患者（80%[CI，51%至95%]对41%[CI，26%至57%]；P = 0.01）。
中度高同型半胱氨酸血症可能在过早发生的静脉和动脉闭塞性疾病中具有致病意义，应纳入静脉和动脉血栓形成倾向（遗传性）疾病中。
