Glueck Charles J, Wang Ping, Bell Howard, Rangaraj Venkat, Goldenberg Naila
Cholesterol Center, Jewish Hospital, Cincinnati, Ohio 45229, USA.
Clin Appl Thromb Hemost. 2005 Oct;11(4):375-89. doi: 10.1177/107602960501100404.
We prospectively assessed whether thrombophilia and hypofibrinolysis, amplified by thrombophilic hormone replacement therapy (HRT), were associated with retinal vein occlusion (RVO). We studied 44 cases (18 men, 26 women), > or = 3 months after RVO, 42 with central RVO, 2 with branch RVO, in the consecutive order of their referral by 2 community-based ophthalmologists. PCR and serologic coagulation assays were compared to 83 and 40 healthy adult normal controls, respectively. The 4G allele frequency of the plasminogen activator inhibitor-1 (PAI-1) gene, associated with hypofibrinolysis, was 56 of 88 (64%) in cases vs 79 of 166 (48%) in controls, X(2) = 5.95, p = .015. The PAI-1 gene product, plasminogen activator inhibitor activity (PAI-Fx), was higher in cases than controls (age-race-sex- adjusted mean 12.2 U/mL vs 6.3, p = .013). By stepwise logistic regression, the PAI-1 gene 4G allele was associated with RVO, odds ratio 1.94, 95% CI 1.12-3.34, p = .018. Thrombophilic resistance to activated protein C (RAPC) was present in 6 of 32 (19%) of cases vs 0 of 40 (0%) controls, Fisher's p [p(f)] = .006. Thrombophilic high factor VIII (> 150%) was present in 3 of 30 (10%) cases vs 0 of 40 (0%) controls, p = .041, p(f) = .07. Comparing 23 RVO cases < or = age 55 and controls < or = age 55 (n = 44 for PCR, n = 40 for serologic measures), RAPC was present in 17% of cases vs 0% controls (p(f) = .026), high Factor VIII in 17% vs 0% (p(f) = .026), heterozygosity for the G1691A Factor V Leiden mutation in 13% vs 2% (p(f) = 0.11), and the 4G allele frequency of the PAI-1 gene 74% vs 39% (p = .0001). PAI-Fx was higher in cases than controls (age-race-sex adjusted mean 12.7 U/mL vs 6.7, p = .016). The case-control odds ratio for the PAI-1 4G allele was 5.54, 95% CI = 1.86-16.7, p = .002. Of the 26 women, 9 (35%) took HRT; 4 of the 9 had PAI-1 gene 4G4G homozygosity, 2 had thrombophilic high anticardiolipin antibody (IgG), 1 was heterozygous for the G1691A Factor V Leiden mutation, and 2 were heterozygous for the thrombophilic PL A1/A2 mutation of the platelet glycoprotein IIb/IIIa gene. Associations between heritable coagulation disorders and RVO, most marked in cases < or = age 55, and often amplified in women by thrombophilic HRT, are, speculatively, causal.
我们前瞻性地评估了由血栓形成倾向激素替代疗法（HRT）增强的血栓形成倾向和纤维蛋白溶解功能减退是否与视网膜静脉阻塞（RVO）相关。我们研究了44例患者（18名男性，26名女性），在RVO发生3个月或更长时间后，由2名社区眼科医生按转诊顺序连续纳入，其中42例为中央RVO，2例为分支RVO。分别将PCR和血清学凝血检测结果与83名和40名健康成年正常对照进行比较。与纤维蛋白溶解功能减退相关的纤溶酶原激活物抑制剂-1（PAI-1）基因的4G等位基因频率在病例组88例中有56例（64%），对照组166例中有79例（48%），X² = 5.95，p = 0.015。病例组的PAI-1基因产物纤溶酶原激活物抑制剂活性（PAI-Fx）高于对照组（年龄、种族、性别校正后的平均值分别为12.2 U/mL和6.3 U/mL，p = 0.013）。通过逐步逻辑回归分析，PAI-1基因的4G等位基因与RVO相关，比值比为1.94，95%置信区间为1.12 - 3.34，p = 0.018。32例病例中有6例（19%）存在对活化蛋白C的血栓形成倾向抵抗（RAPC），而40名对照组中无1例（0%），Fisher's p [p(f)] = 0.006。30例病例中有3例（10%）存在血栓形成倾向的高因子VIII（＞150%），40名对照组中无1例（0%），p = 0.041，p(f) = 0.07。比较年龄≤55岁的23例RVO病例和年龄≤55岁的对照组（PCR检测n = 44，血清学检测n = 40），病例组中17%存在RAPC，对照组为0%（p(f) = 0.026）；病例组中17%存在高因子VIII，对照组为0%（p(f) = 0.026）；病例组中13%为因子V Leiden突变G1691A杂合子，对照组为2%（p(f) = 0.11）；PAI-1基因的4G等位基因频率病例组为74%，对照组为39%（p = 0.0001）。病例组的PAI-Fx高于对照组（年龄、种族、性别校正后的平均值分别为12.7 U/mL和6.7 U/mL，p = 0.016）。PAI-1 4G等位基因的病例对照比值比为5.54，9%置信区间为1.86 - 16.7，p = 0.002。26名女性中，9名（35%）接受了HRT；这9名女性中，4名PAI-1基因4G4G纯合，2名存在血栓形成倾向性高抗心磷脂抗体（IgG），1名是因子V Leiden突变G1691A杂合子，2名是血小板糖蛋白IIb/IIIa基因血栓形成倾向性PL A1/A2突变杂合子。遗传性凝血障碍与RVO之间的关联，在年龄≤55岁的病例中最为明显，且在接受血栓形成倾向性HRT的女性中常被增强，推测可能存在因果关系。
