Rintelen C, Pabinger I, Knöbl P, Lechner K, Mannhalter C
First Department of Medicine, Division of Hematology and Blood Coagulation, University of Vienna, Austria.
Thromb Haemost. 1996 Feb;75(2):229-32.
Activated protein C (APC) resistance is a common risk factor for venous thromboembolism and is associated with the replacement of Arg 506 by Gln in the factor V gene (factor V Leiden). We investigated the risk of recurrence of venous thromboembolism in APC resistant patients heterozygous for FV Leiden and compared these patient groups with a group of patients, who had a history of venous thromboembolism, but had neither APC resistance nor the FV Leiden mutation. APC resistance was determined in frozen blood samples from patients with a history of venous thromboembolism, who were not receiving oral anticoagulant (OAC) treatment. The plasma samples were collected between 1984 and 1991. Twenty-one patients in whom APC resistance was found in the stored plasma samples were reinvestigated in 1994 (5 males, 16 females, median [m] age 49 years, range 21-71 years). Twenty-one sex and age matched patients with venous thromboembolism (5 males, 16 females, age m = 50 years, range 25-73 years) investigated during the same time period who had a normal APC resistance test served as a control group. Patients with APC resistance as well as controls were reinvestigated for the presence of FV Leiden by genetic analysis in 1994. Of the 21 APC resistant patients, 5 were homozygous and 16 heterozygous for FV Leiden. Before the study entry homozygous patients had a significantly higher recurrence rate (5/5 patients) compared to the control group in heterozygous patients (9/16) and controls (9/21) the recurrence rate was not significantly different. The total observation time was 21 years in patients with homozygous FV Leiden, 83 years in patients with heterozygous FV Leiden and 108 years in controls, excluding the time when patients were on OAC treatment. During the observation time the recurrence rate was highest in patients with homozygous FV Leiden (9.5% per patient per year), but was similar in patients with heterozygous FV Leiden (4.8% per patient per year) and controls (5% per patient per year). Two of five (40%) homozygous patients, 4/16 (25%) heterozygous and 5/21 (24%) controls had a least one recurrent event during the observation period. The probability for development of thrombosis in the Kaplan-Meyer-Plot analysis was not different between the three groups. Bearing limitations of our study in mind (retrospective design, relatively small patient number) we conclude that the risk of recurrence after a thromboembolic event is not higher in patients with heterozygous FV Leiden than in patients without this mutation. Thus, it appears that the identification of heterozygous FV Leiden mutation is not an indication for long-term OAC treatment. Also, long-term OAC treatment cannot generally be recommended for homozygous patients with a single thromboembolic event. More definitive conclusions will require larger prospective studies.
活化蛋白C（APC）抵抗是静脉血栓栓塞的常见危险因素，与因子V基因中第506位精氨酸被谷氨酰胺取代（因子V莱顿突变）有关。我们研究了FV莱顿杂合的APC抵抗患者静脉血栓栓塞复发的风险，并将这些患者组与一组有静脉血栓栓塞病史但既无APC抵抗也无FV莱顿突变的患者进行比较。APC抵抗在有静脉血栓栓塞病史且未接受口服抗凝剂（OAC）治疗的患者的冷冻血样中测定。血浆样本于1984年至1991年期间采集。1994年对在储存血浆样本中发现APC抵抗的21例患者进行了重新研究（5例男性，16例女性，中位年龄49岁，范围21 - 71岁）。同期研究的21例性别和年龄匹配的有静脉血栓栓塞且APC抵抗试验正常的患者（5例男性，16例女性，中位年龄50岁，范围25 - 73岁）作为对照组。1994年通过基因分析对APC抵抗患者以及对照组再次进行FV莱顿检测。21例APC抵抗患者中，5例为FV莱顿纯合子，16例为杂合子。在研究入组前，纯合子患者的复发率（5/5例患者）显著高于杂合子患者（对照组9/16例，复发率无显著差异）和对照组（9/21例）。FV莱顿纯合子患者的总观察时间为21年，FV莱顿杂合子患者为83年，对照组为108年，不包括患者接受OAC治疗的时间。在观察期内，FV莱顿纯合子患者的复发率最高（每年每位患者9.5%），但FV莱顿杂合子患者（每年每位患者4.8%）和对照组（每年每位患者5%）相似。5例纯合子患者中有2例（40%）、16例杂合子患者中有4例（25%）和21例对照组患者中有5例（24%）在观察期内至少有一次复发事件。在Kaplan - Meyer曲线分析中，三组发生血栓形成的概率无差异。考虑到我们研究的局限性（回顾性设计、患者数量相对较少），我们得出结论，FV莱顿杂合患者血栓栓塞事件后的复发风险并不高于无此突变的患者。因此，似乎鉴定出FV莱顿杂合突变并非长期OAC治疗的指征。同样，对于有单次血栓栓塞事件的纯合子患者，一般也不推荐长期OAC治疗。更明确的结论需要更大规模的前瞻性研究。
