Hereditary Thrombophilia as a Model for Multigenic Disease
Hereditary Thrombophilia as a Model for Multigenic Disease
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DOI：
10.1055/s-0037-1615894
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发表时间：
1999-08
影响因子：
6.7
通讯作者：
E. Bovill;S. Hasstedt;M. Leppert;G. Long
中科院分区：
文献类型：
--
作者：
E. Bovill;S. Hasstedt;M. Leppert;G. Long
近150年前，Virchow假设血栓形成是由血液流动、血管壁或血液成分的变化引起的。这一概念为随后研究遗传性和获得性高凝状态奠定了基础。本文将重点介绍一个应用现代遗传流行病学分析评价青少年血栓形成倾向综合征多基因发病机制的例子。自Virchow时代以来，在临床上已观察到青少年血栓形成倾向，其特征为静脉血栓形成在年轻时发作、复发性血栓形成和血栓形成阳性家族史。青少年血栓形成倾向的发病机制一直不清楚，直到1965年Egeberg观察到一个四代青少年血栓形成倾向家族，该家族与杂合抗凝血酶缺陷相关，后来被鉴定为抗凝血酶奥斯陆（编码Ala 404的三联体中的G到A）。1，2抗凝血酶III的遗传性缺乏与血栓形成的相关性似乎支持这一假设，1958年，Astrup首次提出血栓出血平衡。3他假设，在凝块形成和溶解之间存在一个精心控制的平衡，并且条件的变化，如Virchow广泛涵盖的三元组，可以使平衡向血栓形成倾斜。高凝状态下血栓出血平衡的重要性来自两方面的研究：支持止血机制的紧张性激活的证据，以及随后描述的抗凝血酶缺乏症和其他遗传性异常止血蛋白与遗传性血栓形成倾向相关的其他家族。通过多种措施评估体内止血机制的激活，包括对凝血酶活性产生的激活肽的测定。激活肽，如凝血酶原片段1 +2，在正常个体中是可测量的，由于紧张性止血活性，并且在某些青少年血栓形成障碍家族中出现升高。4在Egeberg描述抗凝血酶缺乏症后的过去25年中，许多看似单基因的常染色体显性遗传性疾病已被确定为静脉血栓栓塞性疾病的风险因素。这些疾病包括蛋白C缺乏症、蛋白S缺乏症、抗凝血酶III缺乏症、凝血因子V Leiden突变的存在以及最近报道的G20210 A凝血酶原多态性。5，6这些遗传性血栓形成综合征在其临床表现的严重程度上表现出相当大的变异性。纯合子蛋白C或蛋白S缺乏症会导致严重的、危及生命的血栓形成风险，如果不治疗，会导致死亡。7，8纯合子抗凝血酶III缺乏症尚未报道，但也可能是一种致死性疾病。凝血因子V Leiden或G20210 A多态性的纯合子状态仅赋予血栓形成中度风险。9，10与纯合子相反，这些单基因疾病的杂合子风险评估因具有相同基因型的家族成员的可变临床表达而复杂化。11考虑环境相互作用尚未阐明临床表达的可变性。因此，人们推测，一种以上的遗传风险因素可能共分离，从而对血栓形成风险产生累积或协同效应。12在过去几年中，已经描述了许多共分离风险因素。最好的相互作用可能是常见的凝血因子V Leiden突变，存在于3%至6%的高加索人群中，13，14和不太常见的蛋白C，蛋白S和抗凝血酶III缺乏症之间的相互作用。凝血因子V Leiden突变本身不会增加血栓形成的风险。然而，突变的高流行率为与其他风险因素的相互作用创造了充足的机会。G20210 A凝血酶原多态性在高加索人群中的患病率为1%至2%，因此可能与凝血因子V Leiden起相似的作用。一些小型研究记录了G20210 A与其他风险因素的相互作用。15 -17对患有抗凝血酶III、蛋白C或蛋白S缺乏症的个体进行的有限评估显示，G20210 A多态性的频率为7.9%，而对照组的频率为0.7%。18在6名蛋白C缺乏患者中仅1名中观察到G20210 A多态性。18在目前的状态下，静脉血栓栓塞性疾病的危险因素的阐明证明了从Virchow三联征的分子组分构建的分析框架的有效性，在血栓出血平衡假说的背景下进行分析。两种研究策略已被用于研究血栓形成：临床病例对照研究和遗传流行病学研究。基于过去二十年来分子生物学的显著进步，后一种策略已经获得了相当大的实用性。现代家庭遗传分析技术为确定危险因素与疾病的共分离提供了重要机会。19遗传流行病学策略的实质是临床疾病与特定基因等位基因的关联。它可以通过直接测序候选基因或通过证明与遗传标记的连锁来实现。
Introduction Nearly 150 years ago, Virchow postulated that thrombosis was caused by changes in the flow of blood, the vessel wall, or the composition of blood. This concept created the foundation for subsequent investigation of hereditary and acquired hypercoagulable states. This review will focus on an example of the use of modern genetic epidemiologic analysis to evaluate the multigenic pathogenesis of the syndrome of juvenile thrombophilia. Juvenile thrombophilia has been observed clinically since the time of Virchow and is characterized by venous thrombosis onset at a young age, recurrent thrombosis, and a positive family history for thrombosis. The pathogenesis of juvenile thrombophilia remained obscure until the Egeberg observation, in 1965, of a four generation family with juvenile thrombophilia associated with a heterozygous antithrombin deficiency subsequently identified as antithrombin Oslo (G to A in the triplet coding for Ala 404).1,2 The association of a hereditary deficiency of antithrombin III with thrombosis appeared to support the hypothesis, first put forward by Astrup in 1958, of a thrombohemorrhagic balance.3 He postulated that there is a carefully controlled balance between clot formation and dissolution and that changes in conditions, such as Virchow’s widely encompassing triad, could tip the balance toward thrombus formation. The importance of the thrombohemorrhagic balance in hypercoagulable states has been born out of two lines of investigation: evidence supporting the tonic activation of the hemostatic mechanism and the subsequent description of additional families with antithrombin deficiency and other genetically abnormal hemostatic proteins associated with inherited thrombophilia. Assessing the activation of the hemostatic mechanism in vivo is achieved by a variety of measures, including assays for activation peptides generated by coagulation enzyme activity. Activation peptides, such as prothrombin fragment1+2, are measurable in normal individuals, due to tonic hemostatic activity and appear elevated in certain families with juvenile thrombophilia.4 In the past 25 years since Egeberg’s description of antithrombin deficiency, a number of seemingly monogenic, autosomal dominant, variably penetrant hereditary disorders have been well established as risk factors for venous thromboembolic disease. These disorders include protein C deficiency, protein S deficiency, antithrombin III deficiency, the presence of the factor V Leiden mutation, and the recently reported G20210A prothrombin polymorphism.5,6 These hereditary thrombophilic syndromes exhibit considerable variability in the severity of their clinical manifestations. A severe, life-threatening risk for thrombosis is conferred by homozygous protein C or protein S deficiency, which if left untreated, leads to death.7,8 Homozygous antithrombin III deficiency has not been reported but is also likely to be a lethal condition. Only a moderate risk for thrombosis is conferred by the homozygous state for factor V Leiden or the G20210A polymorphism.9,10 In contrast to homozygotes, the assessment of risk in heterozygotes, with these single gene disorders, has been complicated by variable clinical expression in family members with identical genotypes.11 Consideration of environmental interactions has not elucidated the variability of clinical expression. Consequently, it has been postulated that more than one genetic risk factor may co-segregate with a consequent cumulative or synergistic effect on thrombotic risk.12 A number of co-segregating risk factors have been described in the past few years. Probably the best characterized interactions are between the common factor V Leiden mutation, present in 3% to 6% of the Caucasian population,13,14 and the less common deficiencies of protein C, protein S, and antithrombin III. The factor V Leiden mutation does not, by itself, confer increased risk of thrombosis. The high prevalence of the mutation, however, creates ample opportunity for interaction with other risk factors when present. The G20210A prothrombin polymorphism has a prevalence of 1% to 2% in the Caucasian population and, thus, may play a similar role to factor V Leiden. A number of small studies have documented an interaction of G20210A with other risk factors.15-17 A limited evaluation of individuals with antithrombin III, protein C, or protein S deficiency revealed a frequency of 7.9% for the G20210A polymorphism, as compared to a frequency of 0.7% for controls.18 The G20210A polymorphism was observed in only 1 of the 6 protein C-deficient patients.18 In the present state, the elucidation of risk factors for venous thromboembolic disease attests to the effectiveness of the analytical framework constructed from the molecular components of Virchow’s triad, analyzed in the context of the thrombohemorrhagic balance hypothesis. Two investigative strategies have been used to study thromobophilia: clinical case-control studies and genetic epidemiologic studies. The latter strategy has gained considerable utility, based on the remarkable advances in molecular biology over the past two decades. Modern techniques of genetic analysis of families offer important opportunities to identify cosegregation of risk factors with disease.19 The essence of the genetic epidemiologic strategy is the association of clinical disease with alleles of specific genes. It is achieved either by the direct sequencing of candidate genes or by demonstration of linkage to genetic markers.