Mahmoud Abu Arra Caesar, Samarah Fekri, Sudqi Abu Hasan Nael
Medicare Labs, Tulkarm, State of Palestine.
Department of Medical Laboratory Sciences, Arab American University (AAUP), Jenin, State of Palestine.
Scientifica (Cairo). 2020 Sep 25;2020:3428648. doi: 10.1155/2020/3428648. eCollection 2020.
Hemophilia A is an X-linked recessive bleeding disorder caused by mutations in FVIII gene with an incidence of 1 in 5,000 to 10,000 live born males. The Inv22 mutation is a major cause of the disease worldwide, accounting for up to 40%-50% of severe FVIII mutations. The aim of the present study was to screen Inv22 of the FVIII gene in Palestinian patients with severe HA and reveal its role as a predisposing factor for the development of inhibitors.
A cohort of 77 HA individuals including 5 carrier females from 52 unrelated families registered at governmental hemophilia centers in the West Bank area of Palestine was investigated. The demographic data and the clinical history were retrieved from medical files. Molecular analysis of Inv22 mutation in severe HA (30 cases) from Palestine was performed using the subcycling polymerase reaction (S-PCR). FVIII coagulant activities were carried out on an aPTT-based 1-stage clotting assay. FVIII inhibitors were quantified using the Nijmegen modification of the Bethesda assay.
Overall, 41.7% (30/72) of the studied cases were classified as having severe HA, 22.2% (16/72) had moderate HA, and 36.1% (26/72) had mild HA. Five randomly selected carrier mothers were screened for the Inv22 mutation to confirm its transmission to their sons. The Inv22 mutation was detected in 11 severe HA patients (36.6%). Among the severe HA patients with positive Inv22, 45.5% (5/11) had developed inhibitors. The current study showed that there was no association (=0.53) between inhibitor development and the Inv22 mutation.
Findings on Inv22 are in agreement with worldwide reports, being a major genetic mutation in severe HA. The S-PCR is a simple, rapid, and cost-effective method for the diagnosis of Inv22 in severe HA patients. Although the Inv22 mutation was associated with 36.6% of severe HA phenotype cases, it was not a major predisposing factor for inhibitor formation.
甲型血友病是一种X连锁隐性出血性疾病，由FVIII基因突变引起，在活产男性中的发病率为1/5000至1/10000。Inv22突变是全球该疾病的主要病因，占严重FVIII突变的40%-50%。本研究的目的是筛查巴勒斯坦严重甲型血友病患者的FVIII基因Inv22突变，并揭示其作为抑制剂形成的易感因素的作用。
对来自巴勒斯坦西岸地区政府血友病中心登记的52个无关家庭的77名甲型血友病患者进行了队列研究，其中包括5名携带者女性。从医疗档案中获取人口统计学数据和临床病史。使用亚循环聚合酶反应（S-PCR）对巴勒斯坦30例严重甲型血友病患者的Inv22突变进行分子分析。基于活化部分凝血活酶时间（aPTT）的1期凝血试验检测FVIII凝血活性。使用尼美根改良的贝塞斯达试验对FVIII抑制剂进行定量。
总体而言，41.7%（30/72）的研究病例被分类为严重甲型血友病，22.2%（16/72）为中度甲型血友病，36.1%（26/72）为轻度甲型血友病。随机选择5名携带者母亲进行Inv22突变筛查，以确认其向儿子的传递。在11名严重甲型血友病患者（36.6%）中检测到Inv22突变。在Inv22阳性的严重甲型血友病患者中，45.5%（5/11）已产生抑制剂。目前的研究表明，抑制剂形成与Inv22突变之间无关联（P=0.53）。
关于Inv22的研究结果与全球报告一致，是严重甲型血友病的主要基因突变。S-PCR是诊断严重甲型血友病患者Inv22的一种简单、快速且经济有效的方法。虽然Inv22突变与36.6%的严重甲型血友病表型病例相关，但它不是抑制剂形成的主要易感因素。
