Recessive type 3 von Willebrand disease (VWD) is caused by homozygosity or double heterozygosity for two non-sense mutations (null alleles). Type 3 VWD is easy to diagnose by the combination of a strongly prolonged bleeding time (BT), absence of ristocetine-induced platelet aggregation (RIPA), absence of von Willebrand factor (VWF) protein, and prolonged activated partial thromboplastin time (aPTT) due to factor VIII:coagulant (FVIII:C) deficiency. VWD type 3 is associated with a pronounced tendency to mucocutaneous and musculoskeletal bleedings since early childhood. Carriers of one null allele are usually asymptomatic at VWF levels of 50% of normal. Recessive severe type 1 VWD is caused by homozygosity or double heterozygosity for a missense mutation. Recessive type 1 VWD differs from type 3 VWD by the presence of detectable von Willebrand factor: antigen VWF:Ag and FVIII:C levels between 0.09 and 0.40 U/mL. Patients with recessive type 1 VWD show an abnormal VWF multimeric pattern in plasma and/or platelets consistent with severe type 2 VWD. Carriers of a missense mutation may have mild bleeding and mild VWF deficiency and can be diagnosed by a double VWF peak on cross immunoelectrophoresis (CIE). There will be cases of mild and moderate recessive type 1 VWD due to double heterozygosity of two missense mutations, or with the combination of one missense mutation with a non-sense or bloodgroup O. Mild deficiency of VWF in the range of 0.20 to 0.60 U/mL, with normal ratios of von Willebrand factor: ristocetine cofactor/antigen VWF:RCo/Ag and VWF:collagen binding/antigen (VWF:CB/Ag), normal VWF multimers, and a completely normal response to desmopressin acetate (DDAVP) with VWF level rising from below to above 1.00 U/mL are very likely cases of so-called pseudo-VWF deficiency in individuals with normal VWF protein and gene. Autosomal dominant type 1 VWD variants are in fact type 2 variants caused by a heterozygous missense mutation in the VWF gene that produces a mutant VWF protein that has a dominant effect on normal VWF protein produced by the normal VWF allele with regard to the synthesis, processing, storage, secretion, and/or proteolysis of VWF in endothelial cells. A DDAVP challenge test clearly differentiates between dominant type 1 VWD phenotype and dominant type 2 M VWD.

译文

:隐性3型von Willebrand病(VWD)是由两个无义突变的纯合子或双重杂合子(无效等位基因)引起的。通过强烈延长出血时间(BT),不存在瑞斯托汀诱导的血小板聚集(RIPA),不存在von Willebrand因子(VWF)蛋白和延长活化部分凝血活酶时间(aPTT)的组合,很容易诊断3型VWD由于VIII因子:凝血剂(FVIII:C)缺乏。自幼儿期以来,VWD 3型与明显的粘膜皮肤和肌肉骨骼出血倾向有关。一个无效等位基因的携带者在VWF正常水平的50%时通常是无症状的。隐性严重1型VWD是由错义突变的纯合或双重杂合引起的。隐性1型VWD与3型VWD的区别在于存在可检测的von Willebrand因子:抗原VWF:Ag和FVIII:C水平在0.09至0.40 U / mL之间。隐性1型VWD患者在血浆和/或血小板中显示出异常的VWF多聚体模式,与严重的2型VWD一致。错义突变的携带者可能有轻度出血和轻度VWF缺乏症,可以通过交叉免疫电泳(CIE)上的双VWF峰进行诊断。由于两个错义突变的双重杂合性,或者一个错义突变与无义或血型O的组合,将出现轻度和中度隐性1型VWD。VWF的轻度缺乏在0.20至0.60 U的范围内/ mL,具有正常比例的von Willebrand因子:ristocetine辅因子/抗原VWF:RCo / Ag和VWF:胶原结合/抗原(VWF:CB / Ag),正常的VWF多聚体,以及对醋酸去氨加压素(DDAVP)的反应完全正常VWF水平从低于1.00 U / mL升至1.00 U / mL以上的人,很有可能在具有正常VWF蛋白和基因的个体中发生所谓的伪VWF缺乏症。常染色体显性1型显性VWD变体实际上是2型变异,由VWF基因中的杂合错义突变引起,该突变产生突变的VWF蛋白,在合成,加工方面对正常VWF等位基因产生的正常VWF蛋白具有显性作用内皮细胞中VWF的储存,分泌,和/或蛋白水解。 DDAVP挑战测试清楚地区分了显性1型VWD表型和显性2 M VWD型。

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