Mohri H, Motomura S, Kanamori H, Matsuzaki M, Watanabe S, Maruta A, Kodama F, Okubo T
First Department of Internal Medicine, Division of Blood Transfusion and Laboratory Medicine, Yokohama City University, Yokohama, Japan.
Blood. 1998 May 15;91(10):3623-9.
Of 260 patients enrolled, 25 patients (9.6%) were associated with acquired von Willebrand syndrome (AvWS). We studied 25 patients with AvWS, retrospectively. AvWS was diagnosed by reduced levels of von Willebrand factor (vWF) (decrease of von Willebrand factor antigen [vWF:Ag] and von Willebrand ristocetin cofactor [vWF:RCoF]), a decrease of ristocetin-induced platelet agglutination (RIPA), sometimes decreased high-molecular-weight multimers, and prolonged bleeding time with neither prior nor family histories of bleeding problems and the evidence of normal vWF:RCoF in their families. The inhibitor of vWF was determined by mixing patient plasma with pooled normal plasma. Eight patients in this study had the inhibitors to vWF that were of the IgG class; the subclasses were IgG1 (7 cases) and IgG2 (1 case). Multimeric analysis of vWF showed selective loss of large multimers in most patients with AvWS similar to that of congenital type-2 von Willebrand disease (vWD). All inhibitors blocked ristocetin-mediated vWF binding to platelets. Five out of 6 IgGs evaluated here recognized the 39/34-kD fragment (residues 480/481-718) and Fragment III (residues 1-1365) that implied binding domain of glycoprotein Ib (GPIb), whereas 1 recognized Fragment I (residues 911-1365). A close relationship was found between the presence of the inhibitor and bleeding tendency. Of the 7 patients with inhibitors, 6 patients (86%) had a bleeding tendency, as well as 1 of the 15 patients without inhibitors (6%). The efficacy of treatment of underlying diseases and/or therapy with deamino D-arginine vasopressin (DDAVP) for the treatment of AvWS also depends on the presence of an inhibitor. Four of 8 patients with inhibitors (50%) had poor response to treatment of the underlying disease and/or therapy with DDAVP, as well as 1 of the 16 patients without inhibitors (6%). These results indicate that patients with AvWS developing inhibitors to vWF are likely to have bleeding problems and might be resistant to treatment of underlying diseases and/or therapy with DDAVP for bleeding to AvWS. We also showed evidence that intravenous immunoglobulin therapy (0.3 g/kg, 3 days) was effective to correct a hemostatic defect and manage severe bleeding in a patient with AvWS developing inhibitors. We might consider an additional treatment including expensive high-dose immunoglobulin therapy when uncontrollable bleeding is continued after the treatment of the underlying diseases and/or therapy with DDAVP.
在纳入研究的260例患者中，25例（9.6%）患有获得性血管性血友病综合征（AvWS）。我们对25例AvWS患者进行了回顾性研究。AvWS的诊断依据为血管性血友病因子（vWF）水平降低（血管性血友病因子抗原[vWF:Ag]和血管性血友病因子瑞斯托霉素辅因子[vWF:RCoF]降低）、瑞斯托霉素诱导的血小板凝集（RIPA）降低、有时高分子量多聚体减少、出血时间延长，且患者既往无出血问题家族史，其家族中vWF:RCoF正常。通过将患者血浆与混合的正常血浆混合来测定vWF抑制剂。本研究中有8例患者存在IgG类vWF抑制剂；亚类为IgG1（7例）和IgG2（1例）。vWF的多聚体分析显示，大多数AvWS患者的大分子量多聚体选择性丢失，类似于先天性2型血管性血友病（vWD）。所有抑制剂均阻断瑞斯托霉素介导的vWF与血小板的结合。在此评估的6种IgG中，有5种识别39/34-kD片段（残基480/481 - 718）和片段III（残基1 - 1365），这意味着其与糖蛋白Ib（GPIb）的结合域，而1种识别片段I（残基911 - 1365）。发现抑制剂的存在与出血倾向之间存在密切关系。在7例有抑制剂的患者中，6例（86%）有出血倾向，在15例无抑制剂的患者中有1例（6%）有出血倾向。治疗基础疾病和/或使用去氨加压素（DDAVP）治疗AvWS的疗效也取决于抑制剂的存在。8例有抑制剂的患者中有4例（50%）对基础疾病治疗和/或DDAVP治疗反应不佳，16例无抑制剂的患者中有1例（6%）反应不佳。这些结果表明，AvWS患者出现vWF抑制剂可能有出血问题，并且可能对基础疾病治疗和/或DDAVP治疗AvWS出血有抵抗性。我们还证明，静脉注射免疫球蛋白治疗（0.3 g/kg，3天）对于纠正一名出现抑制剂的AvWS患者的止血缺陷和处理严重出血有效。当基础疾病治疗和/或DDAVP治疗后仍持续出现无法控制的出血时，我们可能会考虑包括昂贵的高剂量免疫球蛋白治疗在内的额外治疗。
