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首页> 外文期刊>Haemophilia: the official journal of the World Federation of Hemophilia >Native plasma-derived FVIII/VWF complex has lower sensitivity to FVIII inhibitors than the combination of isolated FVIII and VWF proteins. Impact on Bethesda assay titration of FVIII inhibitors
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Native plasma-derived FVIII/VWF complex has lower sensitivity to FVIII inhibitors than the combination of isolated FVIII and VWF proteins. Impact on Bethesda assay titration of FVIII inhibitors

机译：天然血浆衍生的FVIII / VWF复合物对FVIII抑制剂的敏感性低于分离的FVIII和VWF蛋白的组合。 FVIII抑制剂对Bethesda测定滴定的影响

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Sensitivity to FVIII inhibitors of the native plasma-derived (pd) FVIII/VWF complex vs. the complexes formed after exogenous FVIII infusion in the haemophilic patient has not been thoroughly studied. The role of VWF in the interaction of FVIII with inhibitors was studied in vitro using different combinations of VWF and FVIII concentrates. Normal plasma, pdFVIII/VWF and isolated FVIII (recombinant FVIII, B-domain deleted and pdFVIII) were used. Titre (BU) was kinetically determined (up to 2h) in serial dilutions of inhibitor IgG (purified from a pool of plasmas with inhibitors) mixed with VWF and then incubated with the different FVIII. Inhibitor was also added to previously mixed VWF+FVIII. Residual FVIII:C was determined. TGA assays were performed with FVIII-deficient plasma spiked with the FVIII-VWF mixtures with/without an ESH-8 antibody. Inhibitor titres for plasma and pdFVIII/VWF were comparable at all time points. Titres for all concentrates of isolated FVIII were significantly higher than those for plasma or pdFVIII/VWF (1.4-1.9 fold) even after preincubation with VWF. At t=0h, titres for plasma or pdFVIII/VWF were unquantifiable, but were detectable for isolated FVIII (0.6-1.6 BU). In contrast to pdFVIII/VWF, the decrease in thrombin generation parameters by isolated FVIII in the presence of ESH-8 was significant (P<0.01) even when previously combined with VWF. In conclusion, VWF protection against FVIII inhibitor activity might be higher with native pdFVIII/VWF complex than with the corresponding compound formed from the isolated proteins. Bethesda assay titration using different FVIII concentrates would be advisable to guide the treatment of inhibitor patients.
机译：还没有彻底研究血友病患者中天然血浆衍生（pd）FVIII / VWF复合物对FVIII抑制剂的敏感性与外源FVIII输注后形成的复合物的敏感性。使用VWF和FVIII浓缩物的不同组合体外研究了VWF在FVIII与抑制剂相互作用中的作用。使用正常血浆，pdFVIII / VWF和分离的FVIII（重组FVIII，B结构域缺失和pdFVIII）。在抑制剂IgG（从含有抑制剂的血浆中纯化）的系列稀释液中动力学测定（最长2h）滴定度（BU），然后与不同的FVIII孵育。抑制剂也被添加到先前混合的VWF + FVIII中。确定了残留的FVIII：C。 TGA分析是在掺有FSH-VWF的FVIII缺陷血浆中加入或不加入ESH-8抗体进行的。在所有时间点，血浆和pdFVIII / VWF的抑制剂效价均相当。即使与VWF预孵育，分离出的FVIII的所有浓缩物的滴度也显着高于血浆或pdFVIII / VWF的滴度（1.4-1.9倍）。在t = 0h时，血浆或pdFVIII / VWF的滴度无法定量，但分离出的FVIII（0.6-1.6 BU）可以检测。与pdFVIII / VWF相比，即使在以前与VWF联合使用时，在ESH-8存在下，分离的FVIII引起的凝血酶生成参数的降低也很明显（P <0.01）。总之，天然pdFVIII / VWF复合物的VWF对FVIII抑制剂活性的保护作用可能比由分离的蛋白质形成的相应化合物要高。建议使用不同的FVIII浓缩物进行Bethesda测定滴定，以指导抑制剂患者的治疗。

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