Recombinant porcine factor VIII for high-risk surgery in paediatric congenital haemophilia A with high-titre inhibitor.
Recombinant porcine factor VIII for high-risk surgery in paediatric congenital haemophilia A with high-titre inhibitor.
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重组猪因子 VIII 用于具有高滴度抑制剂的儿童先天性血友病 A 的高风险手术。
DOI：
10.1111/hae.13157
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Monahan,PE
中科院分区：
文献类型：
--
作者：
Croteau,SE;Abajas,YL;Wolberg,AS;Nielsen,BI;Marx,GR;Baird,CW;Neufeld,EJ;Monahan,PE
简介高滴度因子 VIII (FVIII) 抑制剂使围手术期止血变得复杂。重组猪 FVIII (r-pFVIII) 可以为高风险手术提供替代止血剂，并允许监测 FVIII 活性。目的制定有效的止血计划，用于修复患有免疫耐受诱导 (ITI) 难治性高滴度 FVIII 的 5 岁男性进行性症状性主动脉缩窄 方法术前人 FVIII 抑制剂滴度为 58 贝塞斯达单位 mL−1(BU)，并进行交叉反应以中和 30 BU 的猪 FVIII。每日 ITI 血浆衍生 FVIII 浓缩物辅以抗 B 细胞和抗浆细胞免疫疗法，以降低 FVIII 抑制剂滴度。通过比较体外凝血酶生成测定 (TGA) 评估潜在的止血剂。结果免疫抑制后 4 周，人和猪抑制剂滴度分别下降至 16 和 2 BU。 r-pFVIII 的 TGA 不如活化凝血酶原复合物浓缩物 (aPCC) 稳健；然而，选择 r-pFVIII 进行心脏手术是为了确保能够在整个高出血风险手术中测定 FVIII 水平。 r-pFVIII 的止血效果非常好；初始谷值 FVIII 活性水平范围为 0.81–1.17 IU mL−1。术后第 3 天，峰值和谷值水平显着下降，表明猪抑制剂滴度上升。术后预防转为 aPCC，由 TGA 通知。结论 R-pFVIII 提供有效的围手术期止血，无不良事件。尽管存在强烈的免疫抑制，但在最初 60 小时后 r-pFVIII 会被快速中和，这凸显了仔细监测的重要性。使用 TGA 可以支持绕过恢复期药物选择。 r-pFVIII 的相对成本可能会限制其在高发病率临床场景中的使用。
IntroductionHigh‐titre factor VIII (FVIII) inhibitors complicate peri‐operative haemostasis. Recombinant porcine FVIII (r‐pFVIII) may provide an alternative haemostatic agent for high‐risk procedures and allow FVIII activity monitoring.AimDevise an effective haemostatic plan for repair of a progressively symptomatic aortic coarctation in a 5‐year‐old male with immune tolerance induction (ITI) refractory high‐titre FVIII inhibitors.MethodsPreprocedure human FVIII inhibitor titre was 58 Bethesda Units mL−1(BU) and cross‐reacted to neutralize porcine FVIII at 30 BU. Daily ITI with plasma‐derived FVIII concentrate was supplemented with anti‐B‐cell and anti‐plasma cell immunotherapy to reduce FVIII inhibitor titres. Potential haemostatic agents were evaluated in comparativeex vivothrombin generation assays (TGA).ResultsFour weeks after immunosuppression, human and porcine inhibitor titres declined to 16 and 2 BU respectively. TGA with r‐pFVIII was less robust than with activated prothrombin complex concentrate (aPCC); however, r‐pFVIII was selected for cardiac surgery to secure the ability to assay FVIII levels throughout this high‐bleeding risk procedure. Haemostasis with r‐pFVIII was excellent; initial trough FVIII activity levels ranged from 0.81–1.17 IU mL−1. On postoperative day 3, peak and trough levels markedly declined suggesting a rising porcine inhibitor titre. Postprocedure prophylaxis was transitioned to aPCC, informed by TGA.ConclusionsR‐pFVIII provided effective peri‐procedural haemostasis with no adverse events. Rapid neutralization of r‐pFVIII after the first 60 hours, despite intensive immune suppression, accentuates the importance of careful monitoring. Use of TGA can support bypassing agent selection for convalescence. The comparative cost of r‐pFVIII may limit its use to high morbidity clinical scenarios.