Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands.
Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.
J Thromb Haemost. 2017 Jul;15(7):1422-1429. doi: 10.1111/jth.13711. Epub 2017 Jun 2.
Essentials Research suggests that intensive treatment episodes may increase the risk to develop inhibitors. We performed an international nested case-control study with 298 non-severe hemophilia A patients. Surgery and a high dose of factor VIII concentrate were associated with increased inhibitor risk. Physicians need to review arguments for factor VIII dose and elective surgery extra critically.
Background Inhibitor development is a major complication of treatment with factor VIII concentrates in hemophilia. Findings from studies among severe hemophilia A patients suggest that intensive treatment episodes increase the risk of developing inhibitors. Objectives We set out to assess whether intensive treatment is also associated with an increased risk of inhibitor development among non-severe hemophilia A patients. Patients/Methods We performed a nested case-control study. A total of 75 inhibitor patients (cases) and 223 control patients were selected from 2709 non-severe hemophilia A patients (FVIII:C, 2-40%) of the INSIGHT cohort study. Cases and controls were matched for date of birth and cumulative number of exposure days (EDs) to FVIII concentrates. Conditional logistic regression was used to calculate both unadjusted and adjusted odds ratios (aOR); the latter were adjusted for a priori specified confounders. Results Peak treatment of 5 or 10 consecutive EDs did not increase inhibitor risk (aOR, 1.0; 95% confidence interval (CI), 0.4-2.5; and aOR, 1.8; CI, 0.6-5.5, respectively). Both surgical intervention (aOR, 4.2; CI, 1.7-10.3) and a high mean dose (> 45 IU kg /ED) of FVIII concentrate (aOR, 7.5; CI, 1.6-35.6) were associated with an increased inhibitor risk. Conclusions Our findings suggest that high-dose FVIII treatment and surgery increase the risk of inhibitor development in non-severe hemophilia A. Together with the notion that non-severe hemophilia A patients are at a lifelong risk of inhibitor development, we suggest that in the future physicians will review the arguments for the FVIII dose and elective surgery extra critically.
抑制剂的产生是血友病 A 患者接受因子 VIII 浓缩物治疗的主要并发症。来自重度血友病 A 患者研究的结果表明，强化治疗会增加产生抑制剂的风险。目的：评估非重度血友病 A 患者中强化治疗是否也与抑制剂的产生风险增加相关。
患者/方法：我们进行了一项巢式病例对照研究。从 INSIGHT 队列研究的 2709 例非重度血友病 A 患者（FVIII：C，2-40%）中，共选择了 75 例抑制剂患者（病例）和 223 例对照患者。病例和对照按出生日期和接受 FVIII 浓缩物的累积暴露天数（ED）进行匹配。采用条件逻辑回归计算未经调整和调整后的比值比（aOR）；后者根据预先指定的混杂因素进行调整。
5 或 10 个连续 ED 的峰值治疗并未增加抑制剂的风险（aOR，1.0；95%置信区间（CI），0.4-2.5；和 aOR，1.8；CI，0.6-5.5）。手术干预（aOR，4.2；CI，1.7-10.3）和高平均剂量（>45 IU kg /ED）的 FVIII 浓缩物（aOR，7.5；CI，1.6-35.6）均与抑制剂风险增加相关。
我们的研究结果表明，高剂量 FVIII 治疗和手术会增加非重度血友病 A 患者抑制剂产生的风险。考虑到非重度血友病 A 患者终身存在产生抑制剂的风险，我们建议未来医生将更加仔细地审查 FVIII 剂量和择期手术的理由。
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