Madani Rami, Khan Mohammad Z, Ayoub Adam, Al-Assil Talal, Usman Muhammad
Hematology and Medical Oncology, Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, USA.
Internal Medicine, California University of Science and Medicine, Colton, USA.
Cureus. 2025 Jul 24;17(7):e88651. doi: 10.7759/cureus.88651. eCollection 2025 Jul.
Hemophilia A (HA) is an X-linked recessive bleeding disorder caused by a deficiency of factor VIII (FVIII), leading to impaired secondary hemostasis. The cornerstone of HA management is replacement therapy; however, this can induce the formation of neutralizing inhibitors, resulting in a refractory FVIII deficiency that is unresponsive to recombinant therapy. This case report describes the postoperative development of FVIII inhibitors in a patient with mild HA and explores two likely etiologies contributing to inhibitor formation. A man in his late 50s with a history of renal cell carcinoma (RCC) and mild HA (baseline FVIII: 22%; reference range: 55-200%) presented with right forearm and left lower leg swelling and pain two weeks after undergoing a radical nephrectomy. Preoperatively, he received 15 units/kg of recombinant FVIII, followed by 25-50 units/kg daily for six days postoperatively. After emergent causes were ruled out, laboratory evaluation revealed FVIII inhibitor levels of 9.1 Bethesda units (<0.5 BU) and FVIII activity <1%. The patient was started on monthly emicizumab therapy, resulting in resolution of inhibitor levels to <0.5 BU and improvement in FVIII levels to 6% within six months. This case presents a diagnostic challenge in distinguishing the underlying mechanism of acquired hemophilia A (AHA). While inhibitor formation from recombinant FVIII therapy is well documented in severe HA, it is less common in mild cases with limited exposure. Alternatively, malignancy-associated immune dysregulation has been hypothesized to induce AHA, although the mechanism remains poorly understood. Given the rapid onset of inhibitor development following FVIII replacement and the absence of inhibitors during active RCC or resolution immediately after nephrectomy, FVIII exposure appears to be the more likely contributor in this case. This case underscores the importance of careful monitoring for inhibitor formation even in patients with mild or previously asymptomatic HA, particularly in the perioperative setting. Clinicians should maintain a high index of suspicion for AHA in the appropriate clinical context, regardless of severity, to ensure timely diagnosis and management.
甲型血友病（HA）是一种X连锁隐性出血性疾病，由凝血因子VIII（FVIII）缺乏引起，导致二期止血功能受损。HA治疗的基石是替代疗法；然而，这可能会诱导中和性抑制剂的形成，导致对重组疗法无反应的难治性FVIII缺乏。本病例报告描述了一名轻度HA患者术后FVIII抑制剂的发生情况，并探讨了导致抑制剂形成的两种可能病因。一名50多岁的男性，有肾细胞癌（RCC）病史和轻度HA（基线FVIII：22%；参考范围：55 - 200%），在接受根治性肾切除术后两周出现右前臂和左小腿肿胀疼痛。术前，他接受了15单位/千克的重组FVIII，术后六天每天接受25 - 50单位/千克。排除紧急病因后，实验室评估显示FVIII抑制剂水平为9.1贝塞斯达单位（<0.5 BU），FVIII活性<1%。患者开始每月接受艾美赛珠单抗治疗，六个月内抑制剂水平降至<0.5 BU，FVIII水平升至6%。本病例在区分获得性甲型血友病（AHA）的潜在机制方面提出了诊断挑战。虽然重组FVIII治疗导致抑制剂形成在重度HA中已有充分记录，但在暴露有限的轻度病例中较少见。另外，恶性肿瘤相关的免疫失调被认为可诱导AHA，但其机制仍知之甚少。鉴于FVIII替代后抑制剂迅速出现，且在活动性RCC期间无抑制剂或肾切除术后立即消失，FVIII暴露似乎是该病例中更可能的原因。本病例强调了即使在轻度或既往无症状的HA患者中，尤其是围手术期，仔细监测抑制剂形成的重要性。临床医生在适当的临床背景下，无论严重程度如何，都应高度怀疑AHA，以确保及时诊断和治疗。
