Factor VIII Inhibitors in the Context of Renal Cell Carcinoma and Hemophilia A: A Tale of Two Causes

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.