Surgery in Patients with Factor VIII Inhibitors: A Retrospective Case Series at the Largest Canadian Hemophilia Care Centre

Introduction: Factor VIII (FVIII) inhibitors develop in a significant proportion of patients with severe congenital hemophilia A (CHA) and is also rarely acquired (AHA). These patients are at high risk of bleeding, particularly with surgical challenge. FVIII bypassing therapy and porcine factor VIII products have decreased the risk of bleeding complications and provided the opportunity for elective surgical intervention in this patient population. Factor VIII bypassing agents include activated Prothrombin Complex Concentrate (aPCC or FEIBA) and activated recombinant Factor VII (rFVIIa, Niastase). Porcine factor VIII products include plasma-derived Hyate C (historically) and currently, recombinant Obizur. To our knowledge, this is the largest Canadian review of perioperative management and outcomes in patients with factor VIII inhibitors.

Methods: We conducted a retrospective review of CHA with FVIII inhibitors and AHA who underwent surgery at the largest Canadian Hemophilia Treatment Center (HTC) between January 1, 1998 - December 31, 2015. The primary objectives were to describe perioperative characteristics, hemostatic therapy use (including adjunctive), bleeding and thromboembolic outcomes. All included patients had to have an evidence of high responding inhibitor either previously or at the time of surgical intervention.

Results: Twenty-two patients (10/22 with AHA) had surgical procedures at our institution between 1998 and 2015. All CHA were male, with the average age of 33 years (ranging 16 to 50 years) at first surgery at our center. Two out of 10 AHA were women. Mean age at first surgery for AHA patients was 59 years (ranging 24 to 85 years).

A total of 21 major procedures and 26 minor procedures were performed (using World Hemophilia Federation definitions). The major procedures included 11 orthopedic procedures, nine abdominal surgeries and one breast surgery. Minor procedures included 11 oesophagogastroduodenoscopies (OGDs), three tracheostomies, two colonoscopies, two cystoscopies, two dental extractions, one nasopharyngoscopy, one bronchoscopy, one arthroscopy, one pacemaker insertion, one burr hole for subdural hemorrhage and one arteriovenous fistula creation.

For each procedure, a hemophilia-focused hematologist tailored the hemostatic strategy. aPCC was used in six procedures and rFVIIa was used in 18 procedures. Two procedures required first rFVIIa then transition to aPCC; one procedure was managed with FVIII then rFVIIa and aPCC sequentially due to minor bleeding. One patient with subdural hematoma received high dose FVIII followed by porcine FVIII and aPCC in preparation for an urgent burr hole for hematoma evacuation. High dose FVIII alone was used in seven procedures, while a combination of FVIII and rFVIIa was used in three procedures and FVIII with aPCC in three procedures.

Three patients, all of whom were AHA patients, experienced adverse perioperative outcomes. One patient had six urgent laparotomies for hepatojejunostomy complicated by abdominal compartment syndrome, recurrent hemorrhage, intra-abdominal abscess drainage and large ventral hernia mesh repair. Despite the severity of her illness, this patient made a full recovery and remains in complete remission. Another patient undergoing partial bowel resection for Crohn's disease had an intra-abdominal hemorrhage requiring repeat laparotomy. The third patient had esophageal cancer with recurrent bleeding from radiation gastritis. He underwent four OGDs and later died from metastatic disease.

Conclusions: FVIII bypassing agents and porcine FVIII products have allowed for the safe performance of a variety of major and minor surgical procedures at our HTC in patients with FVIII inhibitors. Excessive perioperative bleeding despite hemostatic therapy that required repetitive surgical/endoscopic intervention occurred exclusively in AHA patients.