Considerations for the Hemophiliac Patient with Inhibitors to Factor VIII

Hemophilia A, a bleeding disorder resulting from a congenital deficiency of coagulation factor VIII (FVIII), is the third most common X-linked disorder, with an incidence of approximately 1 in 5000 male births (1). Hemophiliacs may present for a variety of surgical procedures, from vascular access procedures to major orthopedic reconstructions. An important management issue with these patients has been the development of endogenous FVIII inhibitors, which may render traditional therapy ineffective. Patients are usually either “low responders” or “high responders” with regard to FVIII inhibitor production. This case illustrates the impact of undetected responder status changes in a hemophiliac A patient, highlighting the importance of vigilance on the part of the anesthesiologist, who must ensure the adequacy of hemostatic monitoring in these patients before surgery. Case Report The patient was a 55-yr-old man with hemophilia A who was scheduled for a right total knee arthroplasty secondary to degenerative joint disease after hemarthrosis in the past. He had undergone both a left total knee replacement and a right total hip replacement 2 yr before admission without complication. He denied any bleeding episodes within the past 10 yr and had not required any replacement therapy other than the human FVIII prophylaxis he received for his previous surgeries. Baseline laboratory studies revealed a prothrombin time of 13.6 s (control value, 10.6–12.7 s), an activated partial thromboplastin time of 91 s (control value, 25–34 s), and a platelet count of 179,000 per mm3. His preoperative FVIII activity was <1% of normal, with endogenous inhibitors present that reacted with both human and porcine FVIII in the amounts of 5 and 2 Bethesda units (BU), respectively. Because these were considered to be low titer inhibitors, the consulting hematologists determined that preoperative porcine FVIII therapy would be the most appropriate management option for this patient. Recommendations also provided for at least 7 days of additional postoperative therapy in an attempt to maintain a postoperative FVIII activity of at least 50% of normal. As scheduled, the patient received 4000 U of porcine FVIII before surgery and tolerated the infusion well. He was then transported to the operating room, where an uneventful induction of anesthesia was performed. A tourniquet was placed around the right leg, and the operation began without incident. At the hematologist’s request, a plasma FVIII activity was obtained during the operation and was found to be critically low, at 5% of normal activity. Although hemostasis was grossly intact, another plasma FVIII activity was obtained. The repeated FVIII activity was 1%, with a concurrent activated partial thromboplastin time of 66 s. At this point, the surgery was almost completed, and although this patient had critically low plasma FVIII activity, adequate hemostasis was achieved with suture and compression dressings. An urgent infusion of additional porcine FVIII was initiated, with a total of 20,000 U administered within the first 24 h. His FVIII activity finally reached 58% of normal by Day 1 after surgery, and his clinical course remained stable. In accordance with the hematology protocol for such a case, he was administered an additional 35,000 U over the next 5 days. However, his FVIII activity again decreased to <1% of normal, and repeat inhibitor titers were found to be 9000 BU and 1500 BU for porcine and human FVIII, respectively. Although this patient had in fact become a high responder, knee drainage remained within normal limits and physical therapy was well tolerated, making additional FVIII therapy unwarranted. It was of interest that neither immunopathology nor hematopathology staff members could offer a plausible explanation for clinical hemostasis in this patient other than that he had a particularly robust tissue factor clotting pathway. Fortunately, despite the markedly low plasma FVIII activity, the patient healed well and was discharged home on Day 9 after surgery. Discussion The development of inhibitors to FVIII can complicate the safe anesthetic management of hemophiliac patients. These immunoglobulin G antibodies are thought to develop in 20%–33% of moderate to severe hemophiliacs (1). High responding inhibitors are those that react to repeated FVIII exposure and develop high titer inhibition very quickly. When such inhibitors exist, hemostasis cannot be maintained with FVIII therapy alone without posttherapy surveillance (2). FVIII inhibitor activity may also decrease to very low values between exogenous FVIII exposures, as they did in this case (1). FVIII inhibitors tend to occur in members of the same family, in patients with severe disease, and in individuals of African descent (1). Typical prophylactic FVIII treatment involves the IV administration of 50 U per kilogram of body weight with a plasma FVIII activity immediately determined to ascertain if the activity is 80% of normal in the preoperative period, with postoperative administration tailored to maintain 50% of normal activity. Treatment options for patients with inhibitors include replacement therapy with porcine FVIII, plasmapheresis, prothrombin complex concentrate administration, and recombinant FVIIa therapy. Porcine FVIII, derived from pig plasma, is similar to human FVIII, augmenting the clotting mechanism, yet antigenetically distinct enough to avoid inhibition. In situations where low titer inhibition is thought to exist, porcine FVIII is an acceptable option. Porcine FVIII can, however, stimulate the development of antibodies to both porcine and human FVIII. In our patient, low titer inhibition was originally thought to exist until FVIII therapy triggered high responding inhibition. Although large-dose porcine FVIII may still be used in such a case, with an acquisition cost of around US$1.83 per unit, patients such as ours may require more than US$100,000 of therapy. Scharf et al. (2) describe a similar case, in which plasmapheresis was used successfully to treat a previously undiagnosed high responder who underwent an emergent operation. Although significantly less expensive than large-dose porcine FVIII, plasmapheresis tends to be palliative in nature and is used only in emergent situations. Prothrombin complex concentrate and rFVIIa are products which, with varying degrees of success, bypass the hematologic defect in those hemophiliacs with high titer inhibition (3–5). Immunotolerance is another option aimed at decreasing inhibitor activity through an involved process of repeated preoperative exposures to FVIII products (1,3). Our institution has adopted the use of FVIII inhibitor bypassing activity, a mixture of several activated and nonactivated clotting factors, for bleeding patients not responding to large-dose porcine FVIII. This therapy is very effective and costs about half as much as porcine FVIII (6,7). Had our patient developed a bleeding diathesis, FVIII inhibitor bypassing activity would have been administered. In conclusion, this case illustrates the importance of plasma FVIII activity monitoring in patients with FVIII inhibitor activity after therapeutic FVIII administration. When caring for the patient with hemophilia, it is critical to assess the patient before surgery, especially with regard to FVIII inhibitor activity. Further, it is important, by use of appropriate monitoring to assess the efficacy of therapeutic FVIII administration, to determine if the patient has changed responder status. Had this patient’s posttreatment FVIII activity been verified before surgery, his high responding inhibitor status would have been detected earlier, resulting in more aggressive FVIII administration to avoid potential hemorrhagic complications.