Therapeutic choices for patients with hemophilia and high‐titer inhibitors

Abstract

Effective treatment of bleeding episodes in hemophilia with high titer inhibitors (HTI) remains a challenge, despite the fact that the therapeutic armamentarium has expanded considerably over the past few years. Treatment safety has improved with the availability of porcine factor VIII (FVIII) and bypassing products such as recombinant factor VIIa (rFVIIa), and plasma-derived activated Prothrombin Complex Concentrates (aPCCs) that are virally inactivated. The major drawbacks of rFVIIa and aPCCs are their unpredictable hemostatic effect, lack of laboratory assays to monitor efficacy and dosing frequency, and the risk of thrombosis. The proceedings of a one-day workshop of physicians who specialized in treating patients with hemophilia held in Vienna on May 13, 2000 have been summarized. In making a decision regarding the choice of product, physicians often consider the type of bleeding episode (life or limb threatening), age of the patient, volume of the reconstituted product, previous exposure to plasma derived products, cost, efficacy, and safety. For plasma naïve patients, to achieve rapid hemostasis a majority of the panelists used porcine FVIII (for patients who lack porcine inhibitory antibodies) or rFVIIa. For patients previously treated with plasma derived factors, in addition to the above concentrates, aPCCs were recommended. Although no data exists regarding safety and efficacy, switching products was routinely practiced either because of availability or cost. Furthermore, the panelists were uncertain about the efficacy of bypassing agents in the prevention of joint disease in inhibitor patients. The workshop participants felt that future research offers the best solution to resolve some of the dilemmas faced by clinicians and may help individualise treatment in a hemophilia patient with a high titer inhibitor. Am. J. Hematol. 67:240-246, 2001.

Phenotypic correction of hemophilia A in sheep by postnatal intraperitoneal transplantation of FVIII-expressing MSC

“…Before transplant, #911 had Bethesda titers against hFVIII of only ~3, yet this lifesaving procedure resulted in a rise in Bethesda titer to ~800 against the vector-encoded pFVIII and nearly 700 to hFVIII (Supplementary Figure 3A). The formation of such high titer inhibitors with cross-reactivity to the human protein is surprising, given the well established ability to successfully use porcine FVIII products in human patients to bypass existing anti-hFVIII inhibitors [26-29]. Similarly, despite having no detectable inhibitors prior to transplant, animal #905 developed titers of ~150 Bethesda units against the vector-encoded pFVIII following transplantation (Supplementary Figure 3B) which, like those in #911, exhibited cross-reactivity to the human protein.…”

“…This was perhaps further confounded by the treatment of both animals with human FVIII prior to receiving the transplant. Given the successful clinical use of pFVIII in human patients who harbor inhibitors to human FVIII [26-29], it is unlikely that the porcine origin of the transgene is the sole/major causative factor in the formation of high titer inhibitors. Nevertheless, the only way to eliminate this possibility will be to perform studies employing cells which have been transduced with a lentivector encoding ovine FVIII, rather than the pFVIII construct we utilized in the present studies.…”

Treatment of Hemophilia A in Utero and Postnatally using Sheep as a Model for Cell and Gene Delivery

“…Before transplant, this first animal had Bethesda titers against hFVIII of only ~3, yet this lifesaving procedure resulted in a rise in Bethesda titer to ~800 against the vector-encoded pFVIII and nearly 700 to hFVIII. The formation of such high titer inhibitors with cross-reactivity to the human protein was surprising, given the well established ability to successfully use porcine FVIII products in human patients to bypass existing anti-hFVIII inhibitors [236–239]. Similarly, despite having no detectable inhibitors prior to transplant, the second animal receiving the higher FVIII-expressing cell dose developed titers of ~150 Bethesda units against the vector-encoded pFVIII following transplantation which also exhibited cross-reactivity to the human protein.…”

Evaluating the Immunogenicity of Protein Drugs by ApplyingIn VitroMHC Binding Data and the Immune Epitope Database and Analysis Resource

“…Examples for such adverse immune responses include the development of antibodies against factor VIII in hemophiliacs [16, 17], calcitonin in patients treated for osteoporosis [18, 19], erythropoietin in patients undergoing therapy for chronic renal failure [20, 21], and IFN- β in individuals undergoing treatment for multiple sclerosis [22]. …”