Influence of Inhibitor Characteristics on Response to Hemostatic and Immunosuppressive Treaments in Acquired Hemophilia Patients: The Ciha Project

INTRODUCTION

Acquired hemophilia (AH) is a disease induced by autoantibodies targeting coagulation factors, mostly factor VIII (FVIII). The disease manifests as bleeding episodes in unusual locations that usually prompt physicians to establish hemostatic and immunosuppressive treatments (IST) for hemorrhage cessation and inhibitor eradication respectively. The specificity of the so-called inhibitors varies among patients. We present herein the main findings of the CIHA project, which is a pilot study aimed to test the hypothesis that the inhibitor's features, i.e., its FVIII domain specificity, influences AH patient evolution and response to hemostatic and immunosuppressive therapies.

METHODS

This is a prospective, descriptive, observational and non-interventional study. Between September 2011 and September 2013, 16 patients who had been diagnosed with AH caused by FVIII inhibitors were recruited, and their clinical and epidemiologic features were assessed. Inhibitors were titrated by the Bethesda method according to the Nijmegen modification. The inhibitor specificities were determined by Western blot: first, FVIII was cleaved by thombin in order to obtain the fragments corresponding to the light chain (LC), and the A1 and the A2 domains of the heavy chain. Once electrophoresed and transferred to a polyvinylidine difluoride membrane, this material was incubated with the patient´s plasma. Finally, an anti-human IgG antibody carrying a chemiluminiscent substrate was incorporated. The luminiscent pattern should be dependent on the molecular weight of the FVIII domains recognized by the inhibitor, allowing us to assess the inhibitor's specificity. In order to analyze the association between inhibitors' specificities and individual responses to therapies, sampling was performed at the time of diagnosis, 14 days afterwards, and, provided that remission was reached, 56 days after IST was withdrawn. When immunosuppression failed, a similar sampling pattern was applied after a second line of therapy was initiated.

RESULTS

Three patients died in the course of the study due to complications linked to their underlying pathologies related neither to the hemostatic treatment nor to the IST.

According to the literature, inhibitors targeted mostly the LC (11 out of 16; 69%) or the A2 domain (8 out of 16; 50%). Two of them (12%) were directed against the A1 domain. It must be remarked that, in disagreement with the literature, the inhibitors targeted more than one domain in a non-negligible number of cases [5 out of 16 (31%): A2-LC, three cases; A1-A2-CL and A1-A2, one case each].

Bypass agents, i.e., recombinant activated factor VII or activated prothrombin complex, were used for hemorrhage cessation. The inhibitor features did not influence the response to hemostatic treatment, since this efficiently stopped blood loss in all patients.

The first line immunosuppressive drugs most commonly used were steroids (14 out of 16), alone or with concomitant cyclophosphamide (6 out of 14). Nine patients (56%) reached remission, and the rest of them required a second IST to eradicate the inhibitor. Interestingly, inhibitors targeted LC in 6 out of 7 (86%) patients that did not respond to the first IST. Conversely, inhibitors targeted LC only in 4 out of 9 (44%) patients who reached remission with the first line IST. Finally, 30 days after IST had started, inhibitor specificity changed in one of the IST responders, from multidomain targeting (A1-A2-LC) to LC-only targeting.

CONCLUSIONS

Antibody recognition of more than one FVIII domain is not uncommon in AH. More importantly, this pilot study suggests that inhibitors that interact with the LC of FVIII may induce a worse response to IST in AH patients. Since this finding may be clinically relevant, these results encourage us to carry out a larger study to confirm such observations.