Treatment of Acute Bleeds in Acquired Hemophilia: Analysis from the Hemophilia Research Society (HRS) and Hemophilia and Thrombosis Research Society (HTRS) Registry.
Authors: Sood Suman , Konkle Barbara A. , Kessler Craig M. , Cooper David L ,   HRS-HTRS Registry Investigators
Published: April 2020

Abstract
Acquired hemophilia A (AH) is a rare disorder marked by the development of autoantibodies to factor VIII. Patients present with a prolonged aPTT that does not correct with mixing and clinically evident bleeding. HRS and its successor, HTRS, have maintained a registry to study treatment strategies for acute bleeds in hemophilia and related disorders. Data from the HRS (1999–2003) and HTRS (2004–2008) registries were examined to identify acute bleeding episodes in patients with AH.
In total, 49 patients were identified with AH, 28 of whom had 50 acute bleeding episodes recorded. 23 (46%) of such bleeds were treated with recombinant Factor VIIa (rFVIIa) alone, 9 (18%) with rFVIIa and other hemostatic agents, 12 (24%) with other hemostatic agents alone, 1 did not require treatment, and 5 no treatment information recorded. Of patients with bleeding episodes and recorded demographic information, there were 22 males and 12 females; 38 were Caucasian and 7 African American. Mean (median) age at time of the acute bleed was 69 (72) years for patients ever treated with rFVIIa and 66 (70) years for those treated exclusively with other agents. Remaining data are presented as mean (median, mode) unless otherwise indicated.
For those ever treated with rFVIIa, the initial dose was 98 (100, 90) mcg/kg, mean treatment dose was 95 (100, 90) mcg/kg, and total cumulative treatment dose was 2520 (702, 300) mcg/kg. The highest single bolus dose given was 160 mcg/kg. There was no significant variation in initial or mean dose over the 9-year data collection period. The total number of doses of rFVIIa was 27 (7, 3) over a mean of 5.2 (1, 1) days for total treatment duration of 6.8 (2.5, 1) days per bleeding episode. Treatment within the first 24 hrs was a mean of 478 (311, 300) mcg/kg representing 63% (81%, 100%) of total rFVIIa dose.
True efficacy was difficult to assess in this registry. As rated by the physician for the primary outcome of the bleed stopped at 72 hrs, efficacy was 64%. However, in 9 additional bleeding episodes (32%), documentation of efficacy was unclear. In 4 the dose of rFVIIa was not increased and no other hemostatic agents were given, 2 switched from porcine FVIII (pFVIII) to rFVIIa and 3 switched from rFVIIa to other agents, including aPCC (after a single inadequate 30 mcg/kg dose of rFVIIa), pFVIII and plasma derived FVIII (pdFVIII), for an overall efficacy rate of 82%. One patient with preeclampsia and bleeding after a Caesarean section experienced transient neurologic symptoms after receiving rFVIIa 90 mcg/kg q2h for 113 consecutive doses; brain MRI showed multifocal ischemia.
Patients who did not receive rFVIIa were treated with pFVIII (7 bleeds, 58%), aPCC (4 bleeds, 33%) and pdFVIII concentrate (1 bleed, 8%) for a mean of 12 (8, 6) days. Efficacy as rated by the physician for the outcome of bleed stopped at 72 hrs was 55% in those specified (4/7 bleeds treated with pFVIII, 1/4 aPCC and 1/1 pdFVIII). In 5 bleeding episodes (45%), documentation of efficacy was unclear.
While registry data can only show the treatment reported in selected bleeds captured, HRS-HTRS demonstrates rFVIIa efficacy similar to prior reports in the AH population. rFVIIa dosing was consistent over time with most patients receiving ~100 mcg/kg for 7 doses. Despite publication on higher dosing regimens in patients with congenital hemophilia, there were no documented doses above 160 mcg/kg in this series. Although rFVIIa is approved for use every 2–3 hrs, the data indicate that dosing was generally at more prolonged intervals, and often over long periods of time. In the absence of randomized prospective studies and the limited number of evaluable patients with this rare disorder, this registry data provide proof of principle that rFVIIa is an effective and safe treatment for acute bleeding episodes in AH. As this registry was originally intended in part to track the safety of rFVIIa, these derived data may be somewhat biased and selective. Nevertheless, they are certainly indicative that rapid and safe hemostasis can be achieved in an aging adult population where thrombogenicity of hemostatic agents is of major concern. This registry will continue to collect data on AH patients to determine whether dose, dosing interval and dosing frequency trends are maintained as experience with rFVIIa expands. Definitive comparative safety and efficacy data with various hemostatic agents in AH ideally will require prospective randomized trials, which will be challenging in such a rare disorder.