The findings also indicate that an unusually large proportion of patients were on antithrombotic therapy, which may have led to misdiagnosis or delayed diagnosis of acquired hemophilia A (AHA) in some cases, Marıa-Eva Mingot-Castellano, MD, PhD, of Hospital Universitario Virgen del Rocıo, Seville, Spain, and Hospital Regional Universitario de Malaga (Spain) and colleagues reported on behalf of the Acquired Haemophilia-A Spanish Registry (AHASR).
Dr. Nigel Key
The report was published online in Blood Advances.
These data provide useful clinical information about a rare disease, and they underscore the need for vigilance when prescribing immunosuppressive therapy for frail, elderly patients with AHA, hematologist Nigel Key, MD, said in an interview.
“The findings point to the fact that we still have a high death rate with this disorder, whether directly or indirectly related,” said Dr. Key, the Harold R. Roberts Distinguished Professor and vice chief for research in the division of hematology at the University of North Carolina at Chapel Hill. “[AHA] is still a high-morbidity, high-mortality condition, and these are very high-risk patients.”
The Spanish AHA registry data
The authors retrospectively collected data on 154 patients who were diagnosed with AHA at 36 Spanish hospitals from May 2014 through September 2020 and followed for a median of 12 months.
The patients were mostly men (56.3%) and had a median age of 74 years at diagnosis.
A third were on antithrombotic therapy at diagnosis, and hemostatic treatment was used in 70% of cases.
“Only one patient did not achieve control of hemorrhage. Complete remission (CR) was achieved by 84.2% of cases after immunosuppressive therapy,” the authors wrote, noting that “steroids alone were less efficient than the other strategies (68.2% vs. 87.2%), whereas no differences existed among these (steroids/cyclophosphamide, 88.5%; vs. steroids/calcineurin inhibitors, 81.2%; vs. rituximab-based regimens, 87.5%).
Women and those with high inhibitor levels were less likely to achieve CR, they said.
Of the 154 registry participants, 36 died, and 15 (9.9%) of those died as a result of infection, the leading cause of death. Five (3.3%) died as a result of hemorrhage. All of the hemorrhage-related deaths and half of the infection-related deaths occurred within 2 months of diagnosis, they noted, adding that “prior antithrombotic therapy was inversely associated with survival, irrespective of age.”
The median age of nonsurvivors was significantly higher than that of survivors (79 vs. 73 years), and the median age of those who died from infection was significantly higher than that of patients who died from other causes (85 vs. 78 years).
Additional insights
“One remarkable finding, not described before in AHA, was the high proportion of patients on antithrombotic therapy in the days before AHA diagnosis, namely one-third of the whole series,” the authors wrote. “This proportion is comparable to that of the Spanish population of similar age groups.”
Further, the use of antithrombotic therapy prior to AHA diagnosis was associated with mortality during follow-up in patients aged 75 years and older, they noted.
The older age and comorbidity burden among affected patients underscores their vulnerability and the importance of prompt diagnosis, they added, explaining how misdiagnosis might occur: “Attributing the bleeding episode to a hemostatic imbalance caused by the antithrombotic therapy may entail a risk of misdiagnosis. Frail patients could be admitted to hospital shortly after having been administered anticoagulants. In these cases, misdiagnosis would prevent early [immunosuppressive therapy], and patients could be exposed to potentially life-threatening bleedings.”
Delayed diagnoses have also been described in other registries. For example, in the China Acquired Hemophilia Registry (CARE), nearly half of participants had a delayed diagnosis, and younger patients were more likely than older patients to be referred for consultation, the authors explained.
“Interestingly, antiplatelet therapy has been described to delay AHA diagnosis or lead to misdiagnosis of AHA patients. Furthermore, the underlying diseases that prompted antithrombotic therapy highlight the vulnerability of these patients and could contribute to a negative outcome,” they noted.
Given the high rate of fatal infection in the first months of immunosuppressive therapy in the series, and the association between antithrombotic therapy and mortality, particular care should be taken to avoid misdiagnosis, the authors stressed.
They noted, however, that the study has some important limitations inherent in retrospective analyses and studies with limited sample size and missing data.
Still, the findings add value, they said.
“AHA is not well-known among clinicians unfamiliar with hemostatic disorders. Lack of awareness may preclude early diagnosis, thus exposing patients to an unacceptably high bleeding risk,” they explained, adding that existing management guidelines for the use of immunosuppressive therapy “rely on registry findings and authors’ experience rather than on comparative studies.”
“Therefore, any valuable knowledge regarding clinical experience in managing this disorder should be helpful,” they wrote. “The rarity of the condition prompts the design of registries to compile as much information as possible concerning baseline status, diagnosis, treatment, and follow-up ... to continuously update guidelines on disease management procedures.”
Indeed, the AHASR is “a good-sized registry” and these data are valuable, Dr. Key said.
“I like the fact that they focused on a couple of things here to do with outcomes, particularly analyzing the causes of death,” he said, noting that the reported death is not remarkably different from what has been reported previously, but it does “raise the question of morbidity also related to the therapy – particularly infection.”
The data are especially useful with respect to use of immunosuppressive regimens, he said.
“These are, for the most part, old or frail patients. ... They can’t just be put on cyclophosphamide and sent away without monitoring blood counts and being given advice about what to look out for regarding infection and when to seek treatment,” he said, adding that immunosuppressive regimens are “given for very good and necessary reasons, but are not benign.”
“There ought to be consideration, if necessary, of advice from an infectious disease specialist,” he added, noting that “rheumatologists deal with this all the time, but hematologists often underestimate the infectious morbidity of [immunosuppressive therapy].”
The study authors reported having no conflicts of interest to disclose. Dr. Key has served at the chair of a grant committee for Novo Nordisk.