See the main features of prophylactic emicizumab in acquired hemophilia

Morbidity and mortality remain high for patients with acquired hemophilia A, and progress in immunotherapy and hemostatic therapy is needed to improve outcomes.

Morbidity and mortality rates are high for acquired patients Hemophilia A (AHA), and advances in immunotherapy and hemostatic therapy are necessary to improve outcomes, according to A reconsidering Posted in transfusion medicine reviews. The authors highlight emicizumab prophylaxis as a potential game-changer in the treatment of AHA.

AHA is a rare disorder caused by autoantibodies that neutralize and therefore inhibit coagulation factor VIII. It can lead to potentially life-threatening bleeding and often appears spontaneously but sometimes co-exists with other autoimmune diseases or malignancies. It is more prevalent in older patients, and the typical treatment for those with severe bleeding is to restore hemostasis during factor VIII suppression by immunosuppressive therapy (IST). But this treatment strategy presents challenges.

“About 30% of patients develop complications from immunosuppression such as life-threatening infections, and overall, there is a high mortality rate of 28 to 33%,” the authors wrote. “Understanding these challenges, grading risks, adjusting IST and new hemostatic agents show great potential for improving the morbidity and mortality of these patients.”

Accurate AHA diagnosis and risk classification can help identify patients who can be treated with or without immunosuppression to reduce associated morbidity and mortality. While the Nijmegan-modified Bethesda (NBA) assay for factor VIII inhibitor titer is the standard method for risk stratification, the review authors note that an ELISA-based assay may be a better option based on recent studies. It is not affected by lupus anticoagulants or drugs that interfere with activated partial thromboplastin time (aPTT) – both factors that affect NBA outcomes. However, more research is needed to determine if the ELISA method is superior.

Risk rating information is also largely based on information from registries rather than randomized controlled trials, a product of AHA’s paucity. This, combined with the heterogeneity of comorbidities and treatment makes prognosis difficult. Therefore, identifying patients who will enter recovery without IST is currently challenging and requires further investigation into potential drivers of spontaneous sedation, including immunoglobulin classes or anti-factor VIII subclasses.

Typical therapy includes a combination of immunosuppression with glucocorticoids and cyclophosphamide, which has shown better complete response rates than glucocorticoids alone. However, remission takes approximately 5 weeks with this regimen and leaves patients at high risk of bleeding in the meantime, along with possible infections due to immunosuppression. Rather than developing new ISTs, recent research emphasizes reducing IST use while improving risk classification.

“More severe reduction or delay in immunosuppression may be critical to seeing better outcomes in patients with higher (FVIII) and lower inhibitory criterion at presentation,” the authors wrote. “Improved hemostatic therapies may also allow a reduction in immunosuppression regardless of risk.”

Hemostatic therapy is needed in most patients with AHA, and the presence of autoantibodies causes the clotting factor concentrates used in congenital hemophilia without effective inhibitors to be minimally effective in AHA. Bypassing agents, such as recombinant factor VIIa and activated prothrombin complex concentrate, are effective in more than 90% of patients, but are given intravenously and usually require hospitalization. The alternative agent is recombinant porcine (FVIII), but porcine-reactive antibody (FVIII) can be present at baseline or develop after treatment. None of these options have been approved as a method for preventing bleeding in the AHA.

A new hemostatic agent, emicizumab, is an approved treatment for hemophilia A with or without inhibitors and may show promise for AHA. Limited data show that emicizumab may be a feasible option for hemostatic prophylaxis in the outpatient setting, which, if effective, could reduce the need for immunosuppression. Ongoing trials in Europe aim to determine if a delay in immunosuppression is possible.

One notable concern with emicizumab is its interference with the PTT and thus with the PTT-based assays used to measure IST response. Emicizumab corrects PTT and overestimates FVIII activity, and interferes with NBA testing. The chromogenic FVIII assay with bovine reagents is an alternative assay option, but is not usually available in clinical laboratories. The risk of thrombosis after remission is unknown in patients with AHA treated with emicizumab, and future studies are intended to provide insight into the risk of thrombosis in these patients.

While trials of AHA therapies may be difficult due to their rarity, ongoing single-arm trials and observational studies will help guide future treatment strategies as well as the potential for new bleeding prevention agents to reduce the need for immunosuppression.


Poston JN, Kruse-Jarres R. Progress in acquired hemophilia A. Blood transfusion with Rev. Published online September 7, 2022. doi: 10.1016/j.tmrv.2022.07.001