The clinical management of acquired hemophilia A still puzzles physicians and hematologists globally. Early diagnosis is difficult because symptoms usually diverge from those observed in congenital hemophilia A. However, the rarity of the disease compromises the development of randomized clinical trials. Therefore, treatment decisions are often made empirically.
Franchini et al wrote, “While a rapid recognition of suspected cases of [acquired hemophilia A] is essential to make a correct diagnosis and appropriately and timely treat the hemorrhagic manifestations, the multidisciplinary approach to this challenging, rare, and life-threatening bleeding disorder is of equal importance to improve patients’ outcome.”
Raising Suspicion of Acquired Hemophilia A
Several reasons contribute to the difficulty in establishing an early diagnosis of acquired hemophilia A. These patients often have no history of bleeding or anticoagulant use. Also, bleeding episodes are usually nonspecific, as they tend to involve skin, muscles, and mucous membranes, instead of hemarthroses, commonly observed in congenital hemophilia A.
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Evidence suggests that acquired hemophilia A may be associated with pregnancy, autoimmune diseases, or cancer. However, that is not always the case. In an article recently published in the journal Case Reports in Medicine, Rinaldi et al presented the cases of 3 patients with acquired hemophilia A, 2 of idiopathic origin. One of the cases, an 18-year-old female, was later diagnosed with acquired hemophilia A unrelated to pregnancy or autoimmune disease.
“According to the cases above, an isolated subcutaneous hematoma without any bleeding history or other risk factors should warrant suspicion of [acquired hemophilia A],” the authors said.
Establishing the Diagnosis
When acquired hemophilia A is suspected, measurement of activated partial thromboplastin time (aPTT) could provide relevant information. In acquired hemophilia A, there is often an isolated prolonged aPTT, ie, without other abnormalities in coagulation. However, this finding is not exclusive from acquired hemophilia A. It can also be caused by deficiencies in other coagulation factors (eg, FIX, FXI, and FXII).
However, the best test to follow with if alterations are verified during the aPTT test remains a subject of debate. Although some authors suggest an aPTT mixing test as the most appropriate choice, others recommend the FVIII activity concentration test.
An aPTT mixing test might help to disclose the underlying cause of the isolated prolonged aPTT. “In a mixing test, the patient’s plasma is mixed with an equivalent volume of normal plasma. If a coagulation factor inhibitor is present, such as in [acquired hemophilia A], the mixed plasma will still result in a prolonged aPTT due to the inhibition of coagulation factors. On the other hand, in a patient with only a coagulation factor deficiency (FVIII, FIX, FXI, and FXII), the mixing test would normalize the coagulation factors,” Rinaldi et al explained.
Nonetheless, some authors argue that the aPTT mixing test is only necessary if the FVIII activity concentration test is unavailable. The FVIII activity concentration test enables the differential diagnosis between acquired hemophilia A and lupus anticoagulants. Hence, there is usual consensus in recommending its use in the context of acquired hemophilia A diagnosis, despite being before or after the aPTT mixing test. On the other hand, the aPTT mixing test lacks adequate standardization, which is seen as a major drawback of the method.
Ultimately, the establishment of an acquired hemophilia A diagnosis requires the measurement of FVIII autoantibodies through the Bethesda assay.
Improving the Treatment
According to Rinaldi et al, healthcare providers have 3 main objectives in acquired hemophilia A therapy:
- Control and prevent further bleeding, if present;
- Eradicate FVIII inhibitors in order to achieve complete remission;
- Treat the underlying cause of the disease, if there is any.
Currently, clinicians have 3 therapeutics to control bleeding in acquired hemophilia A: recombinant activated FVII, activated prothrombin complex concentrate, and recombinant porcine FVIII. Generally, these drugs are effective. However, they are difficult to work with as the therapeutic regimen requires frequent intravenous administration and strict laboratory monitoring. There is also the risk of thromboembolic complications, which have to be carefully monitored.
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On the other hand, evidence suggests that the use of immunosuppression to suppress, or even eradicate, autoantibodies may have a greater mortality risk than hemorrhages themselves.
Recently, Knoebl et al disclosed a promising therapeutic approach that combined the bispecific, FVIII-mimetic therapeutic antibody, emicizumab, with immunosuppression. “The clinical experience now reported by Knoebl et al used an innovative treatment of bleeding control along with reduced-intensity immunosuppression for eradicating inhibitors, which may help overcome the current limits of combined therapy for [acquired hemophilia A],” wrote Siragusa and Napolitano in the journal Blood.
The study by Knoebl et al enrolled 12 patients diagnosed with acquired hemophilia A, of which 8 developed severe bleeding. Treatment involved emicizumab 3 mg/kg subcutaneously followed a weekly regimen for 2 to 3 doses. Then, the dose was reduced to the lowest effective FVIII levels (ie, 1.5 mg/kg every 3 weeks). In addition, patients received immunosuppression with steroids and/or the monoclonal antibody rituximab.
The activated partial thromboplastin time normalized within 1 to 3 days after the first dose of emicizumab. Complete remission was achieved after 115 (67 to 185) days, and emicizumab was stopped after 31 (15 to 79) days. The authors did not report deaths due to bleeding or thromboembolism. Also, no breakthrough bleeding episode was observed after the first dose of emicizumab.
These findings suggested good hemostatic efficacy for emicizumab in acquired hemophilia A. Additional advantages included early discharge and reduction of immunosuppression and adverse events.
Hence, results are encouraging, but a long journey is still ahead. “Although promising, the safety and efficacy of the clinical use of emicizumab in [acquired hemophilia A] needs to be validated by trials including an adequate number of patients, before registering the drug also for this indication,” Franchini et al advised.
Rinaldi I, Prasetyawaty F, Fazlines S, et al. Diagnosis and management of acquired hemophilia A: case reports and a literature review. Case Rep Med. Published online September 15, 2021. doi:10.1155/2021/5554664
Siragusa S, Napolitano M. Future directions in acquired hemophilia A. Blood. 2021;137(3):294-295. doi:10.1182/blood.2020008379
Franchini M, Schiavulli M, Liumbruno GM. Hemostatic therapy as a management strategy for acquired hemophilia: what does the future hold? Expert Rev Hematol. 2021;14(3):263-270. doi:10.1080/17474086.2021.1892483
Knoebl P, Thaler J, Jilma P, Quehenberger P, Gleixner K, Sperr WR. Emicizumab for the treatment of acquired hemophilia A. Blood. 2021;137(3):410-419. doi:10.1182/blood.2020006315