Discussion

Our case presents a diagnostic challenge, since AHA and LAC prolong aPTT, and both produce an abnormal mixing study. The undetectable F VIII level should not be found with the LAC; thus, the diagnosis of acquired hemophilia A is achieved. Meanwhile, the abnormal dilute Russell’s Viper Venom Time (dRVVT) together with a confirmatory excess phospholipid test (hexagonal phase assay) confirms the finding of the lupus anticoagulant. The patient presented to the hospital with a prolonged aPTT of 103.9 seconds and a retroperitoneal hematoma. Throughout his hospitalization, the hematoma improved over time, but he remained easily bruised. His aPTT gradually decreased over time in response to dual steroid and rituximab therapy. The patient had no prior history of major bleeding or any autoimmune diseases. Upon review of his home medications, it was deemed that the antibodies that formed on F VIII were unlikely to be medication-induced.

The pathophysiology of AHA is thought to be mediated by polyclonal IgG antibodies with proteolytic properties, leading to the hydrolysis of F VIII into smaller fragments and therefore neutralizing them. This disrupts the intrinsic coagulation pathway, leading to spontaneous bleeding. In normal healthy individuals, low-titer anti-F VIII antibodies do exist, indicating that our immune tolerance, mediated by regulatory T cells, normally prevents the development of a pathologic immune response [6].

The concomitant presence of AHA and LAC found in our case highlights the importance of avoiding confounding factors during the workup of acquired hemophilia A [7, 8]. The acquired antibodies against F VIII in AHA predispose to hemorrhages, and conversely, the presence of lupus anticoagulant increases the risk of thrombosis. Therefore, patients having both autoantibodies can exhibit an array of symptoms ranging from thrombosis to hemorrhage, or both. It is crucial to distinguish between these two conditions, as both can prolong the aPTT, and neither would correct on mixing studies. In AHA, there would be markedly reduced F VIII activity, and immunoassays for anti-F VIII IgG4 would be positive, whereas LAC would show normal F VIII levels and no presence of anti-F VIII IgG4 [4]. Specialized coagulation testing, such as chromogenic Bethesda assays, hexagonal phase assay, and enzyme-linked immunosorbent assays, can be used to further identify both inhibitors and establish an accurate diagnosis [8]. In our patient, he had severely low F VIII activity, prolonged aPTT mixing time, highly increased Bethesda units, and a positive hexagonal phase assay, which confirmed the diagnosis of concurrent AHA and LAC.

The treatment of acquired hemophilia A can be divided into three categories: increasing F VIII levels, F VIII bypassing agents, and suppression of the inhibitor. The choice of treatment relies mainly on the presence or absence of active bleeding and the inhibitor titer levels. In patients with life-threatening bleeding and high inhibitor titer levels, bypassing agents like recombinant activated factor VII, activated prothrombin complex concentrate, or recombinant porcine F VIII can be used. Suppression of inhibitor levels can be achieved by immunosuppressive therapy, with the main goal of attaining remission. The limited existing literature regarding patients with coexisting AHA and LAC describes a combination therapy consisting of prednisone with cyclophosphamide or rituximab, which was found to be helpful for patients [7-8]. A prior 2012 study reviewed 331 patients who had AHA to check their response to immunosuppressive therapy. A total of 166 patients received steroids alone, 83 received steroids plus cyclophosphamide, 51 received rituximab-based regimens, and 31 received other regimens. It showed that steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as undetectable inhibitor level, F VIII more than 70 IU/dL, and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%) of patients [9-10].

An updated international recommendation from 2020 for AHA management outlined that those with F VIII <1% or >20 BU/ml can be started on steroids with rituximab or cyclophosphamide [9, 11]. This can be considered as first-line therapy for those who have high inhibitor titers [12]. Both AHA and LAC are caused by pathogenic autoantibodies that are produced by CD20+ B cells, and rituximab directly lowers CD20+ B cells, targeting the root cause of both conditions and making rituximab a favorable treatment [13-15]. Based on the guidelines, our patient was started on steroids and rituximab and showed a great response, as reflected in his down-trending aPTT and repeat inhibitor titers. Current recommendations for post-hospitalization include a 4-6-month glucocorticoid taper, which the patient completed [14].