Acquired Hemophilia A in a Case of Relapsed Immune Thrombotic Thrombocytopenic Purpura

Hemostasis is a highly regulated physiological process governed by a series of enzymatic pathways that maintains a delicate balance between procoagulant and anticoagulant mechanisms. Both congenital and acquired alterations in coagulation can result in thrombotic events when procoagulant forces dominate, or hemorrhagic events when clotting mechanisms are impaired/absent. While hereditary coagulation deficiencies have a significant impact due to their wide-ranging clinical consequences, acquired coagulopathies pose equally complex diagnostic and therapeutic challenges. These conditions can develop in individuals with no prior personal/familial history of hemorrhagic or thrombotic disorders, often because of underlying diseases that affect coagulation factor synthesis and function.[1] Acquired hemophilia A (AHA) and immune-mediated thrombotic thrombocytopenic purpura (iTTP) are both individually rare autoimmune disorders that disrupt hemostasis, though they have distinct pathogenetic mechanisms and clinical manifestations, with an incidence of 1.5 to 6 and 1.5 cases per million per year, respectively.[2] [3] [4] [5] [6] [7] [8] [9] AHA is a rare bleeding disorder caused by neutralizing autoantibodies against coagulation factor VIII (FVIII) and occurs in both men and women without a previous history of bleeding. Patients typically present with an isolated prolonged activated partial thromboplastin time (aPTT), due to functional FVIII deficiency, and spontaneous and severe bleeding.[2] [3] [4] [5] Instead, TTP is a rare thrombotic microangiopathy. First described by Moschcowitz in 1924[6], TTP was initially described as a pentad of anemia, thrombocytopenia, renal failure, fever, and neurological symptoms. In the absence of treatment, the disease was rapidly fatal. In later decades, there were reports of patients responding to plasma infusions that helped develop the idea that those affected were lacking a plasma protein. This was later found to be a von Willebrand factor (VWF) cleaving protease, later identified as ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). ADAMTS13 is essential in the cleavage of ultralarge VWF multimers; in TTP, these uncleaved ultralarge VWF multimers unfold in the microvasculature under conditions of high shear stress, resulting in the formation of platelet-rich microthrombi. Microangiopathic hemolytic anemia (MAHA) results from the mechanical hemolysis caused by the action of microthrombi on circulating erythrocytes. Microthrombi typically occur in the brain and heart but can also affect other organs, including the kidneys. The majority (>80%) of cases of TTP are immune (iTTP), with the formation of anti-ADAMTS13 autoantibodies resulting in a marked reduction in ADAMTS13 activity.[7] [8] [9] Despite these differences, AHA and iTTP share several common features, including their acquired nature, as they typically arise in individuals with no prior history of bleeding or thrombotic disorders. They may also be associated with other underlying conditions such as autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis), malignancies, infections, pregnancy, or the use of certain medications.[2] [3] [4] [5] [6] [7] [8] [9] Clinically, both conditions present acutely with severe, potentially life-threatening symptoms. AHA is characterized by spontaneous bleeding in soft tissues, muscles, or mucosal bleeding, often disproportionate to trauma and unresponsive to standard coagulation factor replacement. Conversely, iTTP presents with widespread microvascular thrombosis, leading to thrombocytopenia, MAHA, neurological symptoms, renal impairment, and fever.[2] [3] [4] [5] [6] [7] [8] [9] The disruption of normal hemostasis in both disorders requires urgent medical intervention. Common treatment strategies focus on immunosuppression[2] [3] [4] [5] [6] [7] [8] [9] to reduce autoantibody production, along with supportive measures tailored to the specific clinical manifestations of each condition.

Herein, we describe a challenging clinical case of a patient who was initially treated for relapsing iTTP and later developed AHA, successfully managed with rituximab. To the best of our knowledge, this is the first reported case highlighting the paradoxical transition from an initial prothrombotic state to a subsequent hemorrhagic disorder, posing significant diagnostic and therapeutic challenges.

A 55-year-old woman with a history of iTTP, first diagnosed in 2018, experienced a relapse in November 2022. She underwent treatment with corticosteroids, followed by a gradual tapering of immunosuppressive therapy (IST). Her medical history included arterial hypertension, obesity, diabetes, hypercholesterolemia, asymptomatic multivessel atherosclerosis with bilateral iliac arterial dissection, severe osteoporosis, and a prior diagnosis of breast cancer in 2013, treated with 5 years of hormonal therapy and radiotherapy. Additionally, she experienced lower limb deep vein thrombosis (DVT) in 2018, followed by her first episode of iTTP, a few months later.

During the tapering phase, in November 2023, she developed hemorrhagic mucocutaneous and muscular manifestations, with severe anemia (Hb 7.3 g/dL) requiring transfusion. On initial physical examination, a large muscular hematoma was observed in the left thigh, causing displacement of the femoral vessels and compression of the femoral vein. Extensive hematomas were also evident on both arms. Since she had no prior personal or family history of bleeding disorders, this clinical presentation raised suspicion of an acquired bleeding disorder. Laboratory testing revealed an isolated prolongation of the aPTT, with a ratio of 3.3 (reference range: 0.8–1.2), while prothrombin time (PT) and platelet count were within normal limits. The mixing test with normal plasma failed to normalize aPTT (ratio 1.5), prompting further coagulation studies, which showed a low FVIII activity of 0.7% (reference range 50–130%). Inhibitory autoantibodies against FVIII were detected at a titer of 14 Bethesda Units (BU; reference range <0.5 BU/mL), confirming the diagnosis of AHA. ADAMTS13 activity was normal (74.8%). Factor IX levels were 167%, factor XI 125%, and factor XII 99%. Lupus anticoagulant was negative. Immunosuppressive treatment was intensified with prednisone at a dose of 1 mg/kg daily. However, after approximately 1 week, FVIII:C levels remained low (0.6%). Since there was no significant response to steroids after 4 weeks (FVIII activity 3.8%; [Fig. 1]), and a vertebral collapse was detected at the L2 level, therapy with the anti-CD20 monoclonal antibody rituximab (375 mg/m²) was initiated with weekly intravenous (IV) administrations, for a total of four doses. Simultaneously, the prednisone dose was reduced to 50 mg/day. Following the second rituximab infusion, prednisone was further tapered to 35 mg/day, leading to a subsequent therapeutic response. Oncological recurrence was excluded. Systemic autoimmune disorders were excluded. Furthermore, there was no recent infection or vaccination for SARS-CoV-2, and the test for SARS-CoV-2 RNA upon admission was negative. For hemostatic management, activated recombinant factor VII concentrate (rFVIIa) 90 μg/kg IV every 4 to 6 hours for a total of 5 days was administered. Low daily doses of rFVIIa were adopted for the high thromboembolic risk of the patient (previous DVT and multivessel atherosclerosis).

Fig. 1 Representation of the factor VIII and aPTT levels over time and in relation to the addition of rituximab. aPTT, activated partial thromboplastin time.

Although the association between AHA or iTTP and autoimmune diseases has long been recognized, the joint presentation of AHA and iTTP presents an exceedingly rare and complex clinical scenario that further supports the well-established and intricated link between the coagulation and immune systems, reinforcing recent evidence that underscores how dysfunction in one of the pathways may affect the other.[1] [10] [11] [12] The unusual sequence of events observed in this case raises important questions about not only the immunopathogenesis of autoimmune coagulopathies and their potential interconnections, but also the impact of immunomodulatory treatments on immune homeostasis. Hemostasis dysfunction related to autoimmunity may manifest either with bleeding manifestations or thrombosis, depending on the types of antibodies generated.[1] Antibodies against procoagulant clotting factors may lead to inhibition of their function, with the development of bleeding diathesis, such as in AHA. Alternatively, antibodies may be generated against components of the hemostasis pathways that act to control procoagulant activity (e.g., antibodies against ADAMTS13 in iTTP lead to clearance/reduction in ADAMTS13 activity, and the resultant excess of VWF promotes a thrombotic milieu). At the same time, coagulation dysregulation can influence the development of autoimmune diseases.[1] Studies have demonstrated that proteins involved in the coagulation process, including thrombin and fibrinogen, can significantly impact B-cell activation. Thrombin not only plays a key role in fibrin production but also interacts with the immune system, stimulating B-cell proliferation and antibody production, which is especially evident in pathological conditions.[11] [12] In this context, the observed increase in thrombin in patients with iTTP may have potentially contributed to the initiation of a second autoimmune disorder in our patient, providing a mechanistic explanation for the interplay between coagulation and autoimmunity in this case. The sequential development of iTTP and AHA provides a unique opportunity to explore the mechanisms underlying autoimmunity in hemostatic disorders and highlights the need for further research into the interplay between immune dysregulation, endothelial injury, and autoantibody formation. At the core of this process, as observed in the described clinical case, appears to be an exacerbation of the preexisting immune dysregulation (a relapse of iTTP, in this specific instance), which may have ultimately led to the clonal selection of B cells capable of producing specific autoantibodies, including those targeting FVIII. The real challenge for clinicians lies not only in the early diagnosis of these two still individually underdiagnosed conditions, but also in the timely and effective management of the arising disease.

Rituximab, a chimeric anti-CD20 monoclonal antibody active against normal and malignant B cells, has proven to be effective in the treatment of CD-20-positive lymphomas. Its B-cell cytotoxic action has also been explored in many non-malignant autoimmune disorders with the aim of interfering with the production of pathological antibodies, including antibody-associated disorders of hemostasis (i.e., iTTP, TTP, AHA, acquired inhibitors against coagulation factors).[13] [14] Rituximab provided an alternative option for patients who do not respond to conventional therapy—such as our steroid-refractory patient—or for those experiencing multiple relapses. More recently, rituximab has become routinely recommended even as frontline therapy, with high response rates both in high-risk AHA patients and in iTTP.[3] [4] [6] [13] In both diseases, the use of anti-CD-20 monoclonal antibody treatment not only facilitates disease remission but also reduces relapse rates, ultimately improving the patient's quality of life.[14] [15] To date, our patient has remained in complete remission for 17 months of follow-up. A first-line IST with rituximab would have been useful in our clinical case, instead of intensification of steroids, considering the patient's comorbidities, including diabetes, hypertension, severe osteoporosis, and previous cancer. Reducing adverse events of IST, in particular infections or secondary malignancies, is a crucial clinical need in patients with multimorbidity (i.e., patients with autoimmune disease already receiving long-term IST, diabetic patients, and elderly patients).[15] [16] [17] With this aim, tailored IST approaches (delayed initiation, no use, or reduced dose) or combined regimens have been attempted to reduce adverse events.[15] Based on recent evidence, if bleeding risk can be appropriately controlled by effective antihemorrhagic therapeutic or prophylactic treatment (including emicizumab), tailored IST approaches such as dose reduction, no use, or delayed initiation of IST, based on each patient's specific condition, could be considered.[15] [16] [17]

Publikationsverlauf

Artikel online veröffentlicht:
17. Juni 2025

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