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Abstract: Immune thrombotic thrombocytopenic purpura (iTTP) is a chronically relapsing disorder caused by autoantibody-mediated deficiency of ADAMTS13. Rituximab is frequently administered to prevent relapses, but whether the durability of rituximab effect is maintained with subsequent treatment courses has not been studied. Using the United States Thrombotic Microangiopathy Consortium (USTMA) retrospective iTTP registry, we evaluated clinical relapse-free survival (RFS) with subsequent courses of rituximab treatment in multiply relapsing patients. Separately, we evaluated overall RFS (composite of time to clinical relapse, ADAMTS13 relapse, or preemptive rituximab) in a prospective iTTP cohort from the Johns Hopkins University and the University of Minnesota. In the USTMA registry, median clinical RFS was shorter after the second or subsequent rituximab-treated episode than the first (2.1 vs 6.0 years; P = .04). White patients' clinical relapse risk after the second and subsequent rituximab courses was not significantly different compared with the first (hazard ratio [HR], 1.86; 95% confidence interval [CI], 0.22-15.80; P = .57), whereas for Black patients, clinical relapse risk was significantly higher after the second or subsequent courses (HR, 2.82; 95% CI, 1.52-5.24; P = .001). In the prospective cohort, overall RFS progressively shortened after each episode of rituximab treatment with the first episode having the longest RFS (2.8 years; interquartile range, 2.0-6.0) and this loss of response durability was most pronounced in Black patients. The durability of rituximab's effect declines with subsequent treatments, which is more pronounced in Black patients, who may benefit from closer monitoring and alternative immunomodulatory approaches such as maintenance rituximab and consideration of other agents., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

A 64-year-old woman with hereditary hemorrhagic telangiectasia (HHT) characterized by a pathological variant in ACVRL1 presents to the clinic for follow-up. Manifestations of HHT include frequent epistaxis and gastrointestinal bleeding, leading to iron-deficiency anemia. Bevacizumab is initiated, with resolution of the anemia. While maintained on a regimen of bevacizumab every 6 weeks, she continues to report frequent epistaxis and has ongoing iron-deficiency requiring periodic iron infusions. She also finds the bevacizumab infusions inconvenient. She is interested in discussing other options for managing her disease., (Copyright © 2024 by The American Society of Hematology.)

Hereditary hemorrhagic telangiectasia (HHT) is characterized by arteriovenous malformations and telangiectasia, with primary clinical manifestations of epistaxis and gastrointestinal bleeding and resultant anemia. HHT negatively affects health-related quality of life (HR-QoL); however, existing tools to measure HR-QoL are not HHT specific. Our objective was to develop an HHT-specific HR-QoL (HHT-QoL) instrument and evaluate its performance in a cross-sectional survey of individuals with HHT. Four HHT-specific questions were developed to evaluate the impact of HHT on productivity and social and personal interactions. An anonymous e-mail survey was conducted through Cure HHT. Participants also indicated their perceived HHT severity and completed 3 Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires: Discretionary Social Activities, Social Roles, and Emotional Distress. Complete data were available for 290 participants who self-identified their HHT severity as mild (29%), moderate (46%), or severe (25%). The HHT-QoL scale was reliable (Cronbach's-α, 0.83). Principal components analysis indicated the instrument was unidimensional. Participants had low levels of QoL with their ability to participate in discretionary social activities (PROMIS mean 36.4 [standard deviation 14.3]) and perform in social roles (41.5 [17.2]), and the presence of a high level of emotional distress (64.8 [24.2]). The HHT-QoL score correlated negatively with PROMIS Discretionary Social Activities (r = -0.65) and Social Roles (r = -0.68) and positively correlated with PROMIS Emotional Distress (r = 0.51). In conclusion, the 4-item HHT-QoL instrument provides valuable insight and may be a useful addition to future clinical research in HHT., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Hereditary hemorrhagic telangiectasia (HHT), the second most common inherited bleeding disorder, is associated with the development of malformed blood vessels. Abnormal blood vessels may be small and cutaneous or mucosal (telangiectasia), with frequent complications of bleeding, or large and visceral (arteriovenous malformations [AVMs]), with additional risks that can lead to significant morbidity and even mortality. HHT can present in many different ways and can be difficult to recognize, particularly in younger patients in the absence of a known family history of disease or epistaxis, its most common manifestation. HHT is commonly diagnosed using the established Curaçao clinical criteria, which include (1) family history, (2) recurrent epistaxis, (3) telangiectasia, and (4) visceral AVMs. Fulfillment of 3 or more criteria provides a definite diagnosis of HHT, whereas 2 criteria constitute a possible diagnosis of HHT. However, these criteria are insufficient in children to rule out disease due to the age-dependent development of some of these criteria. Genetic testing, when positive, can provide definitive diagnosis of HHT in all age groups. Clinical course is often complicated by significant epistaxis and/or gastrointestinal bleeding, leading to anemia in half of adult patients with HHT. The management paradigm has recently shifted from surgical approaches to medical treatments aimed at control of chronic bleeding, such as antifibrinolytic and antiangiogenic agents, combined with aggressive iron replacement with intravenous iron. Guidelines for management of HHT, including screening and treatment, were determined by expert consensus and originally published in 2009 with updates and new guidelines in 2020., (Copyright © 2021 by The American Society of Hematology.)

Heyde syndrome, the co-occurrence of aortic stenosis and bleeding gastrointestinal (GI) angiodysplasia, is managed with aortic valve replacement. However, severe bleeding and anemia can preclude safe use of the antiplatelet or anticoagulant therapy required for this intervention. We present a case of the novel and successful treatment of severe, refractory bleeding and transfusion dependence with antiangiogenic therapy in a patient with Heyde syndrome. After systemic bevacizumab was initiated, the patient achieved durable hemostasis with normalization of hemoglobin and liberation from red cell transfusion and dependence on iron infusion; aspirin therapy was successfully initiated where it had previously failed. This durable hemostasis facilitated her subsequent successful transcatheter aortic valve replacement. Plasma vascular endothelial growth factor levels, which were monitored during therapy, paradoxically rose after bevacizumab was initiated but normalized after it was discontinued. Given the angiogenic dysregulation of Heyde syndrome, systemic bevacizumab may be an effective and safe targeted therapy for managing refractory GI bleeding, which thereby facilitates antiplatelet therapy and aortic valve replacement in these challenging cases. Additional investigation into the therapeutic role of inhibiting angiogenesis as a hemostatic modality in Heyde syndrome is warranted., (© 2021 by The American Society of Hematology.)

Acquired hemophilia A (AHA) is a rare bleeding disorder in which acquired autoantibodies to endogenous factor VIII (FVIII) decrease FVIII activity and lead to a bleeding phenotype. A substantial majority of individuals who develop AHA present with severe bleeding. Effective treatment requires both immunosuppressive therapy and prompt hemostatic treatment. Bleeding is commonly treated with bypassing agents (BPAs) such as recombinant activated FVII (rFVIIa) or activated prothrombin complex concentrates Disadvantages to BPAs include the inability to monitor response with standard laboratory assays, inconsistent hemostatic efficacy, and thrombosis. Recombinant porcine FVIII (rpFVIII: Obizur, Baxter, Deerfield, IL) was approved by the US Food and Drug Administration (FDA) for bleed treatment in AHA in 2014, and has the advantage of laboratory monitoring of FVIII activity levels and known hemostatic efficacy in the presence of anti-human FVIII inhibitors and after failure of BPAs. Using an algorithm-based approach, rpFVIII has been used to successfully treat 18 patients with AHA at our center with substantially lower doses than the current FDA-recommended dosing. Additionally, data from our cohort show that the preexposure anti-porcine Bethesda titer does not reliably predict the clinical response to rpFVIII treatment and is not correlated with the anti-human Bethesda titer. We also present data showing lower total rpFVIII use for initial bleed resolution when rpVIII is used upfront, as compared with use as rescue therapy. We validated our dosing algorithm, which uses much lower than FDA-recommended doses with 14 more patients than in our previously reported patient series., (© 2020 by The American Society of Hematology.)