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Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait and caused by loss-of-function pathogenic variants in genes encoding proteins of the BMP signalling pathway. Up to 90% of disease-causal variants are observed in ENG and ACVRL1, with SMAD4 and GDF2 less frequently responsible for HHT. In adults, the most frequent HHT manifestations relate to iron deficiency and anaemia owing to recurrent epistaxis (nosebleeds) or bleeding from gastrointestinal telangiectases. Arteriovenous malformations (AVMs) in the lungs, liver and the central nervous system cause additional major complications and often complex symptoms, primarily due to vascular shunting, which is right-to-left through pulmonary AVMs (causing ischaemic stroke or cerebral abscess) and left-to-right through systemic AVMs (causing high cardiac output). Children usually experience isolated epistaxis; in rare cases, childhood complications occur from large AVMs in the lungs or central nervous system. Management goals encompass control of epistaxis and intestinal bleeding from telangiectases, screening for and treatment of iron deficiency (with or without anaemia) and AVMs, genetic counselling and evaluation of at-risk family members. Novel therapeutics, such as systemic antiangiogenic therapies, are actively being investigated. Although HHT is associated with increased morbidity, the appropriate screening and treatment of visceral AVMs, and the effective management of bleeding and anaemia, improves quality of life and overall survival., Competing Interests: Competing interests: C.L.S. is listed as the inventor in the patent application filed by Imperial College London for the use of MEK1 inhibitors to treat telangiectasia in HHT (European Patent Application 23705641.1). O.F.E. is a consultant for Microvention, CERENOVUS and Balt, and is also a member of DSMB and on the advisory board for STREAM Study. All other authors declare no competing interests., (© 2025. Springer Nature Limited.)

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.)

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 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 2nd or subsequent rituximab-treated episode compared to the first (2.1 vs 6.0 years, P = 0.04). White patients' clinical relapse risk after the second and subsequent rituximab courses was not significantly different compared to the first [HR=1.86 (95% CI 0.22-15.80), P=0.57], while 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=0.001]. 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 IQR 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., (Copyright © 2024 American Society of Hematology.)

Background: Hereditary hemorrhagic telangiectasia (HHT) is characterized by extensive telangiectasias and arteriovenous malformations. The primary clinical manifestation is epistaxis that results in iron-deficiency anemia and reduced health-related quality of life., Methods: We conducted a randomized, placebo-controlled trial to evaluate the safety and efficacy of pomalidomide for the treatment of HHT. We randomly assigned patients, in a 2:1 ratio, to receive pomalidomide at a dose of 4 mg daily or matching placebo for 24 weeks. The primary outcome was the change from baseline through week 24 in the Epistaxis Severity Score (a validated bleeding score in HHT; range, 0 to 10, with higher scores indicating worse bleeding). A reduction of 0.71 points or more is considered clinically significant. A key secondary outcome was the HHT-specific quality-of-life score (range, 0 to 16, with higher scores indicating more limitations)., Results: The trial was closed to enrollment in June 2023 after a planned interim analysis met a prespecified threshold for efficacy. A total of 144 patients underwent randomization; 95 patients were assigned to receive pomalidomide and 49 to receive placebo. The baseline mean (±SD) Epistaxis Severity Score was 5.0±1.5, a finding consistent with moderate-to-severe epistaxis. At 24 weeks, the mean difference between the pomalidomide group and the placebo group in the change from baseline in the Epistaxis Severity Score was -0.94 points (95% confidence interval [CI], -1.57 to -0.31; P = 0.004). The mean difference in the changes in the HHT-specific quality-of-life score between the groups was -1.4 points (95% CI, -2.6 to -0.3). Adverse events that were more common in the pomalidomide group than in the placebo group included neutropenia, constipation, and rash., Conclusions: Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified. (Funded by the National Heart, Lung, and Blood Institute; PATH-HHT Clinicaltrials.gov number, NCT03910244)., (Copyright © 2024 Massachusetts Medical Society.)

Background: The Accelerating COVID-19 Therapeutic Interventions and Vaccines-4c (ACTIV-4c) trial investigated prophylactic apixaban for 30 days following hospitalization for COVID-19. The overall incidence of early postdischarge death or thromboembolism was low, and the trial was closed early., Objectives: To identify a high-risk patient population who might benefit from postdischarge thromboprophylaxis through subgroup analyses stratified by age, race/ethnicity, obesity, D-dimer elevation, World Health Organization score, and modified International Medical Prevention Registry on Venous Thromboembolism score on 30-day composite outcome of all-cause death, arterial thromboembolism (ATE), and venous thromboembolism (VTE)., Methods: Cumulative incidences of all-cause death, ATE, and VTE within 30 days were described for each subgroup. Time to death, ATE, or VTE by 30 days was analyzed using Cox proportional hazard models with interaction testing for each subgroup., Results: Among 1217 patients randomized to apixaban or placebo group, 32% were >60 years old. Modified International Medical Prevention Registry on Venous Thromboembolism score was ≥4 in 2% and 2 or 3 with an elevated D-dimer in an additional 9% of participants. The overall incidence of the primary endpoint was 2.13% in the apixaban group and 2.31% in the placebo group. At day 30, similar rates of the primary endpoint occurred within subgroups, except for participants aged >60 years. No benefit of thromboprophylaxis was seen in any subgroup., Conclusion: The combined incidence of 30-day death, ATE, and VTE was low in patients who survived COVID-19 hospitalization, except in patients over age 60 years. Due to the limited number of events, the findings remain inconclusive; nonetheless, the study did not identify a high-risk subgroup that would derive benefits from extended thromboprophylaxis., (© 2024 The Author(s).)

Background: Mortality due to immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains significant. Predicting mortality risk may potentially help individualize treatment. The French Thrombotic Microangiopathy (TMA) Reference Score has not been externally validated in the United States. Recent advances in machine learning technology can help analyze large numbers of variables with complex interactions for the development of prediction models., Objectives: To validate the French TMA Reference Score in the United States Thrombotic Microangiopathy (USTMA) iTTP database and subsequently develop a novel mortality prediction tool, the USTMA TTP Mortality Index., Methods: We analyzed variables available at the time of initial presentation, including demographics, symptoms, and laboratory findings. We developed our model using gradient boosting machine, a machine learning ensemble method based on classification trees, implemented in the R package gbm., Results: In our cohort ( n = 419), the French score predicted mortality with an area under the receiver operating characteristic curve of 0.63 (95% CI: 0.50-0.77), sensitivity of 0.35, and specificity of 0.84. Our gradient boosting machine model selected 8 variables to predict acute mortality with a cross-validated area under the receiver operating characteristic curve of 0.77 (95% CI: 0.71-0.82). The 2 cutoffs corresponded to sensitivities of 0.64 and 0.50 and specificities of 0.76 and 0.87, respectively., Conclusion: The USTMA Mortality Index was acceptable for predicting mortality due to acute iTTP in the USTMA registry, but not sensitive enough to rule out death. Identifying patients at high risk of iTTP-related mortality may help individualize care and ultimately improve iTTP survival outcomes. Further studies are needed to provide external validation. Our model is one of many recent examples where machine learning models may show promise in clinical prediction tools in healthcare., (© 2024 The Author(s).)

Background: Patients hospitalized with COVID-19 have an increased incidence of thromboembolism. The role of extended thromboprophylaxis after hospital discharge is unclear., Objective: To determine whether anticoagulation is superior to placebo in reducing death and thromboembolic complications among patients discharged after COVID-19 hospitalization., Design: Prospective, randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT04650087)., Setting: Done during 2021 to 2022 among 127 U.S. hospitals., Participants: Adults aged 18 years or older hospitalized with COVID-19 for 48 hours or more and ready for discharge, excluding those with a requirement for, or contraindication to, anticoagulation., Intervention: 2.5 mg of apixaban versus placebo twice daily for 30 days., Measurements: The primary efficacy end point was a 30-day composite of death, arterial thromboembolism, and venous thromboembolism. The primary safety end points were 30-day major bleeding and clinically relevant nonmajor bleeding., Results: Enrollment was terminated early, after 1217 participants were randomly assigned, because of a lower than anticipated event rate and a declining rate of COVID-19 hospitalizations. Median age was 54 years, 50.4% were women, 26.5% were Black, and 16.7% were Hispanic; 30.7% had a World Health Organization severity score of 5 or greater, and 11.0% had an International Medical Prevention Registry on Venous Thromboembolism risk prediction score of greater than 4. Incidence of the primary end point was 2.13% (95% CI, 1.14 to 3.62) in the apixaban group and 2.31% (CI, 1.27 to 3.84) in the placebo group. Major bleeding occurred in 2 (0.4%) and 1 (0.2%) and clinically relevant nonmajor bleeding occurred in 3 (0.6%) and 6 (1.1%) apixaban-treated and placebo-treated participants, respectively. By day 30, thirty-six (3.0%) participants were lost to follow-up, and 8.5% of apixaban and 11.9% of placebo participants permanently discontinued the study drug treatment., Limitations: The introduction of SARS-CoV-2 vaccines decreased the risk for hospitalization and death. Study enrollment spanned the peaks of the Delta and Omicron variants in the United States, which influenced illness severity., Conclusion: The incidence of death or thromboembolism was low in this cohort of patients discharged after hospitalization with COVID-19. Because of early enrollment termination, the results were imprecise and the study was inconclusive., Primary Funding Source: National Institutes of Health.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by recurring episodes of thrombotic microangiopathy, causing ischemic organ impairment. Black patients are overrepresented in iTTP cohorts in the United States, but racial disparities in iTTP outcome and response to therapy have not been studied. Using the United States Thrombotic Microangiopathies Consortium iTTP Registry, we evaluated the impact of race on mortality and relapse-free survival (RFS) in confirmed iTTP in the United States from 1995 to 2020. We separately examined the impact of rituximab therapy and presentation with newly diagnosed (de novo) or relapsed iTTP on RFS by race. A total of 645 participants with 1308 iTTP episodes were available for analysis. Acute iTTP mortality did not differ by race. When all episodes of iTTP were included, Black race was associated with shorter RFS (hazard ratio [HR], 1.60; 95% CI, 1.16-2.21); the addition of rituximab to corticosteroids improved RFS in White (HR, 0.37; 95% CI, 0.18-0.73) but not Black patients (HR, 0.96; 95% CI, 0.71-1.31). In de novo iTTP, rituximab delayed relapse, but Black patients had shorter RFS than White patients, regardless of treatment. In relapsed iTTP, rituximab significantly improved RFS in White but not Black patients. Race affects overall relapse risk and response to rituximab in iTTP. Black patients may require closer monitoring, earlier retreatment, and alternative immunosuppression after rituximab treatment. How race, racism, and social determinants of health contribute to the disparity in relapse risk in iTTP deserves further study., (© 2022 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.)

Purpose: Thrombocytopenia is common among critically ill patients and heparin-induced thrombocytopenia (HIT) is often on the differential. Professional guidelines recommend calculating a pre-test probability score before performing HIT testing. The 4Ts score is widely utilized but accuracy has been questioned in critically ill patients. The HIT Expert Probability (HEP) score is available, but complexity limits use. Our objective was to compare a modified intensive care unit (ICU)-4Ts score to available scoring tools., Materials and Methods: This was a single-center retrospective pilot study. Adult ICU patients that were tested for HIT and had a documented 4Ts score were included. A blinded investigator retrospectively calculated the HEP and ICU-4Ts score. Receiver operating characteristics (ROC) area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were compared., Results: In 194 included patients, ROC AUC was significantly higher for the ICU-4Ts compared to the 4Ts score (0.80 versus 0.66, respectively; p = 0.044). The ICU-4Ts score had the highest specificity, PPV, and NPV. The sensitivity was similar between the HEP and ICU-4Ts score., Conclusions: The ICU-4Ts score better predicted the diagnosis of HIT compared to the 4Ts score. Prospective validation studies are needed to confirm these results., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)