Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.

BACKGROUND: Congenital thrombotic thrombocytopenic purpura (TTP) results from severe hereditary deficiency of ADAMTS13. The efficacy and safety of recombinant ADAMTS13 and standard therapy (plasma-derived products) administered as routine prophylaxis or on-demand treatment in patients with congenital TTP is not known. METHODS: In this phase 3, open-label, crossover trial, we randomly assigned patients in a 1:1 ratio to two 6-month periods of prophylaxis with recombinant ADAMTS13 (40 IU per kilogram of body weight, administered intravenously) or standard therapy, followed by the alternate treatment; thereafter, all the patients received recombinant ADAMTS13 for an additional 6 months. The trigger for this interim analysis was trial completion by at least 30 patients. The primary outcome was acute TTP events. Manifestations of TTP, safety, and pharmacokinetics were assessed. Patients who had an acute TTP event could receive on-demand treatment. RESULTS: A total of 48 patients underwent randomization; 32 completed the trial. No acute TTP event occurred during prophylaxis with recombinant ADAMTS13, whereas 1 patient had an acute TTP event during prophylaxis with standard therapy (mean annualized event rate, 0.05). Thrombocytopenia was the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy). Adverse events occurred in 71% of the patients with recombinant ADAMTS13 and in 84% with standard therapy. Adverse events that were considered by investigators to be related to the trial drug occurred in 9% of the patients with recombinant ADAMTS13 and in 48% with standard therapy. Trial-drug interruption or discontinuation due to adverse events occurred in no patients with recombinant ADAMTS13 and in 8 patients with standard therapy. No neutralizing antibodies developed during recombinant ADAMTS13 treatment. The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment was 101%, as compared with 19% after standard therapy. CONCLUSIONS: During prophylaxis with recombinant ADAMTS13 in patients with congenital TTP, ADAMTS13 activity reached approximately 100% of normal levels, adverse events were generally mild or moderate in severity, and TTP events and manifestations were rare. (Funded by Takeda Development Center Americas and Baxalta Innovations; ClinicalTrials.gov number, NCT03393975.).

A machine learning approach to predict mortality due to immune-mediated thrombotic thrombocytopenic purpura.

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.

Race and ethnicity reporting and representation in hemophilia clinical trials.

ABSTRACT: Racial and ethnic representativeness in clinical trials is crucial to mitigate disparities in outcomes; however, diversity among hemophilia trials is unknown. The aim of this study is to examine the reporting and representation of race and ethnicity in trials of people with hemophilia (PwH). In this cross-sectional study, the ClinicalTrials.gov database was queried in April 2023 for interventional clinical trials involving PwH between 2007 and 2022. The distribution of participants (observed) was compared with expected proportions based on US Hemophilia Treatment Center (HTC) and country-specific census data with observed-to-expected ratios (OERs). Of 129 trials included, 94.6% were industry sponsored, with a mean of 62 participants and mean age of 26.8 years. Overall, 52.0% (n = 66) of trials reported data on race and ethnicity, increasing from 13.9% in 2007-2012 to 22.5% in 2013-2016 to 100% in 2017-2022 (P = .001). Among these 66 trials, 65.8%, 22.8%, 5.1%, 3.9% of participants were White, Asian, Hispanic, and Black, respectively. OERs were 10% to 20% lower for White participants vs US HTC, and US, UK, and Canadian census populations and ∼75% lower for Black or Hispanic participants when compared with US HTC and US census population. OERs for Asian participants were 1.6 to 3 times higher than Canada, US, and UK census populations. The reporting of race and ethnicity in hemophilia trials has drastically improved; however, Black and Hispanic PwH remain especially underrepresented. To address these disparities, stakeholders across the clinical trial enterprise need to implement strategies to ensure equitable participation.

Racial and ethnic differences in reported haemophilia death rates in the United States.

INTRODUCTION: People with haemophilia's life expectancies have improved over time. Whether progress has been experienced equitably is unknown. AIM: To examine recorded haemophilia death (rHD) rates according to race and ethnicity in the United States (US). METHODS: In this cohort study, rHDs were examined with US National Vital Statistics' 1999-2020 Multiple Cause-of-Death data. rHD was defined as having a haemophilia A (D66) or B (D67) ICD-10 code in the death certificate (underlying or multiple causes of death). Age-adjusted rHD rates were compared with age-adjusted rate ratios (aRR) and 95% Confidence Intervals (CI). RESULTS: There were 3115 rHDs in males with an rHD rate of 0.98 per 1 million males. Between 1999 and 2020, rHD rates declined by 46% in NH (Non-Hispanic) White, 44% in NH Black (aRR = 0.56, 95%CI 0.43, 0.74), and 42% in Hispanic (aRR = 0.58, 95%CI 0.39, 0.88) males. However, rHD rates remained higher and were on average 30% greater in NH Black versus NH White males (aRR = 1.30 95% CI 1.16, 1.46). Among males with rHD, the median age at death rose from 54.5 to 65.5 years between 1999 and 2020 and was 12 years lower in NH Black (56 years) versus NH White (68 years) males in 2010-2020. There were 930 females with rHD, with an age-adjusted rate of 0.22 per 1 million females, which was consistent between 1999 and 2020. CONCLUSION: Reported haemophilia-death rates improved in males across all race/ethnicities, but rates were higher Black versus White males. Given the inherent limitations of the current study's data source, further investigation of survival rates and disparities in haemophilia are needed.

Racial and Ethnic Differences in Distress, Depression, and Quality of Life in people with hemophilia.

Hemophilia-related distress (HRD) has been shown to be higher among those with lower educational attainment, but potential racial/ethnic differences have not been previously described. Thus, we examined HRD according to race/ethnicity. This cross-sectional study was a planned secondary analysis of the hemophilia-related distress questionnaire (HRDq) validation study data. Adults aged ≥ 18 years with Hemophilia A or B were recruited from one of two hemophilia treatment centers between July 2017-December 2019. HRDq scores can range from 0-120, and higher scores indicate higher distress. Self-reported race/ethnicity was grouped as Hispanic, non-Hispanic White (NHW) and non-Hispanic Black (NHB). Unadjusted and multivariable linear regression models were used to examine mediators of race/ethnicity and HRDq scores. Among 149 participants enrolled, 143 completed the HRDq and were included in analyses. Approximately 17.5% of participants were NHB, 9.1% were Hispanic and 72.0% were NHW. HRDq scores ranged from 2 to 83, with a mean of 35.1 [standard deviation (SD) = 16.5]. Average HRDq scores were significantly higher among NHB participants (mean = 42.6,SD = 20.6; p-value = .038) and similar in Hispanic participants (mean = 33.8,SD = 16.7, p-value = .89) compared to NHW (mean = 33.2,SD = 14.9) participants. In multivariable models, differences between NHB vs NHW participants persisted when adjusting for inhibitor status, severity, and target joint. However, after household income was adjusted for, differences in HRDq scores were no longer statistically significant (ß = 6.0 SD = 3.7; p-value = .10). NHB participants reported higher HRD than NHW participants. Household income mediated higher distress scores in NHB compared to NHW participants, highlighting the urgent need to understand social determinants of health and financial hardship in persons with hemophilia.

Race, rituximab, and relapse in TTP.

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.

How I treat immune-mediated thrombotic thrombocytopenic purpura after hospital discharge.

Immune-mediated thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy characterized by an acquired ADAMTS13 deficiency as a result of the presence of an antibody inhibitor of ADAMTS13 leading to the formation of ultralarge von Willebrand multimers. Treatment of iTTP includes plasma exchange, high-dose glucocorticoids, rituximab, and, more recently, caplacizumab, to prevent the development of exacerbations. There is the risk of both relapse and long-term complications that include neurocognitive deficits and cardiovascular events that occur in patients in remission after recovery from an acute iTTP episode. Data on the risk factors for the development of these complications, the appropriate screening, and treatment are limited due to the paucity of research. This article is a review of the current understanding on the risk factors for exacerbation, relapse, and long-term complications of iTTP and discusses an approach to observing patients with iTTP after hospital discharge and during the long-term follow-up in the outpatient setting.

Longitudinal Changes in Hematologic Parameters Among Transgender People Receiving Hormone Therapy.

CONTEXT: The effect of gender-affirming hormone therapy (HT) on erythropoiesis is an area of priority in transgender health research. OBJECTIVE: To compare changes in hematologic parameters and rates of erythrocytosis and anemia among transgender people to those of cisgender controls. DESIGN: Longitudinal observational study. PARTICIPANTS AND SETTING: We compared 559 transfeminine (TF) and 424 transmasculine (TM) people enrolled in 3 integrated health care systems to matched cisgender referents. INTERVENTIONS AND OUTCOME: Hormone therapy receipt was ascertained from filled prescriptions. Hemoglobin (Hb) and hematocrit (Hct) levels were examined from the first blood test to HT initiation, and from the start of HT to the most recent blood test. Rates of erythrocytosis and anemia in transgender participants and referents were compared by calculating adjusted hazard ratios and 95% confidence intervals (CI). RESULTS: In the TF group, there was a downward trend for both Hb and Hct. The corresponding changes in the TM cohort were in the opposite direction. TM study participants experienced a 7-fold higher rate (95% CI: 4.1-13.4) of erythrocytosis relative to matched cisgender males, and an 83-fold higher rate (95% CI: 36.1-191.2) compared to cisgender females. The corresponding rates for anemia were elevated in TF subjects but primarily relative to cisgender males (hazard ratio 5.9; 95% CI: 4.6-7.5). CONCLUSIONS: Our results support previous recommendations that hematological parameters of transgender people receiving HT should be interpreted based on their affirmed gender, rather than their sex documented at birth. The clinical significance of erythrocytosis following testosterone therapy, as well as anemia following feminizing HT, requires further investigation.

The effect of psychological distress on health outcomes: A systematic review and meta-analysis of prospective studies.

Distress effects are widely examined in cross-sectional studies with less known about effects on future health. This review summarizes distress impacts on health among adults in prospective studies and describes available distress measurement tools. Four inter-disciplinary databases were searched. Effects of distress on mortality and other outcomes were reviewed and estimated in a meta-analysis. A total of 19 studies were assessed which incorporated 10 distress tools. Distress had a detrimental effect on health regardless of the population studied, distress tool used, and health outcome examined. There was an increased mortality risk among those reporting high versus low distress (pooled hazard ratio (95% confidence interval) = 1.29 (1.15-1.46)).

Exploring changes in distress among individuals with bleeding disorders: What is linked to improvements in distress?

Adults with chronic bleeding disorders report high distress, but it is unclear how distress varies over time. Patients rated their distress on a 10-point scale at two clinic visits. Of 83 patients, roughly one-quarter reported consistent no/low distress (29%), one-quarter reported consistent distress (22%), and half (49%) reported a change in distress of at least two points. Overall activity levels, depressive symptoms, and non-White race were significantly associated with worsening and consistent distress in adjusted analyses while improvements in activity levels and depressive symptoms during the study period were associated with distress improvement. Our results suggest that distress is modifiable.

Peritransplantation Red Blood Cell Transfusion Is Associated with Increased Risk of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.

More than 90% of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients receive red blood cell (RBC) or platelet transfusions in the peritransplantation period. We tested the hypothesis that transfusions are associated with the development of severe (grade III-IV) acute graft-versus-host disease (aGVHD) or mortality after allo-HSCT in a retrospective study of 322 consecutive patients receiving an allogeneic bone marrow or granulocyte colony-stimulating factor-mobilized blood stem cell graft for a hematologic malignancy. Counting transfused RBC and platelet units between day -7 pretransplantation and day +27 post-transplantation, but excluding transfusions administered after a diagnosis of aGVHD, yielded medians of 5 RBC units and 2 platelet units transfused. Sixty-three patients (20%) developed a maximal grade III-IV aGVHD with onset up to day +150 post-transplantation (median aGVHD onset of 28 days). HLA mismatch (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.2 to 4.7; P = .01), and transfusion of more than the median number of RBC units (HR, 2.1; 95% CI, 1.1 to 3.7; P = .02) were independently associated with greater risk of grade III-IV aGVHD in a multivariable analysis model. Disease risk strata (HR, 1.7; 95% CI, 1.2 to 2.4 for high risk versus low risk; P = .005) and transfusion of more than the median number of RBC units (HR, 1.4; 95% CI, 1.0 to 2.0; P = .054) were independently associated with inferior overall survival. These data support our hypothesis that peritransplantation RBC transfusions are associated with the risk of developing severe aGVHD and worse overall survival following allo-HSCT, and suggest that strategies to reduce routine RBC transfusion may favorably reduce the incidence and severity of GVHD.

Venous access catheter-related thrombosis in patients with cancer.

Patients with cancer are at high risk for developing venous thromboembolism (VTE), and the presence of a central venous catheter (CVC) further increases this risk. CVC-related VTE has serious implications related to the loss of vascular access, development of pulmonary embolism, recurrent VTE, infections and post-thrombotic syndrome. The pathogenesis of CVC-related VTE is complex and multifactorial, with risk factors associated with the catheter, the vessel selected for insertion and the underlying cancer as well as the anti-cancer therapy. Clinical presentation of CVC-related VTEs is often non-specific, and ultrasonography is the most commonly used radiological diagnostic test. Management of CVC-related VTE in patients with cancer requires a balance between the need for venous access, the risk of VTE recurrence and the risk of bleeding from treatment-induced thrombocytopenia. Effective VTE prophylaxis methods have yet to be defined. Ongoing studies are evaluating the role of newer oral antithrombotic agents and alternative interventional strategies for the prevention and treatment of CVC-related VTE in patients with cancer.

Epsilon aminocaproic acid prevents bleeding in severely thrombocytopenic patients with hematological malignancies.

BACKGROUND: Despite prophylactic platelet transfusions, bleeding remains a significant problem in thrombocytopenic patients. METHODS: The antifibrinolytic agent epsilon aminocaproic acid (EACA) was administered to 44 chronically (median duration, 273 days) and severely (platelet count, 8 × 10(9)/L; range, 1 × 10(9)/L-19 × 10(9)/L) thrombocytopenic patients with hematological malignancies. Prophylactic EACA at a dose of 1 g twice daily was orally administered for a median duration of 47 days (range, 7 days-209 days) until the platelet count recovered to > 30; × 10(9) /L. Platelets were only transfused if bleeding occurred. RESULTS: While receiving EACA, 59% of the patients did not bleed, 25% had 19 episodes of spontaneously resolving minor bleeding that did not require platelet transfusion, and 16% received a median of 4 platelet transfusions (range, 1 transfusion-8 transfusions) for 1 major traumatic and 9 spontaneous grade 2 to grade 3 bleeding (based on the World Health Organization classification of idiopathic thrombocytopenic purpura). No EACA toxicities were noted, and venous thromboses were not observed. CONCLUSIONS: EACA is well tolerated and is associated with a low risk of major bleeding in patients with hematological malignancies who are experiencing chronic severe thrombocytopenia.

Is the incidence of heparin-induced thrombocytopenia affected by the increased use of heparin for VTE prophylaxis?

BACKGROUND: The increased exposure to heparin products for thromboprophylaxis against VTE in hospitalized patients raises concerns for an increase in the incidence of heparin-induced thrombocytopenia(HIT). METHODS: We analyzed, among 90,875 patients exposed to heparin products between 2005 and 2009, the number of hematologic consultations for thrombocytopenia, requests for heparin induced antibodies by enzyme-linked immunosorbent assay, and cases given a diagnosis of HIT by the hematology consult service. RESULTS: We observed that despite a doubling in the number of patients receiving pharmacoprophylaxis with heparin, there was no significant increase in the number of consultations for thrombocytopenia,the number of requests for HIT tests, the number of positive HIT test results, or the number of HIT diagnoses. The number of cases of HIT was low and represented < 0.1% of patients exposed to heparin. CONCLUSIONS: We conclude that concerns about HIT should not be a limiting factor for the systematic implementation of heparin-based VTE prophylaxis.

Pneumonectomy for bronchogenic carcinoma: analysis of factors predicting survival.

BACKGROUND: The aim of this study was to identify risk factors associated with survival after pneumonectomy for non-small cell lung cancer. METHODS: This was a retrospective study of 155 patients who underwent a pneumonectomy for non-small cell lung cancer at Roswell Park Cancer Institute between 1986 and 2002. Medical record review ascertained information on preoperative assessment including pulmonary function tests and clinical characteristics, postoperative complications, and overall survival. Multivariate Cox proportional hazards models to calculate the hazard ratios and 95% confidence intervals were used. Kaplan-Meier cumulative survival curves (with log-rank p values) were generated for selected variables. RESULTS: The median age was 58 years at the time of surgery; 65% of patients were males. Squamous cell carcinoma (54%) and adenocarcinoma (33%) were the predominant histologic types. The median time to relapse was 11 months, and the overall median survival was 15.6 months. An American Society of Anesthesiology score of less than 3, squamous histology, and lower pathologic stage were significant independent predictors of improved survival. Current smoking status (hazard ratio = 1.87, 95% confidence interval: 1.30 to 2.70) and left tumor location (hazard ratio = 1.40, 95% confidence interval: 0.97 to 2.03) were associated with a trend toward poorer survival. Sixty-four patients (41%) had postoperative complications. The operative mortality from pneumonectomy was 9 of 155 (5.8%). CONCLUSIONS: American Society of Anesthesiology score, histology, pathologic stage, smoking status, and location of the tumor were important predictors of survival in this patient sample. Pneumonectomy for non-small cell lung cancer carries an acceptable operative mortality and provides an important survival benefit.