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.

Frequency and characteristics of chemotherapy-associated thrombotic microangiopathy: Analysis from a large pharmacovigilance database.

We used the information component (IC), a disproportionate Bayesian analysis comparing the number of observed versus expected adverse drug reactions, to determine the potential association between anti-neoplastic agents and thrombotic microangiopathy (TMA). The IC025 indicates the lower end of 95% of IC, in which a value >0 suggests a disproportionality signal between the drug of interest and the adverse drug reaction. Carfilzomib had the highest IC025 for TMA among all studied chemotherapies followed by gemcitabine, mitomycin, bevacizumab, and bortezomib.

Evidence-based consensus guidelines for the diagnosis and management of erythropoietic protoporphyria and X-linked protoporphyria.

Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic photodermatoses. Limited expertise with these disorders among physicians leads to diagnostic delays. Here, we present evidence-based consensus guidelines for the diagnosis, monitoring, and management of erythropoietic protoporphyria and X-linked protoporphyria. A systematic literature review was conducted, and reviewed among subcommittees of experts, divided by topic. Consensus on guidelines was reached within each subcommittee and then among all members of the committee. The appropriate biochemical and genetic testing to establish the diagnosis is reviewed in addition to the interpretation of results. Prevention of symptoms, management of acute phototoxicity, and pharmacologic and nonpharmacologic treatment options are discussed. The importance of ongoing monitoring for liver disease, iron deficiency, and vitamin D deficiency is discussed with management guidance. Finally, management of pregnancy and surgery and the safety of other therapies are summarized. We emphasize that these are multisystemic disorders that require longitudinal monitoring. These guidelines provide a structure for evidence-based diagnosis and management for practicing physicians. Early diagnosis and management of these disorders are essential, particularly given the availability of new and emerging therapies.

Maternal and fetal outcomes of pregnancy occurring after a diagnosis of immune-mediated thrombotic thrombocytopenic purpura.

Pregnancy is a well-established trigger for a first episode or relapse of immune thrombotic thrombocytopenic purpura (iTTP). Other outcomes of subsequent pregnancy after a diagnosis of iTTP are less well described. We conducted this retrospective cohort study to evaluate maternal and fetal outcomes of pregnancy in women with prior iTTP from the Johns Hopkins Thrombotic Microangiopathy Cohort. Of 168 women in the cohort, 102 were of reproductive age at diagnosis. Fourteen pregnancies (in 9 women) that occurred after the initial iTTP episode were included in the analysis. iTTP relapse occurred in 9 (64%) pregnancies. Out of the 9 instances of relapse, 5 relapses occurred in 2 women. Seven pregnancies (50%) ended in fetal death or miscarriage in the setting of iTTP relapse and three were electively terminated due to fear of relapse. Four pregnancies (50% of the 8 that progressed beyond 20 weeks) were complicated by preeclampsia or HELLP syndrome, which is over ten-fold higher than that of the general population. No maternal deaths occurred. Only 4 pregnancies resulted in live births, of which, 2 were pre-term. Pregnancy in women with prior iTTP is associated with a substantial risk of iTTP relapse and fetal loss. Preeclampsia and HELLP syndrome is also more common than that in the general population. ADAMTS13 monitoring and preemptive therapy may improve pregnancy outcomes, which needs to be evaluated prospectively.

Caplacizumab for congenital thrombotic thrombocytopenic purpura.

Caplacizumab rapidly increased platelet count which likely shorted the hospital stay and reduced plasma transfusion requirement.

How targeted therapy disrupts the treatment paradigm for acquired TTP: the risks, benefits, and unknowns.

Insights into immune-mediated thrombotic thrombocytopenic purpura (iTTP) pathophysiology have led to novel targeted therapies. Immunomodulatory strategies target anti-ADAMTS13 antibodies: rituximab is effective in inducing responses in refractory/relapsed TTP and increasing relapse-free survival; caplacizumab targets the von Willebrand factor-platelet interaction to hasten platelet count recovery and reduce mortality and TTP-related ischemic events. Bortezomib and recombinant ADAMTS13 are under investigation. This review examines how targeted therapies are disrupting current treatment paradigms to improve outcomes of iTTP.

Major adverse cardiovascular events in survivors of immune-mediated thrombotic thrombocytopenic purpura.

Cardiovascular disease is a leading cause of death in survivors of immune-mediated thrombotic thrombocytopenic purpura (iTTP), but the epidemiology of major adverse cardiovascular events (MACE) in iTTP survivors is unknown. We evaluated the prevalence and risk factors for MACE, defined as the composite of non-fatal or fatal myocardial infarction (MI), stroke, and cardiac revascularization, during clinical remission in two large iTTP cohorts (Johns Hopkins University and Ohio State University). Of 181 patients followed for ≥ 3 months after recovery from acute iTTP, 28.6% had a MACE event over a median follow up of 7.6 years. Stroke was the most common type of MACE (18.2%), followed by non-fatal MI (6.6%), cardiac revascularization (4.9%) and fatal MI (0.6%). Compared to the general United States population, iTTP survivors were younger at first stroke in remission (males [56.5 years vs. 68.6 years, p = 0.031], females [49.7 years vs. 72.9 years, p < 0.001]) or MI in remission (males [56.5 years vs. 65.6 years, p < 0.001] and females [53.1 years vs. 72.0 years, p < 0.001]). Age (HR 1.03 [95% CI 1.002-1.054]), race (Black/Other vs. White) (HR 2.32 [95% CI 1.12-4.82]), and diabetes mellitus (HR 2.37 [95% CI 1.09-0.03]) were associated with MACE in a Cox regression model also adjusted for sex, hypertension, obesity, hyperlipidemia, chronic kidney disease, atrial fibrillation, autoimmune disease, and relapsing iTTP. Remission ADAMTS13 activity was not significantly associated with MACE. In conclusion, iTTP survivors experience high rates of MACE and may benefit from aggressively screening for and managing cardiovascular risk factors.

Therapeutic plasma exchange taper does not decrease exacerbations in immune thrombotic thrombocytopenic purpura patients.

BACKGROUND: Despite rapid and intensive treatments with therapeutic plasma exchange (TPE) and immunosuppression, immune thrombotic thrombocytopenic purpura (TTP) patients are at risk of disease exacerbation, i.e., early recurrence of TTP within 30 days of achieving treatment response. TPE taper, a practice of performing additional TPE procedures after achieving treatment response, is commonly performed for decreasing exacerbations, although no evidence supports this practice. STUDY DESIGN AND METHODS: In this prospective observational investigation over four years, our center switched its standard of care for treating all TTP patients from not performing TPE taper after achieving treatment response (i.e., no-taper cohort) to performance of TPE taper (i.e., yes-taper cohort) to characterize impacts on exacerbations. Continuous and categorical data were analyzed by Mann-Whitney, Fisher's exact, and log-rank tests; significance was defined as p < 0.05. RESULTS: The two cohorts were well matched and had no significant differences in demographics, presentation laboratory values, or TTP history (p > 0.05 for all). The yes-taper cohort of 26 patients with 29 consecutive episodes did not have a significantly different exacerbation rate from the no-taper cohort of 24 patients with 27 consecutive episodes (exacerbation rates of 37.9% vs. 33.3%, respectively; p = 0.78); however, treatment-related complications directly attributed to the TPE procedures, blood products, or central venous catheters were significantly greater in the yes-taper cohort (nine vs. one events, respectively; p = 0.01). CONCLUSION: Since TPE taper did not reduce exacerbations in our TTP patients, we no longer advocate for TPE taper and have reverted to our original standard of care.

Opioid exposure in haemophilia patients is common and underreported.

INTRODUCTION: In an era of increased opioid awareness, data on opioid exposure in haemophilia patients are lacking. AIM: The objectives of this study were to (a) provide a detailed description of opioid exposure in haemophilia patients based on written prescription data, (b) compare our findings to national haemophilia-specific and general population datasets and (c) identify predictors of opioid exposure in haemophilia patients. METHODS: Medical records of 183 adult and 135 paediatric patients from two haemophilia treatment centres (HTC) were reviewed over a 42-month period. Chronic exposure and acute opioid exposure were recorded, and results were compared to national haemophilia (ATHNdataset) and general population (CDC) data. RESULTS: We found that 56% of adult and 21% of paediatric patients were exposed to opioids, rates substantially higher than reported in the ATHNdataset (6%) and national population data from the CDC. In adults, but not children, severity of haemophilia was a significant predictor of opioid exposure. Most acute opioid prescriptions were not written by the HTC. CONCLUSIONS: This is the first study in the haemophilia population to examine opioid exposure based on prescription data. Opioid exposure was more common than predicted in both adult and paediatric study populations and was most often prescribed for acute pain or procedures by non-HTC providers. Haemophilia treatment centres need to take the lead in assessing pain in haemophilia patients, guiding treatment promoting non-opioid options, strengthen efforts to monitor opioid exposure and collect data on pain treatment in the haemophilia population.

Heparin-induced thrombocytopenia associated with collection of hematopoietic progenitor cells by apheresis.

Heparin-induced thrombocytopenia (HIT) can occur following exposure to heparin and is characterized by thrombocytopenia with increased risk for thrombosis. This condition is mediated by formation of immunoglobulin G antibodies against platelet factor 4/heparin complexes that can subsequently lead to platelet activation. Herein, we detail the clinical and laboratory findings, treatments, and outcomes of two patients who developed HIT and thrombosis after undergoing collection of hematopoietic progenitor cells by apheresis (HPC-A) for autologous HPC transplant. Given that heparin may be used during HPC-A collections, these cases emphasize the importance of prompt consideration of HIT in patients that develop thrombocytopenia and thrombosis following HPC-A collection with heparin anticoagulation.

Endothelial alterations in a canine model of immune thrombocytopenia.

Bleeding heterogeneity amongst patients with immune thrombocytopenia (ITP) is poorly understood. Platelets play a role in maintaining endothelial integrity, and variable thrombocytopenia-induced endothelial changes may influence bleeding severity. Platelet-derived endothelial stabilizers and markers of endothelial integrity in ITP are largely underexplored. We hypothesized that, in a canine ITP model, thrombocytopenia would lead to alterations in the endothelial ultrastructure and that the Von Willebrand factor (vWF) would serve as a marker of endothelial injury associated with thrombocytopenia. Thrombocytopenia was induced in healthy dogs with an antiplatelet antibody infusion; control dogs received an isotype control antibody. Cutaneous biopsies were obtained prior to thrombocytopenia induction, at platelet nadir, 24 hours after nadir, and on platelet recovery. Cutaneous capillaries were assessed by electron microscopy for vessel thickness, the number of pinocytotic vesicles, the number of large vacuoles, and the number of gaps between cells. Pinocytotic vesicles are thought to represent an endothelial membrane reserve that can be used for repair of damaged endothelial cells. Plasma samples were assessed for vWF. ITP dogs had significantly decreased pinocytotic vesicle numbers compared to control dogs (P = 0.0357) and the increase in plasma vWF from baseline to 24 hours correlated directly with the endothelial large vacuole score (R = 0.99103; P < 0.0001). This direct correlation between plasma vWF and the number of large vacuoles, representing the vesiculo-vacuolar organelle (VVO), a permeability structure, suggests that circulating vWF could serve as a biomarker for endothelial alterations and potentially a predictor of thrombocytopenic bleeding. Overall, our results indicate that endothelial damage occurs in the canine ITP model and variability in the degree of endothelial damage may account for differences in the bleeding phenotype among patients with ITP.

Men with severe hemophilia in the United States: birth cohort analysis of a large national database.

The availability of longitudinal data collected prospectively from 1998 to 2011 at federally funded US hemophilia treatment centers provided an opportunity to construct a descriptive analysis of how outcomes of men with severe hemophilia have been altered by the incremental advances and setbacks in hemophilia care in the last 50 years in the United States. This surveillance collaboration with the US Centers for Disease Control and Prevention assembled the largest uniformly examined population with severe hemophilia (n = 4899 men with severe factor VIII and IX deficiency). To address the heterogeneity of this population, 4 successive birth cohorts, differentially affected by eras of hemophilia care, were examined separately in regard to demographics, complications of hemophilia and its treatment, and mortality. Severely affected men in each birth cohort were compared also with the corresponding mild hemophilia birth cohorts (n = 2587 men total) to control for outcomes that might be attributable to aging and environment independent of severely defective hemostasis. The analysis demonstrates improving access to standard of care therapy, correlating the proportion of men on prophylactic factor replacement and reduced bleeding frequency for the youngest men. Frequent bleeding persisted in one third to one half of men across all ages, however, and the disability gap between severe and mild hemophilia did not narrow. The greatest cause of death was liver failure, but attempted anti-hepatitis C virus therapy and cure were low. The study suggests a continued need for national surveillance to monitor and inform hemophilia interventions and outcomes.

Bortezomib for Refractory Immune-Mediated Thrombocytopenia Purpura.

The treatment of refractory immune-mediated thrombocytopenia purpura (ITP) can be challenging. This case report describes treatment of refractory ITP with bortezomib, a proteasome inhibitor. This strategy has been successful in relapsing thrombotic thrombocytopenic purpura but is a novel therapeutic approach for ITP. Further research use of proteasome inhibition in refractory ITP may be warranted.

Treatment of acquired Thrombotic Thrombocytopenic Purpura in the U.S. remains heterogeneous: Current and future points of clinical equipoise.

BACKGROUND: The purpose of this survey was to describe current practices in the U.S. for treatment of acquired Thrombotic Thrombocytopenic Purpura (TTP), compare these with prior U.S. and current Canadian practices, and identify areas of clinical equipoise. STUDY DESIGN AND METHODS: A research team member administered the survey by telephone. Questions included an estimate of the annual patient volume treated, apheresis and medical therapy practices for acquired TTP. RESULTS: 32 centers from 22 states were surveyed. ADAMTS13 activity is used for confirmation of the diagnosis of acquired TTP (97%). Most commonly, daily plasma exchange (therapeutic plasma exchange [TPE]) is initiated with plasma as replacement fluid (91%) at 1.0 Plasma Volume (72%) and stopped with a platelet count of 150 × 109 /L (66%), and then TPE is tapered off (69%). Compared with a U.S. survey from 1998, a greater proportion of centers use plasma exclusively as the replacement fluid exclusively (29/32 vs 2/14 in 1998; P < .0001) and taper TPE (22/32 vs 8/20 in 1998, P = .0499). Compared with Canadian survey in 2016, a greater proportion of U.S. centers use plasma over cryosupernatant (29/32 vs 2/13 CAG centers, P < .0001) and initiate TPE with 1.0 PV compared with 1.5 PV (23/32 vs 0/14 CAG centers, P < .0001). Corticosteroid use is common but not universal (U.S. and CAG) and use of rituximab heterogeneous. CONCLUSION: Treatment of acquired TTP in the U.S. remains heterogeneous. Points of clinical equipoise identified were PV exchanged (1.0 vs >1.0), tapering of TPE versus none, and rituximab use.

Two cases of asymptomatic massive fetomaternal hemorrhage.

Evaluation of fetomaternal hemorrhage (FMH) in the immediate postpartum period is critical for the timely administration of Rh immunoglobulin (RhIG) prophylaxis to minimize the risk of alloimmunization in D-negative mothers of D-positive newborns. We report a series of two clinically-unsuspected cases of massive FMHs identified at our university medical center. Retrospective records of two cases of massive FMH were investigated using the electronic medical record. After positive fetal bleed screens, flow cytometric analysis for hemoglobin F was performed to quantify the volume of the hemorrhages in both cases. Flow cytometric enumeration with anti-D was also performed in one case. The two patients had 209.5 and 75 mL of fetal blood in circulation, resulting in 8 and 4 doses of RhIG administered, respectively. For the former patient, flow cytometric analysis with anti-D ruled out hereditary persistence of fetal hemoglobin and supported the fetal origin of the red cells. Due to the clinically-silent nature of both hemorrhages, further evaluation of the newborns' blood was not performed. These cases highlight the importance of rapidly obtaining accurate measurements of fetal blood loss via flow cytometric analysis in cases of FMH, particularly in clinically-unsuspected cases, to ensure timely administration of adequate immunoprophylaxis to D-negative mothers.