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.

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.

Cardiovascular Disease and Stroke in Immune TTP-Challenges and Opportunities.

Advances in the management of immune thrombotic thrombocytopenic purpura (iTTP) have dramatically improved outcomes of acute TTP episodes, and TTP is now treated as a chronic, relapsing disorder. It is now recognized that iTTP survivors are at high risk for vascular disease, with stroke and myocardial infarction occurring at younger ages than in the general population, and cardiovascular disease is the leading cause of premature death in this population. iTTP appears to have a phenotype of accelerated vascular aging with a particular predilection for cerebral circulation, and stroke is much more common than myocardial infarction. In addition to traditional cardiovascular risk factors, low ADAMTS13 activity during clinical remission may be a risk factor for some of these outcomes, such as stroke. Recent studies also suggest that Black patients, who are disproportionately affected by iTTP in the United States, are at higher risk of adverse cardiovascular outcomes, likely due to multifactorial reasons. Additional research is required to establish the risk factors and mechanisms underlying these complications in order to institute optimal screening strategies and identify interventions to improve outcomes.

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.

Caplacizumab for congenital thrombotic thrombocytopenic purpura.

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

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.

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.

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.

The Impact of an Undergraduate Biology Class on Donor Recruitment at a Hospital-Based Blood Donor Center.

OBJECTIVES: A biology class, BIOL 294H, taught undergraduates about platelet donation while partnering with the University of North Carolina's (UNC's) hospital-based Blood Donation Center to recruit apheresis platelet donors. We identified our platelet donors' demographics and learned how BIOL 294H affected recruitment. METHODS: Every platelet donor presenting to the UNC Blood Donation Center from February 7, 2017, to March 10, 2017, was asked to complete an electronic 10-question survey. RESULTS: A total of 159 unique donors completed the survey; 64% were female and 75% were between ages 18 and 25 years. Overall, 70% were UNC undergraduate students. Over half (56%) reported first learning about platelet donation through word of mouth, and 22% cited specific efforts associated with BIOL 294H. CONCLUSIONS: Recruitment of undergraduate platelet donors primarily included BIOL 294H peer interactions and deliverables from the class, such as social media updates and events on campus. The sustained recruiting efforts of our students over many years contributed to recruitment of a majority of our platelet donors.

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.

Taking Empiricism out of Immune Thrombotic Thrombocytopenic Purpura: Current and Future Treatment Strategies.

Immune thrombotic thrombocytopenic purpura (iTTP) is a chronically relapsing, humorally-mediated autoimmune disorder characterized by unpredictable episodes of microangiopathic hemolytic anemia and thrombocytopenia, commonly associated with neurologic dysfunction, kidney injury, and fever. Episodes are caused by immune destruction or inhibition of the von Willebrand Factor (vWF) cleaving protease ADAMTS13. Currently, the standard of care is therapeutic plasma exchange (TPE), and most add immunosuppression with corticosteroids - a standard that is unchanged for nearly 30 years. There are multiple strategies for adding corticosteroids to TPE and the limited data available suggests that corticosteroids reduce the duration of ADAMTS13 deficiency in iTTP. Rituximab is also frequently used in the treatment of iTTP and evidence suggests that while it may not reduce the number TPE procedures required to induce remission, it likely increases relapse-free survival. Novel approaches to immunosuppression that have been reported include low-dose rituximab (also currently in clinical trials) and proteasome inhibition. A more targeted approach includes the anti-vWF nanobody, caplacizumab, recently approved for iTTP in Europe and United States, which in two large randomized controlled trials significantly shortened the time to normalization of platelet count, appreciably lowered the 30-day recurrence rate, and decreased the rate of the composite endpoint of death, recurrence, and major thromboembolic events. Recombinant ADAMTS13 has been tested in congenital TTP and could be tested in iTTP as well, along with novel approaches of modifying the enzyme to avoid the immune response or leveraging other vWF cleaving proteases such as plasmin to bypass ADAMTS13. Also, therapies that target preformed antibodies that are currently being tested in other humorally-mediated disorders could cross over to iTTP. Finally, progress has long been hampered in iTTP due to difficulty with accrual and disagreement about trial design. A good surrogate endpoint for relapse-free survival is also needed. Despite these challenges, a new era of precision medicine is likely soon emerging for treatment of iTTP, and with it comes the opportunity to further improve outcomes in this rare and deadly disease.