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.

Low recurrent thrombosis rates in single positive antiphospholipid syndrome regardless of type of anticoagulation.

Thrombotic antiphospholipid syndrome (TAPS) is characterized by thrombosis and persistently positive tests for antiphospholipid antibodies or lupus anticoagulant (LAC). Triple-positive APS has the highest risk of recurrent thrombosis, but no studies have focused on recurrent thrombosis in patients with single-positive TAPS. We conducted a retrospective cohort study of patients with single-positive TAPS diagnosed at Lifespan Health System, Rhode Island, to determine the rates and risk factors for recurrent thrombosis. Between January 2001 and April 2022, 128 patients were assessed who had single-positive APS (LAC = 98, aCL = 21, aß2GPI = 9) and who had been followed for a total of 1453.8 patient-years (median follow-up 3.04 years). The initial antithrombotic regimen was warfarin in 44 %, a direct oral anticoagulant (DOAC) in 34 %, enoxaparin in 2 %, and no antithrombotic therapy or antiplatelet therapy only in 20 %. Recurrent thrombosis occurred in 16 (12.5 %) with a recurrent thrombosis rate of 3.08 per 100 patient-years. Systemic lupus erythematosus was the only variable significantly associated with recurrent thrombosis in a model adjusted for age, sex, body mass index, and type of positive APS test. All 16 patients with recurrent thrombosis were initially treated with warfarin, and, at the time of recurrent thrombosis, 13 patients remained on warfarin and three were off anticoagulation. In conclusion, the recurrent thrombosis rate in single-positive APS is low, and not all patients with a single-positive test may need indefinite anticoagulation with warfarin. Larger prospective studies are required to confirm this finding and establish optimal anticoagulation regimens for low-risk TAPS.

Clinical Outcomes, Blood Utilization, and Ethical Considerations for Pediatric Patients in a Bloodless Medicine and Surgery Program.

BACKGROUND: Pediatric patients requesting bloodless care represent a challenging clinical situation, as parents cannot legally refuse lifesaving or optimal interventions for their children. Here, we report clinical outcomes for the largest series of pediatric inpatients requesting bloodless care and also discuss the ethical considerations. METHODS: We performed a single-institution retrospective cohort study assessing 196 pediatric inpatients (<18 years of age) who requested bloodless care between June 2012 and June 2016. Patient characteristics, transfusion rates, and clinical outcomes were compared between pediatric patients receiving bloodless care and those receiving standard care (including transfusions if considered necessary by the clinical team) (n = 37,271). Families were informed that all available measures would be undertaken to avoid blood transfusions, although we were legally obligated to transfuse blood if the child's life was threatened. The primary outcome was composite morbidity or mortality. Secondary outcomes included percentage of patients transfused, individual morbid events, length of stay, total hospital charges, and total costs. Subgroup analyses were performed after stratification into medical and surgical patients. RESULTS: Of the 196 pediatric patients that requested bloodless care, 6.1% (n = 12) received an allogeneic blood component, compared to 9.1% (n = 3392) for standard care patients ( P = .14). The most common indications for transfusion were perioperative bleeding and anemia of prematurity. None of the transfusions were administered under a court order. Overall, pediatric patients receiving bloodless care exhibited lower rates of composite morbidity compared to patients receiving standard care (2.6% vs 6.2%; P = .035). There were no deaths in the bloodless cohort. Individual morbid events, length of stay, and total hospital charges/costs were not significantly different between the 2 groups. After multivariable analysis, bloodless care was not associated with a significant difference in composite morbidity or mortality (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.12-1.11; P = .077). CONCLUSIONS: Pediatric patients receiving bloodless care exhibited similar clinical outcomes compared to patients receiving standard care, although larger studies with adequate power are needed to confirm this finding. There were no mortalities among the pediatric bloodless cohort. Although a subset of our pediatric bloodless patients received an allogeneic transfusion, no patients required a court order. When delivered in a collaborative and patient-centered manner, blood transfusions can be safely limited among pediatric patients.

Medical consult: aHUS, TTP? How to distinguish and what to do.

Immune thrombotic thrombocytopenic purpura (iTTP) caused by an autoantibody-mediated deficiency of ADAMTS13 and atypical hemolytic syndrome (aHUS) caused by alternative complement dysregulation are the most common primary thrombotic microangiopathies (TMAs). The evaluation of a patient with TMA is a medical emergency since it is critical to quickly distinguish iTTP and aHUS from other causes of TMA. Untreated iTTP is rapidly fatal, and delays in initiating complement inhibition in aHUS increase the risk of irreversible renal failure. An ADAMTS13 activity level of less than 10% is diagnostic of iTTP in the appropriate clinical setting. In settings where rapid-turnaround ADAMTS13 testing is not available, clinical features and clinical prediction tools are useful to identify patients who should receive emergent plasma exchange. We present an evidence-based approach to the initial (first 24 hours) diagnosis and management of iTTP and review the clinical and laboratory features that can be used to identify patients with aHUS who will benefit from early C5 blockade. We also discuss the potential use of complement blockade to improve outcomes in selected patients with secondary TMA.

Complement biomarkers in the antiphospholipid syndrome - Approaches to quantification and implications for clinical management.

Complement is a major driver of antiphospholipid syndrome (APS) and a promising therapeutic target in refractory and catastrophic APS. Complement testing in APS is largely limited to research settings, and reliable, rapid-turnaround biomarkers are needed to predict those at risk for adverse clinical outcomes and most likely to benefit from complement inhibition. We review complement biomarkers and their association with thrombosis and obstetric outcomes, including: (i) complement proteins and activation fragments in the fluid phase; (ii) assays that evaluate complement on cell membranes (e.g. in vivo cell-bound complement fragments, hemolytic assays, and ex vivo 'functional' cell-based assays, and (iii) sequencing of complement genes. Current studies highlight the inconsistencies in testing both between studies and various aPL/APS subgroups, suggesting that either cell-based testing or multiplex panels employing a combination of biomarkers simultaneously may be most clinically relevant. Standardization of complement assays is needed to ensure reproducibility and establish clinically relevant applications.

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.

Treatment preference and quality of life impact: ravulizumab vs eculizumab for atypical hemolytic uremic syndrome.

Aim: Ravulizumab and eculizumab are complement C5 inhibitors approved for the treatment of atypical hemolytic uremic syndrome (aHUS). Ravulizumab requires less frequent infusions than eculizumab, which may reduce treatment burden. This study investigated patients' treatment preferences and the impact of both treatments on patient and caregiver quality of life. Materials & methods: Two surveys were conducted (one for adult patients with aHUS and one for caregivers of pediatric patients with aHUS) to quantitatively assess treatment preference and the patient- and caregiver-reported impact of ravulizumab and eculizumab on quality of life. Patients were required to have a diagnosis of aHUS, to be currently receiving treatment with ravulizumab and to have received prior treatment with eculizumab. Participants were recruited via various sources: the Alexion OneSource™ patient support program, the Rare Patient Voice recruitment agency, the aHUS Foundation and directly via a clinician involved in the study. Results: In total, 50 adult patients (mean age: 46.5 years) and 16 caregivers of pediatric patients (mean age: 10.1 years) completed the surveys. Most adult patients (94.0%) and all caregivers reported an overall preference for ravulizumab over eculizumab; infusion frequency was one of the main factors for patients when selecting their preferred treatment. Fewer patients reported disruption to daily life and the ability to go to work/school due to ravulizumab infusion frequency (4.0% and 5.7%, respectively) than eculizumab infusion frequency (72.0% and 60.0%), with similar results for caregivers. Conclusion: Adult patients and caregivers of pediatric patients indicated an overall preference for ravulizumab than eculizumab for the treatment of aHUS, driven primarily by infusion frequency. This study contributes to the emerging real-world evidence on the treatment impact and preference in patients with aHUS.

Silent cerebral infarction during immune TTP remission: prevalence, predictors, and impact on cognition.

Immune thrombotic thrombocytopenic purpura (iTTP) survivors have increased risk of cardiovascular disease, including strokes, and report persistent cognitive difficulties during remission. We conducted this prospective study involving iTTP survivors during clinical remission to determine the prevalence of silent cerebral infarction (SCI), defined as magnetic resonance imaging (MRI) evidence of brain infarction without corresponding overt neurodeficits. We also tested the hypothesis that SCI is associated with cognitive impairment, assessed using the National Institutes of Health ToolBox Cognition Battery. For cognitive assessments, we used fully corrected T scores adjusted for age, sex, race, and education. Based on the diagnostic and statistical manual 5 criteria, we defined mild and major cognitive impairment as T scores with a 1 or 2 standard deviation (SD) and >2 SD below the mean on at least 1 test, respectively. Forty-two patients were enrolled, with 36 completing MRIs. SCI was present in 50% of the patients (18), of which 8 (44.4%) had prior overt stroke including during acute iTTP. Patients with SCI had higher rates of cognitive impairment (66.7% vs 27.7%; P = .026), including major cognitive impairment (50% vs 5.6%; P = .010). In separate logistic regression models, SCI was associated with any (mild or major) cognitive impairment (odds ratio [OR] 10.5 [95% confidence interval (95% CI), 1.45-76.63]; P = .020) and major cognitive impairment (OR 7.98 [95% CI, 1.11-57.27]; P = .039) after adjusting for history of stroke and Beck depression inventory scores. MRI evidence of brain infarction is common in iTTP survivors; the strong association of SCI with impaired cognition suggests that these silent infarcts are neither silent nor innocuous.

Immune thrombotic thrombocytopenic purpura: Spotlight on long-term outcomes and survivorship.

Advances in diagnosis and treatment have dramatically improved survival of acute immune thrombotic thrombocytopenic purpura (iTTP) and iTTP has evolved from an acute fatal condition to a chronic relapsing disorder. In addition to the risk of iTTP relapse, iTTP survivors are at risk of multiple adverse health outcomes including higher than expected rates of all-cause mortality, increased rates of stroke and other cardiovascular disease, and higher rates of morbidities such as obesity, hypertension, and autoimmune disorders. iTTP survivors also report neurocognitive impairment, depression, and reduced quality of life. Women with iTTP are at risk for recurrent iTTP, preeclampsia, and other maternal and fetal complications in subsequent pregnancies. ADAMTS13 activity during clinical remission has emerged as an important targetable risk factor for iTTP relapse and other outcomes including stroke and all-cause mortality. This review summarizes current literature regarding the epidemiology and potential mechanisms for adverse long-term sequelae of iTTP, outlines current best practices in iTTP survivorship care, and highlights a research agenda to improve long-term iTTP outcomes.

Characterization of myeloproliferative neoplasms in the paediatric and young adult population.

The aim of this study was to compare the genomic features and clinical outcomes between paediatric and young adult patients (PAYA, <40 years) and older adults (OA, ≥40 years) with myeloproliferative neoplasms (MPN) to gain insight into pathogenesis, disease prognosis and management. Of 630 MPN patients, 171 (27%) were PAYA with an average age at diagnosis of 31 years. Females were more prevalent in PAYA than OA (71% vs 58%; p = 0.002), and PAYA more frequently presented with essential thrombocytosis (ET) at diagnosis (67% vs 39%; p < 0.001). The presence of a JAK2 somatic mutation was higher in OA (80.4% vs 64.3%; p < 0.001), while a CALR mutation or lack of any traditional driver mutation was more common in PAYA (20.5% vs 10.5%; p = 0.001, 8.8% vs 3.7%; p = 0.01 respectively). Venous thrombosis was more common in PAYA compared to OA (19.8% vs 10.7%; p = 0.002). PAYA had a higher prevalence of familial MPN and familial cancer predisposition, and two PAYA patients harboured pathogenic germline JAK2 lesions. PAYA demonstrated longer survival from diagnosis than OA (median not reached vs 13 years), while disease transformation was less frequent (19.3% vs 37.9%).

Hypercoagulability and Inflammatory Markers in a Case of Congenital Thrombotic Thrombocytopenic Purpura Complicated by Fetal Demise.

BACKGROUND: Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare disorder caused by an inherited genetic deficiency of ADAMTS13 and affects less than one per million individuals. Patients who are diagnosed with TTP during pregnancy are at increased risk of maternal and fetal complications including fetal demise. We present a case of a 32-year-old G3P0 (gravida 3, para 0) who presented at 20 weeks gestation with a new diagnosis of congenital TTP (cTTP) and fetal demise. METHODS: We describe the pathophysiology of pregnancy complications in a patient with cTTP using platelet procoagulant membrane dynamics analysis and quantitative proteomic studies, compared to four pregnant patients with gestational hypertension, four pregnant patients with preeclampsia, and four healthy pregnant controls. RESULTS: The cTTP patient had increased P-selectin, tissue factor expression, annexin-V binding on platelets and neutrophils, and localized thrombin generation, suggestive of hypercoagulability. Among 15 proteins that were upregulated, S100A8 and S100A9 were distinctly overexpressed. CONCLUSIONS: There is platelet-neutrophil activation and interaction, platelet hypercoagulability, and proinflammation in our case of cTTP with fetal demise.

Factors mediating cancer risk in systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) are at an elevated risk for certain cancers compared to the population at large. Cancers seen at higher rates in the SLE population include hematologic malignancies, such as non-Hodgkin lymphoma, and cancers of the lung and thyroid. SLE patients also have a decreased risk for certain malignancies, such as breast cancer, melanoma, and prostate cancer. We review the literature on risk factors for malignancy in patients with SLE and discuss the exogenous and innate factors that are thought to contribute to the unique pattern of cancer risk observed in this patient population. These risk factors are important for providers of SLE patients to understand in order to maintain high clinical suspicion and detect malignancy as soon as possible. Further research is needed to determine the most effective guidelines on counseling patients on cancer screening and prevention.

Methods of Bloodless Care, Clinical Outcomes, and Costs for Adult Patients Who Decline Allogeneic Transfusions.

BACKGROUND: Providing bloodless medical care for patients who wish to avoid allogeneic transfusion can be challenging; however, previous studies have demonstrated favorable outcomes when appropriate methods are used. Here, we report one of the largest series of patients receiving bloodless care, along with the methods used to provide such care, and the resulting outcomes. METHODS: In a retrospective cohort study, 1111 adult inpatients (age ≥18 years) at a single institution who declined allogeneic transfusion for religious or personal reasons between June 2012 and June 2016 were included, and the patient blood management methods are described. Patient characteristics, laboratory data, and transfusion rates, as well as clinical outcomes (morbidity, mortality, and length of stay) were compared to all other patients in the hospital who received standard care, including transfusions if needed (n = 137,009). Medical and surgical patients were analyzed as subgroups. The primary outcome was composite morbidity (any morbid event: infectious, thrombotic, ischemic, renal, or respiratory). Secondary outcomes included individual morbid events, in-hospital mortality, length of stay, total hospital charges, and costs. RESULTS: The bloodless cohort had more females and a lower case mix index, but more preadmission comorbidities. Mean nadir hemoglobin during hospitalization was lower in the bloodless (9.7 ± 2.6 g/dL) compared to the standard care (10.1 ± 2.4 g/dL) group (P < .0001). Composite morbidity occurred in 14.4% vs 16.0% (P = .16) of the bloodless and standard care patients, respectively. Length of stay and in-hospital mortality were similar between the bloodless and standard care patients. After Bonferroni adjustment for multiple comparisons, hospital-acquired infection occurred less frequently in the bloodless compared to the standard care cohort (4.3% vs 8.3%) (P < .0001) in the medical patient subgroup, but not in the surgical subgroup. After propensity score adjustment in a multivariable model and adjustment for multiple comparisons, bloodless care was associated with less risk of hospital-acquired infection (OR, 0.56; 95% CI, 0.35-0.83; P = .0074) in the medical subgroup, but not in the surgical subgroup. Median total hospital charges (by 8.5%; P = .0017) and costs (by 8.7%; P = .0001) were lower in the bloodless compared to the standard care cohort, when all patients were included. CONCLUSIONS: Overall, adult patients receiving bloodless care had similar clinical outcomes compared to patients receiving standard care. Medical (but not surgical) bloodless patients may be at less risk for hospital-acquired infection compared to those receiving standard care. Bloodless care is cost-effective and should be considered as high-value practice.