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, 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.

Peripheral edema: A common and persistent health problem for older Americans.

Peripheral edema (i.e., lower limb swelling) can cause pain, weakness, and limited range of motion. However, few studies have examined its prevalence in the U.S. or its association with demographics, comorbidities, activity, or mobility. This study used data from the Health and Retirement Study, a nationally representative longitudinal survey of U.S. adults (age 51+/ N = 19,988 for 2016), to evaluate time trends and correlates of peripheral edema using weighted descriptive statistics and logistic regressions, respectively. Peripheral edema was assessed with the question "Have you had… // Persistent swelling in your feet or ankles?" The weighted prevalence of edema among older U.S. adults was 19% to 20% between 2000 and 2016. Peripheral edema was associated with older age, female sex, non-white race, low wealth, obesity, diabetes, hypertension, pain, low activity levels, and mobility limitations (odds ratios ranging from 1.2-5.6; p-values ≤0.001). This study provides the first estimates of national prevalence and correlates of peripheral edema among older Americans. Peripheral edema is common and strongly associated with comorbidities, pain, low activity levels, and mobility limitations, and disproportionately affects poorer and minority groups. Peripheral edema should be a focus of future research in order to develop novel and cost-effective interventions.

Preoperative anemia management program reduces blood transfusion in elective cardiac surgical patients, improving outcomes and decreasing hospital length of stay.

BACKGROUND: Anemia is an independent risk factor for hospitalization, readmission, prolonged length of stay (LOS), diminished quality of life, and mortality. A multidisciplinary program was implemented to manage anemia preoperatively as a patient blood management (PBM) initiative. METHODS AND MATERIALS: From March 2016 to August 2018, 240 patients were screened for anemia during their preoperative cardiovascular visit. About 52/240 (22%) were found to be anemic and met out inclusion criteria. Also, 45/52 (87%) had iron deficiency anemia and 7 (13%) had anemia without iron deficiency. A similar historical cohort of patients undergoing elective cardiovascular surgery with hemoglobin (Hb) < 12 g/dl from September 2014 to February /2016 (n = 52) served as control group. The primary outcome was perioperative red blood cell (RBC) transfusion. Secondary outcomes were date-of-surgery Hb, intensive care unit (ICU) and hospital LOS, complication rates, and transfusion cost. RESULTS: The two most common treatments were IV iron ± folate (n = 36/45; 80%) and oral iron (n = 9/45; 20%). As compared to historical patients, study patients had significantly higher day-of-surgery Hb (10.6 ± 1.4 vs. 9.8 ± 1.3 g/dl, p < .001), lower utilization of RBC transfusion (0.86 ± 1.4 vs. 2.78 ± 2.4, p < .001), fewer days in the ICU (2.1 ± 2.0 vs. 4.0 ± 3.5, p = .002), and shorter total LOS (6.9 ± 4.8 vs. 12.9 ± 6.8, p < .0001). Study patients also showed lower overall complication rates (p < .0001). Analysis of RBC acquisition cost and transfusion cost also showed significant saving of 69% ($293 vs. $945 and $656 vs. $2116, respectively). CONCLUSION: When corrected for type of procedures and surgeon, our pilot anemia program in elective cardiovascular surgeries showed higher day-of-surgery Hb and significant reduction in RBC transfusion rates, ICU and hospital LOS, and overall complication rates.

Enhanced Recovery After Surgery in Patients Implanted with Left Ventricular Assist Device.

INTRODUCTION: We sought to develop and implement a comprehensive enhanced recovery after surgery (ERAS) protocol for patients implanted with a left ventricular assist device (LVAD). METHODS AND RESULTS: In this article, we describe our approach to the development and phased implementation of the protocol. Additionally, we reviewed prospectively collected data for patients who underwent LVAD implantation at our institution from February 2019 to August 2020. To compare early outcomes in our patients before and after protocol implementation, we dichotomized patients into two 6-month cohorts (the pre-ERAS and ERAS cohorts) separated from each other by 6 months to allow for staff adoption of the protocol. Of the 115 LVAD implants, 38 patients were implanted in the pre-ERAS period and 46 patients in the ERAS period. Preoperatively, the patients` characteristics were similar between the cohorts. Postoperatively, we observed a decrease in bleeding (chest tube output of 1006 vs 647.5 mL, P < .001) and blood transfusions (fresh frozen plasma 31.6% vs 6.7%, P = .04; platelets 42.1% vs 8.7%, P = .001). Opioid prescription at discharge were 5-fold lower with the ERAS approach (P < .01). Furthermore, the number of patients discharged to a rehabilitation facility decreased significantly (20.0% vs 2.4%, P = .02). The index hospitalization length of stay and survival were similar between the groups. CONCLUSIONS: ERAS for patients undergoing LVAD implantation is a novel, evidence-based, interdisciplinary approach to care with multiple potential benefits. In this article, we describe the details of the protocol and early positive changes in clinical outcomes. Further studies are needed to evaluate benefits of an ERAS protocol in an LVAD population.Lay Summary: Enhanced recovery after surgery (ERAS) is the implementation of standardized clinical pathways that ensures the use of best practices and decreased variation in perioperative care. Multidisciplinary teams work together on ERAS, thereby enhancing communication among health care silos. ERAS has been used for more than 30 years by other surgical services and has been shown to lead to a decreased length of stay, fewer complications, lower mortality, fewer readmissions, greater job satisfaction, and lower costs. Our goal was to translate these benefits to the perioperative care of complex patients with a left ventricular assist device. Early results suggest that this goal is possible; we have observed a decrease in transfusions, discharge on opioids, and discharge to a rehabilitation facility.

A Case-Based Approach to Transition of Care for Patients With Sickle Cell Disease.

Young adults with sickle cell disease must navigate a difficult road to independence once they age out of pediatric care. The anxiety surrounding transition, the challenges of medical complications, and chronic psychosocial stressors are obstacles to a seamless transition to adult medical care. The two cases presented here demonstrate that a team-based, multidisciplinary approach can facilitate a successful transition.

The potential of target-specific oral anticoagulants for the acute and long-term treatment of venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) comprises both deep vein thrombosis and pulmonary embolism. VTE is a leading cause of morbidity and mortality worldwide and its increasing incidence and prevalence are a major health concern. The primary medical objective during the acute phase of VTE treatment is to prevent thrombus extension and embolization. Extended treatment aims to prevent or minimize long-term complications, such as recurrent VTE, post-thrombotic syndrome and chronic thromboembolic pulmonary hypertension. SCOPE: Anticoagulant therapy has been the mainstay of treatment for VTE and traditionally involves initial therapy with heparin, overlapping with and followed by a vitamin K antagonist. Although effective, standard heparin/vitamin K antagonist therapy has several limitations that can be overcome by more recently developed target-specific oral anticoagulants (TSOACs). These agents have predictable pharmacokinetics, a rapid onset of action and few drug-drug or drug-food interactions. Furthermore, TSOACs offer convenient anticoagulation without the need for routine coagulation monitoring and dose adjustment. FINDINGS: The efficacy and safety data from phase III clinical trials support the use of TSOACs for VTE treatment, including in special patient populations. Risk-stratification tools and strategies have been developed to assist physicians in managing anticoagulation treatment. CONCLUSIONS: Rivaroxaban is the first TSOAC to gain widespread approval for the treatment of acute deep vein thrombosis and pulmonary embolism and the long-term prevention of recurrent VTE as monotherapy. Dabigatran has also been approved for this indication recently. TSOACs, especially as monotherapy, represent a paradigm shift in clinical practice for the management of patients with VTE.

Treatment of bleeding complications when using oral anticoagulants for prevention of strokes.

OPINION STATEMENT: Major bleeding in patients taking oral anticoagulants for stroke prevention can progress to catastrophic bleeding if it is not controlled. This is especially of concern if the bleeding is related to the use of a novel oral anticoagulant (NOAC) such as dabigatran or rivaroxaban, given the dearth of literature addressing the reversal of their anticoagulant effects. The goal of treatment is to prevent progression to catastrophic hemorrhage or exsanguination, and decrease bleeding-related morbidity and mortality. Clinical decisions in such instances should be made in a timely fashion to address the necessity for intervention. Animal models have shown potential for the use of 'fresh frozen plasma (FFP) or prothrombin complex concentrate (PCC) in reversing bleeding related to novel oral anticoagulants. However, there is paucity of clinical trials assessing the efficacy of these agents in humans in such clinical scenarios. Hence, there are no guidelines or ideal agents to use in such a scenario. We do not recommend the use of FFP for bleeding related to NOACs. In the setting of early overdose of dabigatran (within 3-4 hours), activated charcoal may be given, and hemodialysis may be used if there is evidence of critical organ bleeding. In our opinion, 4-factor PCC or 3-factor PCC at a dose of about 50 U/kg may be given in an emergency setting to manage bleeding related to factor Xa inhibitors such as rivaroxaban or apixaban, but not direct thrombin inhibitors such as dabigatran. We are also of the opinion that aPCC (FEIBA®) would not be helpful for management of direct thrombin inhibitor (dabigatran)-related bleeding, based on current available efficacy data in humans. We reserve the use of Novoseven® as a last resort, given the lack of pre-clinical or clinical data supporting its ability to reverse the anticoagulant effects of NOACs, except in one case report where it was used in combination with hemodialysis.

Novel oral anticoagulants: a review of the literature and considerations in special clinical situations.

Novel oral anticoagulants (OACs), including dabigatran etexilate, rivaroxaban, and apixaban, are available alternative anticoagulant therapy to vitamin K antagonists. The US Food and Drug Administration (FDA) has approved dabigatran, rivaroxaban, and apixaban for the treatment of appropriate patients for specific clinical indications. Therapeutic advantages of prescribing the new OACs are related to their predictable pharmacokinetic and pharmacodynamic properties. Dabigatran, rivaroxaban, and apixaban have all been shown to be noninferior to warfarin treatment for stroke prevention in respective phase 3 clinical trials; dabigatran and apixaban were shown to be superior to warfarin as preventive therapy. Dabigatran, rivaroxaban, and apixaban are all approved agents for stroke prevention in patients with nonvalvular atrial fibrillation in the United States and Europe. Among these agents, rivaroxaban is the only FDA-approved drug for the treatment of venous thromboembolism. This article reviews the major clinical trials that investigated the efficacy and safety of the new OACs and the use of these agents in special clinical situations.

Surrogate end points for long-term outcomes in chronic myeloid leukemia.

The natural history of the chronic phase (CP) of chronic myeloid leukemia (CML) and the high response rates achieved with BCR-ABL inhibitor therapy necessitate long-term evaluation of survival-based outcome measures. Prior to the availability of long-term BCR-ABL inhibitor data, short-term surrogate end points predictive of longer-term outcomes have been identified using data from clinical trials of patients with CML-CP treated with interferon-α-based therapy and approved BCR-ABL inhibitors. In patients with newly diagnosed CML-CP treated with imatinib, achieving a complete cytogenetic response (CCyR) by 12 months has been associated with more favorable outcomes, and both CCyR and major cytogenetic response have been used as surrogate end points for regulatory approval. Following approval of second-generation BCR-ABL inhibitors in the first-line setting (nilotinib, dasatinib), which have significantly faster and deeper response rates than imatinib, molecular-based surrogate markers at earlier time points of 3 and 6 months are also being explored, although longer follow-up is needed. As patients who achieve early responses show the greatest long-term benefit, these end points may help to identify patients with suboptimal responses early in treatment who might benefit from switching to a different, more effective therapy.

Factors binding a non-classical Cis-element prevent heterochromatin effects on locus control region activity.

A locus control region (LCR) is a cis-acting gene-regulatory element capable of transferring the expression characteristics of its gene locus of origin to a linked transgene. Furthermore, it can do this independently of the site of integration in the genome of transgenic mice. Although most LCRs contain subelements with classical transcriptional enhancer function, key aspects of LCR activity are supported by cis-acting sequences devoid of the ability to act as direct transcriptional enhancers. Very few of these "non-enhancer" LCR components have been characterized. Consequently, the sequence requirements and molecular bases for their functions, as well as their roles in LCR activity, are poorly understood. We have investigated these questions using the LCR from the mouse T cell receptor (TCR) alpha/Dad1 gene locus. Here we focus on DNase hypersensitive site (HS) 6 of the TCRalpha LCR. HS6 does not support classical enhancer activity, yet has gene regulatory activity in an in vivo chromatin context. We have identified three in vivo occupied factor-binding sites within HS6, two of which interact with Runx1 and Elf-1 factors. Deletion of these sites from the LCR impairs its activity in vivo. This mutation renders the transgene locus abnormally inaccessible in chromatin, preventing the normal function of other LCR subelements and reducing transgene mRNA levels. These data show these factor-binding sites are required for preventing heterochromatin formation and indicate that they function to maintain an active TCRalpha LCR assembly in vivo.