Hepatocyte growth factor and risk of incident stroke in Black and White Americans in the Reasons for Geographic and Racial Differences in Stroke study.

Background: Hepatocyte growth factor (HGF) is a cytokine produced in response to endothelial damage. Higher levels correlate with cardiovascular risk factors, including hypertension and diabetes. Objectives: We hypothesized that HGF is associated with stroke. Methods: The Reasons for Geographic And Racial Differences in Stroke (REGARDS) study enrolled 30,239 Black and White Americans aged ≥45 years from 2003 to 2007. In this case-cohort study, after 5.5 years of follow-up, circulating baseline HGF was measured in 557 participants with incident ischemic stroke and in a cohort random sample of 964 participants. Hazard ratios (HRs) per SD log-transformed HGF and by HGF quintile were calculated using Cox proportional hazards models adjusting for stroke risk factors and other correlates of HGF. Differences by race and sex were tested using interaction terms. Results: Median HGF was 295 (IQR, 209-402) pg/mL. HGF was higher with older age, male sex, prevalent cardiovascular disease, smoking, and warfarin use, but did not differ by race. The adjusted HR of incident ischemic stroke per SD higher baseline HGF (145 pg/mL) was 1.30 (CI, 1.00-1.70), with no difference by sex or race. HGF in the highest (>434 pg/mL) vs lowest quintile (<135 pg/mL) was associated with an adjusted HR of incident stroke of 2.12 (CI, 1.31-3.41). Conclusion: In the REGARDS study, higher HGF was associated with increased risk of incident ischemic stroke in Black and White adults, with a doubling in risk of HGF in the top quintile compared with the lowest quintile after adjusting for other stroke risk factors.

Cytokines, C-Reactive Protein, and Risk of Incident Hypertension in the REGARDS Study.

BACKGROUND: Hypertension is a highly prevalent cardiovascular disease risk factor that may be related to inflammation. Whether adverse levels of specific inflammatory cytokines relate to hypertension is unknown. The present study sought to determine whether higher levels of IL (interleukin)-1ß, IL-6, TNF (tumor necrosis factor)-α, IFN (interferon)-γ, IL-17A, and CRP (C-reactive protein) are associated with a greater risk of incident hypertension. METHODS: The REGARDS study (Reasons for Geographic and Racial Difference in Stroke) is a prospective cohort study that recruited 30 239 community-dwelling Black and White adults from the contiguous United States in 2003 to 2007 (visit 1), with follow-up 9 years later in 2013 to 2016 (visit 2). We included participants without prevalent hypertension who attended follow-up 9 years later and had available laboratory measures and covariates of interest. Poisson regression estimated the risk ratio of incident hypertension by level of inflammatory biomarkers. RESULTS: Among 1866 included participants (mean [SD] aged of 62 [8] years, 25% Black participants, 55% women), 36% developed hypertension. In fully adjusted models comparing the third to first tertile of each biomarker, there was a greater risk of incident hypertension for higher IL-1ß among White (1.24 [95% CI, 1.01-1.53]) but not Black participants (1.01 [95% CI, 0.83-1.23]) and higher TNF-α (1.20 [95% CI, 1.02-1.41]) and IFN-γ (1.22 [95% CI, 1.04-1.42]) among all participants. There was no increased risk with IL-6, IL-17A, or CRP. CONCLUSIONS: Higher levels of IL-1ß, TNF-α, and IFN-γ, representing distinct inflammatory pathways, are elevated in advance of hypertension development. Whether modifying these cytokines will reduce incident hypertension is unknown.

Development and validation of a risk model for hospital-acquired venous thrombosis: the Medical Inpatients Thrombosis and Hemostasis study.

BACKGROUND: Regulatory organizations recommend assessing hospital-acquired (HA) venous thromboembolism (VTE) risk for medical inpatients. OBJECTIVES: To develop and validate a risk assessment model (RAM) for HA-VTE in medical inpatients using objective and assessable risk factors knowable at admission. METHODS: The development cohort included people admitted to medical services at the University of Vermont Medical Center (Burlington, Vermont) between 2010 and 2019, and the validation cohorts included people admitted to Hennepin County Medical Center (Minneapolis, Minnesota), University of Michigan Medical Center (Ann Arbor, Michigan), and Harris Health Systems (Houston, Texas). Individuals with VTE at admission, aged <18 years, and admitted for <1 midnight were excluded. We used a Bayesian penalized regression technique to select candidate HA-VTE risk factors for final inclusion in the RAM. RESULTS: The development cohort included 60 633 admissions and 227 HA-VTE, and the validation cohorts included 111 269 admissions and 651 HA-VTE. Seven HA-VTE risk factors with t statistics ≥1.5 were included in the RAM: history of VTE, low hemoglobin level, elevated creatinine level, active cancer, hyponatremia, increased red cell distribution width, and malnutrition. The areas under the receiver operating characteristic curve and calibration slope were 0.72 and 1.10, respectively. The areas under the receiver operating characteristic curve and calibration slope were 0.70 and 0.93 at Hennepin County Medical Center, 0.70 and 0.87 at the University of Michigan Medical Center, and 0.71 and 1.00 at Harris Health Systems, respectively. The RAM performed well stratified by age, sex, and race. CONCLUSION: We developed and validated a RAM for HA-VTE in medical inpatients. By quantifying risk, clinicians can determine the potential benefits of measures to reduce HA-VTE.

Impact of preexisting autoimmune disease on myelodysplastic syndromes outcomes: a population analysis.

Preexisting autoimmune disease affects between 10% and 30% of patients with myelodysplastic syndromes (MDS). Studies comparing outcomes in patients with MDS with and without autoimmune disease show discordant results. Using the Surveillance, Epidemiology, and End Results Medicare database, we conducted a population analysis to define the impact of autoimmunity on MDS outcomes. Cases were ascertained between 2007 and 2017 and claim algorithms used to identify autoimmune disease, demographic characteristics, comorbidity scores, MDS histology, transfusion burden, treatment with hypomethylating agents, and hematopoietic stem cell transplantation. Cox regression models estimated the impact on survival, and competing-risk regression models defined the effect on leukemic transformation. We analyzed 15 277 patients with MDS, including 2442 (16%) with preexisting autoimmune disease. The epidemiologic profile was distinctive in cases with preexisting autoimmunity, who were younger, were predominantly female, and had higher transfusion burden without difference in MDS histologic distribution. Autoimmune disease was associated with 11% decreased risk of death (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.85-0.94; P < .001). The effect on risk of leukemic transformation differed based on MDS histology. In low-risk MDS histologies, autoimmunity was associated with a 1.9-fold increased risk of leukemia (HR, 1.87; 95% CI, 1.17-2.99; P = .008), whereas no significant effect was seen in other groups. These results suggest that autoimmune disease affects survival in MDS and is associated with decreased mortality. The survival effect was evident in low-risk histologies despite higher risk of progression to leukemia. This could represent inflammation-driven hematopoiesis, simultaneously favoring less aggressive phenotypes and clonal expansion, which warrants further investigation.

Venous thromboembolism mortality and trends in older US adults, 2011-2019.

Venous thromboembolism (VTE) affects 1.2 million people per year in the United States. With several clinical changes in diagnosis and treatment approaches in the past decade, we evaluated contemporary post-VTE mortality risk profiles and trends. Incident VTE cases were identified from the 2011-2019 Medicare 20% Sample, which is representative of nearly all Americans aged 65 and older. The social deprivation index was linked from public data; race/ethnicity and sex were self-reported. The all-cause mortality risk 30 days and 1 year after incident VTE was calculated in demographic subgroups and by prevalent cancer diagnosis status using model-based standardization. Risks for major cancer types, risk differences by age, sex, race/ethnicity, and socio-economic status (SES), and trends over time are also reported. The all-cause mortality risk among older US adults following incident VTE was 3.1% (95% CI 3.0-3.2) at 30 days and 19.6% (95% CI 19.2-20.1) at 1 year. For cancer-related VTE events, the age-sex-race-standardized risk was 6.0% at 30 days and 34.7% at 1 year. The standardized 30-day and 1-year risks were higher among non-White beneficiaries and among those with low SES. One-year mortality risk decreased 0.28 percentage points per year (95% CI 0.16-0.40) on average across the study period, with no trend observed for 30-day mortality risk. In sum, all-cause mortality risk following incident VTE has decreased slightly in the last decade, but racial and socio-economic disparities persist. Understanding patterns of mortality among demographic subgroups and in cancer-associated events is important for targeting efforts to improve VTE management.

Bleeding risk in patients with multiple myeloma treated for venous thromboembolism: a MarketScan analysis.

Background: Multiple myeloma (MM) is associated with high risk of venous thromboembolism (VTE). Thromboprophylaxis is thoroughly studied in MM. Contrarily, studies assessing the risk of bleeding in people with MM on anticoagulation are lacking. Objectives: To determine the rate of serious bleeding in patients with MM receiving anticoagulation for VTE and the clinical factors associated with bleeding risk. Methods: Using the MarketScan commercial database, we identified 1298 people with MM treated with anticoagulation for incident VTE events between 2011 and 2019. Hospitalized bleeding was identified using the Cunningham algorithm. Rates of bleeding were calculated and Cox regression identified risk factors for bleeding. Results: Bleeding occurred in 51 (3.9%) cases during median follow-up of 1.13 years. Rate of bleeding among patients with MM on anticoagulation was 24.0 per 1000 person-years. In adjusted regression, factors associated with increased bleeding included age (HR, 1.31 per 10-year increase; 95% CI, 1.03-1.65), Charlson comorbidity index (HR, 1.29 per SD increase; 95% CI, 1.02-1.58), use of antiplatelet agents (HR, 2.4; 95% CI, 1.03-5.68), diabetes (HR, 1.85; 95% CI, 1.06-3.26), and renal disease (HR, 1.80; 95% CI, 1.05-3.16). Cumulative incidence of bleeding was 4.7%, 3.2%, and 3.4% for warfarin, low molecular weight heparin, and direct oral anticoagulants, respectively. Conclusion: In this real-world analysis, the rate of bleeding in people with MM on anticoagulation was comparable to those in other subsets of cancer-related VTE. Bleeding rate was lower with low molecular weight heparin and direct oral anticoagulants than warfarin. Higher comorbidity index, diabetes, antiplatelet agent use, and renal disease were risk factors for serious bleeding.

Derivation and Validation of a Clinical Risk Assessment Model for Cancer-Associated Thrombosis in Two Unique US Health Care Systems.

PURPOSE: Venous thromboembolism (VTE), especially pulmonary embolism (PE) and lower extremity deep vein thrombosis (LE-DVT), is a serious and potentially preventable complication for patients with cancer undergoing systemic therapy. METHODS: Using retrospective data from patients diagnosed with incident cancer from 2011-2020, we derived a parsimonious risk assessment model (RAM) using least absolute shrinkage and selection operator regression from the Harris Health System (HHS, n = 9,769) and externally validated it using the Veterans Affairs (VA) health care system (n = 79,517). Bootstrapped c statistics and calibration curves were used to assess external model discrimination and fit. Dichotomized risk strata using integer scores were created and compared against the Khorana score (KS). RESULTS: Incident VTE and PE/LE-DVT at 6 months occurred in 590 (6.2%) and 437 (4.6%) patients in HHS and 4,027 (5.1%) and 3,331 (4.2%) patients in the VA health care system. Assessed at the time of systemic therapy initiation, the new RAM included components of the KS with the modified cancer subtype, cancer staging, systemic therapy class, history of VTE, history of paralysis/immobility, recent hospitalization, and Asian/Pacific Islander race. The c statistic was 0.71 in HHS and 0.68 in the VA health care system (compared with 0.65 and 0.60, respectively, for KS). Furthermore, the new RAM appropriately reclassified 28% of patients and increased the proportion of VTEs in the high-risk group from 37% to 68% in the validation data set. CONCLUSION: The novel RAM stratified patients with cancer into a high-risk group with 8%-10% cumulative incidence of VTE and 7% PE/LE-DVT at 6 months (v 3% and 2%, respectively, in the low-risk group). The model had improved performance over the original KS and doubled the number of VTE events in the high-risk stratum. We encourage additional external validation from prospective studies.[Media: see text].

Association between peripheral blood cytopenia and cancer mortality: A race-specific risk factor for cancer death.

BACKGROUND: Cytopenia is associated with cancer through mechanisms including clonal hematopoiesis and chronic inflammation. Cytopenia is more prevalent in Black people but its relationship with racial disparities in cancer mortality is unknown. METHODS: Cytopenia was defined in 19,028 Black and White participants recruited between 2003 and 2007 for the REasons for Geographic and Racial Differences in Stroke cohort, based on age-, sex-, and race-adjusted ranges for blood counts. Cancer death was ascertained from Social Security Death and National Death Indexes. Multivariable Cox models estimated the risk of cancer mortality associated with cytopenia, adjusting for demographics (model1), anemia and cancer risk factors (model2), and socioeconomics (model3). Racial differences in the cytopenia-cancer death association were tested by cross-product interaction terms. RESULTS: Cytopenia was identified in 383 (2%) participants, 250 (65%) White, and 113 (35%) Black people. With median follow-up 11.3 years, 1,224 (6.4%) cancer deaths occurred. Cytopenia was associated with increased risk of cancer mortality in model1 (HR = 1.57, 95%CI 1.15-2.24), model2 (HR = 1.67, 95%CI 1.22-2.30), and model3 (HR = 1.59, 95%CI 1.17-2.17). Participants with cytopenia had twofold increased cumulative incidence of cancer death (13% vs. 6.5%, p < 0.01). Race by cytopenia interaction terms showed higher HR for cancer death in Black compared to White participants: 2.01 versus 1.41 (pinteraction  = 0.016, model1), 2.12 versus 1.45 (pinteraction  = 0.009, model2), and 1.82 versus 1.44 (pinteraction  = 0.04, model3). CONCLUSION: In this large, observational biracial prospective study, cytopenia was a risk factor for cancer death, with stronger association in Black than White people. Though race impacted the association of cytopenia with cancer mortality, cytopenia was not a mediator of the racial disparity in cancer mortality.

Risk of venous thromboembolism in pediatric hospitalized patients undergoing noncardiac surgery: A report from the Children's Hospital-Acquired Thrombosis consortium.

Background: Surgery is a known risk factor for hospital-acquired venous thromboembolism (HA-VTE) in children. Objectives: To assess whether the odds of HA-VTE differs across six anatomic sites of noncardiac surgery and to identify risk factors for HA-VTE in these children. Methods: This was a multicenter, case-control study. Anatomic sites of surgery and risk factors for HA-VTE were collected on hospitalized pediatric patients who had undergone a single noncardiac surgery and developed HA-VTE (cases), and those who did not develop HA-VTE (controls), via the Children's Hospital-Acquired Thrombosis (CHAT) Registry. Logistic regression estimated the odds ratio (OR) and 95% confidence intervals (CIs) between six anatomic sites of surgery and 16 putative HA-VTE risk factors. Variables with a p value of 0.10 or less in unadjusted analyses were included in adjusted models for further evaluation. The final model used backward selection, with a significance level of 0.05. Results: From January 2012 to March 2020, 163 cases (median age, 5.7 years; interquartile range [IQR], 0.3-14.2) and 208 controls (median age of 7.5 years; IQR, 3.7-12.9) met our criteria. There was no statistically significant increased odds of VTE among the types of noncardiac surgery. In the final adjusted model, central venous catheter (CVC; OR, 14.69; 95% CI, 7.06-30.55), intensive care unit (ICU) stay (OR, 5.31; 95% CI, 2.53-11.16), and hospitalization in the month preceding surgery (OR, 2.75; 95% CI, 1.24-6.13) were each independently significant risk factors for HA-VTE. Conclusion: In children undergoing noncardiac surgery, placement of CVCs, admission/transfer to the ICU, or hospitalization in the month prior to surgery were positively associated with HA-VTE.

Geographic disparities in cardiovascular mortality among patients with myelodysplastic syndromes: A population-based analysis.

INTRODUCTION: Clonal hematopoiesis, a precursor to myelodysplastic syndromes (MDS), constitutes a novel cardiovascular disease (CVD) risk factor, causing growing interest in cardiovascular outcomes in MDS. Rurality is associated with increased CVD but studies on cardiovascular geographic disparities in MDS are lacking. METHODS: Using the U.S. Surveillance, Epidemiology, and End Results (SEER) registry, we identified 52,750 MDS patients between 2001 and 2016. Rurality was defined using Rural-Urban Continuum Codes. Cox regression estimated the association of rurality and cardiovascular death. RESULTS: MDS incidence was equal in urban and rural populations (6.7 per 100,000). Crude probability of cardiovascular death was higher among rural MDS patients. Adjusting for age, sex, race/ethnicity, marital status, insurance, and MDS risk (defined from histology), rural patients had 12% increased risk of CVD death compared to urban patients (HR=1.12, 95%CI 1.03-1.21). HR for CVD death was 1.22 (95%CI 1.01-1.5) in patients from the most rural areas (less than 2500 urban population). Among MDS patients younger than 65 years, rurality was associated with 25% increased risk of CVD death (HR=1.25, 95%CI 1.01-1.59). DISCUSSION: This population-based analysis suggests that rural residence is linked to higher burden of cardiovascular death in patients with MDS. The disparity is not explained by demographic factors or MDS risk. Interventions targeting CVD may improve outcomes in rural MDS patients.

Developing and optimizing a computable phenotype for incident venous thromboembolism in a longitudinal cohort of patients with cancer.

Background: Research on venous thromboembolism (VTE) that relies only on the International Classification of Diseases (ICD) can misclassify outcomes. Our study aims to discover and validate an improved VTE computable phenotype for people with cancer. Methods: We used a cancer registry electronic health record (EHR)-linked longitudinal database. We derived three algorithms that were ICD/medication based, natural language processing (NLP) based, or all combined. We then randomly sampled 400 patients from patients with VTE codes (n = 1111) and 400 from those without VTE codes (n = 7396). Weighted sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated on the entire sample using inverse probability weighting, followed by bootstrapped receiver operating curve analysis to calculate the concordance statistic (c statistic). Results: Among 800 patients sampled, 280 had a confirmed acute VTE during the first year after cancer diagnosis. The ICD/medication algorithm had a weighted PPV of 95% and a weighted sensitivity of 81%, with a c statistic of 0.90 (95% confidence interval [CI], 0.89-0.91). Adding Current Procedural Terminology codes for inferior vena cava filter removal or early death did not improve the performance. The NLP algorithm had a weighted PPV of 80% and a weighted sensitivity of 90%, with a c statistic of 0.93 (95% CI, 0.92-0.94). The combined algorithm had a weighted PPV of 98% at the higher cutoff and a weighted sensitivity of 96% at the lower cutoff, with a c statistic of 0.98 (95% CI, 0.97-0.98). Conclusions: Our ICD/medication-based algorithm can accurately identify VTE phenotype among patients with cancer with a high PPV of 95%. The combined algorithm should be considered in EHR databases that have access to such capabilities.

A New Risk Assessment Model for Hospital-Acquired Venous Thromboembolism in Critically Ill Children: A Report From the Children's Hospital-Acquired Thrombosis Consortium.

OBJECTIVES: To create a risk model for hospital-acquired venous thromboembolism in critically ill children upon admission to an ICU. DESIGN: Case-control study. SETTING: ICUs from eight children's hospitals throughout the United States. SUBJECTS: Critically ill children with hospital-acquired venous thromboembolism (cases) 0-21 years old and similar children without hospital-acquired venous thromboembolism (controls) from January 2012 to December 2016. Children with a recent cardiac surgery, asymptomatic venous thromboembolism, or a venous thromboembolism diagnosed before ICU admission were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The multi-institutional Children's Hospital-Acquired Thrombosis registry was used to identify cases and controls. Multivariable logistic regression was used to determine the association between hospital-acquired venous thromboembolism and putative risk factors present at or within 24 hours of ICU admission to develop the final model. A total of 548 hospital-acquired venous thromboembolism cases (median age, 0.8 yr; interquartile range, 0.1-10.2) and 187 controls (median age, 2.4 yr; interquartile range, 0.2-8.3) were analyzed. In the multivariable model, recent central venous catheter placement (odds ratio, 4.4; 95% CI, 2.7-7.1), immobility (odds ratio 3.6, 95% CI, 2.1-6.2), congenital heart disease (odds ratio 2.9, 95% CI, 1.7-4.7), length of hospital stay prior to ICU admission greater than or equal to 3 days (odds ratio, 2.5; 95% CI, 1.1-5.6), and history of autoimmune/inflammatory condition or current infection (odds ratio, 2.1; 95% CI, 1.2-3.4) were each independently associated with hospital-acquired venous thromboembolism. The risk model had an area under the receiver operating characteristic curve of 0.79 (95% CI, 0.73-0.84). CONCLUSIONS: Using the multicenter Children's Hospital-Acquired Thrombosis registry, we identified five independent risk factors for hospital-acquired venous thromboembolism in critically ill children, deriving a new hospital-acquired venous thromboembolism risk assessment model. A prospective validation study is underway to define a high-risk group for risk-stratified interventional trials investigating the efficacy and safety of prophylactic anticoagulation in critically ill children.

Inpatient Versus Outpatient Acute Venous Thromboembolism Management: Trends and Postacute Healthcare Utilization From 2011 to 2018.

Background Acute outpatient management of venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is perceived to be as safe as inpatient management in some settings. How widely this strategy is used is not well documented. Methods and Results Using MarketScan administrative claims databases for years 2011 through 2018, we identified patients with International Classification of Diseases (ICD) codes indicating incident VTE and trends in the use of acute outpatient management. We also evaluated healthcare utilization and hospitalized bleeding events in the 6 months following the incident VTE event. A total of 200 346 patients with VTE were included, of whom 50% had evidence of PE. Acute outpatient management was used for 18% of those with PE and 57% of those with DVT only, and for both DVT and PE its use increased from 2011 to 2018. Outpatient management was less prevalent among patients with cancer, higher Charlson comorbidity index scores, and whose primary treatment was warfarin as compared with a direct oral anticoagulant. Healthcare utilization in the 6 months following the incident VTE event was generally lower among patients managed acutely as outpatients, regardless of initial presentation. Acute outpatient management was associated with lower hazard ratios of incident bleeding risk for both patients who initially presented with PE (0.71 [95% CI, 0.61, 0.82]) and DVT only (0.59 [95% CI, 0.54, 0.64]). Conclusions Outpatient management of VTE is increasing. In the present analysis, it was associated with lower subsequent healthcare utilization and fewer bleeding events. However, this may be because healthier patients were managed on an outpatient basis.

Multiple Blood Biomarkers and Stroke Risk in Atrial Fibrillation: The REGARDS Study.

Background Atrial fibrillation is associated with increased stroke risk; available risk prediction tools have modest accuracy. We hypothesized that circulating stroke risk biomarkers may improve stroke risk prediction in atrial fibrillation. Methods and Results The REGARDS (Reasons for Geographic and Racial Differences in Stroke) study is a prospective cohort study of 30 239 Black and White adults age ≥45 years. A nested study of stroke cases and a random sample of the cohort included 175 participants (63% women, 37% Black adults) with baseline atrial fibrillation and available blood biomarker data. There were 81 ischemic strokes over 5.2 years in these participants. Adjusted for demographics, stroke risk factors, and warfarin use, the following biomarkers were associated with stroke risk (hazard ratio [HR]; 95% CI for upper versus lower tertile): cystatin C (3.16; 1.04-9.58), factor VIII antigen (2.77; 1.03-7.48), interleukin-6 (9.35; 1.95-44.78), and NT-proBNP (N-terminal B-type natriuretic peptide) (4.21; 1.24-14.29). A multimarker risk score based on the number of blood biomarkers in the highest tertile was developed; adjusted HRs of stroke for 1, 2, and 3+ elevated blood biomarkers, compared with none, were 1.75 (0.57-5.40), 4.97 (1.20-20.5), and 9.51 (2.22-40.8), respectively. Incorporating the multimarker risk score to the CHA2DS2VASc score resulted in a net reclassification improvement of 0.34 (95% CI, 0.04-0.65). Conclusions Findings in this biracial cohort suggested the possibility of substantial improvement in stroke risk prediction in atrial fibrillation using blood biomarkers or a multimarker risk score.

HIGH-2-LOW risk model to predict venous thromboembolism in allogeneic transplant patients after platelet engraftment.

Venous thromboembolism (VTE) after allogeneic hematopoietic cell transplantation (HCT) is a significant treatment-associated complication, although optimal timing of thromboprophylaxis remains uncertain when weighing concurrent risks of bleeding. We aimed to derive and internally validate a risk assessment model (RAM) using patients who underwent first allogeneic HCT from 2006 through 2015 (n = 1703). Index date was defined as the 30th day after transplant, at which point we estimated >75% of patients would have achieved platelet engraftment >50 × 109/L. Stepwise logistic regression modeling was used for model development, and internal validation was achieved by fitting a logistic regression model with 1000 bootstrapped resamples to estimate the optimism-corrected c-statistic. The final RAM, "HIGH-2-LOW," included 7 predictors obtained at 30 days after transplant: History of catheter-related deep venous thrombosis (DVT), Inpatient at day 30, Graft-versus-host disease grade 3 to 4, History of pulmonary embolism or lower-extremity DVT, Lymphoma diagnosis, Obesity with body mass index ≥35 kg/m2, and White blood cell count ≥11 × 109/L. Approximately 16% of patients were stratified as high risk, with incident VTE rate of 10.3% at 100 days compared with 1.5% for those at low risk. VTE odds ratios at 100 days were 5.87 (95% confidence interval [CI], 2.98-11.57) and 2.71 (95% CI, 1.38-5.35) in the high- and intermediate-risk vs low-risk groups, respectively. HIGH-2-LOW model serves as a novel and potentially clinically meaningful tool to identify high-risk allogeneic HCT patients who may benefit from early thromboprophylaxis after platelet engraftment.

Development of a Risk Model for Pediatric Hospital-Acquired Thrombosis: A Report from the Children's Hospital-Acquired Thrombosis Consortium.

OBJECTIVE: To identify pertinent clinical variables discernible on the day of hospital admission that can be used to assess risk for hospital-acquired venous thromboembolism (HA-VTE) in children. STUDY DESIGN: The Children's Hospital-Acquired Thrombosis Registry is a multi-institutional registry for all hospitalized participants aged 0-21 years diagnosed with a HA-VTE and non-VTE controls. A risk assessment model (RAM) for the development of HA-VTE using demographic and clinical VTE risk factors present at hospital admission was derived using weighted logistic regression and the least absolute shrinkage and selection (Lasso) procedure. The models were internally validated using 5-fold cross-validation. Discrimination and calibration were assessed using area under the receiver operating characteristic curve and Hosmer-Lemeshow goodness of fit, respectively. RESULTS: Clinical data from 728 cases with HA-VTE and 839 non-VTE controls, admitted between January 2012 and December 2016, were abstracted. Statistically significant RAM elements included age <1 year and 10-22 years, cancer, congenital heart disease, other high-risk conditions (inflammatory/autoimmune disease, blood-related disorder, protein-losing state, total parental nutrition dependence, thrombophilia/personal history of VTE), recent hospitalization, immobility, platelet count >350 K/µL, central venous catheter, recent surgery, steroids, and mechanical ventilation. The area under the receiver operating characteristic curve was 0.78 (95% CI 0.76-0.80). CONCLUSIONS: Once externally validated, this RAM will identify those who are at low-risk as well as the greatest-risk groups of hospitalized children for investigation of prophylactic strategies in future clinical trials.

Nivolumab-Induced Thrombotic Thrombocytopenic Purpura in a Patient with Anal Squamous Cell Carcinoma: A Lesson on Hematologic Toxicity from Immunotherapy.

Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening microangiopathic hemolytic anemia characterized by thrombocytopenia, hemolytic anemia, and ischemic organ damage. It is mainly caused by an autoreactive antibody directed at ADAMTS13. Immunotherapy is frequently associated with autoimmune complications in patients with cancer, but only three cases of TTP have been reported, none implicating single treatment with the anti-programmed cell death receptor 1 ligand antibody nivolumab. We present the first identified and reported case of nivolumab-associated TTP in a 51-year-old woman with stage IIIc anal carcinoma who achieved complete response following chemoradiation and received adjuvant nivolumab as part of a randomized clinical trial. Twelve weeks into treatment, she presented with dark urine, progressive fatigue, and headache. TTP diagnosis was based on laboratory evidence of hemolytic anemia, thrombocytopenia, and ADAMTS13 activity of 9% associated with an inhibitor. She was treated with daily plasma exchange and oral prednisone and responded well to treatment, with platelet counts over 100 K/cmm within 4 days. We reviewed and summarized data from all reported cases of TTP associated with cancer immunotherapy. We provide guidance on identification and management of this devastating hematologic complication, focusing on the importance of early recognition, as most patients achieve complete recovery with appropriate treatment. KEY POINTS: Thrombotic thrombocytopenic purpura (TTP) was originally excluded from previous reviews of hematologic immune-related adverse events; however, several cases have been reported in the past 2 years in patients treated with either single agent or combination of cytotoxic T-lymphocyte-associated antigen 4 and the programmed cell death receptor 1 (PD-1) or the PD-1 ligand inhibitors. Although rare, TTP is a life-threatening condition that could be challenging to diagnose, and early recognition is key as delayed treatment is associated with significant increase in mortality. The pathophysiology of immunotherapy-induced TTP is likely related to autoimmune inhibition of ADAMTS13; the addition of prednisone and rituximab to urgent plasmapheresis appears to be effective and should be part of the up-front management for these patients.

Identifying Genetic and Biological Determinants of Race-Ethnic Disparities in Stroke in the United States.

In the United States, causes of racial differences in stroke and its risk factors remain only partly understood, and there is a long-standing disparity in stroke incidence and mortality impacting Black Americans. Only half of the excess risk of stroke in the United States Black population is explained by traditional risk factors, suggesting potential effects of other factors including genetic and biological characteristics. Here, we nonsystematically reviewed candidate laboratory biomarkers for stroke and their relationships to racial disparities in stroke. Current evidence indicates that IL-6 (interleukin-6), a proinflammatory cytokine, mediates racial disparities in stroke through its association with traditional risk factors. Only one reviewed biomarker, Lp(a) (lipoprotein[a]), is a race-specific risk factor for stroke. Lp(a) is highly genetically determined and levels are substantially higher in Black than White people; clinical and pharmaceutical ramifications for stroke prevention remain uncertain. Other studied stroke risk biomarkers did not explain racial differences in stroke. More research on Lp(a) and other biological and genetic risk factors is needed to understand and mitigate racial disparities in stroke.