Assessment of the CLOT (children's likelihood of thrombosis) real-time risk prediction model of hospital-associated venous thromboembolism in children with congenital heart disease.

BACKGROUND: Children with congenital heart disease (CHD) are at high risk for hospital-associated venous thromboembolism (HA-VTE). The children's likelihood of thrombosis (CLOT) trial validated a real-time predictive model for HA-VTE using data extracted from the EHR for pediatric inpatients. We tested the hypothesis that addition of CHD specific data would improve model prediction in the CHD population. METHODS: Model performance in CHD patients from 2010 to 2022, was assessed using 3 iterations of the CLOT model: 1) the original CLOT model, 2) the original model refit using only data from the CHD cohort, and 3) the model updated with the addition of cardiopulmonary bypass time, STAT Mortality Category, height, and weight as covariates. The discrimination of the three models was quantified and compared using AUROC. RESULTS: Our CHD cohort included 1457 patient encounters (median 2.0 IQR [0.5-5.2] years-old). HA-VTE was present in 5% of our CHD cohort versus 1% in the general pediatric population. Several features from the original model were associated with thrombosis in the CHD cohort including younger age, thrombosis history, infectious disease consultation, and EHR coding of a central venous line. Lower height and weight were associated with thrombosis. HA-VTE rate was 12% (18/149) amongst those with STAT Category 4-5 operation versus 4% (49/1256) with STAT Category 1-3 operation (P < .001). Longer cardiopulmonary bypass time (124 [92-205] vs. 94 [65-136] minutes, P < .001) was associated with thrombosis. The AUROC for the original (0.80 95% CI [0.75-0.85]), refit (0.85 [0.81-0.89]), and updated (0.86 [0.81-0.90]) models demonstrated excellent discriminatory ability within the CHD cohort. CONCLUSION: The automated approach with EHR data extraction makes the applicability of such models appealing for ease of clinical use. The addition of cardiac specific features improved model discrimination; however, this benefit was marginal compared to refitting the original model to the CHD cohort. This suggests strong predictive generalized models, such as CLOT, can be optimized for cohort subsets without additional data extraction, thus reducing cost of model development and deployment.

Representation of Authors by Gender, Race, and Ethnicity in Pathology Clinical Practice Guidelines.

CONTEXT.­: United States' clinical practice guidelines (CPGs) are often produced by professional societies and used worldwide in daily medical practice. However, studies in various medical specialties demonstrate underrepresentation of women and racial and ethnic minority groups in CPGs. The representation of authors by gender, race, and ethnicity of US pathology CPGs has not been previously evaluated. OBJECTIVE.­: To assess if women and individuals from racial and ethnic minority groups are underrepresented as authors of pathology CPGs. DESIGN.­: The gender, race, ethnicity, and terminal degrees of authors of 18 CPGs from the College of American Pathologists were coded by using photographs and other available information online and compared to their representation in academic pathology per Association of American Medical Colleges benchmark data. RESULTS.­: Two hundred seventy-five author positions (202 physician author positions) were analyzed. Women overall (119 of 275; 43.3%) and women physicians (65 of 202; 32.2%) held fewer positions than all men and men physicians. Women physicians were significantly underrepresented in physician author positions, while White men physicians were significantly overrepresented in all, first, senior, and corresponding authorship roles when compared to the proportion of women and White men physicians among pathology faculty, respectively. Asian men and women physicians were underrepresented as compared to their representation among pathology faculty. CONCLUSIONS.­: Men, particularly White men physicians, are overrepresented among pathology CPG author positions, while women physicians and some physicians from racial and ethnic minority groups are underrepresented. Further research is needed to understand the impact of these findings on the careers of underrepresented physicians and the content of guidelines.

Model-Guided Decision-Making for Thromboprophylaxis and Hospital-Acquired Thromboembolic Events Among Hospitalized Children and Adolescents: The CLOT Randomized Clinical Trial.

Importance: Rates of hospital-acquired venous thromboembolism (HA-VTE) are increasing among pediatric patients. Identifying at-risk patients for whom prophylactic interventions should be considered remains challenging. Objective: To determine whether use of a previously validated HA-VTE prognostic model, together with pediatric hematologist review, could reduce pediatric inpatient rates of HA-VTE. Design, Setting, and Participants: This pragmatic randomized clinical trial was performed from November 2, 2020, through January 31, 2022, at a single-center academic children's hospital (Monroe Carell Jr Children's Hospital at Vanderbilt). All pediatric hospital admissions (aged <22 years) under inpatient status were included and randomized. Intervention: All patients had an HA-VTE probability automatically calculated daily, which was visible to the hematology research team for patients in the intervention group. Patients with an elevated risk (predicted probability ≥2.5%) underwent additional medical record review by the research team to determine eligibility for thromboprophylaxis. Main Outcomes and Measures: The primary outcome was rate of HA-VTE. Secondary outcomes included rates of prophylactic anticoagulation and anticoagulation-associated bleeding events. Results: A total of 17 427 hospitalizations met eligibility criteria, were randomized, and were included in the primary analysis: patients had a median (IQR) age of 1.7 (0 to 11.1) years; there were 9143 (52.5%) female patients and 8284 (47.5%) male patients, and there were 445 (2.6%) Asian patients, 2739 (15.9%) Black patients, and 11 752 (67.4%) White patients. The 2 groups were evenly balanced in number (8717 in the intervention group and 8710 in the control group) and patient characteristics. A total of 58 patients (0.7%) in the control group and 77 (0.9%) in the intervention group developed HA-VTE (risk difference: 2.2 per 1000 patients; 95% CI, -0.4 to 4.8 per 1000 patients; P = .10). Recommendations to initiate thromboprophylaxis were accepted by primary clinical teams 25.8% of the time (74 of 287 hospitalizations). Minor bleeding events were rare among patients who received anticoagulation (3 of 74 [4.1%]), and no major bleeding events were observed during the study period. Among patients randomized to the control group, the model exhibited high discrimination accuracy (C statistic, 0.799, 95% CI, 0.725 to 0.856). Conclusions and Relevance: In this randomized clinical trial of the use of a HA-VTE prognostic model to reduce pediatric inpatient rates of HA-VTE, despite the use of an accurate and validated prognostic model for HA-VTE, there was substantial reluctance by primary clinical teams to initiate thromboprophylaxis as recommended. In this context, rates of HA-VTE between the control and intervention groups were not different. Future research is needed to identify improved strategies for prevention of HA-VTE and to overcome clinician concerns regarding thromboprophylaxis. Trial Registration: ClinicalTrials.gov Identifier: NCT04574895.

Use of a real-time risk-prediction model to identify pediatric patients at risk for thromboembolic events: study protocol for the Children's Likelihood Of Thrombosis (CLOT) trial.

BACKGROUND: Pediatric patients have increasing rates of hospital-associated venous thromboembolism (HA-VTE), and while several risk-prediction models have been developed, few are designed to assess all general pediatric patients, and none has been shown to improve patient outcomes when implemented in routine clinical care. METHODS: The Children's Likelihood Of Thrombosis (CLOT) trial is an ongoing pragmatic randomized trial being conducted starting November 2, 2020, in the inpatient units at Monroe Carell Jr. Children's Hospital at Vanderbilt in Nashville, TN, USA. All admitted patients who are 21 years of age and younger are automatically enrolled in the trial and randomly assigned to receive either the current standard-of-care anticoagulation practice or the study intervention. Patients randomized to the intervention arm are assigned an HA-VTE risk probability that is calculated from a validated VTE risk-prediction model; the model is updated daily with the most recent clinical information. Patients in the intervention arm with elevated risk (predicted probability of HA-VTE ≥ 0.025) have an additional review of their clinical course by a team of dedicated hematologists, who make recommendations including pharmacologic prophylaxis with anticoagulation, if appropriate. The anticipated enrollment is approximately 15,000 patients. The primary outcome is the occurrence of HA-VTE. Secondary outcomes include initiation of anticoagulation, reasons for not initiating anticoagulation among patients for whom it was recommended, and adverse bleeding events. Subgroup analyses will be conducted among patients with elevated HA-VTE risk. DISCUSSION: This ongoing pragmatic randomized trial will provide a prospective assessment of a pediatric risk-prediction tool used to identify hospitalized patients at elevated risk of developing HA-VTE.  TRIAL REGISTRATION: ClinicalTrials.gov NCT04574895. Registered on September 28, 2020. Date of first patient enrollment: November 2, 2020.

Coagulation factor inhibitors in COVID-19: From SARS-CoV-2 vaccination to infection.

Background: Recent reports have highlighted patients with COVID-19 and vaccine recipients diagnosed with coagulation factor inhibitors. This is challenging. as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been identified as a prothrombotic risk factor, with heparin treatment decreasing mortality. However, both infection and vaccination have been associated with immune-mediated hematologic abnormalities, including thrombocytopenia, further rendering these groups at risk for both hemorrhagic and thrombotic events. Objectives: We sought to characterize the incidence and clinical findings of coagulation factor inhibitors in patients with COVID-19 and vaccine recipients. Methods: We queried the US Centers for Disease Control and Prevention's Vaccine Adverse Event Reporting System (VAERS), a publicly accessible database, for reports of potential bleeding episodes or coagulation disturbances associated with SARS-CoV-2 vaccination. We performed an additional comprehensive literature review to identify reports of SARS-CoV-2 infection or vaccination-associated coagulation factor inhibitors. Results: VAERS data showed 58 cases of coagulation factor inhibitors, suggesting a rate of 1.2 cases per 10 million doses. A total of 775 articles were screened and 15 were suitable for inclusion, with six reports of inhibitors after vaccination and nine reports of inhibitors after infection. Inhibitor specificity for factor VIII was most common. Among reported cases, two patients expired due to hemorrhage, one following infection and one following vaccination. Conclusion: The incidence of coagulation factor inhibitors in patients with SARS-CoV-2 vaccination and infection appears similar to the general population. Nonetheless, given the importance of heparin therapy in treating hospital patients, recognition of inhibitors is important.

Case Series of Thrombosis With Thrombocytopenia Syndrome After COVID-19 Vaccination-United States, December 2020 to August 2021.

BACKGROUND: Thrombosis with thrombocytopenia syndrome (TTS) is a potentially life-threatening condition associated with adenoviral-vectored COVID-19 vaccination. It presents similarly to spontaneous heparin-induced thrombocytopenia. Twelve cases of cerebral venous sinus thrombosis after vaccination with the Ad26.COV2.S COVID-19 vaccine (Janssen/Johnson & Johnson) have previously been described. OBJECTIVE: To describe surveillance data and reporting rates of all reported TTS cases after COVID-19 vaccination in the United States. DESIGN: Case series. SETTING: United States. PATIENTS: Case patients receiving a COVID-19 vaccine from 14 December 2020 through 31 August 2021 with thrombocytopenia and thrombosis (excluding isolated ischemic stroke or myocardial infarction) reported to the Vaccine Adverse Event Reporting System. If thrombosis was only in an extremity vein or pulmonary embolism, a positive enzyme-linked immunosorbent assay for antiplatelet factor 4 antibodies or functional heparin-induced thrombocytopenia platelet test result was required. MEASUREMENTS: Reporting rates (cases per million vaccine doses) and descriptive epidemiology. RESULTS: A total of 57 TTS cases were confirmed after vaccination with Ad26.COV2.S (n = 54) or a messenger RNA (mRNA)-based COVID-19 vaccine (n = 3). Reporting rates for TTS were 3.83 per million vaccine doses (Ad26.COV2.S) and 0.00855 per million vaccine doses (mRNA-based COVID-19 vaccines). The median age of patients with TTS after Ad26.COV2.S vaccination was 44.5 years (range, 18 to 70 years), and 69% of patients were women. Of the TTS cases after mRNA-based COVID-19 vaccination, 2 occurred in men older than 50 years and 1 in a woman aged 50 to 59 years. All cases after Ad26.COV2.S vaccination involved hospitalization, including 36 (67%) with intensive care unit admission. Outcomes of hospitalizations after Ad26.COV2.S vaccination included death (15%), discharge to postacute care (17%), and discharge home (68%). LIMITATIONS: Underreporting and incomplete case follow-up. CONCLUSION: Thrombosis with thrombocytopenia syndrome is a rare but serious adverse event associated with Ad26.COV2.S vaccination. The different demographic characteristics of the 3 cases reported after mRNA-based COVID-19 vaccines and the much lower reporting rate suggest that these cases represent a background rate. PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention.

Increased Plasma Hyaluronan Levels are Associated With Acute Traumatic Coagulopathy.

INTRODUCTION: Acute traumatic coagulopathy (ATC) is an endogenous impairment in hemostasis that often contributes to early mortality after trauma. Endothelial glycocalyx damage is associated with trauma-induced coagulation abnormalities; however, the specific relationship between hyaluronan (HA), a key glycocalyx constituent, and ATC has not been evaluated. METHODS: We performed a secondary analysis of prospectively collected data from a recent study in which trauma patients (>18 years) admitted to our Level I trauma center with an ABC Score≥2 were enrolled. Partial thromboplastin time (PTT), international normalized ratio (INR), and thromboelastography (TEG) parameters were recorded at arrival. Injury characteristics and clinical outcomes were obtained. Plasma HA levels were measured in healthy controls (HC) and in trauma subjects at arrival (t = 0 h) and 12, 24, and 48 h. ATC was defined as admission INR>1.2 or PTT≥36.5 s. Comparisons of HA levels were assessed, and Spearman's correlations were performed between 0 h and 24 h HA levels, coagulation measures and clinical outcomes. P values < 0.05 were considered significant. RESULTS: Forty-eight trauma patients and 22 controls were enrolled for study. Sixteen trauma subjects were coagulopathic at admission. HA levels in subjects with ATC were higher than non-coagulopathic subjects at all time points and elevated above HC levels at 24 and 48 h. At arrival, HA levels correlated with TEG R-time, PTT, and INR. HA levels at 24 h correlated with increased transfusion requirements and intensive care unit and hospital lengths of stay. CONCLUSION: Shed HA is associated with early coagulation abnormalities in trauma patients, which may contribute to worse outcomes. These findings highlight the need for additional studies to evaluate the mechanistic role of HA in ATC.

Isolated CNS Relapse in 2 High-Risk B-cell Acute Lymphoblastic Leukemia Patients Following SARS-CoV-2 Infection.

B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy with a highly favorable overall prognosis. Central nervous system (CNS) relapse of B-ALL is relatively rare and is associated with inferior survival outcomes. We present two patients with B-ALL who developed isolated CNS relapse following confirmed infection with severe acute respiratory syndrome coronavirus 2. In addition to individual and disease factors, we posit that delays in therapy together with immune system modulation because of severe acute respiratory syndrome coronavirus 2 may account for these 2 cases of CNS relapsed B-ALL. We report on this clinical observation to raise awareness of this potential association.

Respiratory failure and shock in an infant with severe anemia.

Patients with severe anemia can present with non-specific symptoms, including shock and respiratory distress. Ensuring a rapid, targeted workup is initiated and providing prompt transfusions as necessary are critical for both diagnostic success and clinical improvement.

A Real-time Risk-Prediction Model for Pediatric Venous Thromboembolic Events.

BACKGROUND: Hospital-associated venous thromboembolism (HA-VTE) is an increasing cause of morbidity in pediatric populations, yet identification of high-risk patients remains challenging. General pediatric models have been derived from case-control studies, but few have been validated. We developed and validated a predictive model for pediatric HA-VTE using a large, retrospective cohort. METHODS: The derivation cohort included 111 352 admissions to Monroe Carell Jr. Children's Hospital at Vanderbilt. Potential variables were identified a priori, and corresponding data were extracted. Logistic regression was used to estimate the association of potential risk factors with development of HA-VTE. Variable inclusion in the model was based on univariate analysis, availability in routine medical records, and clinician expertise. The model was validated by using a separate cohort with 44 138 admissions. RESULTS: A total of 815 encounters were identified with HA-VTE in the derivation cohort. Variables strongly associated with HA-VTE include history of thrombosis (odds ratio [OR] 8.7; 95% confidence interval [CI] 6.6-11.3; P < .01), presence of a central line (OR 4.9; 95% CI 4.0-5.8; P < .01), and patients with cardiology conditions (OR 4.0; 95% CI 3.3-4.8; P < .01). Eleven variables were included, which yielded excellent discriminatory ability in both the derivation cohort (concordance statistic = 0.908) and the validation cohort (concordance statistic = 0.904). CONCLUSIONS: We created and validated a risk-prediction model that identifies pediatric patients at risk for HA-VTE development. We anticipate early identification of high-risk patients will increase prophylactic interventions and decrease the incidence of pediatric HA-VTE.

US Case Reports of Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination, March 2 to April 21, 2021.

Importance: Cerebral venous sinus thrombosis (CVST) with thrombocytopenia, a rare and serious condition, has been described in Europe following receipt of the ChAdOx1 nCoV-19 vaccine (Oxford/AstraZeneca), which uses a chimpanzee adenoviral vector. A mechanism similar to autoimmune heparin-induced thrombocytopenia (HIT) has been proposed. In the US, the Ad26.COV2.S COVID-19 vaccine (Janssen/Johnson & Johnson), which uses a human adenoviral vector, received Emergency Use Authorization (EUA) on February 27, 2021. By April 12, 2021, approximately 7 million Ad26.COV2.S vaccine doses had been given in the US, and 6 cases of CVST with thrombocytopenia had been identified among the recipients, resulting in a temporary national pause in vaccination with this product on April 13, 2021. Objective: To describe reports of CVST with thrombocytopenia following Ad26.COV2.S vaccine receipt. Design, Setting, and Participants: Case series of 12 US patients with CVST and thrombocytopenia following use of Ad26.COV2.S vaccine under EUA reported to the Vaccine Adverse Event Reporting System (VAERS) from March 2 to April 21, 2021 (with follow-up reported through April 21, 2021). Exposures: Receipt of Ad26.COV2.S vaccine. Main Outcomes and Measures: Clinical course, imaging, laboratory tests, and outcomes after CVST diagnosis obtained from VAERS reports, medical record review, and discussion with clinicians. Results: Patients' ages ranged from 18 to younger than 60 years; all were White women, reported from 11 states. Seven patients had at least 1 CVST risk factor, including obesity (n = 6), hypothyroidism (n = 1), and oral contraceptive use (n = 1); none had documented prior heparin exposure. Time from Ad26.COV2.S vaccination to symptom onset ranged from 6 to 15 days. Eleven patients initially presented with headache; 1 patient initially presented with back pain and later developed headache. Of the 12 patients with CVST, 7 also had intracerebral hemorrhage; 8 had non-CVST thromboses. After diagnosis of CVST, 6 patients initially received heparin treatment. Platelet nadir ranged from 9 ×103/µL to 127 ×103/µL. All 11 patients tested for the heparin-platelet factor 4 HIT antibody by enzyme-linked immunosorbent assay (ELISA) screening had positive results. All patients were hospitalized (10 in an intensive care unit [ICU]). As of April 21, 2021, outcomes were death (n = 3), continued ICU care (n = 3), continued non-ICU hospitalization (n = 2), and discharged home (n = 4). Conclusions and Relevance: The initial 12 US cases of CVST with thrombocytopenia after Ad26.COV2.S vaccination represent serious events. This case series may inform clinical guidance as Ad26.COV2.S vaccination resumes in the US as well as investigations into the potential relationship between Ad26.COV2.S vaccine and CVST with thrombocytopenia.

COVID-19 pneumonia in a pediatric sickle cell patient requiring red blood cell exchange.

Patients with sickle cell disease are already at high risk for respiratory complications, which SARS-CoV-2 can rapidly worsen. The case emphasizes the importance of efficiently maximizing standard therapies in sickle cell patients with COVID-19.

Novel Blood Component Therapies in the Pediatric Setting.

There have been recent advances in safer blood component preparation and use of adjuvant blood derivatives, which have limited safety and efficacy data on use in children. This article reviews the literature on use of whole blood, solvent/detergent-treated plasma, pathogen-reduced platelets, and fibrinogen concentrate in pediatric patients. Many countries have adopted pathogen-reduced blood product technology, and hospitals in the United States are slowly adopting these products. The pediatric transfusion medicine community needs to appraise the evidence for their use and continue to advocate the inclusion of children in the most robust randomized clinical trials for novel blood components.

Associations of Plasma Angiopoietins-1 and -2 and Angiopoietin-2/-1 Ratios With Measures of Organ Injury and Clinical Outcomes in Children With Sepsis: A Preliminary Report.

OBJECTIVES: Results from preclinical and adult sepsis studies suggest that the balance of circulating angiopoietin-1 and -2 levels, represented as angiopoietin-2/-1 ratios, plays a pivotal role in mediating vascular dysfunction and organ injury during sepsis. However, the relationship of plasma angiopoietins with organ injury and clinical outcomes in children with sepsis remains unknown. We sought to determine whether plasma angiopoietin-1 and -2 levels and angiopoietin-2/-1 ratios in the acute phase of sepsis correlated with measures of organ injury and clinical outcomes in children with sepsis. DESIGN: Prospective observational cohort study. SETTING: PICU within a tertiary freestanding children's hospital. PATIENTS: Children 18 years old or less and greater than 3 kg admitted to the PICU for sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma angiopoietin-1 and -2 levels were measured in 38 children with sepsis 0-6, 24, 48, and 72 hours following PICU admission. Children with elevated pediatric Sequential Organ Failure Assessment scores on the third day after PICU admission demonstrated significantly higher 24-72-hour angiopoietin-2/-1 ratios predominantly as a function of higher angiopoietin-2 levels. In children with sepsis-induced organ dysfunction, angiopoietin-2/-1 ratios correlated with oxygenation indices and serum levels of creatinine and bilirubin. Forty-eight- and 72-hour angiopoietin-2/-1 ratios correlated with PICU length of stay (Spearman rho = 0.485, p = 0.004 and rho = 0.440, p = 0.015, respectively). CONCLUSIONS: In the acute phase of sepsis in children, plasma angiopoietin-2/-1 ratios rise significantly above control levels and correlate with measures of organ injury and worse clinical outcomes after 24 hours. Our findings suggest that angiopoietin dysregulation begins early in sepsis and, if sustained, may promote greater organ injury that can lead to worse clinical outcomes.

Temporal Dysregulation of the Angiopoietin-2/-1 Ratio After Trauma and Associations With Injury Characteristics and Outcomes.

Traumatic injury and hemorrhagic shock result in endothelial cell activation and vascular dysfunction that, if not corrected, can propagate multiorgan failure. Angiopoietin-1 and angiopoietin-2 are important regulators of endothelial cell function, and the ratio of plasma angiopoietin-2-to-1 is a useful indicator of overall vascular health. We therefore characterized plasma angiopoietin-2/-1 ratios over time after trauma in adults in an effort to gain insight into the pathophysiology that may drive post-traumatic vasculopathy and organ injury. We performed a single-center prospective observational study to measure plasma angiopoietin-1 and -2 levels and determine angiopoietin-2/-1 ratios in adult trauma patients upon hospital arrival and after 12, 24, and 48 h. Compared with levels in healthy adults, angiopoietin-1 levels were significantly elevated at hospital arrival, and angiopoietin-2 levels were significantly elevated at 12, 24, and 48 h. These kinetics translated in angiopoietin-2/-1 ratios that were significantly greater than controls at 24 and 48 h. After regression analysis, elevated angiopoietin-2 levels were independently associated with blunt injuries at admission, with coagulopathy at admission and 12 h, and with hemorrhagic shock at 24 and 48 h. Significant correlations were observed between both angiopoietins and 24-h transfusion requirements. Angiopoietin-2/-1 ratios correlated with mechanical ventilation duration and intensive care unit and hospital lengths of stay. In this study, we demonstrate novel temporal associations between angiopoietin dysregulation and blunt injuries, acute coagulopathy, and hemorrhagic shock. Moreover, our findings highlight the presence of endothelial activation following traumatic insults in adults that may contribute to worse clinical outcomes.