Risk Factors for Venous Thromboembolic Events in Children With Acute Musculoskeletal Infections.

BACKGROUND AND OBJECTIVES: Venous thromboembolic events (VTE) complicate acute hematogenous musculoskeletal infections (MSKIs) among hospitalized children. However, there is limited guidance for which specific MSKI patients are at the greatest VTE risk. This study aimed to identify VTE risk factors for children hospitalized with MSKIs. METHODS: A retrospective chart review was performed of children hospitalized with MSKIs at a single quaternary care pediatric hospital during a 9-year period. Patients with chronic MSKIs, non-hematogenous infections, or significant contributing comorbidities were excluded. Demographic and clinical characteristics were compared between patients with and without VTE using forward stepwise conditional multivariable logistic regression to identify VTE risk factors. RESULTS: Among 335 included patients, 7 (2.1%) developed a VTE. There was no difference in age, sex, or obesity rates for those with or without VTE. Patients with methicillin-resistant Staphylococcus aureus (MRSA) infections and/or critical illness were more likely to develop a VTE with summative adjusted odds ratios of 31.7 and 26.4, respectively. In addition, patients with VTEs had longer hospitalizations (median 4.7 vs. 12.8 d, P <0.001), longer courses of intravenous antimicrobials (median 3.7 vs. 13.5 d, P =0.001), and longer time to fever resolution (median 25.7 vs. 162 h, P =0.004). CONCLUSIONS: VTE prevalence among children with acute MSKIs is low. MRSA infection and critical illness significantly increase the risk for VTE development in these patients. Future prospective studies are needed to determine if VTEs in high-risk MSKI patients can be prevented.

Disseminated Intravascular Coagulation Is an Independent Predictor of Adverse Outcomes in Children in the Emergency Department with Suspected Sepsis.

OBJECTIVE: To evaluate the impact of early disseminated intravascular coagulation (DIC) on illness severity in children using a database of emergency department ED encounters for children with suspected sepsis, in view of similar associations in adults. STUDY DESIGN: Laboratory and clinical data were extracted from a registry of emergency department encounters of children with suspected sepsis between April 1, 2012, and June 26, 2017. International Society of Thrombosis and Hemostasis DIC scores were calculated from laboratory values obtained within 24 hours of emergency department admission. Univariate logistic regression, multivariable logistic regression, and Cox regression were used to assess the influence of DIC scores on vasopressor use (primary outcome), mortality, ventilator requirement, pediatric intensive care unit admission, and hospital duration (secondary outcomes). The optimal DIC score cutoff for outcome prediction was determined. RESULTS: Of 1653 eligible patients, 284 had DIC scores within 24 hours, including 92 who required vasopressors and 23 who died within 1 year. An initial DIC score of ≥3 was the most sensitive and specific DIC score for predicting adverse outcomes. Those with a DIC score of ≥3 vs <3 had increased odds of vasopressor use in both univariate (OR, 4.48; 95% CI, 2.63-7.62; P < .001) and multivariable (OR, 3.78; 95% CI, 1.82-7.85; P < .001) analyses. Additionally, those with a DIC score of ≥3 vs <3 had increased 1-year mortality with a hazard ratio of 3.55 (95% CI, 1.46-8.64; P = .005). CONCLUSIONS: A DIC score of ≥3 was an independent predictor for both vasopressor use and mortality in this pediatric cohort, distinct from the adult overt DIC score cutoff of ≥5.

Postoperative bleeding complications in patients with hemophilia undergoing major orthopedic surgery: A prospective multicenter observational study.

BACKGROUND: Persons with hemophilia (PWH) are at risk for chronic hemophilic arthropathy (HA). Joint replacement surgery may be used to relieve intractable pain and/or restore joint function. OBJECTIVES: This multicenter, prospective, observational cohort study evaluated the rate of bleeding during the postoperative period after total hip (THA) or knee arthroplasty (TKA). PATIENTS/METHODS: We included PWH of any severity ≥18 years of age who were undergoing THA or TKA. Clinical decisions were made at the discretion of the treating physician according to local standards of care. Clinical data were prospectively recorded. Major bleeding was defined as bleeding in a critical site, bleeding that resulted in either a 2 g/dl or greater decrease in hemoglobin during any 24-h period, or transfusion of two or more units of packed red blood cells. RESULTS: One hundred thirty-one procedures (98 TKA and 33 THA) were performed, 39 (29.8%) of which were complicated by major bleeding, including 46% of THA and 25% of TKA. The risk of major bleeding was increased in THA compared to TKA (OR 2.50, p = .05), and by the presence of an inhibitor (OR 4.29, p = .04), increased BMI (OR 4.49 and 6.09 for overweight and obese, respectively, compared to normal BMI, each p < .01), and non-use of an antifibrinolytic medication (OR 3.00, p = .03). Neither continuous clotting factor infusion (versus bolus infusion) nor pharmacologic thromboprophylaxis were associated with bleeding risk. CONCLUSIONS: The bleeding risk remains substantial after THA and TKA in PWH, despite factor replacement. Use of antifibrinolytic medications is associated with decreased risk.

Clinic Follow up and Neurological Disability in Children Following Pregnancies Complicated by Preterm Rupture of Membranes and Preeclampsia.

Context: Preeclampsia and preterm premature rupture of membranes (PPROM) have been associated with perinatal brain injury. Despite a strong understanding of the relationships between preterm birth and neurologic deficits, and between PPROM and preeclampsia and preterm birth, the relationship between PPROM and preeclampsia and neurologic disability is not well characterized. Objective: We compared trends in neurologic deficits in children born to mothers with these conditions and described differences in patient characteristics among follow up visit attendance. Methods: We conducted a prospective cohort study of women with preeclampsia or PPROM. Neurologic deficits were assessed with the Pediatric Stroke Outcome Measure at follow up visits through age 10 years. Eighty nine of the 178 women enrolled completed at least one follow up. Results: Among children born >32 weeks, PPROM showed higher left and right sided sensorimotor deficits at initial follow (p=0.045, p=0.01). In children born ≤ 32 weeks, preeclampsia had higher language production deficits at 3 year follow up (p=0.05).Sensorimotor deficits were greater and sustained in PPROM. Language production deficits were predominant among after 2 years of age in preeclampsia. Racial disparities were found in clinic attendance rates, with Black families most affected. Conclusion: Differences in neurodevelopmental patterns suggest differences in underlying neuronal injuries. Neurologic assessment should occur routinely throughout early childhood to detect delayed deficits after PPROM and preeclampsia and ensure inclusion of underserved or at risk populations.

Inflammatory cytokines, placental pathology, and neurological outcomes in infants born to preterm preeclamptic mothers.

Preeclampsia is both a vascular and inflammatory disorder. Since the placenta is a conduit for fetal development, preeclampsia should be a presumed cause of adverse infant outcomes. Yet, the relationship of placental pathology, inflammation and neurological outcomes after preeclampsia are understudied. We prospectively examined a cohort of maternal-infant dyads with preeclampsia for maternal inflammatory cytokines at time of preeclampsia diagnosis and delivery, and fetal cord blood cytokines (IL-1ß, IL-6, IL-8, and TNF-α). Placentas were analyzed for inflammatory and vascular pathologies. Neurodevelopmental assessment of infants utilizing the Pediatric Stroke Outcome Measure (PSOM) was conducted at 6-month corrected gestational age. Eighty-one maternal-newborn dyads were examined. Worse neurological outcomes were not associated with elevated maternal / fetal cytokines. Early preterm birth (gestational age ≤ 32 weeks) was associated with worse neurological outcomes at 6-months regardless of maternal/ fetal cytokine levels, placental pathology, or cranial ultrasound findings (OR 1.70, [1.16-2.48], p = 0.006). When correcting for gestational age, elevated IL-6 approached significance as a predictor for worse developmental outcome (OR 1.025 [0.985-1.066], p = 0.221). Pathological evidence of maternal malperfusion and worse outcomes were noted in early preterm, although our sample size was small. Our study did not demonstrate an obvious association of inflammation and placental pathology in preeclampsia and adverse neurodevelopmental outcome at 6-month corrected age but does suggest maternal malperfusion at earlier gestational age may be a risk factor for worse outcome.

Emicizumab initiation and bleeding outcomes in people with hemophilia A with and without inhibitors: A single-center report.

BACKGROUND: Emicizumab, a bispecific antibody factor VIII mimetic, is approved for prophylaxis in hemophilia, and has different risks and side effects compared to factor VIII products. OBJECTIVE: To better understand the early impact of emicizumab on our patients at the University of Colorado Hemophilia and Thrombosis Center (UCHTC), we evaluated adverse reactions, factor prophylaxis overlap, and bleeding rates after starting emicizumab through a quality improvement project. PATIENTS/METHODS: A retrospective chart review and structured phone interview were conducted from June to September 2019 for all patients who had started emicizumab at the UCHTC. Data about emicizumab dosing, reactions, bleeding events, and bleeding treatment were collected in 68 children and adults (aged 0.55-79.8 years, on emicizumab a median 213 days; range, 51-1229 days) with hemophilia A (35.3% with past or current inhibitor). RESULTS: Adverse reactions were primarily skin reactions, with no anaphylactic reactions or thrombosis. Bleeding events, defined as pain or swelling treated with factor or supportive measures, demonstrated wide variability, with 25 of 68 experiencing zero bleeds and 5 of 68 experiencing >8 bleeds per year. The most prevalent bleed type was traumatic musculoskeletal bleeding. Bleeding events occurred more often in the first 10 weeks after starting emicizumab, but no time period was without bleeding events. The majority of patients were prescribed every-week or every-2-week dosing, but some had alternative dosing frequency. CONCLUSIONS: Real-world emicizumab use in our center was characterized by variations in prescribing practices and bleeding outcomes and lack of severe adverse reactions.

Validation of Outcome Instruments for Pediatric Postthrombotic Syndrome: Introducing the Peds-VEINES-QOL, a New Health-Related Quality of Life Instrument.

BACKGROUND: There is need for validated outcome measures for postthrombotic syndrome (PTS) following pediatric venous thromboembolism (VTE), with a focus on quality of life (QoL). AIMS: This article assesses reliability and validity of two PTS and two QoL scales for children following lower extremity VTE. METHODS: Pediatric patients following lower extremity VTE were recruited from three thrombosis clinics. The Manco-Johnson (MJ) and the modified Villalta (MV) PTS scales were compared with each other and with the generic pediatric health-related QoL, PedsQL, and a newly developed pediatric venous-specific QoL, the Peds-VEINES-QOL. RESULTS: Eighty children following VTE and 60 healthy control children were enrolled. Internal consistency measured by Cronbach's α was high for the two QoL scales, and moderate for the two PTS scales. Inter-rater reliability using intraclass correlation coefficients was moderate to high for the MJ, MV, and Peds-VEINES-QOL, and moderate for the PedsQL. Evidence of high internal consistency by Cronbach's α coefficients, and moderate to high interitem correlations support the premise that a single construct was measured by each instrument. Correlations between the four instruments indicate convergent validity. CONCLUSION: The MJ and MV scales detect similar outcomes in children following VTE. As used, the MJ is slightly more sensitive to QoL because a positive diagnosis requires pain which is the leading factor in reduced QoL following deep vein thrombosis. When using the MV, a requirement for pain or abnormal use to diagnose PTS would make the MV a better predictor of QoL.

Validity and reliability of the Colorado Adult Joint Assessment Scale in adults with moderate-severe hemophilia A.

BACKGROUND: The Colorado Adult Joint Assessment Scale (CAJAS) is designed to assess joint health in adults with hemophilia. The CAJAS comprises nine items (swelling, muscle atrophy, axial deformity, crepitus, range of motion, contracture, instability, strength, gait) and assesses six joints. OBJECTIVE: To assess CAJAS content validity and psychometric properties. PATIENTS/METHODS: Data were obtained from the Trial to Evaluate the Effect of Secondary Prophylaxis With rFVIII Therapy in Severe Hemophilia A Adult and/or Adolescent Subjects Compared to That of Episodic Treatment (SPINART) study and a separate CAJAS validation study. CAJAS assessments in SPINART were performed by physical therapists (PTs) from the United States, Romania, Bulgaria, and Argentina. In the validation study, content validity was assessed from interviews with six PTs at three US hemophilia centers; cultural equivalence was assessed with seven non-US PTs from SPINART. Reliability data were collected from 30 subjects at four US centers. Test-retest reliability was evaluated by having the same PT perform CAJAS examinations at two visits, 7-10 days apart. Inter-rater reliability was assessed by comparing CAJAS scores of two different PTs performing separate examinations of the same patient several hours apart at the same visit. Psychometric properties were assessed using SPINART and validation study data. RESULTS: The CAJAS demonstrated good content validity. Test-retest reliability was high (intraclass correlation coefficient, 0.98), as was inter-rater reliability (intraclass correlation coefficient, 0.88). Internal consistency reliability was strong (α = .90). The CAJAS demonstrated good convergent/divergent validity, known-groups validity, and ability to detect change. CONCLUSIONS: The CAJAS is a valid and reliable measure of joint health in adults with moderate-severe hemophilia and is appropriate for use in clinical practice.

Young adult outcomes of childhood prophylaxis for severe hemophilia A: results of the Joint Outcome Continuation Study.

The Joint Outcome Study (JOS), a randomized controlled trial, demonstrated that children with severe hemophilia A (HA) initiating prophylactic factor VIII (FVIII) prior to age 2.5 years had reduced joint damage at age 6 years compared with those treated with episodic FVIII for bleeding. The Joint Outcome Continuation Study (JOS-C) evaluated early vs delayed prophylaxis effects on long-term joint health, following JOS participants to age 18 years in an observational, partially retrospective study. Index joint magnetic resonance imaging (MRI) scores of osteochondral (OC) damage (primary outcome), joint physical examination scores, and annualized rates of joint/other bleeding episodes (secondary outcomes) were collected. Thirty-seven of 65 JOS participants enrolled in JOS-C, including 15 randomized to prophylaxis at mean age 1.3 years ("early prophylaxis"); 18 initially randomized to episodic treatment, starting "delayed prophylaxis" at mean age 7.5 years; and 4 with high-titer inhibitors. At JOS-C exit, MRI OC damage was found in 77% of those on delayed and 35% of those on early prophylaxis for an odds ratio of OC damage, in the delayed vs early prophylaxis group, of 6.3 (95% confidence interval, 1.3, 29.9; P = .02). Annualized bleeding rates were higher with delayed prophylaxis (mean plus or minus standard deviation, 10.6 ± 6.6 vs 3.5 ± 2.1; P < .001), including when only comparing time periods on prophylaxis (6.2 ± 5.3 vs 3.3 ± 1.9; P < .05). In severe HA, early initiation of prophylaxis provided continued protection against joint damage throughout childhood compared with delayed initiation, but early prophylaxis was not sufficient to fully prevent damage. This trial was registered at www.clinicaltrials.gov as #NCT01000844.

Venous Thromboembolism: A Survey of Oral Anticoagulant Preferences in the Treatment of Challenging Patient Populations.

Venous thromboembolism (VTE) is a highly morbid condition with several available oral anticoagulant treatment options. Numerous studies have been published comparing warfarin to direct oral anticoagulants; however, several populations remain underrepresented in these reports. We surveyed members of The Venous ThromboEmbolism Network U.S. working group regarding their oral anticoagulant preferences for the treatment of VTE in different and challenging populations. In individuals with VTE and no other medical comorbidities, respondents preferred either rivaroxaban (48.7%) or apixaban (48.7%). Apixaban (53.3%) was preferred in elderly individuals with an increased risk of bleeding. Warfarin was preferred in individuals with liver or kidney dysfunction (42% and 47%), altered metabolism (>55%), and antiphospholipid antibody syndrome (84.2%). Low-molecular-weight heparin was preferred in individuals with malignancy (56.6%), followed by edoxaban (23.7%). These findings may help guide clinicians when choosing an anticoagulant in these challenging situations and demonstrate the urgent need for additional study in these groups.

Venous thromboembolism in children with cystic fibrosis: Retrospective incidence and intrapopulation risk factors.

INTRODUCTION: Pediatric venous thromboembolism (VTE) is a rare but serious medical condition. Cystic fibrosis (CF) is a risk for recurrent pediatric VTE and has potential thrombophilic tendency. However, much remains unknown, including incidence and intrapopulation risk factors. METHODS: A retrospective cohort of pediatric CF patients followed at Children's Hospital Colorado from January 1st 2003 through May 20th 2016 was examined. Cases were identified by informatics and validated manually. Data on CF severity, co-morbidities and treatment, central venous catheter (CVC) use, and thrombophilia were obtained from an institutional CF database and chart review. RESULTS: Nineteen VTE occurred in 458 participants followed for 3595 person-years, yielding an incidence rate of 53 VTE per 10,000 children with CF. VTE cases had additional co-morbidities including CF-related diabetes (p=0.002) and sinus disease (p=0.04), more total admissions (p<0.001), admit days (p<0.001), positive respiratory cultures (p<0.001), pseudomonas infections (p<0.001), steroid courses (p=0.001), and total CVC days (PICC p=0.03, port p=0.007). On univariate analysis, older age (RR 1.162, p=0.007), sinus disease (RR 2.62, p=0.05), longer hospital stay (RR 1.03, p<0.001), higher ESR (RR 1.02, p=0.03) and CRP (RR 1.07, p=0.007), and an absence of systemic steroids (RR 0.19, p=0.004) increased the risk of VTE. CONCLUSIONS: In this cohort, children with CF had a higher incidence of VTE when compared to the previously reported incidence in the overall pediatric population at Children's Hospital Colorado. Overall, those with VTE had a greater disease burden and older age, sinus disease, longer hospitalization and increased inflammation were VTE risk factors.

Lexical versus conceptual anticipation during sentence processing: frontal positivity and N400 ERP components.

Although the sensitivity of the N400 to semantic processing is well established, late positive ERP components are also elicited during sentence comprehension. We suggest that there are multiple such components differing in scalp topography, and that a larger frontal positivity often follows the larger N400 elicited by congruent but unexpected sentence endings as compared to predictable endings. We evaluated the lexical versus conceptual specificity of this post-N400-positivity. High- and low-constraint sentences were completed by the words most preferred by a normative group (best completions), by words that were nearly synonymous to those best completions, and by other congruent words that were semantically dissimilar to the best completions. The N400 was sensitive to both the predictability (cloze probability) of the words and their semantic similarity to the best completion, consistent with a sensitivity to conceptual expectations that could be fulfilled by alternate words. In contrast, an anterior positivity was elicited by all final words that were not highly predictable, independent of whether they were semantically similar or dissimilar to the most preferred word, indicating a sensitivity to specific lexical expectations.