Brian R. Branchford

Risk factors for in-hospital venous thromboembolism in children: a case-control study employing diagnostic validation

Background Studies evaluating risk factors for in-hospital venous thromboembolism in children are limited by quality assurance of case definition and/or lack of controlled comparison. The objective of this study is to determine risk factors for the development of in-hospital venous thromboembolism in children. Design and Methods In a case-control study at The Children’s Hospital, Colorado, from 1st January 2003 to 31st December 2009 we employed diagnostic validation methods to determine pediatric in-hospital venous thromboembolism risk factors. Clinical data on putative risk factors were retrospectively collected from medical records of children with International Classification of Diseases, 9th edition codes of venous thromboembolism at discharge, in whom radiological reports confirmed venous thromboembolism and no signs/symptoms of venous thromboembolism were noted on admission. Results We verified 78 cases of in-hospital venous thromboembolism, yielding an average incidence of 5 per 10,000 hospitalized children per year. Logistical regression analyses revealed that mechanical ventilation, systemic infection, and hospitalization duration of five days or over were statistically significant, independent risk factors for in-hospital venous thromboembolism (OR=3.29, 95%CI=1.53–7.06, P=0.002; OR=3.05, 95%CI=1.57–5.94, P=0.001; and OR=1.03, 95%CI=1.01–1.04, P=0.001, respectively). Using these factors in a risk model, post-test probability of venous thromboembolism was 3.6%. Conclusions These data indicate that risk of in-hospital venous thromboembolism in children with this risk factor combination may exceed that of hospitalized adults in whom prophylactic anticoagulation is indicated. Substantiation of these findings via multicenter studies could provide the basis for future risk-stratified randomized control trials of pediatric venous thromboembolism prevention.

Percutaneous Mechanical and Pharmacomechanical Thrombolysis for Occlusive Deep Vein Thrombosis of the Proximal Limb in Adolescent Subjects: Findings from an Institution-based Prospective Inception Cohort Study of Pediatric Venous Thromboembolism

PURPOSE Young individuals with occlusive, proximal-limb deep vein thrombosis (DVT) who have acutely increased plasma levels of factor VIII and D-dimer are at high risk for postthrombotic syndrome (PTS) when treated with conventional anticoagulation alone. The present report is an evaluation of experience with adjunctive percutaneous mechanical thrombolysis (PMT) and/or percutaneous pharmacomechanical thrombolysis (PPMT) in such patients. PATIENTS AND METHODS Among 95 children 11-21 years of age enrolled in a prospective cohort of venous thromboembolism between March 1, 2006, and November 1, 2009, 16 met eligibility criteria and underwent PMT/PPMT, typically with adjunctive catheter-directed thrombolytic infusion (CDTI) of tissue-type plasminogen activator given after the procedure. RESULTS Median age was 16 years (range, 11-19 y). Thirteen cases (81%) involved lower limbs. Underlying stenotic lesions were disclosed in 53%, with endovascular stents deployed in all cases of May-Thurner anomaly. There were no periprocedural major bleeding events and one symptomatic pulmonary embolism. Technical success rate was 94%. Early (< 30 days) locally recurrent DVT developed in 40% of cases, of which 83% were successfully treated with repeat lysis. Late recurrent DVT rate (median follow-up duration, 14 months; range, 1-42 mo) was 27%. Cumulative incidence of physically and functionally significant PTS at 1-2 years was 13%. CONCLUSIONS This experience provides preliminary evidence that PMT/PPMT with adjunctive CDTI can be used safely and effectively in adolescent subjects with DVT at high risk for PTS.

Discovery of Mer Specific Tyrosine Kinase Inhibitors for the Treatment and Prevention of Thrombosis

The role of Mer kinase in regulating the second phase of platelet activation generates an opportunity to use Mer inhibitors for preventing thrombosis with diminished likelihood for bleeding as compared to current therapies. Toward this end, we have discovered a novel, Mer kinase specific substituted-pyrimidine scaffold using a structure-based drug design and a pseudo ring replacement strategy. The cocrystal structure of Mer with two compounds (7 and 22) possessing distinct activity have been determined. Subsequent SAR studies identified compound 23 (UNC2881) as a lead compound for in vivo evaluation. When applied to live cells, 23 inhibits steady-state Mer kinase phosphorylation with an IC50 value of 22 nM. Treatment with 23 is also sufficient to block EGF-mediated stimulation of a chimeric receptor containing the intracellular domain of Mer fused to the extracellular domain of EGFR. In addition, 23 potently inhibits collagen-induced platelet aggregation, suggesting that this class of inhibitors may have utility for prevention and/or treatment of pathologic thrombosis.

Hospital-associated venous thromboembolism in pediatrics: a systematic review and meta-analysis of risk factors and risk assessment models

Hospital-associated venous thromboembolism, including deep vein thrombosis and pulmonary embolism, is increasing in pediatric centers. The objective of this work was to systematically review literature on pediatric hospital-acquired venous thromboembolism risk factors and risk-assessment models, to inform future prevention research. We conducted a literature search on pediatric venous thromboembolism risk via PubMed (1946–2014) and Embase (1980–2014). Data on risk factors and risk-assessment models were extracted from case-control studies, while prevalence data on clinical characteristics were obtained from registries, large (n>40) retrospective case series, and cohort studies. Meta-analyses were conducted for risk factors or clinical characteristics reported in at least three studies. Heterogeneity among studies was assessed with the Cochran Q test and quantified by the I2 statistic. From 394 initial articles, 60 met the final inclusion criteria (20 case-control studies and 40 registries/large case series/cohort studies). Significant risk factors among case-control studies were: intensive care unit stay (OR: 2.14, 95% CI: 1.97–2.32); central venous catheter (OR: 2.12, 95% CI: 2.00–2.25); mechanical ventilation (OR: 1.56, 95%CI: 1.42–1.72); and length of stay in hospital (per each additional day, OR: 1.03, 95% CI: 1.03–1.03). Three studies developed/applied risk-assessment models from a combination of these risk factors. Fourteen significant clinical characteristics were identified through non-case-control studies. This meta-analysis confirms central venous catheter, intensive care unit stay, mechanical ventilation, and length of stay as risk factors. A few pediatric hospital-acquired venous thromboembolism risk scores have emerged employing these factors. Prospective validation is necessary to inform risk-stratified prevention trials.

Microfluidic technology as an emerging clinical tool to evaluate thrombosis and hemostasis.

Assessment of platelet function and coagulation under flow conditions can augment traditional static assays used to evaluate patients with suspected hemostatic or thrombotic disorders. Among the available flow-based assays, microfluidic devices require the smallest blood volume and provide multiple output options. These assays are based on the presence of wall shear stress that mimics in vivo interactions between blood components and vessel walls. Microfluidic devices can generate essential information regarding homeostatic regulation of platelet activation and subsequent engagement of the coagulation cascade leading to fibrin deposition and clot formation. Emerging data suggest that microfluidic assays may also reveal consistent patterns of hemostatic or thrombotic pathology, and could aid in assessing and monitoring patient-specific effects of coagulation-modifying therapies.

Risk factors for hospital-sssociated venous thromboembolism in the neonatal intensive care unit

OBJECTIVE To determine hospital-associated venous thromboembolism (HA-VTE) risk factors in critically ill neonates. METHODS We conducted a case-control study in the neonatal intensive care unit (NICU) of All Childrens Hospital Johns Hopkins Medicine (St. Petersburg, FL), from January 1, 2006 - April 10, 2013. We identified HA-VTE cases using electronic health record. Four NICU controls were randomly selected for each HA-VTE case. Associations between putative risk factors and HA-VTE were estimated using odds ratios (ORs) and ninety-five percent confidence intervals (95%CIs) from univariate and multivariate regression analyses. RESULTS Twenty-three HA-VTE cases and 92 controls were included. The annual HA-VTE incidence was approximately 1.4 HA-VTE cases per 1,000 NICU admissions. In univariate analyses, mechanical ventilation (OR=7.27, 95%CI=2.02-26.17, P=0.002), central venous catheter (CVC; OR=52.95, 95%CI=6.80-412.71, P<0.001), infection (OR=7.24, 95%CI=2.66-19.72, P<0.001), major surgery (OR=5.60, 95%CI=1.82-17.22, P=0.003) and length of stay ≥15days (OR=6.67, 95%CI=1.85-23.99, P=0.004) were associated with HA-VTE. Only CVC (OR=29.04, 95%CI=3.18-265.26, P=0.003) remained an independent risk factor in the multivariate analysis. Based on this result, the estimated risk of HA-VTE in NICU patients with a CVC was 0.9%. CONCLUSION This study identifies CVC as an independent risk factor for HA-VTE in critically ill neonates. However, the level of risk associated with CVC is below the conventional threshold for primary anticoagulation thromboprophylaxis. Larger studies are needed to substantiate these findings and identify novel putative risk factors to further distinguish NICU patients at highest HA-VTE risk.

Making a diagnosis of VWD

A clear understanding of the molecular basis of VWD can guide the choice and interpretation of appropriate diagnostic tests. This review briefly describes the lifecycle and molecular interactions of VWF and how they lead to the current clinical classification. It also includes a brief discussion of the differential diagnosis and general workup of mucocutaneous bleeding, a review of the various VWD subtypes, and pertinent laboratory assays for each, including genetic tests. Finally, common testing pitfalls and diagnostic dilemmas are covered, including the challenge created by the overlap of borderline low VWF levels and mild bleeding.

Development of a new risk score for hospital-associated venous thromboembolism in critically-ill children not undergoing cardiothoracic surgery

BACKGROUND Although risk of hospital-associated venous thromboembolism (HA-VTE) differs between critically and non-critically ill children, studies to date have not led to distinct, pragmatic risk scores. OBJECTIVE To determine risk factors for HA-VTE in critically ill children not undergoing cardiothoracic surgery, in order to derive a novel HA-VTE risk score for this population. METHODS We conducted a retrospective analysis from January 2006 through April 2013 at All Childrens Hospital Johns Hopkins Medicine. HA-VTE cases were identified using ICD-9 discharge diagnosis codes, with subsequent validation via radiologic record review. Cases were restricted to Pediatric Intensive Care Unit (PICU) admissions. Patients who underwent cardiothoracic surgery were excluded; cardiac catheterization per se was not exclusionary. For each case, three non-HA-VTE PICU controls were randomly selected. Data were abstracted on putative risk factors, and associations between risk factors and HA-VTE were estimated using odds ratios (ORs) and 95% confidence intervals (95%CIs). RESULTS There were 57 HA-VTE cases and 171 controls. HA-VTE occurrence was 3 per 1000 PICU admissions (0.3%). Central venous catheter (CVC) (OR:26.64; 95%CI:7.46-95.13), length of stay (LOS) ≥4days (OR:20.22; 95%CI:2.27-180.07), and significant infection (OR:3.41; 95%CI:1.13-10.29) were independent, statistically-significant risk factors for HA-VTE in a multivariate model. A risk score was derived in which HA-VTE risk exceeded 2% (threshold for anticoagulant thromboprophylaxis in hospitalized adults) with a score of 15, and was >1% but <2% (risk zone for mechanical thromboprophylaxis in hospitalized adults) with scores of 7-14. CONCLUSION The presence of a CVC, LOS≥4days and infection are significant risk factors for HA-VTE in critically ill children not undergoing cardiothoracic surgery, forming the basis for a new risk score that warrants prospective validation.

No increase in bleeding identified in type 1 VWD subjects with D1472H sequence variation

The diagnosis of von Willebrand disease (VWD) is complicated by issues with current laboratory testing, particularly the ristocetin cofactor activity assay (VWF:RCo). We have recently reported a sequence variation in the von Willebrand factor (VWF) A1 domain, p.D1472H (D1472H), associated with a decrease in the VWF:RCo/VWF antigen (VWF:Ag) ratio but not associated with bleeding in healthy control subjects. This report expands the previous study to include subjects with symptoms leading to the diagnosis of type 1 VWD. Type 1 VWD subjects with D1472H had a significant decrease in the VWF:RCo/VWF:Ag ratio compared with those without D1472H, similar to the findings in the healthy control population. No increase in bleeding score was observed, however, for VWD subjects with D1472H compared with those without D1472H. These results suggest that the presence of the D1472H sequence variation is not associated with a significant increase in bleeding symptoms, even in type 1 VWD subjects.

Sensitivity of discharge diagnosis ICD-9 codes for pediatric venous thromboembolism is greater than specificity, but still suboptimal for surveillance and clinical research

The poor reliability (specifically, low specificity) of International Classification of Diseases, Ninth Edition (ICD-9) codes in pediatric vascular disease has recently been established for arterial ischemic stroke (AIS) [1,2]. Venous thromboembolism (VTE) is also a significant cause of morbidity and mortality in children. Beyond the neonatal period, its incidence in childhood (estimated at 4.9 per 100,000 children per year) [3] is higher than that of AIS, and appears to have risen dramatically in the past several years [4]. Present knowledge of incidence of pediatric VTE relies mostly upon ICD-9 code data at hospital discharge, but the reliability of discharge diagnosis ICD-9 codes for pediatric VTE has not been well established. This limitation impedes epidemiologic and outcomes research in pediatric VTE, as well as the achievement of surveillance goals of the Centers Disease Control and Prevention and the 2008 U.S. Surgeon General Call-to-Action on Deep Vein Thrombosis and Pulmonary Embolism Prevention [5]. We recently reported, in a single-institutional case–control study at Childrens Hospital Colorado, that discharge diagnosis ICD-9 codes had a specificity of 38% (131 of 345) for VTE, and of 23% (78 of 345) for in-hospital (i.e., hospital-acquired) VTE, in children [6]. However, knowledge of sensitivity of discharge diagnosis ICD-9 codes for pediatric VTE remains limited. We therefore investigated sensitivity by analyzing discharge diagnosis ICD-9 code data on 30 consecutive children followed via our outpatient Thrombosis Clinic at Childrens Hospital Colorado in a prospective inception cohort study of pediatric VTE (COMIRB #05-0339), from the time of acute VTE diagnosis and hospitalization at our institution. Diagnosis of VTE made clinically and for the cohort study was based upon objective radiological findings of venous thrombosis or pulmonary embolus using compression ultrasound with Doppler, computed tomogram venography, magnetic resonance venography, or conventional venography. ICD-9 codes for VTE were as follows: 325 (cerebral venous sinus thrombosis), 415.19 (pulmonary embolism), 453.2 (IVC thrombus), 453.4 (VTE of lower extremity), 453.6 (venous embolism of lower extremity), 453.86 (jugular vein thrombosis), 453.9 (embolism or thrombosis of an unspecified site). This is not an exhaustive list of possible ICD-9 codes for VTE, but rather reflects those present in the study population. VTE types/sites were as follows: Lower limb DVT with/without PE (n=9), upper limb DVT with/without PE (n=5), isolated PE (n=7), cerebral sinovenous thrombosis (n=4), jugular vein thrombosis (n=4), and abdominal vessels (n=2). A discharge diagnosis ICD-9 code for VTE existed in 23 of 30 childrenwith verified VTE enrolled and followed in the cohort, yielding a sensitivity of 77%. This sensitivity is markedly higher than the specificity of discharge diagnosis ICD-9 codes for pediatric VTE as recently reported from the same institution [6]. Explanations for the greater sensitivity than specificity of the IDC-9 codes include the