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Caring for children and adolescents with disorders of hemostasis and thrombosis (HAT) has become more specialized and requires a unique skill set that many providers are not able to obtain in standard pediatric hematology/oncology/bone marrow transplant fellowship training programs. The influx of numerous therapeutic advances and increasing medical complexity has expanded the need for experienced HAT providers and subspecialty collaboration in the inpatient setting due to the nuances in the management of patients with HAT complications and concerns. While there are data highlighting the benefits of an inpatient hemostasis, thrombosis, and anticoagulation management service in adult hospitals, there are limited pediatric data supporting such programs. In this article, we summarize the current practices of various pediatric institutions in the inpatient management of HAT patients and provide a consensus opinion for the development of a pediatric inpatient HAT service at tertiary care referral centers.

Objective: Children presenting in diabetic ketoacidosis (DKA) may require a central venous catheter (CVC) to adequately manage their supportive care. These children are at increased risk of developing CVC-associated venous thromboembolism (VTE), but no predictive indicators have been identified to foretell which patients are at greatest risk. We analyzed demographic and laboratory data from children with DKA undergoing CVC placement to determine which patients may be at increased risk of CVC-associated VTE. Design: A retrospective chart review was conducted for patients aged 0-5 years admitted with DKA, CVC placement, and possible subsequent VTE development over ten years at a single institution. Reported demographic and laboratory variables were compared amongst patients that developed VTE and those that did not using Mann-Whitney rank sum tests. CVC-associated VTE incidence was also compared between children with DKA and all other patients undergoing CVC placement. Results: We identified 149 children with DKA, 17 underwent CVC placement, and 9/17 (52.9%) developed CVC-associated VTE. Length of hospital stay was the only significant difference between those that developed VTE and those that did not. Also, the prevalence of catheter associated VTE in DKA (1.7%) was significantly higher than that for CVC placement for any other reason (p

Glanzmann thrombasthenia (GT) is a rare inherited platelet disorder due to either a quantitative deficiency or qualitative defect in the platelet membrane glycoprotein GPIIb/IIIa. Platelet aggregation studies will show reduced or absent aggregation to all agonists except ristocetin. Bleeding symptoms are mucocutaneous, but may vary in severity. Usually, local measures alone or in combination with antifibrinolytics are sufficient to obtain hemostasis, but if bleeding is refractory, rFVIIa and/or platelet transfusion may be considered. Management of patients with GT should be done under the supervision of a hemophilia treatment center.

Congenital platelet granule disorders are a heterogeneous group of conditions often associated with specific clinical syndromes and either a deficiency or absence of the α-granules or δ-granules or a defect in granule secretion. Platelet storage pool deficiencies and granule secretion defects are associated with mild-to-moderate mucocutaneous bleeding that can usually be managed with local measures alone or in combination with antifibrinolytics and/or desmopressin. Platelet transfusions should be utilized in life-threatening bleeding events or if local control measures, desmopressin, and antifibrinolytics are not sufficient to obtain hemostasis. Congenital platelet granule disorder management requires consultation with a hemophilia treatment center.

MYH9-related disease (MYH-RD) is a syndrome complex associated with macrothrombocytopenia and Dohle-like leukocyte inclusion bodies with a risk of developing nephropathy, sensorineural hearing loss, and presenile cataracts. MYH9-RD is associated with mild to moderate mucocutaneous bleeding, including epistaxis, easy bruising, and heavy menstrual bleeding. Usually, local measures alone, or in combination with antifibrinolytics and/or desmopressin, are sufficient to obtain hemostasis. Platelet transfusions may be needed in the setting of bleeding refractory to first-line measures. Due to the complex nature of the care, management of patients with MYH9-RD should be done under the supervision of a hemophilia treatment center.

Delta-granule platelet storage pool deficiency (δ-PSPD) is a qualitative platelet function defect associated with variable bleeding phenotypes. Platelet electron microscopy (EM) is commonly utilized to evaluate for δ-PSPD, but intrapatient variability in platelet δ-granule numbers by EM is currently unknown. Fifteen young women aged 11 to 17 years presenting to a young women’s hematology clinic for the evaluation of heavy menstrual bleeding underwent platelet EM testing at their initial hematology clinic visit and at 1 and 3 months later. Platelet aggregation of platelet-rich plasma by light transmission was also performed on all patients at their initial visit. Eight patients had average δ-granules per platelet consistently ≥2. Three patients were found to have average δ-granules per platelet

Delta-granule platelet storage pool deficiency (δ-PSPD) is a poorly studied bleeding diathesis resulting from either decreased granule content or decreased average number of platelet δ-granules. Light transmission aggregometry (LTA) is commonly used to evaluate for δ-PSPD and platelet electron microscopy (EM) is used to confirm the diagnosis. Currently, little data exist examining the relationship between the likelihood of abnormal platelet aggregation findings, severity of δ-granule deficiency on platelet EM, and severity of bleeding symptoms in patients with δ-PSPD. Patients diagnosed with δ-PSPD by platelet EM who also underwent LTA testing were identified at a single institution for correlation between severity of bleeding, average number of platelet δ-granules, and number of agonist abnormalities on LTA. No statistically significant association was identified between the average number of δ-granules per platelet and likelihood of an abnormal LTA. LTA abnormalities were quite varied and only 50% diagnosed with δ-PSPD on EM had abnormal aggregation testing. Also, no correlation was seen between the number of clinical bleeding symptoms, number of average δ-granules per platelet, and the number of LTA agonist abnormalities. Our findings highlight the difficulties inherent in the laboratory evaluation of platelet function.

Myeloproliferative neoplasms (MPNs) are a group of clonal disorders characterized by hyperproliferation of hematologic cell lines and have been associated with tyrosine kinase JAK2-V617F mutations. Secondary acute myeloid leukemia (sAML) is a known complication of JAK2-V617F+ MPNs and bears a poor prognosis. Although the evolution of a JAK2-V617F+ MPN to a mixed-lineage leukemia has been reported in the pediatric population, no evolutions into sAML have been described. We present a case of a one-year-old girl diagnosed with JAK2-V617F+ MPN with evolution into sAML. Despite initial morphologic remission, she eventually relapsed and succumbed to her disease.

Venous thromboembolism (VTE) is being increasingly recognized in children with sickle cell disease (SCD). In a retrospective cohort study, we identified bilateral central venous catheter (CVC) placement as an independent risk factor for VTE. At our institution, the only indication for bilateral CVC placement in children with SCD is erythrocytapheresis. To investigate the impact of erythrocytapheresis on coagulation, we measured levels of natural anticoagulants in 11 patients with SCD on chronic erythrocytapheresis, immediately before and after apheresis. We demonstrated a statistically significant reduction in most parameters. Additional studies are needed to further investigate the exact etiology and clinical impact of this acute decrease.

Objectives To describe the cumulative incidence of venous thromboembolism (VTE) in children with sickle cell disease (SCD) followed at a single institution and report on the risk factors associated with VTE development. Study design Charts for all patients with SCD, aged 0-21 years, followed at Nationwide Children's Hospital over a 6-year period (January 1, 2009, to January 31, 2015) were reviewed. Data on VTE diagnosis, sex, body mass index/weight-for-length, SCD genotype, SCD clinical complications, central venous catheter (CVC) placement, and thrombophilia testing were collected. Results Cumulative incidence of VTE in children with SCD followed at a single tertiary care institution was found to be 2.9% (12/414). Nine of the 12 VTE were CVC-associated. On univariate analysis, hemoglobin SS genotype (OR 10.7, 95% CI 1.4-83.5), CVC presence (OR 34.4, 95% CI 8.9-134.6), central nervous system vasculopathy (OR 19.4, 95% CI 5.6-63.4), chronic transfusion therapy (OR 30.6, 95% CI 8.9-122.2), and older age (P = .03) were associated with VTE. However, presence of CVC was the only independent risk factor identified on multivariable logistic regression analysis (OR 33.8, 95% CI 8.7-130.9). Conclusion In our institution, nearly 3% of children with SCD had a history of VTE. CVC is an independent predictor of VTE in children with SCD.

Introduction Pediatric high grade gliomas are rare tumors with poor outcomes and incompletely defined management. We conducted a multi-institutional retrospective study to evaluate association of clinical, pathologic, and treatment characteristics with outcomes.Materials and methodsFifty-one patients treated from 1984-2008 at Ohio State University or University of Michigan were included. Histologic subgroups were compared. Log-rank and stepwise Cox proportional hazard modeling were used to analyze progression-free survival (PFS) and overall survival (OS) within the whole group, grade III subgroup, grade IV subgroup, and subtotal resection/biopsy subgroup. ResultsMedian OS was 27.6 months. Grade III histology, complete tumor resection, and cerebral tumor location correlated with improved PFS and OS. Temozolomide use and chemotherapy after radiotherapy or chemoradiation were associated with better PFS while seizure at presentation was associated with better OS. In multivariate analysis, complete resection and chemotherapy following radiotherapy or chemoradiation were independent predictors for improved PFS and OS. For grade III and IV subgroups, complete resection was associated with improved OS (grade III) and seizure presentation was associated with improved OS (grade IV). In the incompletely resection subgroup, temozolomide use and concurrent chemoradiation independently correlated with improved PFS, while higher radiation dose (≥ 59.4 Gy), and adjuvant chemotherapy were independently associated with improved OS. DiscussionTotal resection and receiving chemotherapy adjuvant to radiation or chemoradiation are most closely associated with improved PFS and OS. For higher risk incompletely-resected patients, temozolomide use and treatment intensification with concurrent chemoradiation, adjuvant chemotherapy, and higher radiation dose were associated with improved outcomes.

Background The number of adolescents who are prescribed hormonal contraception (HC) for contraceptive and noncontraceptive indications is increasing. Approximately 1 of 4 female adolescents will use some form of HC by age 19 years. Venous thromboembolism (VTE) is a rare, but life-threatening complication associated with HC use. Although adolescents aged 15 to 19 years have the lowest absolute HC-associated VTE risk, they still account for 5.9% of HC-associated VTE. The absolute HC-associated VTE risk for those younger than 15 years of age is not well described. Objective The objectives of this report are to describe the current literature regarding HC-associated VTE in adolescents, to review the coagulation cascade and in vivo coagulation, to highlight differences between the adolescent and adult coagulation profiles, to discuss coagulation profile changes related to HC use, and to identify knowledge deficits for future study. Conclusion The mechanisms and confounding variables that lead to HC-associated VTE in all adolescents are not well understood because many large HC studies exclude female adolescents younger than 18 years of age. Because of the paucity of data in this age group, observational studies and randomized controlled trials of VTE risk in adolescents on varying forms of HC are needed. Studies should include female adolescents across the entire adolescent age span (12-21 years) to better understand HC-associated VTE risk in this population.

Purpose: Alveolar rhabdomyosarcoma that harbors the PAX3–FOXO1 fusion gene (t-ARMS) is a common and lethal subtype of this childhood malignancy. Improvement in clinical outcomes in this disease is predicated upon the identification of novel therapeutic targets. Experimental Design: Robust mouse models were used for in vivo analysis, and molecular studies were performed on xenografts treated in parallel. Two independent patient sets (n = 101 and 124) of clinically annotated tumor specimens were used for analysis of FANCD2 levels and its association with clinical and molecular characteristics and outcomes. Results: Our xenograft studies reveal a selective suppression of FANCD2 by m-TOR kinase inhibition and radiosensitization of the t-ARMS line only. In the initial patient set, we show that FANCD2 transcript levels are prognostic in univariate analysis, and are significantly associated with metastatic disease and that the copresence of the translocation and high expression of FANCD2 is independently prognostic. We also demonstrate a significant and nonrandom enrichment of mTOR-associated genes that correlate with FANCD2 gene expression within the t-ARMS samples, but not within other cases. In the second patient set, we show that on a protein level, FANCD2 expression correlates with PAX3–FOXO1 fusion gene and is strongly associated with phospho-P70S6K expression in cases with the fusion gene. Conclusions: Our data demonstrate that FANCD2 may have a significant role in the radiation resistance and virulence of t-ARMS. Indirectly targeting this DNA repair protein, through mTOR inhibition, may represent a novel and selective treatment strategy. Clin Cancer Res; 20(14); 3884–95. ©2014 AACR.

Background Most pediatric venous thromboembolism (VTE) occur in children with at least one complex chronic condition (CCC) admitted to a tertiary care pediatric hospital (Setty et al, Pediatr Blood Cancer2012). Reports estimate 14.6%-29% of all inpatient childhood VTE occur in patients with chronic pediatric heart disease (CPHD) (Andrew et al, Blood 1994; Rafinni et al, Pediatrics 2009). The influence of acute VTE risk factors and the impact of non-cardiac CCCs on VTE in CPHD remain unknown. A large cohort of privately-insured children was used to evaluate the odds of VTE, estimate the healthcare burden, and delineate the risk factors associated with VTE diagnoses in CPHD. Methods Children Results There were 120,884 children 0-17 years of age with a CPHD diagnosis. VTE events occurred in 957 (0.79%) of these children, 802 (83.8%) of which were isolated DVT and 155 (16.2%) were PE with or without concomitant DVT. Male gender was significantly associated with VTE (P All CPHD were associated with a significant VTE risk except those with conduction disorders or dysrhythmias (Table 1). VTE occurred in 2.3% of children with single ventricle physiology, 1.9% of those with acquired CPHD, 1.6% with cardiomyopathy, and 0.5% with double ventricle physiology. Children who experienced VTE were significantly (P All measures of healthcare utilization (mean number of inpatient admissions (2.19 vs 0.62), mean inpatient length of stays (55.14 vs 8.7 days), mean number of outpatient visits (28.6 vs 11.22), and mean number of pharmaceutical claims (13.27vs 4.74)) were significantly higher (P Conclusions Although VTE in CPHD patients is rare, it does carry a significantly increased healthcare resource utilization and in-hospital mortality. All of the co-morbid conditions examined were significantly associated with VTE, but when controlling for non-cardiac CCC the odds of VTE was not affected. All of the non-cardiac CCC were significantly associated with VTE except malignancy and GI CCC when accounting for recent cardiac surgery. This suggests that non-cardiac CCCs may be an important determinant of VTE risk for children with CPHD. Disclosures No relevant conflicts of interest to declare.

CAMT is a bone marrow failure syndrome that usually presents with isolated thrombocytopenia soon after birth. HSCT is curative, and MAC is associated with increased transplant-related morbidity and mortality, especially in the unrelated setting. We used a RIC regimen with alemtuzumab, fludarabine, and melphalan in a seven-month-old patient with CAMT who underwent a MUD HSCT. The transplant was well tolerated with few complications. Neutrophil and platelet engraftment occurred on day +12 and +29, respectively, and she had 100% donor chimerisms on days +19.

Introduction The rate of venous thrombo-embolism (VTE) in patients with sickle cell disease (SCD) is estimated to be 4 - 8%; the incidence of catheter-associated VTE in this cohort is 0.16-0.99 per 1000 catheter days. Possible mechanisms for VTE in patients with SCD include hyperviscosity, ischemia reperfusion injury and chronic vascular inflammation. Additionally, patients with SCD exhibit decreased plasma levels of natural anticoagulants such as proteins C and S compared to healthy adults. A retrospective review at our institution found that the incidence of central venous line (CVL)-associated VTE in children with SCD was 0.12/1000 catheter days. On multivariate analysis, CVLs were identified as the only independent risk factor for VTE. Among patients with CVL, we found an association between bilateral CVLs and VTE (Odds Ratio [95% CI] = 10.3 [1.1-92.2]). Children with SCD frequently require CVLs for intravenous access or chronic erythrocytapharesis to reduce SCD-related complications. It is unknown, however, if erythrocytapharesis may also disrupt their natural anticoagulants levels and further increase their risk for subsequent VTE. We hypothesized that erythrocytapheresis may contribute to the pro-coagulant phenotype by altering patients' natural anticoagulants levels. Methods As part of a quality improvement initiative we measured antithrombin (AT), protein C antigen and activity, protein S antigen (total and free) and activity prior to being placed on the apheresis circuit and after completion of exchange in patients with SCD (0-21 years of age) undergoing chronic erythrocytapheresis who had a CVL (between January 1, 2009 and January 31, 2015). D-Dimer levels were obtained pre exchange only. Protein C and S levels were measured using ELISA based assays; protein C and S activities were measured using a clotting based assay and AT was measured using a chromogenic assay. The resulting levels, pre and post-erythrocytapheresis were analyzed using a paired nonparametric Wilcoxon rank test. Results Eleven patients were eligible for this study (8 females, 3 males). Median age at the time of erythrocytapheresis was 14 years (±3.65 SD) years. Indications for erythrocytapheresis included primary/ secondary stroke prevention or recurrent acute chest syndrome. All patients had bilateral CVLs in place. Four of the included patients had a history of VTE; 2 patients were on anticoagulation with low molecular weight heparin at the time of the study. The mean value for total protein S antigen (65u/dL; normal >72u/dL), free protein S antigen (53u/dL; normal >70u/dL), and protein S activity (51IU/mL; normal 65-138IU/ml) were all abnormal pre- erythrocytapheresis and decreased significantly following erythrocytapheresis (52u/dL, 44u/dL, and 44IU/mL respectively). Mean protein C antigen (71u/dL; normal >55u/dL), protein C activity (71%; normal 55-111%), and AT activity (104%; normal 77-132%) were within the normal range pre-erythrocytapheresis and decreased significantly post-erythrocytapheresis. We demonstrated significantly lower levels of protein C antigen (p=0.01), protein C activity (p=0.01), total protein S antigen (p=0.005), free protein S antigen (p=0.036), protein S activity (p=.04), and AT activity (p=.004) following erythrocytapheresis (Figure). D-Dimer levels were elevated in 6/11 patients (54.5%). Conclusions Pre- and post-erythrocytapheresis levels of natural endogenous anticoagulants investigated in a cohort of patients with SCD undergoing chronic erythrocytapheresis demonstrated that levels of all investigated proteins were significantly lower in patients following erythrocytapheresis. D-dimer levels were elevated in the majority of patients pre exchange but the importance of this finding is unclear. Given the relatively short half-life of the natural anticoagulants (2-3 hours for protein C and 36-60 hours for AT and protein S), it is unclear if this acute decrease of natural anticoagulants is clinically relevant. Further investigation is needed to determine if this acute decrease may contribute to an increased VTE risk in children with SCD undergoing apheresis. Figure 1. Figure 1. Disclosures Woods: Biogen: Other: Educational Grant. Dunn:Novo Nordisk: Consultancy, Other: Educational Grant; CSL Behring: Consultancy, Other: Data Safety Monitoring Board; Bayer: Consultancy, Other: educational grant; Biogen: Consultancy, Other: Educational grant, Research Funding; Baxalta: Consultancy, Other: educational grant, Research Funding; Ohio State University: Employment; Pfizer: Other: Grant Review Board.