Acute thrombosis of a giant perimedullary arteriovenous fistula in a pediatric HHT patient.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant hereditary disorder that results in arteriovenous malformations (AVMs) in the nose, mucocutaneous surfaces and visceral organs, including lung, brain, liver, bowel and rarely spinal cord. We describe a case of a young child with HHT who presented with acute paraparesis due to acute thrombosis of a spinal perimedullary arteriovenous fistula. Patient underwent coil embolization of spinal arteriovenous shunt with resolution of clinical symptoms. This case highlights the possibility of catastrophic complications in young children with HHT, the potential preventive role of screening for spinal AVMs in HHT and the importance of timely intervention.

Oral Contraceptive Use in Obese Adolescents: A Cautionary Tale.

Venous thromboembolism (VTE) is a life-threatening complication rarely encountered with the use of combined oral contraceptives (COCs). Obesity is an additional thrombosis risk factor that has been shown to further increase the risk of VTE with the use of COCs. We present 5 cases of obese adolescents (body mass index >30 kg/m2) who encountered thrombosis complications while on COCs. Although the absolute risk of VTE events in the setting of COCs is rare, caution should be observed when choosing hormonal therapy and safer COCs alternatives discussed with adolescents who are obese.

A prospective, blinded study of a PF4-dependent assay for HIT diagnosis.

Heparin-induced thrombocytopenia (HIT) is a life-threatening, prothrombotic, antibody-mediated disorder. To maximize the likelihood of recovery, early and accurate diagnosis is critical. Widely available HIT assays, such as the platelet factor 4 (PF4) heparin enzyme-linked immunosorbent assay (ELISA) lack specificity, and the gold-standard carbon 14-labeled serotonin release assay (SRA) is of limited value for early patient management because it is available only through reference laboratories. Recent studies have demonstrated that pathogenic HIT antibodies selectively activate PF4-treated platelets and that a technically simpler assay, the PF4-dependent P-selectin expression assay (PEA), may provide an option for rapid and conclusive results. Based upon predefined criteria that combined 4Ts scores and HIT ELISA results, 409 consecutive adults suspected of having HIT were classified as disease positive, negative, or indeterminate. Patients deemed HIT indeterminate were considered disease negative in the primary analysis and disease positive in a sensitivity analysis. The ability of PEA and SRA to identify patients judged to have HIT was compared using receiver operating characteristic curve statistics. Using these predefined criteria, the diagnostic accuracy of PEA was high (area under the curve [AUC], 0.94; 95% confidence interval [CI], 0.87-1.0) and similar to that of SRA (AUC, 0.91; 95% CI, 0.82-1.0). In sensitivity analysis, the AUCs of PEA and SRA were also similar at 0.88 (95% CI, 0.78-0.98) and 0.86 (95% CI, 0.77-0.96), respectively. The PEA, a technically simple nonradioactive assay that uses ∼20-fold fewer platelets compared with the SRA, had high accuracy for diagnosing HIT. Widespread use of the PEA may facilitate timely and more effective management of patients with suspected HIT.

Computer-based simulation to reduce EHR-related chemotherapy ordering errors.

BACKGROUND: The electronic health record (EHR) is a contributor to serious patient harm occurring within a sociotechnical system. Chemotherapy ordering is a high-risk task due to the complex nature of ordering workflows and potential detrimental effects if wrong chemotherapeutic doses are administered. Many chemotherapy ordering errors cannot be mitigated through systems-based changes due to the limited extent to which individual institutions are able to customize proprietary EHR software. We hypothesized that simulation-based training could improve providers' ability to identify and mitigate common chemotherapy ordering errors. METHODS: Pediatric hematology/oncology providers voluntarily participated in simulations using an EHR testing ("Playground") environment. The number of safety risks identified and mitigated by each provider at baseline was recorded. Risks were reviewed one-on-one after initial simulations and at a group "lunch-and-learn" session. At three-month follow-up, repeat simulations assessed for improvements in error identification and mitigation, and providers were surveyed about prevention of real-life safety events. RESULTS: The 8 participating providers identified and mitigated an average of 5.5 out of 10 safety risks during the initial simulation, compared 7.4 safety risks at the follow up simulation (p=0.030). Two of the providers (25%) reported preventing at least one real-world patient safety event in the clinical setting as a result of the initial training session. CONCLUSIONS: Simulation-based training may reduce providers' susceptibility to chemotherapy ordering safety vulnerabilities within the EHR. This approach may be used when systems-based EHR improvements are not feasible due to limited ability to customize local instances of proprietary EHR software.

Clinical Outcomes of May-Thurner Syndrome in Pediatric Patients: A Single Institutional Experience.

Introduction May-Thurner syndrome (MTS) is a vascular anatomic variant resulting in compression of the left common iliac vein by the right common iliac artery, affecting approximately 22% of the population. In adults, following acute deep vein thrombosis (DVT) of the iliofemoral veins, the incidence of postthrombotic syndrome (PTS) and recurrent DVT are high if treated with anticoagulation alone, warranting adjunctive treatment with thrombolysis and stent placement. However, there is paucity of literature documenting the course of treatment and associated outcomes in pediatric patients with MTS. Methods A retrospective chart review of pediatric patients (≤ 18 years of age) with radiologic confirmation of MTS with or without DVT evaluated and/or treated at our institution from January 1, 2005 through December 31, 2015 was conducted. Results Seventeen patients (4 male; 13 female) were identified. Median age was 15.4 years (range 8.8-17.1 years) with a median follow-up of 1.2 years (range 0.4-7.5 years). Thirteen (76.5%) patients presented with left lower extremity DVT. Management included catheter-directed thrombolysis ( n = 5), systemic thrombolysis ( n = 1), and mechanical thrombectomy ( n = 1). Fifteen patients were treated with anticoagulation including two patients with endovascular stents without DVT. Median duration of anticoagulation was 6.3 months (range 3.2-18.7 months). Ten patients (59%) underwent stent placements. Complete and partial thrombus resolution was noted in six patients each and no resolution in one patient. Four patients had recurrence/progression of thrombus ( n = 3 with stents) at a median time of 29 days (range 12-495 days). No bleeding complications were observed. Clinically documented or self-reported PTS was noted in 8 patients (62%). Conclusion There are no clear guidelines for MTS management in children and adolescents. In our cohort, thrombolysis, anticoagulation, or stent placements were not associated with bleeding risks, with recurrence/progression of DVT and signs and symptoms of PTS noted in 30 and 62%, respectively. Further studies are needed to determine a standardized treatment approach of the pediatric patient with MTS with or without thrombosis.

Cerebral sinovenous thrombosis in pediatric hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) may result in thrombotic central nervous system complications. We present a child with diarrhea-associated HUS who developed new-onset focal seizures secondary to cerebral sinovenous thrombosis (CSVT). Her CSVT was treated with low-molecular-weight heparin. The patient's seizures were controlled with levetiracetam, and her HUS was managed supportively with hemodialysis. Repeat imaging nearly 6 months following presentation and initiation of anticoagulation demonstrated cerebral sinus enlargement and persistent intraluminal webbing. Anticoagulation was discontinued after 6 months, and she did not experience long-term gross neurologic sequelae. CSVT is a complication of HUS that has not been previously described. In this report, we summarize the thrombotic central nervous system complications of pediatric HUS.

Case Report: Development of Factor VIII Inhibitor in a Patient with an Uncommon de novo Mutation in the Factor VIII Gene.

The development of factor VIII inhibitors remains a significant clinical challenge in the management of hemophilia A. We present a patient of mixed ethnicity with severe hemophilia A who was found to have a F8 gene hemizygous c.5815G>T mutation resulting in an Ala1939Ser substitution (Ala1920Ser in legacy nomenclature) and possible splice site change that has been reported in only 1 patient previously. He developed an inhibitor shortly after starting replacement recombinant factor VIII (Advate®; Baxalta, Bannockburn, IL, USA) and was successfully treated with immune tolerance therapy. Our report describes the second patient reported to have severe hemophilia due to this mutation and the only case of a factor VIII inhibitor associated with this mutation.

Cross-Cultural Medical Care Training and Education: a National Survey of Pediatric Hematology/Oncology Fellows-in-Training and Fellowship Program Directors.

Pediatric hematologists/oncologists face complex situations such as breaking bad news, treatment/clinical trials discussions, and end-of-life/hospice care. With increasing diversity in patient and physician populations, cultural competency and sensitivity training covering different aspects of pediatric hematology/oncology (PDHO) care can help improve health care delivery and reduce disparities. Though it is considered a required component of fellowship training, there is no clearly defined curriculum meant specifically for PDHO fellows-in-training (PDHO-F). A national online survey of 356 PDHO-F and 67 PDHO program directors (PDHO-PD) was conducted to assess the educational experience, perceptions about identifying barriers including one's own biases and trainee comfort in delivering culturally sensitive care in various PDHO relevant clinical situations. One hundred and eleven (31.2%) PDHO-F and 27 (40.3%) PDHO-PD responded. 30.6% of PDHO-F "strongly agreed/agreed" they received comprehensive cross-cultural communication (CCC) training. The top two teaching methods were faculty role modeling and informal teaching. Majority of CCC training is in medical school or residency and only 10.8% of PDHO-F reported that most of their CCC training was in fellowship. In most clinical situations, there was a modest direct correlation between the fellow's level of agreement that they received comprehensive CCC training and their comfort level. Comfort level with some clinical situations was also significantly different based on year of training. Fellowship training programs should have CCC curricula which use experiential learning models and lay the foundation for promoting cultural awareness, self-reflection, and better patient-physician partnerships which can eventually adapt to and surmount the challenges unique to the physician's chosen field of practice.

Diagnostic laboratory standardization and validation of platelet transmission electron microscopy.

Platelet transmission electron microscopy (PTEM) is considered the gold standard test for assessing distinct ultrastructural abnormalities in inherited platelet disorders (IPDs). Nevertheless, PTEM remains mainly a research tool due to the lack of standardized procedures, a validated dense granule (DG) count reference range, and standardized image interpretation criteria. The aim of this study was to standardize and validate PTEM as a clinical laboratory test. Based on previously established methods, we optimized and standardized preanalytical, analytical, and postanalytical procedures for both whole mount (WM) and thin section (TS) PTEM. Mean number of DG/platelet (plt), percentage of plts without DG, platelet count (PC), mean platelet volume (MPV), immature platelet fraction (IPF), and plt light transmission aggregometry analyses were measured on blood samples from 113 healthy donors. Quantile regression was used to estimate the reference range for DG/plt, and linear regression was used to assess the association of DG/plt with other plt measurements. All PTEM procedures were standardized using commercially available materials and reagents. DG interpretation criteria were established based on previous publications and expert consensus, and resulted in improved operator agreement. Mean DG/plt was stable for 2 days after blood sample collection. The median within patient coefficient of variation for mean DG/plt was 22.2%; the mean DG/plt reference range (mid-95th %) was 1.2-4.0. Mean DG/plt was associated with IPF (p = .01, R2 = 0.06) but not age, sex, PC, MPV, or plt maximum aggregation or primary slope of aggregation (p > .17, R2 < 0.02). Baseline ultrastructural features were established for TS-PTEM. PTEM was validated using samples from patients with previously established diagnoses of IPDs. Standardization and validation of PTEM procedures and interpretation, and establishment of the normal mean DG/plt reference range and PTEM baseline ultrastructural features, will facilitate implementation of PTEM as a valid clinical laboratory test for evaluating ultrastructural abnormalities in IPDs.

EBV-PTLD, Adenovirus, and CMV in Pediatric Allogeneic Transplants With Alemtuzumab as Part of Pretransplant Conditioning: A Retrospective Single Center Study.

The risk of viral infections and reactivation occurring in the setting of pediatric allogeneic hematopoietic stem cell transplantation is a concern in the pediatric patient, especially with the use of Alemtuzumab (Campath) as a conditioning agent. The purpose of this study was to determine the incidence of Epstein-Barr virus posttransplant lymphoproliferative disorder (EBV-PTLD), cytomegalovirus (CMV), and adenovirus among pediatric recipients of alemtuzumab at our institution. We found that EBV-PTLD occurred in 2.1% of transplants (1 matched unrelated donor [MUD] recipient), CMV reactivation occurred in 12.5% of transplants (4 MUD and 2 matched related donor [MRD] recipients) with disseminated CMV in 2.1% of cases (1 MRD recipient), and adenovirus infection occurred in 8.3% of the total transplants (2 MUD and 2 MRD recipients). Alemtuzumab continues to be used as a method of graft-versus-host disease and graft failure prevention among pediatric recipients of hematopoietic stem cell transplantation and seems to be safer than previously reported. At our institution, alemtuzumab has not increased the risk for EBV-PTLD, CMV infection, or adenovirus.

Obesity, sedentary lifestyle, and video games: The new thrombophilia cocktail in adolescents.

Rates of venous thromboembolism have increased in the adolescent population over the last two decades, likely due to advanced diagnostics, increased use of central venous catheters, chronic medical conditions, obesity, and oral contraceptive use. Of these factors, a modifiable risk factor for adolescents is obesity. Sedentary lifestyle and prolonged immobilization are additional prothrombotic risk factors that are often associated with obesity. With ever-increasing screen time, sedentary behavior has risen accordingly, especially among gamers. We present four cases of adolescents who developed life-threatening venous thromboembolic events in the setting of obesity, sedentary lifestyle and/or immobilization, and prolonged video game use.

Hermansky-Pudlak syndrome subtype 5 (HPS-5) novel mutation in a 65 year-old with oculocutaneous hypopigmentation and mild bleeding diathesis: The importance of recognizing a subtle phenotype.

Hermansky-Pudlak syndrome (HPS) - characterized by the distinct clinical phenotypes of both oculocutaneous albinism and mild bleeding diathesis-is caused by mutations in genes that have crucial roles in the assembly of cellular organelles (skin melanosomes, platelet delta [dense] granules, lung lamellar bodies, and cytotoxic T-cell lymphocyte granules). Immunodeficiency, pulmonary fibrosis and granulomatous colitis are associated with some, but not all subtypes of HPS, with varying degrees of clinical severity. We describe a patient diagnosed with platelet dense granule storage pool deficiency (DG-SPD) at age 38 years after he presented with spontaneous intracranial hemorrhage. His mild oculocutaneous hypopigmentation was subtle. In the following 27 years, he did not develop severe bleeding nor pulmonary or gastrointestinal complications. A novel homozygous c.1960A>T; p.Lys654* mutation in the HPS-5 protein gene (HPS5) was identified through next generation sequencing, (NGS) which is consistent with the patient's clinical and laboratory phenotypes. This case underscores the importance of recognizing the mild clinical phenotype of HPS-5 and utilization of both laboratory and molecular testing for diagnosis, prognostication, and surveillance for end organ damage in patients affected with HPS.

Management of pediatric hepatocellular carcinoma: A multimodal approach.

HCC is rare in the pediatric population, but is the second most common liver malignancy in children. Survival rates for primary unresectable HCC have been dismal. The objective of this study was to describe our experience with a multimodal approach for the management of unresectable HCC in two adolescent patients and to review the literature. Both patients are currently alive with no recurrence at 51 and 29 months post-transplant. Multimodality treatment involving chemotherapy with doxorubicin, cisplatin, and sorafenib; TACE; timely liver transplantation; and post-transplant therapy with sorafenib and mTOR inhibitors may help improve outcomes and prolong survival in pediatric patients with unresectable HCC.

Comprehensive Platelet Phenotypic Laboratory Testing and Bleeding History Scoring for Diagnosis of Suspected Hereditary Platelet Disorders: A Single-Institution Experience.

OBJECTIVES: Patients with hereditary/congenital platelet disorders (HPDs) have a broad range of clinical manifestations and laboratory phenotypes. We assessed the performance characteristics of the International Society on Thrombosis and Haemostasis bleeding assessment tool (ISTH-BAT) and clinically validated platelet laboratory tests for diagnosis of HPDs. METHODS: The records of 61 patients with suspected HPDs were reviewed and ISTH-BAT scores calculated. RESULTS: Nineteen (31%) patients had thrombocytopenia, and 46 (75%) had positive ISTH-BAT scores. Thirteen and 17 patients had prolonged PFA-100 (Dade Behring, Miami, FL) adenosine diphosphate and epinephrine closure times, respectively. Twenty-two had abnormal platelet light transmission aggregation. Twenty-four had platelet transmission electron microscopy (PTEM) abnormalities (10 dense granule deficiency, 14 other ultrastructural abnormalities). Positive ISTH-BAT scores were associated with thrombocytopenia (P < .0001) and abnormal PTEM (P = .002). Twenty-three patients had normal results. CONCLUSIONS: ISTH-BAT identified patients with suspected HPDs but lacked a robust association with laboratory abnormalities. Despite comprehensive laboratory testing, some patients may have normal results.

A retrospective review of pediatric antiphospholipid syndrome and thrombosis outcomes.

: Pediatric antiphospholipid syndrome (APS) is characterized by vascular thromboses and multisystem involvement associated with persistently positive antiphospholipid antibodies testing. There is limited literature regarding risk factors for development of thrombosis and long-term thrombotic outcomes in pediatric APS. The objective of our study was to review our institutional experience with pediatric APS and thrombosis outcomes. We conducted a 20-year retrospective review to study the clinical features, management, and long-term outcomes of patients between ages 6 months and 18 years diagnosed with APS. Seventeen patients (7 female; 10 male), with median age at first thrombosis being 15.3 years (range: 0.63-17.98 years) were included. The median follow-up period was 4.3 years (range: 0.8-16.9 years). Venous thrombosis was noted in 11 patients (64.7%) with arterial events occurring in six patients (35.3%). Nine (53%) patients were noted to have primary APS. Recurrent and/or progressive thrombotic events occurred in 10 patients (58.8%), which is higher than reported literature. The median time for recurrence/progression was 1.4 years (range: 0.37-11.85 years). At the time of recurrence/progression, only two (20%) patients were at therapeutic levels of anticoagulation. The high recurrence rate with majority of patients not being on therapeutic levels of anticoagulation at the time of the event along with 60% of recurrent events occurring at least 1 year from first vascular event suggests the possible need for long-term anticoagulation. However, larger pediatric studies are required to assess the need for long-term/indefinite anticoagulation.

Lemierre Syndrome: A Retrospective Study of the Role of Anticoagulation and Thrombosis Outcomes.

Lemierre syndrome (LS) is a multisystemic infection beginning in the oropharynx and leading to thrombosis of the internal jugular vein (IJV) with septic emboli and potential thrombotic extension to the central nervous system. Although patient outcomes have improved with early initiation of antimicrobial therapies, there is no consensus regarding the role of anticoagulation in LS. To better define the role of anticoagulation therapy in LS and determine whether anticoagulation improves thrombosis outcomes, we conducted a retrospective chart review of pediatric and adult patients diagnosed with LS and managed at our institution from January 1998 to December 2014. Eighteen patients (9 females and 9 males) were included in this analysis, 6 of whom received ≥4 weeks of anticoagulation therapy (median 23.1 weeks, range 6.9-32.9 weeks). Six patients were in the pediatric age group (<18 years). All patients received broad-spectrum antibiotics. All patients had improvement in their thrombi by 3 months (nonanticoagulated patient group: complete response [CR], n = 9; partial response [PR], n = 3; anticoagulated patient group: CR, n = 2; PR, n = 4). No patient developed recurrent thrombosis or progression during the follow-up period, regardless of anticoagulation status. Our study suggests that anticoagulation in LS may not affect thrombosis outcomes.