Distinctive phenotypes in two children with novel germline RUNX1 mutations - one with myeloid malignancy and increased fetal hemoglobin.

RUNX1 associated familial platelet disorder (FPD) is a rare autosomal dominant hematologic disorder characterized by thrombocytopenia and/or altered platelet function. There is an increased propensity to develop myeloid malignancy (MM) - acute myeloid leukemia, myeloproliferative neoplasms or myelodysplastic syndrome often in association with secondary somatic variants in other genes. To date, 23 FPD-MM pediatric cases have been reported worldwide. Here, we present two new kindreds with novel RUNX1 pathogenic variants in which children are probands. The first family is a daughter/mother diad, sharing a heterozygous frameshift variant in RUNX1 gene (c.501delT p.Ser167Argfs*9). The daughter, age 13 years, presented with features resembling juvenile myelomonocytic leukemia - severe anemia, thrombocytopenia, high white cell count with blast cells, monocytosis, increased nucleated red cells and had somatic mutations with high allele burden in CUX1, PHF6, and SH2B3 genes. She also had increased fetal hemoglobin and increased LIN28B expression. The mother, who had a long history of hypoplastic anemia, had different somatic mutations- a non-coding mutation in CUX1 but none in PHF6 or SH2B3. Her fetal hemoglobin and LIN28B expression were normal. In the second kindred, the proband, now 4 years old with thrombocytopenia alone, was investigated at 3 months of age for persistent neonatal thrombocytopenia with large platelets. Molecular testing identified a heterozygous intragenic deletion in RUNX1 encompassing exon 5. His father is known to have increased bruising for several years but is unavailable for testing. These two cases illustrate the significance of secondary mutations in the development and progression of RUNX1-FPD to MM.

Utility of thromboelastography for the diagnosis of von Willebrand disease.

Von Willebrand disease (VWD) is an inherited bleeding disorder that is caused by a quantitative or qualitative deficiency of von Willebrand factor (VWF). The National Heart, Lung, and Blood Institute (NHLBI) guidelines for the diagnosis of VWD state that a VWF activity (VWF:RCo) of <30 IU/dL or <50 IU/dL with symptoms of clinical bleeding are consistent with the diagnosis of VWD. However, current gold-standard diagnostic testing takes days to have complete results. Thromboelastography (TEG) is a testing method that provides a graphical trace that represents the viscoelastic changes seen with fibrin polymerization in whole blood, therefore providing information on all phases of the coagulation process. This study describes the TEG characteristics in 160 patients who presented for workup of a bleeding disorder and a subset of those were subsequently diagnosed with VWD. The TEG parameters, K-time (representing the dynamics of clot formation) and the maximal rate of thrombus generation (MRTG), were found to be sensitive in detecting patients with VWF:RCo <30 IU/dL. The TEG, unlike VWF:RCo, can be done in real time, and results are available to the clinician within an hour. This will definitely be beneficial in acute situations such as evaluation of and management of acute bleeding in patients with acquired deficiencies of VWF and may play an important role in the surgical management of patients with VWD.

Evidence for the transmission of parvovirus B19 in patients with bleeding disorders treated with plasma-derived factor concentrates in the era of nucleic acid test screening.

BACKGROUND: Parvovirus B19 (B19V) is a small, nonenveloped virus that typically causes a benign flu-like illness that occurs most frequently in childhood. The virus is resistant to current viral inactivation steps used in the manufacture of antihemophilic factor concentrates and B19V transmission through these products has been documented. Since 2000, B19V nucleic acid test (NAT) screening of plasma pools has been implemented to further decrease the viral burden in these products, but no study has examined populations using these products to assess the impact of the screening on B19V transmission. STUDY DESIGN AND METHODS: Blood specimens obtained from participants of a surveillance system established in federally supported specialized bleeding disorders clinics were used in a B19V seroprevalence study. RESULTS: A total of 1643 specimens from 1043 participants age 2 to 7 years born after B19V NAT screening was implemented were tested. Age-specific prevalence rates were generally higher for subjects exposed to either plasma-derived products alone or in combination with other products compared to subjects with no exposure to antihemophilic products. Overall, compared to participants unexposed to blood or blood products, those exposed to plasma-derived products alone were 1.7 times more likely to have antibodies to B19V (p = 0.002). CONCLUSION: These results are consistent with continued B19V transmission through plasma-derived factor concentrates. Effective viral inactivation and detection processes are needed to protect users of these products from infection with B19V or other new or emerging viruses.

Neonatal ECMO.

Extracorporeal membrane oxygenation (ECMO) is becoming increasingly utilized to manage neonates with cardiac and respiratory failure. The procedure involves extensive anticoagulation in a sick neonate with underlying disease pathology. In addition, the immature hemostatic system in the neonate adds to the complexity of titrating the necessary anticoagulation. This places the infant at greater risk for life threatening hemorrhage and thrombosis. Managing anticoagulation in these infants is extremely challenging and needs the expertise of a physician with a thorough knowledge of the intricacies of developmental hemostasis and limitations of the current laboratory techniques available to manage anticoagulation. This article provides a brief overview of the developing hemostatic system of the neonate and the challenges associated with managing anticoagulation in this vulnerable population of patients.

The Coags Uncomplicated App: Fulfilling Educational Gaps Around Diagnosis and Laboratory Testing of Coagulation Disorders.

BACKGROUND: Patients with coagulation disorders may present to a variety of physician specialties; however, accurate and efficient diagnosis can be challenging for physicians not specialized in hematology, due to identified gaps in knowledge around appropriate laboratory assays and interpretation of test results. Coags Uncomplicated was developed to fill this unmet educational need by increasing practical knowledge of coagulation disorders among nonexpert physicians and other health care professionals (HCPs) in a point-of-care (POC) setting. OBJECTIVE: The aim of this study was to assess patterns of use of the mobile app Coags Uncomplicated, a tool designed to support education regarding accurate and efficient diagnosis of bleeding disorders. METHODS: App metrics were obtained by tracking registered user data. Additionally, a survey was distributed to registered users, to assess circumstances and frequency of use. RESULTS: The most common specialties of 7596 registered US users were hematology-oncology (n=1534, 20.19%), hematology (n=1014, 13.35%), and emergency medicine (n=1222, 16.09%); most identified as physicians (n=4082, 53.74%). Specialties accounting for the greatest numbers of screen views were hematology-oncology (99,390 views), hematology (47,808 views), emergency medicine (23,121 views), and internal medicine (22,586 views). The most common diagnostic endpoints reached were disseminated intravascular coagulation (DIC; 2713 times), liver disease effect (2108 times), and vitamin K deficiency (1584 times). Of 3424 users asked to take the survey, 262 responded (7.65%); most were physicians in direct clinical care (71%) and specialized in hematology-oncology (39%) or emergency medicine (21%). Most frequent use was reported by hematologists (69%, ≥6 times) and hematologists-oncologists (38%, ≥6 times). Most physicians (89.2%) reported using the app for patient-case-related education around appropriate use of laboratory tests in diagnostic evaluation. Physicians rated Lab Value Analyzer (mean 4.43) and Lab Test Algorithm (mean 4.46) tools highly on a 5-point "how helpful" scale and were likely to recommend the app to colleagues. CONCLUSIONS: App use among physicians and other HCPs is consistent with value as a POC educational tool, which may facilitate differential diagnoses and appropriate early consultation with hematologists.

Acute megakaryoblastic leukemia with t(17;22)(q21;q13) and liver dysfunction.

The t(1;22)(p13;q13) is associated with acute megakaryoblastic leukemia (AMKL) seen mostly in young infants and known to have a poor prognosis. A 5-year-old child had prolonged prothrombin and partial thromboplastin times, low albumin, and decreased vitamin K-dependent coagulation factors and factor V activities at the time of AMKL diagnosis. All of these factors normalized following chemotherapy when remission was achieved. Cytogenetic analysis revealed a female karyotype with a balanced t(17;22)(q21;q13). Here, we present an AMKL pediatric case with a novel translocation and significant hepatocellular dysfunction that resolved with chemotherapy. The t(17;22) (q21;q13) may represent a variant of t(1;22)(p13;q13).

Fibrinolytic parameters in children with noncatheter thrombosis: a pilot study.

Although the incidence of pediatric thrombosis has increased over the last decade, noncatheter-related deep venous thrombosis (nCDVT) is rare in children. Congenital and acquired hypercoagulable states may play an important role in the pathogenesis of nCDVT. In this study, we evaluated fibrinolytic parameters by measuring individual concentrations of fibrinolytic proteins and by tissue factor initiated whole blood thromboelastography (TEG), in which a fibrin clot was lyzed by exogenously added tissue plasminogen activator (tPA). Children with nCDVT were compared with age and sex-matched controls. TAFI concentrations were significantly higher in the patient group but there was no difference in the PAI-1, tPA and lipoprotein (a) concentrations. Significantly decreased fibrinolysis was found on TEG in the patient group suggesting that hypofibrinolysis may play an important role in the pathogenesis of nCDVT in children. To our knowledge, this is the first pediatric study that has systematically evaluated the role of fibrinolysis in the pathogenesis of DVT. Given our results, the role of fibrinolysis in the pathogenesis of nCDVT in children should be further evaluated in larger studies.