Severe Dengue Is Associated with Consumption of von Willebrand Factor and Its Cleaving Enzyme ADAMTS-13

Severe dengue infections are characterized by thrombocytopenia, clinical bleeding and plasma leakage. Activation of the endothelium, the inner lining of blood vessels, leads to the secretion of storage granules called Weibel Palade bodies (WPBs). We demonstrated that severe dengue in Indonesian children is associated with a strong increase in plasma levels of the WPB constituents von Willebrand factor (VWF), VWF propeptide and osteoprotegerin (OPG). An increased amount of the hemostatic protein VWF was in a hyperreactive, platelet binding conformation, and this was most pronounced in the children who died. VWF levels at enrollment were lower than expected from concurrent VWF propeptide and OPG levels and VWF levels did not correlate well with markers of disease severity. Together, this suggests that VWF is being consumed during severe dengue. Circulating levels of the VWF-cleaving enzyme ADAMTS-13 were reduced. VWF is a multimeric protein and a subset of children had a decrease in large and intermediate VWF multimers at discharge. In conclusion, severe dengue is associated with exocytosis of WPBs with consumption of VWF and low ADAMTS-13 activity levels. This may contribute to the thrombocytopenia and complications of dengue

Severe Plasmodium falciparum Malaria Is Associated with Circulating Ultra-Large von Willebrand Multimers and ADAMTS13 Inhibition

Plasmodium falciparum infection results in adhesion of infected erythrocytes to blood vessel endothelium, and acute endothelial cell activation, together with sequestration of platelets and leucocytes. We have previously shown that patients with severe infection or fulminant cerebral malaria have significantly increased circulatory levels of the adhesive glycoprotein von Willebrand factor (VWF) and its propeptide, both of which are indices of endothelial cell activation. In this prospective study of patients from Ghana with severe (n = 20) and cerebral (n = 13) P. falciparum malaria, we demonstrate that increased plasma VWF antigen (VWF∶Ag) level is associated with disproportionately increased VWF function. VWF collagen binding (VWF∶CB) was significantly increased in patients with cerebral malaria and severe malaria (medians 7.6 and 7.0 IU/ml versus 1.9 IU/ml; p<0.005). This increased VWF∶CB correlated with the presence of abnormal ultra-large VWF multimers in patient rather than control plasmas. Concomitant with the increase in VWF∶Ag and VWF∶CB was a significant persistent reduction in the activity of the VWF-specific cleaving protease ADAMTS13 (∼55% of normal; p<0.005). Mixing studies were performed using P. falciparum patient plasma and normal pooled plasma, in the presence or absence of exogenous recombinant ADAMTS13. These studies demonstrated that in malarial plasma, ADAMTS13 function was persistently inhibited in a time-dependent manner. Furthermore, this inhibitory effect was not associated with the presence of known inhibitors of ADAMTS13 enzymatic function (interleukin-6, free haemoglobin, factor VIII or thrombospondin-1). These novel findings suggest that severe P. falciparum infection is associated with acute endothelial cell activation, abnormal circulating ULVWF multimers, and a significant reduction in plasma ADAMTS13 function which is mediated at least in part by an unidentified inhibitor

A New Cryogenic Apparatus to Search for the Neutron Electric Dipole Moment

A cryogenic apparatus is described that enables a new experiment, nEDM@SNS, with a major improvement in sensitivity compared to the existing limit in the search for a neutron Electric Dipole Moment (EDM). It uses superfluid $^4$He to produce a high density of Ultra-Cold Neutrons (UCN) which are contained in a suitably coated pair of measurement cells. The experiment, to be operated at the Spallation Neutron Source at Oak Ridge National Laboratory, uses polarized $^3$He from an Atomic Beam Source injected into the superfluid $^4$He and transported to the measurement cells as a co-magnetometer. The superfluid $^4$He is also used as an insulating medium allowing significantly higher electric fields, compared to previous experiments, to be maintained across the measurement cells. These features provide an ultimate statistical uncertainty for the EDM of $2-3\times 10^{-28}$ e-cm, with anticipated systematic uncertainties below this level

The Incidence and Methods for Detecting Aspirin Resistance in Pediatric Patients

Hansamon Poparn,1,2 Yaowaree Kittikalayawong,1,2 Piti Techavichit,1,2 Supanun Lauhasurayotin,1,2 Kanhatai Chiengthong,1,2 Phumin Chaweephisal,2 Darintr Sosothikul1,2 1Division of Pediatric Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand; 2Integrative and Innovative Hematology/Oncology Research Unit, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, ThailandCorrespondence: Darintr Sosothikul, Division of Pediatric Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand, Tel/Fax +66 2-256-4949, Email [email protected]; [email protected]: Since aspirin resistance is rarely assessed in pediatric patients and thrombosis might cause damage in vital organs, such as the myocardium or brain, we aimed to determine its incidence and the pivotal role of routine screening. The point-of-care test by platelet function analyzer (PFA-200) and bedside bleeding time (BT) was compared to standard whole blood impedance aggregometry (IA), the time-consuming and sophisticated assays. This single-center cross-sectional study was investigated in Thai children (≤ 15 years). All participants received at least five-day administrations of aspirin (3 to 5 mg/kg/day or equivalent to a single tablet of 81 mg) for any prior thrombotic risks. Platelet aggregation > 5 ohms on IA with 0.5 mM arachidonic acid, closure time < 180 seconds on collagen/epinephrine PFA-200, and modified Ivy BT ≤ 7 minutes, defined resistance. Of 37 patients, 2.7% had confirmed aspirin resistance to IA. Despite the 100% sensitivity, PFA-200 showed higher specificity than BT (83.3% vs 36.1%). However, both were not comparable (exact McNemar P < 0.05), with a slight/fair reliability (&kgreen;=0.215 vs &kgreen;=0.030 respectively). Aspirin resistance is uncommon in Thai children. Routine screening is discouraged but recommended only in cases with recurrent thrombosis despite good aspirin compliance or the presence of resistant risk factors. Although the gold standard IA could not be replaced, the rapid assay of PFA-200, not bedside BT, can potentially be considered a point-of-care alternative screening test to detect aspirin resistance in children.Keywords: aspirin, pediatrics, platelet function test