Desialylation of platelets induced by Von Willebrand Factor is a novel mechanism of platelet clearance in dengue

Vesla Kullaya 3,4,5¶, Silvita Fitri Riswari1,3,4¶, Rahajeng N. Tunjungputri 2,3,4¶, Fadel M. Garishah 2, Gloria S. R. Utari 2, Nur Farhanah 2, Gijs J. Overheul 4,8, Bachti Alisjahbana1, M. Hussein Gasem 2 , Rolf T. Urbanus 6, Philip. G. de Groot 3, Dirk J. Lefeber 7, Ronald P. van Rij 4,8, Andre van der Ven 3,4, Quirijn de Mast 3,4
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Thrombocytopenia and platelet dysfunction are commonly observed in patients withdengue virus (DENV) infection and may contribute to complications such as bleeding andplasma leakage. The etiology of dengue-associated thrombocytopenia is multifactorialand includes increased platelet clearance. The binding of the coagulation protein vonWillebrand factor (VWF) to the platelet membrane and removal of sialic acid (desialylation)are two well-known mechanisms of platelet clearance, but whether these conditions alsocontribute to thrombocytopenia in dengue infection is unknown. In two observationalcohort studies in Bandung and Jepara, Indonesia, we show that adult patients with denguenot only had higher plasma concentrations of plasma VWF antigen and active VWF, butthat circulating platelets had also bound more VWF to their membrane. The amount ofplatelet-VWF binding correlated well with platelet count. Furthermore, sialic acid levels in dengue patients were significantly reduced as assessed by the binding of Sambucus nigra lectin (SNA) and Maackia amurensis lectin II (MAL-II) to platelets. Sialic acid on the plateletmembrane is neuraminidase-labile, but dengue virus has no known neuraminidaseactivity. Indeed, no detectable activity of neuraminidase was present in plasma ofdengue patients and no desialylation was found of plasma transferrin. Platelet sialylationwas also not altered by in vitro exposure of platelets to DENV nonstructural protein 1 orcultured DENV. In contrast, induction of binding of VWF to glycoprotein 1b on plateletsusing the VWF-activating protein ristocetin resulted in the removal of platelet sialic acidby translocation of platelet neuraminidase to the platelet surface. The neuraminidaseinhibitor oseltamivir reduced VWF-induced platelet desialylation. Our data demonstratethat excessive binding of VWF to platelets in dengue results in neuraminidase-mediatedplatelet desialylation and platelet clearance. Oseltamivir might be a novel treatmentoption for severe thrombocytopenia in dengue infection.