title: Apoptotic Platelet Events Are Not Observed in Severe von Willebrand Disease-Type 2B Mutation p.V1316M.
abstract: Thrombocytopenia and increased platelet clearance observed in von Willebrand disease-type 2B (VWD-2B) may be explained by platelet apoptosis triggered by the constitutive binding of VWF to its receptor, glycoprotein Ib (GPIb). Apoptosis was assessed in platelets from two patients with a severe VWD-2B mutation VWF/p.V1316M and from mice transiently expressing VWF/p.V1316M. We now report that the VWD-2B mutation VWF/p.V1316M which binds spontaneously to its receptor GPIbα does not induce apoptosis. In 2 unrelated patients (P1 and P2) exhibiting different VWF plasma levels (70% and 36%, respectively, compared with normal pooled human plasma given as 100%), inner transmembrane depolarization of mitochondria, characteristic of apoptotic events was undetectable in platelets, whether washed or in whole blood. No or a moderate phosphatidyl serine (PS) exposure as measured by annexin-V staining was observed for P1 and P2, respectively. Expression of pro-apoptotic proteins Bak and Bax, and caspase-3 activity were similar to control platelets. In the VWD-2B mouse model expressing high levels of mVWF/p.V1316M (423%), similar to what is found in inflammatory pathologies, no significant difference was observed between mice expressing mVWF/WT and mVWF/p.V1316M. These results strongly argue against apoptosis as a mechanism for the thrombocytopenia of severe VWD-2B exhibiting the VWF/p.V1316M mutation.
authors.affiliation: INSERM UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, 94276, Le Kremlin-Bicêtre, France.
authors.forename: Eliane
authors.initials: E
authors.lastname: Berrou
authors.affiliation: INSERM UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, 94276, Le Kremlin-Bicêtre, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Kauskot
authors.affiliation: INSERM UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, 94276, Le Kremlin-Bicêtre, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Adam
authors.affiliation: INSERM UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, 94276, Le Kremlin-Bicêtre, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Harel
authors.affiliation: INSERM UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, 94276, Le Kremlin-Bicêtre, France.
authors.forename: Paulette
authors.initials: P
authors.lastname: Legendre
authors.affiliation: INSERM UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, 94276, Le Kremlin-Bicêtre, France.|Service Hématologie Biologique, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Lavenu Bombled
authors.affiliation: Centre Hémophilie, Hôpital Necker, Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Rothschild
authors.affiliation: Kyoto Gakuen University, Kameoka, Japan.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Prevost
authors.affiliation: INSERM UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, 94276, Le Kremlin-Bicêtre, France.
authors.forename: Olivier D
authors.initials: OD
authors.lastname: Christophe
authors.affiliation: INSERM UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, 94276, Le Kremlin-Bicêtre, France.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Lenting
authors.affiliation: INSERM UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, 94276, Le Kremlin-Bicêtre, France.
authors.forename: Cécile V
authors.initials: CV
authors.lastname: Denis
authors.affiliation: INSERM UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, 94276, Le Kremlin-Bicêtre, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Rosa
authors.affiliation: INSERM UMR_S 1176, Univ. Paris-Sud, Université Paris-Saclay, 94276, Le Kremlin-Bicêtre, France.
authors.forename: Marijke
authors.initials: M
authors.lastname: Bryckaert
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D013921:Thrombocytopenia / Q000235:genetics / Q000473:pathology*; D014841:von Willebrand Factor / Q000235:genetics*
chemical_list: D014841:von Willebrand Factor