First description of an IgM monoclonal antibody causing αβ integrin activation and acquired Glanzmann thrombasthenia associated with macrothrombocytopenia
Author(s): ,
Xavier Pillois
Affiliations:
Cardiovascular Adaptation to Ischemia, INSERM U1034, Pessac, France. Reference Center for Platelet Disorders, Pessac, France
,
Alexandre Guy
Affiliations:
Cardiovascular Adaptation to Ischemia, INSERM U1034, Pessac, France. Laboratory Hematology, University Hospital of Bordeaux, Pessac, France
,
Émeline Choquet
Affiliations:
Laboratory Hematology, University Hospital of Bordeaux, Pessac, France. INSERM U1211 ‐ University of Bordeaux, Maladies Rares: Génétique et Métabolisme, Bordeaux, France. Victor Segalen, University of Bordeaux, Bordeaux, France
,
Chloé James
Affiliations:
Cardiovascular Adaptation to Ischemia, INSERM U1034, Pessac, France. Laboratory Hematology, University Hospital of Bordeaux, Pessac, France. Victor Segalen, University of Bordeaux, Bordeaux, France
,
Marie Tuffigo
Affiliations:
Laboratory Hematology, University Hospital of Bordeaux, Pessac, France. Victor Segalen, University of Bordeaux, Bordeaux, France
,
Jean‐François Viallard
Affiliations:
Cardiovascular Adaptation to Ischemia, INSERM U1034, Pessac, France. Victor Segalen, University of Bordeaux, Bordeaux, France. Internal Medecine and Infectious Diseases Department, University Hospital of Bordeaux, Pessac, France
,
Cédric Garcia
Affiliations:
Laboratoire d'Hématologie, CHU de Toulouse, Toulouse, France
,
Jean‐Claude Bordet
Affiliations:
Hôpital Cardiologique Louis Pradel, Université Claude Bernard, Lyon 1, Lyon, France
,
Martine Jandrot‐Perrus
Affiliations:
INSERM U1148, Université Paris Diderot, Centre Hospitalier Universitaire Bichat, Paris, France
,
Bernard Payrastre
Affiliations:
Laboratoire d'Hématologie, CHU de Toulouse, Toulouse, France. INSERM, U1048 and Université Toulouse 3, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Toulouse, France
Mathieu Fiore
Affiliations:
Reference Center for Platelet Disorders, Pessac, France. Laboratory Hematology, University Hospital of Bordeaux, Pessac, France
Correspondence: M. Fiore, Laboratoire d'hématologie, Centre de Référence des Pathologies Plaquettaires Constitutionnelles, CHU de Bordeaux, Hôpital Cardiologique, Pessac, France|Tel.: +33 05 5765 6478|E‐mail: mathieu.fiore@chu-bordeaux.fr
ISTH Academy. Fiore M. May 1, 2019; 273608
Dr. Mathieu Fiore
Dr. Mathieu Fiore
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Background
Acquired Glanzmann thrombasthenia (GT) is a bleeding disorder generally caused by anti‐αβ autoantibodies.
Objectives
We aimed to characterize the molecular mechanism leading to a progressive GT‐like phenotype in a patient with chronic immune thrombocytopenia.
Patient, Methods, and Results
The patient suffered from repeated episodes of gastrointestinal bleeding; further studies indicated a moderate platelet aggregation defect. A few months later, platelet function showed abolished aggregation using all agonists, but normal agglutination with ristocetin. No platelet‐bound antibodies were detected, but the presence of large amounts of an IgM type antibody detected together with αβ in the patient permeabilized platelets suggested that this IgM was an autoantibody causing the internalization of the complex. This was confirmed by the fact that the patient IgM bound to normal platelets but not to platelets from GT type I patients. Moreover, patient′s plasma activated αβ on controls’ platelets as evidenced by increased PAC‐1 binding. We also demonstrated that the patient plasma triggered αβ outside‐in signaling, as β Tyr773 and FAK were phosphorylated, and increased the rate of actin polymerization in resting platelets reflecting an impairment of cytoskeletal reorganization. Because different signs of dysmegakaryopoiesis were also observed in our patient, we evaluated the ability of its serum to impair proplatelets formation and showed that it significantly decreased the number of proplatelet‐bearing megakaryocytes in controls’ bone marrow stem cells culture compared with normal serum.
Conclusions
We present the case of a patient with a progressive and severely perturbed platelet function associated with the presence of an IgM activating autoantibody directed against αβ.
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