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1. A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP

Author

Jean-François Augusto, Naïke Bigé, Lionel Galicier, Alain Wynckel, Nihal Martis, Michael Bubenheim, Ygal Benhamou, Antoine Dossier, Claire Presne, Elie Azoulay, Virginie Rieu, Agnès Veyradier, Sandrine Malot, François Provôt, Christelle Barbet, Miguel Hie, Amélie Seguin, Sten de Witte, Pascale Poullin, M. Ulrich, Paul Coppo, Thierry Krummel, François Lhote, Yahsou Delmas, Pierre Perez, Anne Charvet Rumpler, Ruben Benainous, Olivier Moranne, Salvy-Córdoba, Nathalie, Centre de référence des microangiopathies thrombotiques [CHU Saint-Antoine] (Cnr-mat), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Laboratoire d'Hématologie et d'Immunologie [CHU Saint-Antoine], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Centre d'Investigation Clinique [CHU Rouen] (CIC Rouen), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), Université Paris Cité (UPCité), Service d'Immunopathologie [Hôpital Saint-Louis, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Service d'Anesthésie réanimation [CHU Saint-Antoine], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital de la Timone [CHU - APHM] (TIMONE), Service de Néphrologie [Hôpital Albert Calmette], Hôpital Albert Calmette [Lille], Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Amiens-Picardie, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de médecine interne [Avicenne], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre hospitalier universitaire de Nantes (CHU Nantes), Service de Médecine Interne 2, maladies auto-immunes et systémiques [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Hôpital Maison Blanche, Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Bordeaux [Bordeaux], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital Brabois, CHU, Partenaires INRAE, Service de Médecine Interne [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Delafontaine, Centre Hospitalier de Saint-Denis [Ile-de-France], Centre hospitalier [Valenciennes, Nord], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Libourne, Service de néphrologie et hémodialyse [CHU de Strasbourg], CHU Strasbourg, Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Normandie Université (NU)-Normandie Université (NU), Endothélium, valvulopathies et insuffisance cardiaque (EnVI), Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Compassionate Use Trials, Male, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, MESH: Combined Modality Therapy, MESH: Von Willebrand Factor, medicine.medical_treatment, Plenary Paper, Salvage therapy, 030204 cardiovascular system & hematology, Severity of Illness Index, Biochemistry, MESH: Historically Controlled Study, 0302 clinical medicine, Adrenal Cortex Hormones, Prospective Studies, Thiamine, Prospective cohort study, MESH: Treatment Outcome, MESH: Middle Aged, Plasma Exchange, MESH: Compassionate Use Trials, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Immunosuppression, Hematology, Middle Aged, MESH: Plasma Exchange, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Combined Modality Therapy, [SDV.SP] Life Sciences [q-bio]/Pharmaceutical sciences, Treatment Outcome, MESH: Thromboembolism, 030220 oncology & carcinogenesis, Disease Progression, Drug Therapy, Combination, Female, MESH: Disease Progression, Rituximab, MESH: Rituximab, MESH: Hemorrhage, medicine.drug, Adult, medicine.medical_specialty, MESH: Purpura, Thrombotic Thrombocytopenic, Immunology, Thrombotic thrombocytopenic purpura, ADAMTS13 Protein, Hemorrhage, MESH: Single-Domain Antibodies, MESH: Adrenal Cortex Hormones, 03 medical and health sciences, Thromboembolism, MESH: Severity of Illness Index, Internal medicine, von Willebrand Factor, medicine, Humans, MESH: Platelet Count, MESH: ADAMTS13 Protein, Adverse effect, Immunosuppression Therapy, MESH: Humans, Purpura, Thrombotic Thrombocytopenic, Platelet Count, business.industry, Historically Controlled Study, MESH: Adult, Cell Biology, Single-Domain Antibodies, medicine.disease, MESH: Male, MESH: Prospective Studies, MESH: Drug Therapy, Combination, Regimen, Caplacizumab, business, MESH: Female
Abstract

The anti–von Willebrand factor nanobody caplacizumab was licensed for adults with immune-mediated thrombotic thrombocytopenic purpura (iTTP) based on prospective controlled trials. However, few data are available on postmarketing surveillance. We treated 90 iTTP patients with a compassionate frontline triplet regimen associating therapeutic plasma exchange (TPE), immunosuppression with corticosteroids and rituximab, and caplacizumab. Outcomes were compared with 180 historical patients treated with the standard frontline treatment (TPE and corticosteroids, with rituximab as salvage therapy). The primary outcome was a composite of refractoriness and death within 30 days since diagnosis. Key secondary outcomes were exacerbations, time to platelet count recovery, the number of TPE, and the volume of plasma required to achieve durable remission. The percentage of patients in the triplet regimen with the composite primary outcome was 2.2% vs 12.2% in historical patients (P = .01). One elderly patient in the triplet regimen died of pulmonary embolism. Patients from this cohort experienced less exacerbations (3.4% vs 44%, P < .01); they recovered durable platelet count 1.8 times faster than historical patients (95% confidence interval, 1.41-2.36; P < .01), with fewer TPE sessions and lower plasma volumes (P < .01 both). The number of days in hospital was 41% lower in the triplet regimen than in the historical cohort (13 vs 22 days; P < .01). Caplacizumab-related adverse events occurred in 46 patients (51%), including 13 major or clinically relevant nonmajor hemorrhagic events. Associating caplacizumab to TPE and immunosuppression, by addressing the 3 processes of iTTP pathophysiology, prevents unfavorable outcomes and alleviates the burden of care.

Published
2021
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2. Anti-cysteine/spacer antibodies that open ADAMTS13 are a common feature in iTTP

Author

Andres Männik, Gilles Kaplanski, Kadri Kangro, Elien Roose, Alexandre Curie, Bérangère S. Joly, Claudia Tersteeg, Edwige Tellier, Agnès Veyradier, Paul Coppo, Simon F. De Meyer, Laure De Waele, Karen Vanhoorelbeke, Laboratory for Thrombosis Research, Interdisciplinary Research Center, Catholic University of Leuven, Service de Néphrologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Icosagen Cell Factory, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Service d’Hématologie Biologique [CHU Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de référence des microangiopathies thrombotiques [CHU Saint-Antoine] (Cnr-mat), Service d'hématologie clinique et de thérapie cellulaire [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Icosagen [Tartumaa, Estonia], and Gestionnaire, Hal Sorbonne Université

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, MESH: Purpura, Thrombotic Thrombocytopenic, Thrombotic thrombocytopenic purpura, ADAMTS13 Protein, 030204 cardiovascular system & hematology, Immunoglobulin G, 03 medical and health sciences, 0302 clinical medicine, Affinity chromatography, hemic and lymphatic diseases, medicine, Humans, MESH: Autoantibodies, Cysteine, MESH: ADAMTS13 Protein, Autoantibodies, 030304 developmental biology, MESH: Immunoglobulin G, Purpura, Thrombocytopenic, Idiopathic, 0303 health sciences, MESH: Humans, Purpura, Thrombotic Thrombocytopenic, biology, Chemistry, fungi, MESH: Purpura, Thrombocytopenic, Idiopathic, Autoantibody, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, MESH: Cysteine, medicine.disease, Stimulus Report, Molecular biology, ADAMTS13, 3. Good health, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Healthy individuals, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, biology.protein, Antibody
Abstract

Key Points An open ADAMTS13 conformation is a novel biomarker for iTTP and is induced by anti-ADAMTS13 autoantibodies.The autoantibodies against the CS region play an important role in the appearance of an open ADAMTS13 conformation., Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by an autoantibody-mediated deficiency in ADAMTS13. In healthy individuals, ADAMTS13 has a folded conformation in which the central spacer (S) domain interacts with the C-terminal CUB domains. We recently showed that ADAMTS13 adopts an open conformation in iTTP and that patient immunoglobulin G antibodies (IgGs) can open ADAMTS13. Anti-ADAMTS13 autoantibodies in patients with iTTP are directed against the different ADAMTS13 domains, but almost all patients have autoantibodies binding to the cysteine/spacer (CS) domains. In this study, we investigated whether the autoantibodies against the CS and CUB domains can disrupt the S-CUB interaction of folded ADAMTS13, thereby opening ADAMTS13. To this end, we purified anti-CS and anti-CUB autoantibodies from 13 patients with acute iTTP by affinity chromatography. The successfully purified anti-CS (10/13 patients) and anti-CUB (4/13 patients) autoantibody fractions were tested further in our ADAMTS13 conformation enzyme-linked immunosorbent assay to study whether they could open ADAMTS13. Interestingly, all purified anti-CS fractions (10/10 patients) were able to open ADAMTS13. On the other hand, only half of the purified anti-CUB fractions (2/4 patients) opened ADAMTS13. Our finding highlights that anti-CS autoantibodies that open ADAMTS13 are a common feature of the autoimmune response in iTTP.

Published
2021
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3. Three kidneys, two diseases, one antibody?

Author

Nolwenn Lorcy, Nathalie Rioux-Leclercq, Patrick Le Pogamp, Marie-Laure Lombard, Cécile Vigneau, De Villemeur, Hervé, Service de néphrologie [Rennes], Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Service de néphrologie et d'hémodialyse, Centre hospitalier de Saint Malo-Aide aux Urémiques de Bretagne (AUB), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), CHU Pontchaillou [Rennes]-Hôpital Pontchaillou-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Graft Rejection, membranoproliferative glomerulonephritis, 030232 urology & nephrology, MESH: Antibodies, Anti-Idiotypic, 030204 cardiovascular system & hematology, Kidney Function Tests, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, MESH: Kidney Transplantation, 0302 clinical medicine, Membranoproliferative glomerulonephritis, MESH: Autoantibodies, MESH: Glomerulonephritis, Membranoproliferative, Atypical Hemolytic Uremic Syndrome, Kidney, biology, MESH: Complement C3, Glomerulonephritis, Complement C3, Prognosis, 3. Good health, Antibodies, Anti-Idiotypic, medicine.anatomical_structure, MESH: Complement Factor H, Nephrology, MESH: Kidney Failure, Chronic, MESH: Kidney Function Tests, MESH: Hemolytic-Uremic Syndrome, Factor H, Complement Factor H, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Immunosuppressive Agents, Antibody, Immunosuppressive Agents, Glomerular Filtration Rate, Adult, MESH: Purpura, Thrombotic Thrombocytopenic, [SDV.IMM] Life Sciences [q-bio]/Immunology, Glomerulonephritis, Membranoproliferative, MESH: Graft Rejection, MESH: Prognosis, 03 medical and health sciences, Atypical hemolytic uremic syndrome, medicine, Humans, thombotic microangiopathies, Autoantibodies, Transplantation, complement alternative pathway, MESH: Humans, Purpura, Thrombotic Thrombocytopenic, business.industry, Autoantibody, anti-factor H antibody, MESH: Adult, medicine.disease, Kidney Transplantation, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Complement system, MESH: Glomerular Filtration Rate, Immunology, Hemolytic-Uremic Syndrome, biology.protein, Kidney Failure, Chronic, business, MESH: Female
Abstract

International audience; Anti-factor H antibody has been recently described as responsible for thrombotic microangiopathies (TMA) as well as membranoproliferative glomerulonephritis (MPGN). We report here, for the first time, the case of a woman with an anti-factor H antibody, who developed MPGN on native kidney, rapid recurrence on first graft, and TMA on second graft despite immunosuppressive therapy and plasma exchanges. This case supports the hypothesis that MPGN and TMA are closely linked by common pathogenic mechanisms and the need for complete exploration of complement pathway including factor H activity and autoantibody in front of any MPGN.

Published
2011
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4. Thrombotic thrombocytopenic purpura associated with severe acute pancreatitis in a context of decreased ADAMTS13 activity: a case report

Author

Cyrille Patry, Franck Carbonnel, Gaël Piton, Jean Christophe Navellou, Gilles Capellier, Pierre Morati, Service de gastro-entérologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Agents pathogènes et inflammation - UFC (EA 4266) (API), Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)

Subjects
Hemolytic anemia, MESH: ADAM Proteins, Adult, Abdominal pain, medicine.medical_specialty, Thrombotic microangiopathy, MESH: Purpura, Thrombotic Thrombocytopenic, Adolescent, Thrombotic thrombocytopenic purpura, ADAMTS13 Protein, Gastroenterology, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Internal medicine, hemic and lymphatic diseases, Coagulopathy, Medicine, Humans, 030212 general & internal medicine, MESH: Adolescent, MESH: Humans, MESH: Middle Aged, Hepatology, Purpura, Thrombotic Thrombocytopenic, business.industry, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Middle Aged, medicine.disease, ADAMTS13, 3. Good health, MESH: Pancreatitis, ADAM Proteins, Pancreatitis, MESH: Young Adult, Immunology, Acute Disease, Acute pancreatitis, MESH: Acute Disease, 030211 gastroenterology & hepatology, Female, medicine.symptom, business, MESH: Female
Abstract

International audience; Thrombotic thrombocytopenic purpura (TTP) is a severe multisystemic microvascular disease defined by the association of hemolytic anemia, thrombocytopenia, acute renal failure, fever, and neurological disorders. The pathophysiology has recently been elucidated by the discovery of a von Willebrand factor-cleaving protease (ADAMTS13) deficiency involved in platelet aggregation and ischemia. The association between TTP and acute pancreatitis (AP) has rarely been reported, described either as a cause or a consequence. The role of ADAMTS13 during AP is still unknown. We describe the case of a 41-year-old woman who developed a TTP, with decreased ADAMTS13 activity, associated with severe AP. Published cases of thrombotic microangiopathy associated with AP are reviewed. The pathophysiology, management, prognostic factors, and rationale for treatment are discussed. AP should be sought in patients with TTP presenting with abdominal pain. On the other hand, TTP should be considered in patients with AP and thrombocytopenia.

Published
2008
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5. When vitamin deficiency mimics thrombotic thrombocytopenic purpura

Author

Bayle, Sandrine, Tardy, Bernard, Page, Yves, Diconne, Eric, Zeni, Fabrice, Bertrand, Jean C, Groupe de recherche sur la thrombose (GRT (EA 3065)), Université Jean Monnet [Saint-Étienne] (UJM), Laboratoire de Géodynamique des Chaines Alpines (LGCA), Observatoire des Sciences de l'Univers de Grenoble (OSUG), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut des Sciences de la Terre (ISTerre), Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-PRES Université de Grenoble-Institut de recherche pour le développement [IRD] : UR219-Institut national des sciences de l'Univers (INSU - CNRS)-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS)-PRES Université de Grenoble-Institut de recherche pour le développement [IRD] : UR219-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR), and Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut national des sciences de l'Univers (INSU - CNRS)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Aged, MESH: Humans, MESH: Purpura, Thrombotic Thrombocytopenic, MESH: Diagnosis, Differential, MESH: Biological Markers, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, MESH: Vitamins, ComputingMilieux_MISCELLANEOUS, MESH: Avitaminosis, MESH: Male
Abstract

International audience

Published
2006
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