title: Thrombocytopenia in an animal model of malaria is associated with an increased caspase-mediated death of thrombocytes.
abstract: Infection of mice with Plasmodium Berghei Anka (PbA) leads to a thrombocytopenia, due to a reduced platelet life span, eventually associated with a syndrome of severe or cerebral malaria (CM). Thrombocytopenia was associated with an increase in the number of microparticles (mcp) in plasma. More than >60% of these mcp were of platelet origin, as seen by staining with an anti-platelet antibody. The thrombocytopenia and the amount of mcp were decreased in mice treated with anti CD40L mAb, suggesting that CD40L is the main effector of the thrombocytopenia. Caspase-1, -3, -6, -8, -9 were activated in platelets from infected mice, as seen by the binding of labeled probes or the amount of pro-caspase-3. Treatment of infected mice with the caspases inhibitor ZVAD-fmk decreased the number of mcp and the thrombocytopenia, showing that platelet caspases are responsible for platelet fragmentation. In addition, the caspase inhibitor also caused a decrease in the mortality associated with CM, indicating a critical role of caspases in the expression of CM.
authors.affiliation: Department of Pathology, University of Geneva, CH 1211, Switzerland. pierre.piguet@medecine.unige.ch
authors.forename: P F
authors.initials: PF
authors.lastname: Piguet
authors.forename: C D
authors.initials: CD
authors.lastname: Kan
authors.forename: C
authors.initials: C
authors.lastname: Vesin
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000473:pathology*; D015153:Blotting, Western; D023201:CD40 Ligand / Q000096:biosynthesis; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3; D053178:Caspase 6; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D006224:Cricetinae; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005434:Flow Cytometry; D008288:Malaria / Q000201:enzymology*; D008533:Megakaryocytes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D010455:Peptides / Q000737:chemistry; D010962:Plasmodium berghei / Q000472:pathogenicity; D011485:Protein Binding; D013921:Thrombocytopenia / Q000201:enzymology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D015853:Cysteine Proteinase Inhibitors; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D023201:CD40 Ligand; C505409:Casp3 protein, mouse; C505516:Casp6 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053178:Caspase 6; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D020170:Caspase 1