Thrombocytopenia in an animal model of malaria is associated with an increased caspase-mediated death of thrombocytes

Apoptosis. 2002 Apr;7(2):91-8. doi: 10.1023/a:1014341611412.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Blood Platelets / cytology
  • Blood Platelets / pathology*
  • Blotting, Western
  • CD40 Ligand / biosynthesis
  • Caspase 1 / metabolism
  • Caspase 3
  • Caspase 6
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism
  • Cricetinae
  • Cysteine Proteinase Inhibitors / pharmacology
  • Disease Models, Animal
  • Enzyme Activation
  • Flow Cytometry
  • Malaria / enzymology*
  • Megakaryocytes / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Peptides / chemistry
  • Plasmodium berghei / pathogenicity
  • Protein Binding
  • Thrombocytopenia / enzymology*
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Amino Acid Chloromethyl Ketones
  • Cysteine Proteinase Inhibitors
  • Peptides
  • Tumor Necrosis Factor-alpha
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • CD40 Ligand
  • Casp3 protein, mouse
  • Casp6 protein, mouse
  • Casp8 protein, mouse
  • Casp9 protein, mouse
  • Caspase 3
  • Caspase 6
  • Caspase 8
  • Caspase 9
  • Caspases
  • Caspase 1