title: Thrombotic thrombocytopenic purpura and sporadic hemolytic-uremic syndrome plasmas induce apoptosis in restricted lineages of human microvascular endothelial cells.
abstract: Thrombotic thrombocytopenic purpura (TTP) and sporadic hemolytic-uremic syndrome (HUS) are thrombotic microangiopathies that occur in the absence of an inflammatory response. Ultrastructural features of tissues involved in TTP/sporadic HUS suggest an apoptotic process. Consistent with these findings, we observed that TTP plasmas induce apoptosis in primary human endothelial cells (EC) of dermal microvascular but not umbilical vein origin (Laurence et al, Blood 87:3245, 1996). We now document the ability of plasmas from both TTP and sporadic HUS patients, but not from a patient with childhood/diarrhea-associated HUS, to induce apoptosis and expression of the apoptosis-associated molecule Fas (CD95) in restricted lineages of microvascular EC. EC of small vessel dermal, renal, and cerebral origin were susceptible to induction of Fas and an apoptotic cell death. In contrast, microvascular EC of pulmonary and hepatic origin, as well as EC of a large vessel, coronary artery, were resistant to both processes. This dichotomy parallels the in vivo pathology of TTP/sporadic HUS, with notable sparing of the pulmonary and hepatic microvasculature. Apoptotic EC also had some features of a procoagulant phenotype, including depressed production of prostaglandin I2 (prostacyclin). These phenomena support the pathophysiologic significance of microvascular EC apoptosis in TTP, extend it to a related disorder (sporadic HUS), and suggest consideration of apoptosis inhibitors in the experimental therapeutics of these syndromes.
authors.affiliation: Department of Medicine, Cornell University Medical College, New York, NY 10021, USA.
authors.forename: D
authors.initials: D
authors.lastname: Mitra
authors.forename: E A
authors.initials: EA
authors.lastname: Jaffe
authors.forename: B
authors.initials: B
authors.lastname: Weksler
authors.forename: K A
authors.initials: KA
authors.lastname: Hajjar
authors.forename: C
authors.initials: C
authors.lastname: Soderland
authors.forename: J
authors.initials: J
authors.lastname: Laurence
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D001777:Blood Coagulation / Q000187:drug effects; D001921:Brain / Q000098:blood supply; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002196:Capillaries / Q000166:cytology; D019070:Cell Lineage; D002675:Child, Preschool; D003331:Coronary Vessels / Q000166:cytology; D003967:Diarrhea / Q000150:complications; D004730:Endothelium, Vascular / Q000473:pathology*; D004789:Enzyme Activation; D011464:Epoprostenol / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D015658:HIV Infections / Q000150:complications; D006463:Hemolytic-Uremic Syndrome / Q000097:blood* / Q000209:etiology; D006801:Humans; D007668:Kidney / Q000098:blood supply; D008099:Liver / Q000098:blood supply; D008168:Lung / Q000098:blood supply; D009928:Organ Specificity; D011697:Purpura, Thrombotic Thrombocytopenic / Q000097:blood* / Q000150:complications; D012867:Skin / Q000098:blood supply; D014471:Umbilical Veins / Q000166:cytology; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics
chemical_list: D019014:fas Receptor; D011464:Epoprostenol; D016203:CDC2 Protein Kinase