PLASMA FROM PATIENTS WITH IDIOPATHIC AND HUMAN IMMUNODEFICIENCY VIRUS-ASSOCIATED THROMBOTIC THROMBOCYTOPENIC PURPURA INDUCES APOPTOSIS IN MICROVASCULAR ENDOTHELIAL-CELLS

The pathogenesis of thrombotic thrombocytopenic purpura (TTP) is obscu re. It is manifested classically by platelet thrombi and localized mic rovascular endothelial cell (EC) proliferation, in the absence of an i nflammatory response. It is statistically associated with human retrov iral disease, but pathological studies of TTP lesions have been unable to establish whether perturbation of the endothelium is a primary or secondary event, irrespective of the presence of retroviral infection. We document that plasma from all of four acute TTP patients, with or without human immunodeficiency virus infection, can induce apoptosis i n cultured ECs of microvascular but not large vessel origin. This proc ess was documented by three different methods, (1) laser-illuminated l ight scatter, (2) quantitation of the pre-G(1) A(o) peak on DNA histog rams and direct visualization of chromatin fragmentation by acridine o range and 4'6-diamidino-2-phenylindole staining, and (3) agarose gel e lectrophoresis of low molecular weight cellular DNA. Apoptosis was ind ependent of tumor necrosis factor-alpha secretion or the presence of C D36 on microvascular ECs but was linked to the rapid induction of Fas (CD95) on these cells, Soluble anti-fas antibody, normal plasma deplet ed of cryoprecipitate, and low concentrations (less than or equal to 0 .1 mu mol/L) of aurintricarboxylic acid were capable of suppressing TT P plasma-mediated EC apoptosis. In conclusion, microvascular EC apopto sis may be of pathophysiological importance in TTP may be susceptible to interruption by blockade of initiating signals for, or final common enzyme pathways leading to, programmed cell death. (C) 1996 by The Am erican Society of Hematology.