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.

Fas (CD95, APO‐1) antigen expression and function in murine liver endothelial cells: implications for the regulation of apoptosis in liver endothelial cells

“…Although Fas is expressed in EC (6), little is known about the role of the Fas/FasL system on these cells. Previous in vitro reports suggest that Fas ligation does not lead to induction of EC apoptosis (6); however, there is some in vivo evidence suggesting that the Fas/FasL system may be involved in inducing the death of EC in different organs (17,18,32). There are reports that animals receiving anti-Fas mAb, which acts as an agonist of Fas, or soluble FasL die 6 h after injection due to liver necrosis (20).…”

Characterization of platelet glycoproteins and platelet/endothelial cell antibodies in patients with thrombotic thrombocytopenic purpura

“…Furthermore, inhibition of serum antibody binding to microvascular endothelial cells by a blocking CD36 antibody was observed, supporting the idea that, at least in some patients, anti-CD36 antibodies are generated and may contribute to the microvascular lesion observed in TTP. Since Laurence et al (1996) and Mitra et al (1997) have demonstrated that plasmas from TTP patients can induce apoptosis in cultured HMVEC, our analysis focused on non-apoptotic endothelial cells only. We found that some TTP sera also showed strong reactivity to HUVEC, and many of the sera tested exhibited some reactivity to both types of endothelial cells.…”

Thrombotic thrombocytopenic purpura in pulmonary-renal syndromes

“…TTP and HUS are felt to be different spectra of the same disease process consisting of abnormal formation of platelet and microthrombi in small vessels, coined thrombotic microangiopathy [1]. Typically, these syndromes are reported to spare the lungs [2][3][4][5]. However, as this brief report will show, there are data to the contrary.…”