In this issue of Blood, Stefanescu et al discover the characteristics that distinguish sensitive versus nonsensitive endothelial cells to injury by TTP plasma.
An important factor in the pathogenesis of thrombotic thrombocytopenic purpura (TTP) is injury to microvascular endothelial cells (MVECs). Such injury was demonstrated in earlier work by Mitra et al, who found that apoptosis of MVECs can be induced in vitro by plasma obtained from TTP patients. They further observed that MVECs derived from the brain, kidneys, and skin are most sensitive to TTP plasma, whereas those derived from lung and liver are not.1 Macrovascular endothelial cells derived from major vessels do not share this behavior. In this issue of Blood, Ste-fanescu and coauthors, part of the same research group as Mitra et al, reveal the distinguishing features of sensitive versus nonsensitive MVECs.
In a series of experiments, Stefanescu and colleagues used MVECs derived from the skin as representative of the sensitive group and MVECs derived from the lung as representative of the nonsensitive group. They also studied large-vessel endothelial cells. TTPplasma–induced apoptosis in these endothelial cells was studied in the presence of tumor ne-crosis factor–related apoptosis-inducing li-gand (TRAIL) and IFN-γ. They clarify the mechanism of apoptosis by observing that, in the sensitive MVECs, ubiquitination of the caspase 8 regulator c-FLIP led to degradation of its proteasome. Likewise, c-FLIP silencing with anti-FLIP siRNA in the nonsensitive MVECs rendered them sensitive to apoptosis. Such differences in sensitivity in the various lineages of MVECs are consistent with the clinical manifestations of TTP, being common in the central nervous system and kidneys and rare in the lungs and liver.2
It would, perhaps, have been more exciting if the authors had shown similar findings with the other known sensitive MVECs (those derived from the brain and kidney) and with the other known nonsensitive MVECs (those derived from the liver). Nevertheless, their discovery of the role of c-FLIP in regulation of MVEC apoptosis may have important therapeutic implications for TTP. What is still an enigma is the link between endothelial injury and the development of autoantibodies against ADAMTS13. The presence of the antibodies results in a drastic lowering of blood levels of ADAMTS13, and leads to platelet aggregation and microvascular platelet thrombi formation. Such investigative challenges are not abating, but the present findings represent yet another step toward solving this riddle.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■
