The role of von Willebrand factor in thrombotic microangiopathy

Abstract

Thrombotic microangiopathy (TMA) is caused by thrombus formation in the microvasculature. The disease spectrum of TMA includes, amongst others, thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS). TTP is caused by defective cleavage of von Willebrand factor (VWF), whereas aHUS is caused by overshooting complement activation and subsequent endothelial cell (EC) injury. Despite their distinct pathophysiology, the clinical manifestation of TTP and aHUS consisting of microangiopathic haemolytic anaemia and thrombocytopenia is often similar and difficult to distinguish. Recent evidence hints at both a genetic and functional link between TTP and aHUS, especially between VWF and the complement system. There is novel in vitro evidence that complement activation not only results in VWF release from ECs, but that VWF also functions as a negative complement regulator, thus protecting the EC surface from ongoing complement attack. Although contrary to previous experimental work suggesting that complement can be activated on VWF multimers, there may be an explanation in vivo that rationalizes these apparently contradictory findings, whereby a system primarily meant to regulate becomes overwhelmed or pathologic in the disease state. The importance of unravelling these recent findings for our understanding of TMA pathology becomes even more evident considering that glomerular ECs express VWF in a heterogeneous pattern with an overall decreased expression level, thus potentially leaving the glomerular ECs vulnerable to complement-mediated injury. Taken together, these findings support the concept that TTP and aHUS represent two extreme ends of a TMA disease spectrum rather than isolated disease entities.