Table 1 Causes of TMA

Thrombotic thrombocytopenic purpura (TTP)

Absence of ADAMTS13, the von Willebrand factor cleaving metalloprotease. Acquired due to autoimmune antibody to ADAMTS13, or hereditary (Upshaw-Schulman syndrome).

Infectious hemolytic uremic syndrome (ST-HUS)

Shiga toxins produced by Shigella dysenteriae and some serotypes of Escherichia coli (O157:H7 and O104:H4), cause direct damage to kidney epithelial and mesangial cells, and vascular endothelial cells. Rarely pneumococcus or other infectious agents with neuraminidase can expose the Thomsen-Friedenreich antigen on cell surfaces to result in hemolysis and direct endothelial injury.

Atypical or complement-mediated HUS

Hereditary deficiency of complement regulatory proteins (factor H, factor H related proteins, factor I, membrane cofactor protein, thrombomodulin) that normally regulate and restrict the activation of the alternative complement pathway, or hereditary abnormalities (factor B, C3) that accelerate the activation of the alternative complement pathway, leading to complement-mediated damage to vascular endothelium and kidneys. Acquired deficiency of complement factor H or factor I can be caused by autoimmune antibodies. Recessive mutations in diacylglycerol kinase epsilon (DGKE) is thought to result in a prothrombotic state with TMA in infancy (distinct from DGKE nephropathy). Plasminogen mutation was suggested to be the cause of aHUS in one case report.

Drug-induced TMA

Immune-mediated caused by drug-dependent antibodies that damage platelets, neutrophils and endothelial cells (quinine, gemcitabine, oxaliplatin and quetiapine). Dose-dependent toxicity-mediated caused by direct endothelial damage (gemcitabine, mitomycin, cyclosporine, tacrolimus, sirolimus, bevacizumab, oxymorphone).

Metabolism-mediated TMA

Disorders of intracellular vitamin B12 metabolism due to mutations in the MMACHC gene. Associated with elevated homocysteine and low methionine levels in plasma, with methylmalonic aciduria.