The major advance in the study of the pathogenesis of severe vivax disease was the demonstration of P. vivaxinfected RBCs cythoadhesion on human lung endothelial cells (HLEC) and placental tissue ex vivo [134] . This cythoadhesion was obviously lower than P. falciparuminfected RBCs adhesion, but with similar stability. However the next challenge is to try to link this finding to the in vivo phenomena [155] . The increased adhesion with the addition of LPS in the P. vivax ex vivo model suggests that endothelial activation may be an enhancing event. The role of augmented platelet-derived microparticles [156] and CD4 + CD25 + FoxP3 + regulatory T cells (Tregs) cells found in vivax disease should also be investigated in severe disease. Plasma levels of TNF, IFN-γ and also IFN-γ/IL-10 ratios were increased and exhibited a linear trend with gradual augmentation of disease severity [48] . Patients with severe disease also presented higher haemolysis and higher plasma concentrations of Cu/Zn SOD-1 and lower concentrations of PGE-2 and TGF-β than those with mild disease [157] . Oxidative stress was also proposed as a mechanism for thrombocytopaenia found in vivax disease [158, 159] , as well as its association with TNF [85] . Circulating immune complexes were not associated to vivax thrombocytopaenia [89] , but polymorphisms of the highly immunogenic AMA-1 were associated to platelet count in these patients [160] , suggesting that immunological mechanisms are involved in platelet destruction. In the case of anaemia, there is no correlation between the presence of anti-erythrocyte and anti-cardiolipin antibodies and the presence or intensity of this haematological finding [161] . Auto-immunity induced by secondary cryoagglutinins should be explored [54] . Erythropoiesis seems to be affected [162] , and the finding of parasites inside the bone marrow [43] stimulate the search for mechanisms of diserythropoiesis in this milieu, despite technical limitations to analyse this tissue in humans. The role of the spleen in severe disease is still unknown, as well as the role of the variant subtelomeric multigene vir family, which may influence the sequestration of infected RBCs in this organ [163] . Parasite genetics, such as MSP-1 and CSP polymorphisms, has not been shown to be associated with clinical severity [164] .