3. Pathogenesis, risk factors and prevention
Three-hit hypothesis proposed by Kosala et al (25) and Dvorak et al (2) provide insights on pathogenesis of TA-TMA. For the “first hit” (initiation phase), patients either have an underlying predisposition to complement activation (e.g., racial or genetic factors) or a pre-existing endothelial injury (e.g., prior myeloablative conditioning or prolonged use of calcineurin inhibitors). Genetic predisposition had not been identified in local cohort except identification of a variant of unknown significance in THBD gene forCase 6 (Table 1b) . For the “second hit” (progression phase), delivery of conditioning regimen mediates further endothelial injury. Injured endothelium exposes damage-associated molecular patterns, which activates C3 to initiate alternative pathway activity in the complement system. The “third hit” refers to complement activation by drugs, GVHD, infection or antibodies. Usage of eculizumab in local cohort readily suppressed classical and alternative complement pathway (the “third hit”), normalized haematological parameters, and resolved hypertension and proteinuria, but damage to kidneys and decline in GFR are irreversible (Table 1c) .
Risk factors for development of TA-TMA include female sex (9, 17, 26, 27), older age (9, 16, 17, 26) , genetic variants in complement activation (28), alternative donor transplant (16, 17, 22, 26), blood group incompatibility (15, 26), intensive conditioning regimen (16, 18), particularly those containing high dose busulphan (13) or irradiation (17, 27), use of antithymocyte globulin (14), calcineurin inhibitor as GVHD prophylaxis (13), infections (20, 27), and presence of GvHD (13, 15-18, 20, 22, 26, 27, 29). Vitamin D, eicosapentaenoic acid (EPA), allopurinol, statin, and defibrotide are all potentially useful compounds in preventing TA-TMA but their efficacy and safety has yet to be elucidated.