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.