Table 2.

The “Three-Hit Hypothesis” for development of hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) [7, 15]

Inherent/ non-modifiable risk factors	Transplant-associated risk factors	Post-transplant risk factors
Underlying predispositions:  Female sex  African American ethnicity  Severe aplastic anemia  CMV seropositive recipient  Prior stem cell transplant  Genetic variants	Endothelial injury and procoagulant endothelium:  Transplant conditioning  Total-body irradiation  Unrelated donor transplants  HLA mismatch  Other factors	Post-HSCT initiators of complement activation:  Calcineurin inhibitors  mTOR inhibitors  aGVHD   Infection

Adapted with permission from [7]

Sequential risks facilitate development and progression of HSCT-TMA. The first “hit” comprises inherent or nonmodifiable risk factors, such as underlying predisposition to complement activation via genetic risk factors. The second “hit” involves transplant-associated risk factors such as cytotoxic conditioning regimens that cause endothelial injury. The third “hit” includes post-transplant risk factors that may initiate complement activation, such as medications, aGVHD, infection, and/or circulating antibodies

aGVHD Acute graft-versus-host disease, CMV Cytomegalovirus, HLA Human leukocyte antigen, HSCT Hematopoietic stem cell transplantation, mTOR Mammalian target of rapamycin