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Table 2 The “Three-Hit Hypothesis” for development of hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) [7, 15]

From: Role of the lectin pathway of complement in hematopoietic stem cell transplantation-associated endothelial injury and thrombotic microangiopathy

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
  1. Adapted with permission from [7]
  2. 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
  3. aGVHD Acute graft-versus-host disease, CMV Cytomegalovirus, HLA Human leukocyte antigen, HSCT Hematopoietic stem cell transplantation, mTOR Mammalian target of rapamycin