In vitro evidence of complement activation in transplantation-associated thrombotic microangiopathy

Abstract

Key Points Transplantation-associated thrombotic microangiopathy is associated with complement activation in vitro. This data further supports the use of eculizumab for the treatment of patients with TA-TMA.

Clinical promise of next-generation complement therapeutics

“…Although strong genetic linkage to complement dysregulation has not yet been discerned in most cases, emerging observations and clinical data support a pathogenic involvement of a dysregulated AP and overactive terminal pathway in exacerbating TMA pathology 99 . Consistently, increased levels of activated C3 fragments and terminal effectors (for example, sC5b-9) have been reported in patients undergoing HSC transplantation who develop TA-TMA 161,162 . Encouraging results in attenuating TA-TMA-associated organ injury have been obtained with eculizumab in phase II studies, but clinicians are still debating how to use this drug in a clinically safe, effective and cost-efficient way 163 .…”

Biomarkers for posttransplantation outcomes

“…ST2 was shown to be a reliable early biomarker of TMA independent of aGVHD in several cohorts. 91,92 Routine laboratory measurements (lactate dehydrogenase, creatinine, and thrombocytes) can be used to create a formula called the Endothelial Activation and Stress Index (EASIX), which was found as a predictor of survival in patients with reduced-intensity conditioning. 93…”

Thrombotic Microangiopathy in Cancer

“…Many hematologic and select solid tumors are treated by bone marrow or hematopoietic stem cell transplantation (HSCT), and these patients may develop TMA. [58][59][60][61][62][63][64][65][66][67][68] Transplant-associated TMA (TA-TMA) may result due to multiple risk factors, including the use of calcineurin inhibitors (CNIs) or mammalian target of rapamycin (MTOR) inhibitors, graft versus host disease (GVHD), the number of previous transplants, human leukocyte antigen mismatch, opportunistic infections, and conditioning regimen. The end result of these insults is endothelial damage particularly affecting the kidney but other organs as well.…”

“…62 Several recent studies on TA-TMA point to the development of/or worsening hypertension preceding the development of TA-TMA. 58,59,[62][63][64][65][66][67] It has been postulated that the associated endothelial damage may be due to inflammationinduced alterations in the renin angiotensin system. 61,64 The pathologic findings include thickened capillary walls and occluded vessel lumens; red blood cell fragments can be seen trapped in the mesangial matrix.…”

“…60,61 These findings have been documented in the lungs, associated with pulmonary hypertension, as well as the small bowel associated with ischemia. 60,63 Complement protein C4d deposition in arterioles has also been noted suggesting a role for complement activation. 61,62 These biopsy findings are very similar to those seen in aHUS.…”