New approaches in the diagnosis, pathophysiology, and treatment of pediatric hematopoietic stem cell transplantation-associated thrombotic microangiopathy

Abstract

Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is an understudied complication of HSCT that significantly affects transplant-related morbidity and mortality. Over the past several decades, the cause of TA-TMA has remained unknown, limiting treatment options to non-specific therapies adapted from other diseases. Recent prospective studies dedicated to the study of TA-TMA have provided new insights into the pathogenesis of, and genetic susceptibility to TA-TMA, raising awareness of this important transplant complication and allowing for the identification of potentially novel therapeutic targets. Specifically, many patients with TA-TMA develop multi-organ tissue injury through endothelial damage mediated by the activation of the complement pathway, leading to rational therapeutic strategies including complement blockade. This new knowledge has the potential to favorably influence clinical practice and change the standard of care for how patients with TA-TMA are managed. In this review, we summarize novel approaches to the recognition and management of TA-TMA, using case examples to illustrate key clinical points that hopefully lead to improved short and long-term outcomes for these complex HSCT patients, who remain at significant risk for treatment-related morbidity and mortality.

Keywords: Complement; Eculizumab; Hematopoietic stem cell transplant; TA-TMA; Thrombotic microangiopathy.

Fig. 1

Histologic features of TA-TMA. (A) and (B) show histology from small bowel resection specimen displaying histopathologic changes of transplantation-associated thrombotic microangiopathy (TA-TMA) (H&E ×40). (A) This demonstrates severe acute microangiopathic vascular injury involving submucosal small bowel arterioles. Black arrows show endothelial cells “floating” in the vascular lumen after complete separation from the basement membrane and interstitial hemorrhages (triangle). (B) This shows organizing thrombus occluding submucosal small bowel arteriole with extensive hemorrhages into surrounding tissues (triangle), double stars mark hemosiderin deposits indicating old hemorrhagic areas. (C) C4d staining (×20) of small bowel tissue section shows diffuse positive staining in the degenerating submucosal vessels (dotted arrow) with microangiopathic changes indicating complement deposits in TMA affected vessels. (D), (E) and (F) show lung histology from autopsy specimen displaying histopathologic changes of TA-TMA and pulmonary arterial hypertension (H&E ×40). (A) This demonstrates severe acute microangiopathic vascular injury involving pulmonary arterioles. Black arrows show endothelial cells “floating” in the vascular lumen after complete separation from the basement membrane and interstitial hemorrhages (triangle) (B) lung arterioles affected by TA-TMA that are filled with fibrin debris trapping cells (star), (C) lung arterioles with proliferation of vascular wall (solid double headed arrow) with near obliteration of vascular lumen and red cell extravasation into the vessel wall (triangle).

Fig. 2

TA-TMA pathogenesis. Transplant recipient’s genotype will determine subject at risk to develop TA-TMA under adequate stressors during HSCT like chemotherapy, radiation, infections, and medications. Complement system will be activated by the stressor in susceptible individuals leading to vascular endothelial injury due to activated terminal complement complex resulting in end organ injury.

Fig. 3

Survival in HSCT recipients with high-risk TA-TMA. Survival curves for patients with high-risk TA-TMA who were treated with the terminal complement blocker eculizumab (“Treated”, n = 30) and historical control subjects from prospective observational TA-TMA study with the same high-risk TMA features who did not receive eculizumab (“Untreated”, n = 11) were calculated using Kaplan–Meier and log rank tests starting at TA-TMA diagnosis to assess statistical significance. Patients with high-risk TA-TMA who received eculizumab therapy had better survival than untreated patients (62% versus 9% at 1 year from TA-TMA diagnosis, p = 0.0007).