Emerging therapeutic and preventive approaches to transplant-associated thrombotic microangiopathy

Abstract

Purpose of review Transplant-associated thrombotic microangiopathy (TA-TMA) is a complication that can occur in both allogeneic and autologous haematopoietic cellular therapy (HCT) recipients and is associated with significant morbidity and mortality. Although TA-TMA is a complex disease, there is emerging evidence that complement activation and endothelial dysfunction play a key role in the pathophysiology of the disease. The use of eculizumab has improved survival in patients with high risk and severe disease, but mortality rates in treated patients still exceed 30%, highlighting the need for novel approaches. Recent findings There are multiple ongoing and planned clinical trials investigating novel complement agents in TA-TMA and other TMAs. Drugs vary by targets of the complement system, mechanism, and form of administration. Clinical trial designs include single arm studies that span across multiple age groups including children, and double-blind, randomized, placebo-controlled studies. These studies will provide robust data to inform the care of patients with TA-TMA in the future. In addition to multiple promising therapeutic agents, preventing TA-TMA is an emerging strategy. Agents known to protect the endothelium from damage and augment endothelial function by promoting anti-inflammatory and antithrombotic effects may have a role in preventing TA-TMA or ameliorating the severity, though additional studies are needed. Summary Novel therapeutic agents for TA-TMA inhibition of the complement system are under investigation and prophylactic strategies of endothelial protection are emerging. Further understanding of the pathophysiology of the disease may identify additional therapeutic targets. Multiinstitutional, collaborative clinical trials are needed to determine the safety and efficacy of these agents going forward.

Early vascular endothelial complications after hematopoietic cell transplantation: Role of the endotheliopathy in biomarkers and target therapies development

“…The reported mortality rates in patients with clinically relevant TA-TMA have been up to 75%, partially due to the irreversible organ damage caused by delayed diagnosis on some occasions (37,39). The use of eculizumab, a monoclonal antibody against the fraction C5 of the complement system, has improved survival in patients with severe forms of this complication, although mortality rates in treated patients still exceed 30% (40,41). substantial morbidity and mortality despite significant advances in treatment and supportive care (42,43), and the prevention of GvHD, is, therefore critical to the success of allo-HCT.…”

Prior COVID-19 infection may increase risk for developing endothelial dysfunction following hematopoietic cell transplantation

“…Specific therapeutic targets such as tocilizumab and anakinra are being investigated for their use in severe COVID-19 illness, due to their effects of modulating excess cytokine signaling. Likewise, IL-6 and TNF-α, in addition to a number of other cytokines, are excessively active in patients who have developed HCT-associated endothelial complications ( 21 , 29 ). The use of targeted cytokine antagonists in preventing or treating HCT-associated endotheliopathies has been suggested in the literature, however to our knowledge has not been explored in a large-scale trial.…”

The role of the complement system in kidney glomerular capillary thrombosis

“…In addition to TTP, STEC-induced HUS, and aHUS, a variety of pathological conditions such as autoimmune disease ( 73 , 74 ), drug use ( 75 ), infection ( 76 , 77 ), malignancy ( 78 ), malignant hypertension ( 79 – 81 ), pregnancy ( 82 , 83 ), and transplantation ( 84 , 85 ) can trigger secondary TMA. Although TTP and STEC-HUS have well-established diagnostic tests, the differentiation between aHUS and secondary TMA remains controversial because pathogenic variants in complement-related genes are only identified in about half of the patients with aHUS.…”