Complement System as a New Target for Hematopoietic Stem Cell Transplantation-Related Thrombotic Microangiopathy

Abstract

Thrombotic microangiopathy (TMA) is a complication that may occur after autologous or allogeneic hematopoietic stem cell transplantation (HSCT) and is conventionally called transplant-associated thrombotic microangiopathy (TA-TMA). Despite the many efforts made to understand the mechanisms of TA-TMA, its pathogenesis is largely unknown, its diagnosis is challenging and the case-fatality rate remains high. The hallmarks of TA-TMA, as for any TMA, are platelet consumption, hemolysis, and organ dysfunction, particularly the kidney, leading also to hypertension. However, coexisting complications, such as infections and/or immune-mediated injury and/or drug toxicity, together with the heterogeneity of diagnostic criteria, render the diagnosis difficult. During the last 10 years, evidence has been provided on the involvement of the complement system in the pathophysiology of TA-TMA, supported by functional, genetic, and therapeutic data. Complement dysregulation is believed to collaborate with other proinflammatory and procoagulant factors to cause endothelial injury and consequent microvascular thrombosis and tissue damage. However, data on complement activation in TA-TMA are not sufficient to support a systematic use of complement inhibition therapy in all patients. Thus, it seems reasonable to propose complement inhibition therapy only to those patients exhibiting a clear complement activation according to the available biomarkers. Several agents are now available to inhibit complement activity: two drugs have been successfully used in TA-TMA, particularly in pediatric cases (eculizumab and narsoplimab) and others are at different stages of development (ravulizumab, coversin, pegcetacoplan, crovalimab, avacopan, iptacopan, danicopan, BCX9930, and AMY-101).

Keywords: complement; eculizumab; hematopoietic stem cell transplantation; narsoplimab; thrombotic microangiopathy.

Figure 1

Simplified scheme of the complement system and target sites of the available drugs. Complement can be activated through three pathways: the classical pathway triggered by antibody-antigen complex, the alternative pathway spontaneously activated at a low level or triggered by specific surface antigens and the lectin pathway activated by binding mannose residues on the pathogen surface. The classical pathway starts from the three components of C1, i.e., C1q and the two proteases C1r and C1s. The activation of C1 in turn induces the activation of C2 and C4, which are also activated by the proteases associated with the mannose-binding lectin (MBL), i.e., MASP-1 and MASP-2. The activation of the classical and lectin pathways is controlled by a C1-inhibitor that can block C1r, C1s, MASP-1, and MASP-2. The alternative pathway, composed of C3, Factor B, and Factor D, is regulated by soluble inhibitors such as factor H and factor I as well as by cell-bound inhibitors such as membrane cofactor protein (MCP), complement receptor 1 (CR1), and decay-accelerating factor (DAF). The activation of the three pathways (classical, lectin, and alternative) converges on the common pathway with the formation of strong inflammatory mediators, such as C3a and C5a, and the production of the C5b-9 membrane attack complex (MAC) that lyses target cells. Therapy with eculizumab blocks C5, whereas therapy with narsoplimab blocks MASP-2. Although never used in TA-TMA, other complement inhibitory drugs are available at different stages of development, such as crovalimab for C5, iptacopan for factor B, danicopan for factor D, and pegcetacoplan for C3.