Transplant-associated thrombotic microangiopathy: theoretical considerations and a practical approach to an unrefined diagnosis

Abstract

Transplant-associated thrombotic microangiopathy (TA-TMA) is an increasingly recognized complication of hematopoietic stem cell transplant (HSCT) with high morbidity and mortality. The triad of endothelial cell activation, complement dysregulation, and microvascular hemolytic anemia has the potential to cause end organ dysfunction, multiple organ dysfunction syndrome and death, but clinical features mimic other disorders following HSCT, delaying diagnosis. Recent advances have implicated complement as a major contributor and the therapeutic potential of complement inhibition has been explored. Eculizumab has emerged as an effective therapy and narsoplimab (OMS721) has been granted priority review by the FDA. Large studies performed mostly in pediatric patients suggest that earlier recognition and treatment may lead to improved outcomes. Here we present a clinically focused summary of recently published literature and propose a diagnostic and treatment algorithm.

Fig. 1. Pathophysiology of TA-TMA with the sites of action of proposed treatments.

The illustration is separated into two halves. The upper half demonstrates the numerous mechanisms that promote endothelial damage and the treatments targeting these promoters of injury. The lower half represents the effect the damaged endothelium has on protective factors of the endothelium and the treatments, which enhance these cytoprotective factors. Therapies shown as potential treatment options but have not been widely or rigorously studied include EPA, TNF-α inhibitors (etanercept, infliximab), bosentan, transdermal isosorbide tape, statins, iloprost, and recombinant thrombomodulin. Adapted with copyright permission from Fig. 4 Khosla et al. [101]. Ang2 angiopoietin 2, APC antigen-presenting cell, CAM cell adhesion molecules, CEC circulating endothelial cell, CFP complement factor P, DSA donor-specific antibodies, EMP endothelial microparticles, EPA eicosapentaenoic acid, FH Factor H, Hb hemoglobin, IL interleukin, MAC membrane attack complex, MASP-2 mannose-binding protein-associated serine protease-2, NETs neutrophil extracellular traps, NO nitric oxide, PAI plasminogen-activator inhibitor, PGI2 prostacyclin, RBC red blood cell, TNF-α tumor necrosis factor alpha, RSA recipient-specific antibodies, TF tissue factor, TPE therapeutic plasma exchange, VIIa Factor VIIa, VEGF vascular endothelial growth factor, vWF von Willebrand factor.

Fig. 2. Proposed TA-TMA diagnostic and treatment algorithm.

AIHA autoimmune hemolytic anemia, BP blood pressure, CBC complete blood count, CFH complement factor H, CNI calcineurin inhibitor, DIC disseminated intravascular coagulation, GVHD graft vs. host disease HSCT hematopoietic stem cell transplantation, LDH lactate dehydrogenase, MMF mycophenolate mofetil, MODS multiple organ dysfunction syndrome, mTORi mammalian target of rapamycin inhibitor, PCR polymerase chain reaction, TA-TMA transplant-associated thrombotic microangiopathy, TPE therapeutic plasma exchange, TTP thrombotic thrombocytopenic purpura.