Neurological involvement in hematopoietic stem cell transplantation-associated thrombotic microangiopathy

Abstract

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a well-recognized serious complication of hematopoietic stem cell transplantation (HSCT). The understanding of TA-TMA pathophysiology has expanded in recent years. Dysregulation of the complement system is thought to cause endothelial injury and, consequently, microvascular thrombosis and tissue damage. TA-TMA can affect multiple organs, and each organ exhibits specific features of injury. Central nervous system (CNS) manifestations of TA-TMA include posterior reversible encephalopathy syndrome, seizures, and encephalopathy. The development of neurological dysfunction is associated with a significantly lower overall survival in patients with TA-TMA. However, there are currently no established histopathological or radiological criteria for the diagnosis of CNS TMA. Patients who receive total body irradiation (TBI), calcineurin inhibitors (CNI), and severe acute and chronic graft-versus-host disease (GVHD) are at a high risk of experiencing neurological complications related to TA-TMA and should be considered for directed TA-TMA therapy. However, the incidence and clinical manifestations of TA-TMA neurotoxicity remain unclear. Studies specifically examining the involvement of CNS in TMA syndromes are limited. In this review, we discuss clinical manifestations and imaging abnormalities in patients with nervous system involvement in TA-TMA. We summarize the mechanisms underlying TA-TMA and its neurological complications, including endothelial injury, evidence of complement activation, and treatment options for TA-TMA.

Keywords: Endothelial injury; Hematopoietic stem cell transplantation; Neurological involvement; Thrombotic microangiopathy.

Fig. 1

The illustration is demonstrates complement-mediated endothelial injury and microthrombi formation in transplant-associated thrombotic microangiopathy (TA-TMA). Activated lymphocytes produce IFN-γ, activating APCs. Subsequently, APCs produce TNF-α and IL-1, which damage vascular endothelial cells. The damaged ECs releases IL-8, causing neutrophil activation and release of neutrophil extracellular traps (NETs) leading to complement alternative activation. Activated lymphocytes also produce DSA/RSA and Anti-FH Ab, which similarly activate the complement alternative pathway. All three pathways converge to mediate cleavage of C3, initiating the terminal pathway to form the C5b-9 membrane attack complex and assembly of the MAC. Complement-mediated endothelial injury leads to the release of proinflammatory cytokines such as ICAM-1 and VCAM-1, as well as procoagulant factors like vWF, VIIa and TF. Additionally, there is an increase in the expression of adhesion molecules on the cell surface. All these phenomena promote further endothelial injury and leads to platelet aggregation and the initiation and propagation of the complement cascade. The erythrocytes are sheared and destroyed by platelet-rich microthrombi, leading to schistocyte production and microangiopathic hemolytic anemia. GVHD, graft-versus-host disease; EC, endothelial cell; CEC, circulating endothelial cell; APC, antigen-presenting cell; RBC, red blood cell; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular adhesion molecule 1; vWF, von Willebrand factor; IFN, interferon; TNF, tumour necrosis factor; IL-1, interleukin 1; IL-8, interleukin 8; MAC,membrane attack complex; MASP-2, mannose-binding protein-associated serine protease-2; NETs, neutrophil extracellular traps; DSA, donor-specific antibody; RSA, recipient-specific antibody; Ab,antibody; VIIa, Factor VIIa; TF, tissue factor

Fig. 2

Central nervous system symptoms and other organ complications associated with TA-TMA after HSCT

Fig. 3

Treatment in HSCT-associated thrombotic microangiopathy. TPE, therapeutic plasma exchange