Disorder of Coagulation-Fibrinolysis System: An Emerging Toxicity of Anti-PD-1/PD-L1 Monoclonal Antibodies

Abstract

A disruption of immune checkpoints leads to imbalances in immune homeostasis, resulting in immune-related adverse events. Recent case studies have suggested the association between immune checkpoint inhibitors (ICIs) and the disorders of the coagulation-fibrinolysis system, implying that systemic immune activation may impact a balance between clotting and bleeding. However, little is known about the association of coagulation-fibrinolysis system disorder with the efficacy of ICIs. We retrospectively evaluated 83 lung cancer patients who received ICI at Kumamoto University Hospital. The association between clinical outcome and diseases associated with disorders of the coagulation-fibrinolysis system was assessed along with tumor PD-L1 expression. Among 83 NSCLC patients, total 10 patients (12%) developed diseases associated with the disorder of coagulation-fibrinolysis system. We found that disorders of the coagulation-fibrinolysis system occurred in patients with high PD-L1 expression and in the early period of ICI initiation. In addition, high tumor responses (72%) were observed, including two complete responses among these patients. Furthermore, we demonstrate T-cell activation strongly induces production of a primary initiator of coagulation, tissue factor in peripheral PD-L1high monocytes, in vitro. This study suggests a previously unrecognized pivotal role for immune activation in triggering disorders of the coagulation-fibrinolysis system in cancer patients during treatment with ICI.

Incidence of thromboembolism in patients with melanoma on immune checkpoint inhibitor therapy and its adverse association with survival

“…Production of inflammatory cytokines subsequently suppresses the antithrombotic response of endothelial cells and promotes procoagulant activity. 34 Recent studies have suggested that aberrant activation of the innate immune response is associated with thrombosis and atherothrombosis. 35 Additionally, several studies have investigated the role of PD-1 and its impact on atherogenesis.…”

Identification and validation of stromal-tumor microenvironment-based subtypes tightly associated with PD-1/PD-L1 immunotherapy and outcomes in patients with gastric cancer

“…F2, which encodes the coagulation factor II (also known as thrombin), is a pro-inflammatory and pro-coagulant molecule that is elevated in various cancers, including breast and gastric cancers [46,47]. Recent studies showed that disorders of the coagulation-fibrinolysis system are associated with the efficacy of immune-checkpoint inhibitors [48]. Thrombin activates platelets in the tumor Fig.…”

DNA methylation in the promoters of PD-L1, MMP9, ARG1, galectin-9, TIM-3, VISTA and TGF-β genes in HLA-DR– myeloid cells, compared with HLA-DR+ antigen-presenting cells

“…Mice lacking PD-L1 are susceptible to autoimmune diseases, suggesting the importance of PD-L1 in maintaining immune tolerance [ 51 ]. In vitro work showed that PD-L1 is expressed by APCs, in a steady-state condition, and serve as a self-regulatory mechanism to maintain haemostasis and suppress T cell activation [ 52 ].…”