Pathogenesis of HLH based on antiphagocytic and prophagocytic signaling. In HLH, cytotoxic T lymphocytes are activated by genetic abnormality, infection, malignancy, and autoimmune disease, and then produce inflammatory cytokines and activate macrophages. Activated macrophages engulf mature cells such as RBCs, platelets, and granulocytes, which are susceptible to phagocytosis because of high expression of prophagocytic CRT. In contrast, inflammatory cytokines suppress hematopoiesis by their direct toxic effects and down-regulate CD47 expression on HSCs, resulting in a decreased threshold of antiphagocytic signals. Therefore, HSCs were engulfed by activated macrophages, causing the BM of HLH patients to become hypoplastic, thereby exacerbating pancytopenia.