disorders (e.g., systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Crohn's disease, ulcerative colitis). Less common causes of warm-type AIHA include neoplasms other than lymphoid, and infection. Secondary warm type AIHA has been observed in cases of Covid-19. Secondary cold type AIHA is also caused primarily by lymphoproliferative disorders but is also commonly caused by infection, especially by mycoplasma, viral pneumonia, infectious mononucleosis, and other respiratory infections. Less commonly, it can be caused by concomitant autoimmune disorders. Drug-induced AIHA, though rare, can be caused by a number of drugs, including α-methyldopa and penicillin. This is a type II immune response in which the drug binds to macromolecules on the surface of the RBCs and acts as an antigen. Antibodies are produced against the RBCs, which leads to complement activation. Complement fragments, such as C3a, C4a and C5a, activate granular leukocytes (e.g., neutrophils), while other components of the system (C6, C7, C8, C9) either can form the membrane attack complex (MAC) or can bind the antibody, aiding phagocytosis by macrophages (C3b). This is one type of "penicillin allergy". In about half of cases, the cause of autoimmune hemolytic anemia cannot be determined (idiopathic or primary). This condition can also be caused by or occur with another disorder (secondary) or rarely, occur following the use of certain drugs (such as penicillin) or after a person has a blood and marrow stem cell transplant. Secondary causes of autoimmune hemolytic anemia include: Autoimmune diseases, such as lupus Chronic lymphocytic leukemia Non-Hodgkin's lymphoma and other blood cancers Epstein-Barr virus Cytomegalovirus Mycoplasma pneumonia Hepatitis HIV Pathophysiology AIHA can be caused by a number of different classes of antibody, with IgG and IgM antibodies being the main causative classes. Depending on which is involved, the pathology will differ. IgG is not very effective at activating complement and effectively binds the Fc receptor (FcR) of phagocytic cells, AIHA involving IgG is generally characterized by phagocytosis of RBCs. IgM is a potent activator of the classical complement pathway, thus, AIHA involving IgM is characterized by complement-mediated lysis of RBCs. IgM also leads to phagocytosis of RBCs however, because phagocytic cells have receptors for the bound complement (rather than FcRs as in IgG AIHA). In general, IgG AIHA takes place in the spleen, whereas IgM AIHA takes place in Kupffer cells – phagocytic cells of the liver. Phagocytic AIHA is termed extravascular, whereas complement-mediated lysis of RBCs is termed intravascular AIHA. In