Heme: Modulator of Plasma Systems in Hemolytic Diseases

Hemolytic diseases such as sickle-cell disease, β-thalassemia, malaria, and autoimmune hemolytic anemia continue to present serious clinical hurdles. In these diseases, lysis of erythrocytes causes the release of hemoglobin and heme into plasma. Extracellular heme has strong proinflammatory potential and activates immune cells and endothelium, thus contributing to disease pathogenesis. Recent studies have revealed that heme can interfere with the function of plasma effector systems such as the coagulation and complement cascades, in addition to the activity of immunoglobulins. Any perturbation in such functions may have severe pathological consequences. In this review we analyze heme interactions with coagulation, complement, and immunoglobulins. Deciphering such interactions to better understand the complex pathogenesis of hemolytic diseases is pivotal.

TrendsHeme activates proinflammatory programs in different cell types such as macrophages, neutrophils, and endothelial cells. Heme can bind to the TLR4 receptor and trigger inflammasome activation. It has been proposed that the ability of heme to activate different pathways may contribute to the state of systemic inflammation that is typical of hemolytic disorders.Heme modulates the functions of the essential plasma effector systems – the coagulation cascade, the complement system, and the activity of immunoglobulins.Heme influences hemostasis directly by binding to coagulation factor VIII and fibrinogen, or indirectly by inducing the expression of tissue factor on endothelial cells and leukocytes.A fraction of immunoglobulins in healthy individuals bind to heme. This binding results in a marked diversification of the repertoire of antigens recognized by antibodies.Heme activates the complement system. It interacts with the central complement component C3 and activates the alternative pathway. Conversely, binding of heme to the C1q component of complement results in inhibition of its function, thus explaining in part the preferential activation of the alternative complement pathway following addition of heme to plasma.