Elevated numbers of activated platelets circulate in patients with chronic inflammatory diseases, including
atherosclerosis and
coronary disease. Activated platelets can activate the
complement system. Although complement activation is essential for immune responses and removal of spent cells from circulation, it also contributes to
inflammation and
thrombosis, especially in patients with defective
complement regulation. Proinflammatory activated leukocytes, which interact directly with platelets in response to
vascular injury, are among the main sources of
properdin, a positive regulator of the alternative pathway. The role of
properdin in complement activation on stimulated platelets is unknown. Our data show that physiological forms of human
properdin bind directly to human platelets after activation by strong agonists in the absence of C3, and bind nonproportionally to surface CD62P expression. Activation of the alternative pathway on activated platelets occurs when
properdin is on the surface and recruits C3b or C3(H2O) to form C3b,Bb or a novel cell-bound
C3 convertase [C3(H2O),Bb], which normally is present only in the fluid phase. Alternatively,
properdin can be recruited by C3(H2O) on the platelet surface, promoting complement activation. Inhibition of
factor H-mediated cell surface
complement regulation significantly increases
complement deposition on activated platelets with surface
properdin. Finally,
properdin released by activated neutrophils binds to activated platelets. Altogether, these data suggest novel molecular mechanisms for alternative pathway activation on stimulated platelets that may contribute to localization of
inflammation at sites of
vascular injury and
thrombosis.