Alloantibody induced platelet responses in transplants: potent mediators in small packages

Abstract

The early histological studies of organ allografts noted platelets attached to vascular endothelium. Platelets adhere to vessels before any morphological evidence of endothelial injury. Subsequently, in vitro and in vivo experiments have demonstrated that alloantibodies can induce exocytosis of von Willebrand factor and P-selectin from endothelial cells and attachment of platelets within minutes. Platelets also adhere to and stimulate leukocytes. These interactions are increased by complement activation. After attachment platelets degranulate, releasing preformed mediators. Some chemokines stored together in platelet granules can form heteromers with synergistic functions. Heteromers containing platelet factor 4 (PF4; CXCL4) are specific to platelets and provide insights to unique platelet functions and opportunities for therapeutic intervention.

Figure 1

The laminar flow of blood in arteries and arterioles causes platelets to be more concentrated adjacent to the vessel wall. As illustrated in the inset, alloantibodies cause exocytosis of von Willebrand factor (vWf) from storage granules in endothelial cells. Platelets bind to vWf and become activated. Activated platelets release chemokines from their alpha granules and express P-selectin on their membranes. Heteromers of PF4 and RANTES recruit monocytes, which are further activated by PSGL-1 receptors binding to P-selectin on platelets. Complement activation products provide additional chemoatraction (C3a and C5a) as well as ligands (C3b for CR1) to increase leukocyte localization to the endothelium.

Figure 2

Passive transfer of alloantibodies to C57BL/6 RAG^−/− recipients of B10.A renal transplants causes release of vWf and extensive platelet accumulation in peritubular capillaries and glomeruli within 1 hour. Platelets (stained brown for vWf) interact extensively with endothelial cells and leukocytes (arrows). Leukocytes with adherent platelets are better appreciated on the enlarged image on right.