Platelet factor 4 (PF4) is a platelet-specific
protein that is stored in platelet alpha granules and released following platelet activation. PF4 was the first
chemokine that was isolated, but unlike other
chemokines, it may not have a clear role in
inflammation. Gathering evidence suggests that unlike other
chemokines that bind to specific receptors, PF4's biology depends on its unusually high affinity for heparan
sulfates and other negatively charged molecules at concentrations attained in the immediate vicinity of activated platelets. There has been one report that PF4 binds to CXCR3B, a
chemokine receptor isoform that may be present in some vascular beds, but the
biological relevance of this single observation is not clear. We propose that the main
biological role of PF4 and the basis for its presence in the alpha granules of all known mammalian platelets is to neutralize surface
heparan sulfate side-chains of
glycosaminoglycans and to optimize
thrombus development at sites of
vascular injury. In addition, the binding of PF4 to surface
glycosaminoglycans may also underlie its angiostatic and proatherogenic properties. Additionally, PF4 binds to several other
proteins that are central to
thrombosis, angiogenesis, and
atherogenesis. These interactions may also contribute to its
biological and pathobiological effects. Certainly, future studies using in vivo models to test
biological relevance of each of these proposed mechanisms by which PF4 interacts with the vasculature are needed, as are studies to define the importance of PF4 binding to CXCR3B.