Effect of von Willebrand factor on the pharmacokinetics of recombinant human platelet glycoprotein Ibalpha-immunoglobulin G1 chimeric proteins.

PURPOSE: Recombinant human platelet glycoprotein Ibalpha-immunoglobulin G1 chimeric proteins (GPIbalpha-Ig) have varying levels of anti-thrombotic activities based on their ability to compete for platelet mediated adhesion to von Willebrand Factor (vWF). Valine substituted GPIbalpha-Ig chimeras, at certain position, increase the binding affinity to vWF over its "wild-type" GPIbalpha-Ig analog. The purpose of this study was to determine the pharmacokinetics of two valine substituted GPIbalpha-Ig chimeras, GPIbalpha-Ig/1V (valine substitution at 239 position) and GPIbalpha-Ig/2V (double valine substitution at 233 and 239 position), in mice, rats and dogs. METHODS: Head-to-head comparisons of pharmacokinetics of GPIbalpha-Ig/1V and GPIbalpha-Ig/2V were investigated in rats and dogs after intravenous administration. Since vWF precipitates in the serum but not in plasma preparation, the concentration-time profiles of GPIbalpha-Ig/2V in rats were examined from the same blood samples for determination of matrix effect. The disposition of GPIbalpha-Ig/2V was also compared in vWF-deficient versus wild-type mice. RESULTS: For GPIbalpha-Ig/2V, the serum clearances were 2.62+/-0.27 ml/hr/kg in rats and 1.97+/-0.24 ml/hr/kg in dogs. The serum clearances of less potent GPIbalpha-Ig/1V were 1.08+/-0.08 and 0.97+/-0.19 ml/hr/kg in rats and dogs, respectively. In addition, the serum clearance of GPlbalpha-Ig/2V of 1.53 ml/hr/kg in vWF-deficient mice was lower than that in wild-type mice of 2.79 ml/hr/kg. CONCLUSION: The difference in disposition for valine substituted forms of GPIbalpha-Ig in laboratory animals are likely affected by their enhanced binding affinity for circulating vWF.

Von Willebrand factor receptor GPIb alpha is expressed by human factor XIIIa-positive dermal dendrocytes and is upregulated by mast cell degranulation.

GPIb alpha, a glycoprotein component of the GPIb-IX-V complex, serves as a platelet membrane receptor that mediates adhesion to von Willebrand factor normally present in the vascular subendothelium. Recent data have demonstrated that GPIb alpha is not restricted to platelets, but is also expressed by endothelium in vitro. In this study, we describe the expression and distribution of GPIb alpha in normal adult and neonatal human skin. GPIb alpha is present, as detected by immunohistochemistry, on endothelial cells and on highly dendritic cells localized within the perivascular space, dermal-epidermal junction, and reticular dermis. By dual-labeling immunofluorescence and confocal microscopy, GPIb alpha-positive cells within the dermal interstitium are demonstrated to represent factor XIIIa-positive dermal dendrocytes. In organ cultures of neonatal human foreskin, mast cell degranulation induced by either substance P or compound 48/80 resulted in transiently increased GPIb alpha expression by dermal dendrocytes. Because the GPIb-IX-V complex plays a part in regulating hemostasis and may be important for cellular interactions with extracellular matrix molecules, these data provide additional insight into the potential function of FXIIIa-positive dermal dendrocytes in skin remodeling and repair.