New strategy of platelet substitutes for enhancing platelet aggregation at high shear rates: cooperative effects of a mixed system of fibrinogen gamma-chain dodecapeptide- or glycoprotein Ibalpha-conjugated latex beads under flow conditions.
To construct platelet substitutes that have hemostatic properties over a wide range of shear rates, we used fibrinogen gamma-chain carboxy-terminal sequence HHLGGAKQAGDV (H12), which recognizes activated platelets at low shear rates, and a recombinant water-soluble moiety of the platelet glycoprotein (rGPIbalpha), which recognizes von Willebrand factor at high shear rates. Three kinds of samples were prepared for this purpose: H12-conjugated latex beads (H12-latex beads), rGPIbalpha-latex beads, and H12/rGPIbalpha-latex beads. These samples were evaluated in thrombocytopenia-imitation blood at various flow conditions. Based on ADP-induced platelet aggregation studies, the H12-latex beads significantly enhanced platelet aggregation via H12 binding with GPIIb/IIIa activated on the surface of activated platelets, whereas the rGPIbalpha-latex beads did not support platelet aggregation. In the case of the H12/rGPIbalpha-latex beads, the function of H12 was suppressed by steric hindrance from the larger rGPIbalpha bound to the latex bead. A mixture of the H12-latex beads and the rGPIbalpha-latex beads adhered to a collagen surface over a wide range of shear rates. In particular, at high shear rates, a cooperative effect was observed in the enhancement of platelet thrombus formation compared with H12-latex beads or rGPIbalpha-latex beads alone. We propose that a mixed system of H12- and rGPIbalpha-conjugated nanoparticles is a more effective platelet substitute than each of the beads used alone and has enhanced platelet aggregation properties.
Okamura
Yosuke
Y
Graduate School of Science and Engineering, Waseda University, Tokyo 169-8555, Japan.
Handa
Makoto
M
Suzuki
Hidenori
H
Ikeda
Yasuo
Y
Takeoka
Shinji
S
D001792:Blood Platelets / Q000502:physiology*; D001802:Blood Substitutes / Q000378:metabolism; D018056:Hemorheology / Q000295:instrumentation / Q000379:methods*; D006801:Humans; D008863:Microspheres; D053758:Nanoparticles; D009842:Oligopeptides; D010446:Peptide Fragments / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000494:pharmacology*; D017713:Platelet Transfusion; D033081:Shear Strength; D013314:Stress, Mechanical
D001802:Blood Substitutes; D009842:Oligopeptides; D010446:Peptide Fragments; D019038:Platelet Glycoprotein GPIb-IX Complex; C023592:glycocalicin