From the Cox Laboratory for Biomedical Engineering, Institute of
Biosciences and Bioengineering, Rice University, Houston, Tex (K.K., J.D.H.,
L.V.M.); Speros P. Martel Section of Leukocyte Biology, Department of
Pediatrics, Baylor College of Medicine, Houston, Tex (S.N., A.R.B., E.H.,
C.W.S., S.I.S.); Northwestern Medical School, Chicago, Ill (G.S.K., K.R.S.);
and Protein Design Labs Inc, Mountain View, Calif (E.L.B.)
Correspondence to Scott I. Simon, PhD, Children's Nutrition Research Center, 1100 Bates St, Room 6014, Houston, TX 77030-2600. E-mail ssimon{at}bcm.tmc.edu
Background—After activation,
platelets adhere to neutrophils via P-selectin and
ß2-integrin. The molecular mechanisms and adhesion events
in whole blood exposed to venous levels of hydrodynamic shear in the
absence of exogenous activation remain unknown.
Methods and Results—Whole blood was sheared at
Conclusions—The results are consistent with a model in
which venous levels of shear support platelet adherence to
neutrophils via P-selectin binding PSGL-1. This interaction alone is
sufficient to mediate neutrophil aggregation. Abrogation of
platelet adhesion and aggregation requires blocking Mac-1 in
addition to PSGL-1 or P-selectin. The described mechanisms are likely
of key importance in the pathogenesis and progression of thrombotic
disorders that are exacerbated by leukocyte-platelet aggregation.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Venous Levels of Shear Support Neutrophil-Platelet Adhesion and Neutrophil Aggregation in Blood via P-Selectin and ß2-Integrin
100
s-1. The kinetics of neutrophil-platelet adhesion and
neutrophil aggregation were measured in real time by flow cytometry.
P-selectin was upregulated to the platelet surface in response to
shear and was the primary factor mediating neutrophil-platelet
adhesion. The extent of neutrophil aggregation increased linearly with
platelet adhesion to neutrophils. Blocking either P-selectin, its
glycoprotein ligand PSGL-1, or both
simultaneously by preincubation with a monoclonal
antibody resulted in equivalent inhibition of
neutrophil-platelet adhesion (30%) and neutrophil aggregation
(70%). The residual amount of neutrophil adhesion was blocked with
anti-CD11b/CD18. Treatment of blood with prostacyclin analogue ZK36374,
which raises cAMP levels in platelets, blocked P-selectin
upregulation and neutrophil aggregation to baseline. Complete
abrogation of platelet-neutrophil adhesion required both ZK36374
and anti-CD18. Electron microscopic observations of fixed blood
specimens revealed that platelets augmented neutrophil aggregation
both by forming bridges between neutrophils and through
contact-mediated activation.
Key Words: blood cells • neutrophils • platelets • glycoproteins • integrins
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