Effect of fibrinogen on leukocyte margination and adhesion in postcapillary venules

Objective: To quantitatively evaluate the role of fibrinogen (Fb) as a determinant of leukocyte (WBC) margination in postcapillary venules in light of its ability to induce red blood cell (RBC) aggregation with reductions in shear rate (γ) and increase adhesiveness of WBCs to endothelium (EC). Methods: Red cell aggaregation (RCA), WBC margnation (flux at the EC), rolling velocity, and adhesion to the EC were measured in rat mesenteric posteapillary venules upon reducing γ, prior to and following systemic infusion of Fb. Proximal occlusion of feeding microvessels with a blunted probe facilitated reductions in γ from 600 to 50 s^-1. An index of aggregation (G) was derived from light-scattering properties of RBCs, where G was proportional to the number of RBCs per aggregate. WBC margination was measured as the percentage of total luminal WBC flux that rolled on the EC F· _WBC. Results: For normal levels of Fb (0.07 g%), reductions in γ resulted in a 4-fold rise in F*_WBC and no change in G as γ was reduced to 50 s^-1. Infusion of Fb to achieve a plasma concentration to 0.7 g% caused a modest 20% increase in G and a 2.5-fold increase in F*_WBC at γ = 50 s^-1. WBC-EC adhesion appeared to increase significantly, but much less than with infusion of high molecular weight dextran (Dx). With Dx, G increased 3-fold, with reductions in γ, but F*_WBC increased only half the amount incurred with Fb at low shear. The greater margination in the presence of Fb results from RBC rouleaux that promote radial migration of WBCs. In contrast, clumps of RBCs resulting from high molecular weight Dx entrain WBCs within plasma gaps along the vessel centerline. Conclusions: In the presence of Fb, margination of WBCs increases dramatically at low shear due to rouleaux formation, which enhances radial migration of WBCs. This effect is much greater than with Dx because disruption of the much weaker Fb induced rouleaux precludes reductions in H_MICRO, whereas clumping aggregates induced by Dx form plasma gaps. Thus, modest levels of RCA caused by increased Fb may greatly enhance margination and with an enhancement of adhesiveness synergistically promote firm WBC-EC adhesion in the low flow state.