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Inflammatory mediators promote strong sickle cell adherence to endothelium under venular flow conditions

Adherence of sickle erythrocytes to endothelium in venules is thought to initiate or propagate vaso‐occlusive episodes. Because of blood shear forces with normal microvascular flow, adherence in post‐capillary venules requires binding via high‐affinity receptor‐mediated pathways. Microvascular flow in sickle patients is episodic, even in asymptomatic patients, so adherence may also occur at low shear not requiring high‐affinity binding. Sickle cell binding to endothelium was quantified under flow or static incubation with unusually large vWF, thrombospondin, α4β1/VCAM‐1 or α4β1/fibronectin (FN). Adherence under flow at 0.5 dyne/cm2 shear stress leads to the greatest number of adherent sickle cells. Adherence under flow at 1.0 dyne/cm2 leads to the strongest adherence. Static incubation conditions promote weak adherence of low numbers of sickle cells to endothelium. Following attachment at 1.0 dyne/cm2, adherence strength was 2.5 ± 0.1 or 2.6 ± 0.2 dynes/cm2 for α4β1/VCAM‐1 or α4β1/FN pathways, a level 50% greater than adherence strength mediated by thrombospondin or ULvWF (1.7 ± 0.08 or 1.6 ± 0.07 dynes/cm2, respectively). Sickle cell adhesion promoted by simultaneous activation of α4β1/VCAM‐1 and α4β1/FN pathways is the strongest at 6.2 ± 0.2 dynes/cm2 and adherent red cells resist detachment shear stresses up to 10 dynes/cm2. These data demonstrate that sickle cell adhesion to endothelium is regulated both by receptor/ligand affinity and flow conditions. Thus, both microvascular flow conditions and receptor–ligand interactions may regulate sickle cell adherence in vivo. Am. J. Hematol. 73:215–224, 2003. © 2003 Wiley‐Liss, Inc.