Lung vaso-occlusion in sickle cell disease mediated by arteriolar neutrophil-platelet microemboli

Glycoprotein Ibα inhibitor (CCP-224) prevents neutrophil-platelet aggregation in sickle cell disease

“…Human blood collection procedure has been described in detail elsewhere 10,11 . Blood samples were drawn from steady state (not experiencing a VOC) SCD or control healthy human subjects at the Adult Sickle Cell Clinic of the University of Pittsburgh Medical Center (UPMC) in syringes containing 20 U/ml of heparin as per the protocol approved by the University of Pittsburgh Institutional Review Board.…”

“…Neutrophil-platelet aggregation has also been shown to occur in TNF-α treated cremaster venules of transgenic SCD mice, which was enabled by neutrophil CD11b/CD18 (Mac-1) binding to glycoprotein Ibα (GPIbα) on platelets 9 . Recently 10 , we used intravital microscopy in transgenic SCD mice to show that large neutrophil-platelet aggregates occlude pulmonary arterioles to promote lung vaso-occlusion in SCD. In the same study 10 , we also used quantitative microfluidic fluorescence microscopy (qMFM), an in vitro microfluidic based approach 11 , to reveal that the neutrophil-platelet aggregation under vascular mimetic flow was significantly higher in steady state SCD than race matched control human blood, and partially enabled by Mac-1 on neutrophils binding to GPIbα on platelets.…”

“…Recently 10 , we used intravital microscopy in transgenic SCD mice to show that large neutrophil-platelet aggregates occlude pulmonary arterioles to promote lung vaso-occlusion in SCD. In the same study 10 , we also used quantitative microfluidic fluorescence microscopy (qMFM), an in vitro microfluidic based approach 11 , to reveal that the neutrophil-platelet aggregation under vascular mimetic flow was significantly higher in steady state SCD than race matched control human blood, and partially enabled by Mac-1 on neutrophils binding to GPIbα on platelets. Platelet-neutrophil interactions in SCD human blood were significantly inhibited by function blocking antibodies (Abs) against CD11b or GPIbα 10 .…”

“…In the same study 10 , we also used quantitative microfluidic fluorescence microscopy (qMFM), an in vitro microfluidic based approach 11 , to reveal that the neutrophil-platelet aggregation under vascular mimetic flow was significantly higher in steady state SCD than race matched control human blood, and partially enabled by Mac-1 on neutrophils binding to GPIbα on platelets. Platelet-neutrophil interactions in SCD human blood were significantly inhibited by function blocking antibodies (Abs) against CD11b or GPIbα 10 . Taken together, these studies 7,9,10 suggest that Mac-1-GPIbα interactions also contribute to neutrophil-platelet aggregation in SCD and GPIbα antagonists can be therapeutically beneficial in preventing VOC.…”

“…Platelet-neutrophil interactions in SCD human blood were significantly inhibited by function blocking antibodies (Abs) against CD11b or GPIbα 10 . Taken together, these studies 7,9,10 suggest that Mac-1-GPIbα interactions also contribute to neutrophil-platelet aggregation in SCD and GPIbα antagonists can be therapeutically beneficial in preventing VOC. The Mac-1 binding site is situated within the leucine-rich COOH-terminal flanking region of GPIbα (residues 201-268) 12 .…”