Increased adhesive properties of platelets in sickle cell disease: roles for alphaIIb beta3-mediated ligand binding, diminished cAMP signalling and increased phosphodiesterase 3A activity.
Whilst high pro-coagulant activity is reported in sickle cell disease (SCD), the precise role of platelets (PLTs) in SCD inflammatory and vaso-occlusive processes is unclear. Adhesion of PLTs from healthy controls (CON), SCD individuals (SCD) and SCD patients on hydroxycarbamide (SCDHC) to fibrinogen (FB) was compared using static adhesion assays. PLT adhesion molecules and intraplatelet cyclic adenosine monophosphate (icAMP) were observed by flow cytometry and enzyme-linked immunosorbent assay. SCD-PLTs demonstrated significantly greater adhesion than CON-PLTs to FB. Participation of the alpha(IIb)beta(3)-integrin in SCD-PLT adhesion was implicated by increased alpha(IIb)beta(3) activation and data showing that an alpha(IIb)beta(3)-function-inhibiting antibody significantly diminished SCD-PLT adhesion to FB. Platelet activation was potentiated by reductions in icAMP; cAMP levels were decreased in SCD-PLTs, being comparable to those of thrombin-stimulated CON-PLTs. Furthermore, SCD-PLT adhesion to FB was significantly reduced by cilostazol, an inhibitor of cAMP-hydrolyzing phosphodiesterase 3A (PDE3A). Both alpha(IIb)beta(3)-integrin activation and icAMP correlated significantly with fetal haemoglobin in SCD. Accordingly, hydroxycarbamide therapy was associated with lower PLT adhesion and higher icAMP. SCD-PLTs may be capable of adhering to proteins encountered on the inflamed vascular wall and, potentially, participate in vaso-occlusive processes. Hydroxycarbamide and, speculatively, nitric oxide donor or cyclic-nucleotide-targeted therapies may aid in the reversal of PLT adhesive properties in SCD.
Proença-Ferreira
Renata
R
The Haematology and Haemotherapy Centre, School of Medicine, University of Campinas, Brazil.
Franco-Penteado
Carla F
CF
Traina
Fabiola
F
Saad
Sara T O
ST
Costa
Fernando F
FF
Conran
Nicola
N
D000328:Adult; D000368:Aged; D000755:Anemia, Sickle Cell / Q000097:blood*; D001792:Blood Platelets / Q000378:metabolism; D002478:Cells, Cultured; D000077407:Cilostazol; D003094:Collagen / Q000378:metabolism; D000242:Cyclic AMP / Q000097:blood*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000097:blood*; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010973:Platelet Adhesiveness / Q000187:drug effects / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D055815:Young Adult
D058987:Phosphodiesterase 3 Inhibitors; D010726:Phosphodiesterase Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013777:Tetrazoles; D005340:Fibrinogen; D003094:Collagen; D000242:Cyclic AMP; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D000077407:Cilostazol