Impaired function of platelet membrane glycoprotein IIb-IIIa in end-stage renal disease.
Impaired platelet function and a bleeding tendency are well-recognized complications of chronic renal failure. Because the fibrinogen receptor GPIIb-IIIa plays a central role in platelet aggregation and adhesion to the subendothelium, it was reasoned that a defect in this receptor may underlie the impaired platelet function in uremia. To test this hypothesis, the function of this receptor in the platelets of 11 uremic patients was studied. Aggregation studies were performed with flow cytometric techniques with anti-GPIIb-IIIa conformation-specific monoclonal antibodies (mAb) (anti-LIBS1 and anti-PMI-1). Antifibrinogen and antithrombospondin mAb were used to characterize fibrinogen binding to GPIIb-IIIa and the release of alpha-granules, respectively. Platelets from patients with chronic renal failure showed significantly decreased binding of conformation-dependent anti-LIBS1 mAb after ADP, phorbol myristate acetate, or RGD-peptide stimulation compared with normal controls, suggesting a defect related to the ability of the fibrinogen receptor to undergo a conformational change. Moreover, antifibrinogen and antithrombospondin binding to activated platelets were reduced in uremic patients, implying impairment of both ligand-binding and alpha-granule release. Hemodialysis partially restored GPIIb-IIIa function, which may account for the observed effects of this therapy in restoring platelet aggregation. These findings indicate that platelets of patients with chronic renal failure reveal an aggregation defect at least partially due to an intrinsic GPIIb-IIIa dysfunction and the presence of a putative uremic toxin that inhibits fibrinogen binding to GPIIb-IIIa.
Gawaz
M P
MP
Department Medical Klinik I, Klinikum Grosshadern, University of Munich, Germany.
Dobos
G
G
Späth
M
M
Schollmeyer
P
P
Gurland
H J
HJ
Mujais
S K
SK
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology; D000939:Epitopes / Q000737:chemistry; D004921:Erythropoietin / Q000494:pharmacology; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D005434:Flow Cytometry; D006474:Hemorrhagic Disorders / Q000209:etiology; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000150:complications / Q000628:therapy; D008297:Male; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000276:immunology / Q000502:physiology*; D011485:Protein Binding; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000494:pharmacology; D006435:Renal Dialysis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D000939:Epitopes; D009842:Oligopeptides; D010980:Platelet Membrane Glycoproteins; D011994:Recombinant Proteins; D004921:Erythropoietin; D000244:Adenosine Diphosphate; D005340:Fibrinogen; C058161:glycyl-arginyl-glycyl-aspartyl-seryl-proline; D013755:Tetradecanoylphorbol Acetate