Role for platelet glycoprotein Ib-IX and effects of its inhibition in endotoxemia-induced thrombosis, thrombocytopenia, and mortality.
OBJECTIVE
Poor prognosis of sepsis is associated with bacterial lipopolysaccharide (LPS)-induced intravascular inflammation, microvascular thrombosis, thrombocytopenia, and disseminated intravascular coagulation. Platelets are critical for thrombosis, and there has been increasing evidence of the importance of platelets in endotoxemia. The platelet adhesion receptor, the glycoprotein Ib-IX complex (GPIb-IX), mediates platelet adhesion to inflammatory vascular endothelium and exposed subendothelium. Thus, we have investigated the role of GPIb-IX in LPS-induced platelet adhesion, thrombosis, and thrombocytopenia.


RESULTS
LPS-induced mortality is significantly decreased in mice expressing a functionally deficient mutant of GPIbα. Furthermore, we have developed a micellar peptide inhibitor, MPαC (C13H27CONH-SIRYSGHpSL), which selectively inhibits the von Willebrand factor -binding function of GPIb-IX and GPIb-IX-mediated platelet adhesion under flow without affecting GPIb-IX-independent platelet activation. MPαC inhibits platelet adhesion to LPS-stimulated endothelial cells in vitro and alleviates LPS-induced thrombosis in glomeruli in mice. Importantly, MPαC reduces mortality in LPS-challenged mice, suggesting a protective effect of this inhibitor during endotoxemia. Interestingly, MPαC, but not the integrin antagonist, Integrilin, alleviated LPS-induced thrombocytopenia.


CONCLUSIONS
These data indicate an important role for the platelet adhesion receptor GPIb-IX in LPS-induced thrombosis and thrombocytopenia, and suggest the potential of targeting GPIb as an antiplatelet strategy in managing endotoxemia.
From the Department of Pharmacology, College of Medicine (H.Y., A.S., W.X., A.Z., F.Q., A.K., A.V.L., X.D.), Department of Biopharmaceutical Sciences, College of Pharmacy (Z.J.W.), and Department of Pathology (S.P.), University of Illinois at Chicago; and Department of Physiology and Biophysics, University of Arkansas for Medical Sciences (A.C., J.W.).
Hong
H
Yin
Aleksandra
A
Stojanovic-Terpo
Weidong
W
Xu
Adam
A
Corken
Alexander
A
Zakharov
Feng
F
Qian
Sasha
S
Pavlovic
Aleksandar
A
Krbanjevic
Alexander V
AV
Lyubimov
Zaijie J
ZJ
Wang
Jerry
J
Ware
Xiaoping
X
Du
D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism; D019446:Endotoxemia / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000494:pharmacology; D010973:Platelet Adhesiveness / Q000187:drug effects / Q000502:physiology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013921:Thrombocytopenia / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D013927:Thrombosis / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D014841:von Willebrand Factor / Q000378:metabolism
D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; D011993:Recombinant Fusion Proteins; C094990:adhesion receptor; D014841:von Willebrand Factor
GPIb-IX; endotoxemia; lipopolysaccharide; platelet; platelet inhibitor; thrombocytopenia; thrombosis