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ABSTRACT: A defective platelet glycoprotein (GP) Ib/IX/V complex [von Willebrand factor (VWF) receptor] results in Bernard-Soulier syndrome (BSS), which is characterized by macrothrombocytopenia and impaired ristocetin- and thrombin-induced platelet aggregation. We found 2 independent BSS-variant families: Case I [compound heterozygous mutations, p.Glu331X and a frame shift by a deletion at c.1444delA of GPIbα (GP1BA) terminating at a premature stop codon (p.Thr452ProfsX58)], and case II [homozygous nonsense mutation at c.1723C>T, p.Gln545X]. Case I platelets expressed no GPIbα, resulting in absence of ristocetin-induced platelet aggregation (RIPA) and 50% reduction in thrombin-induced aggregation with no shape change. The mother's platelets had 50% the expression level of A-type GPIbα (4-repeated VNTR: variable number of tandem repeats, p.[Thr145Met; Ser399_Pro411[4]]); the father's platelets had the same expression level of C-type GPIbα (2-repeated VNTR, p.Ser399_Pro411dup) as the mother's platelets. The mother's RIPA was significantly higher than the father's. Thrombin-induced aggregation was normal in both parents. Case II platelets expressed a GPIbα with an abnormal cytoplasmic tail, p.Gln545X-truncated GPIbα, which complexed with GPIX and GPV on the cell surface; its expression level of the complex was normal. Case II platelets had reversible RIPA, with no ATP release, and weak thrombin-induced aggregation without shape change. These results suggest that a signaling process through the GPIbα cytoplasmic tail required for full platelet activation is defective in BSS variant case II and a length polymorphism of GPIbα is associated with a modified level of RIPA heterozygous BSS case I.
Thrombosis Research 02/2013; · 2.44 Impact Factor
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ABSTRACT: Flow cytometric studies demonstrated that the platelets from a patient with Bernard-Soulier syndrome expressed substantial amounts of both GPIX and GPV, although in reduced amounts.
British Journal of Haematology 03/2008; 87(1):185 - 188. · 4.94 Impact Factor
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ABSTRACT: Platelet integrin αβ3 (GPIIb-IIIa) plays important roles in platelet-mediated clot retraction. However, little is known about the mechanisms of
clot retraction mediated by nucleated cells. In this report, we demonstrate that another member of the β3 integrin family, αvβ3, is involved in clot retraction mediated by nucleated cells. Retraction of fibrin clots was observed using a human melanoma
cell line, C32TG, which contains no αβ3 complex. This retraction was inhibited by RGD-containing peptide, monoclonal anti-β3, and anti-αvβ3 antibodies. Immunoelectron microscopic studies revealed a direct interaction between β3 integrin and fibrin fibers at an early stage of clot retraction. We found that another human embryonal cell line, 293, which
is known to express αvβ1, but no αvβ3, lacks fibrin gel retractile activity. Upon transfection of β3 DNA into 293 cells, the β3 subunit formed a complex with an endogenous αv subunit. The β3-bearing transfectants were found to retract fibrin gels, which was specifically inhibited by anti-β3 antibody. In addition, a point mutation at Asp in the β3 ligand binding domain abolished the clot retractile activity of 293 transfectants, indicating the requirement of αvβ3 ligand-binding activity. Our findings suggest that αvβ3 is involved in mediating the interaction between the three-dimensional fibrin network and nucleated cells and in promoting
“post-receptor occupancy” events.
Journal of Biological Chemistry 01/1995; 270(4):1785-1790. · 4.77 Impact Factor
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ABSTRACT: Since glycoprotein IV (GPIV) has been shown to play an important role in the interaction of platelets with collagen and thrombospondin, the aggregation and secretion of GPIV-deficient platelets were examined. Using a binding assay with monoclonal 125I-OKM5 antibody against CD36 antigen and crossed immunoelectrophoresis of the solubilized platelets against anti-GPIV antibody, the platelets from seven (4.1%) out of 170 healthy Japanese donors were found to be deficient in GPIV. The GPIV-deficient platelets showed normal aggregations in response to collagen as well as ADP, epinephrine, arachidonic acid and thrombin in comparison with GPIV-positive platelets. Polyclonal anti-GPIV antibody aggregated GPIV-positive platelets but not the GPIV-negative ones. The F(ab')2 fragments of the anti-GPIV antibody competitively inhibited the anti-GPIV-induced aggregation, but did not affect the collagen-induced aggregation of GPIV-positive platelets. These results suggest that the deficiency of GPIV does not affect platelet aggregability.
British Journal of Haematology 04/1992; 81(1):86 - 92. · 4.94 Impact Factor
