Platelet membrane abnormalities in myeloproliferative disorders: decrease in glycoproteins Ib and IIb/IIIa complex is associated with deficient receptor function

Abstract

The number and functional activity of membrane glycoproteins (GP) Ib and IIb/IIIa were investigated in platelets from 11 patients with myeloproliferative disorders (MPD). Three patients had essential thrombocythaemia, two had chronic myeloid leukaemia and six had polycythaemia vera. The numbers of GPIb and GPIIb/IIIa molecules were detected on the platelet surface using different 125I-labelled monoclonal antibodies. The functional properties of GPIb and GPIIb/IIIa were evaluated using purified 125I-labelled asialo von Willebrand factor (vWF) and purified 125I-labelled fibrinogen, respectively, in a binding assay. Binding of the anti-GPIIb/IIIa antibody was decreased by 40% in almost all patients studied and, when measured, it was accompanied by decreased fibrinogen binding to activated platelets. Binding of anti-GPIb antibodies to platelets was also slightly decreased or virtually the same in eight out of 11 patients. The decrease correlated with decreased binding of asialo vWF. The increased plasma glycocalicin levels, measured in four patients, depended on the high platelet count. Scatchard analysis revealed normal receptor binding affinity for all ligands tested in all but one patient. In this report we demonstrate that abnormalities in the concentrations of GPIIb/IIIa membrane proteins are commonly present in patients with MPD, while a decrease in GPIb concentration is also seen, although in fewer patients. These abnormalities are accompanied by a concurrent decrease in the respective receptor functions. These findings may explain part of the haemorrhagic tendency often encountered in MPD.

Increased platelet activation and abnormal membrane glycoprotein content and redistribution in myeloproliferative disorders

“…Quantitative determination of platelet membrane GP density in MPD has been performed previously using electrophoretic methods or radiolabelled mAbs against GPIb, GPIX, GPIIb/IIIa and GPIV (Eche et al, 1981;Clezardin et al, 1985;Mazzucato et al, 1989;Thibert et al, 1995). Most, although not all, studies find a reduced platelet content of GPIb and GPIIb/IIIa and increased content of GPIV.…”

“…GPIb serves as the major receptor for VWF and GPIV mediates platelet adhesion to monocytes via GPIV-bound thrombospondin (TSP) (Silverstein et al, 1989;Ruggeri, 1991). Variable abnormalities in membrane GP content of non-stimulated platelets have been described previously (Mazzucato et al, 1989;Thibert et al, 1995), however the pattern of membrane GP redistribution upon agonist stimulation has rarely been addressed (Le Blanc et al, 1998).…”

“…The bleeding tendency may in part be related to an acquired von Willebrand factor (VWF) deficiency associated with consumption of high molecular weight VWF multimers, abnormalities in platelet membrane glycoprotein (GP) and agonist receptor contents and defective agonistmediated platelet aggregation (Kaywin et al, 1978;Mazzucato et al, 1989;Balduini et al, 1991;van Genderen et al, 1997). Likewise, a propensity for thrombosis might be multifactually explained by a variety of abnormalities, implying increased platelet activation such as abnormal eicosanoid metabolism, increased granule secretion as assessed by serological measurement of alpha-granule products and spontaneous platelet aggregation (Cortelazzo et al, 1981;Landolfi et al, 1992;van Genderen et al, 1999;Manoharan et al, 1999).…”

Reversible erythrocyte skeleton destabilization is modulated by beta-spectrin phosphorylation in childhood leukemia

“…Some examples of these abnormalities are acquired thalassaemia, 20,21 abnormal piruvate kinase, 22 size and shape changes of erythrocytes, [23][24][25] erythrocyte membrane defects, [26][27][28][29][30][31][32][33] platelet defects of von Willebrand factor 34 and of membrane glycoproteins. 35 Here, we further investigated the erythrocyte membrane abnormalities in childhood leukemias. Our studies demonstrate that an erythrocyte skeletal destabilization is due to an increase of the ␤-spectrin phosphorylation and that it disappears during the remission phase.…”

The human platelet fibrinogen receptor: clinical and therapeutic significance.

“…In situ on the platelet the complex exhibits the properties of a membrane binding site in that binding of fibrinogen is saturable, reversible and dependent on the presence of divalent cations in physiological concentrations (Marguerie et al, 1979;Peerschke et al, 1980). The characterisation of receptor density (Bma,) and affinity (Kd) on platelets has been undertaken in a number of laboratories using radioligand binding methods Marguerie et al, 1987;Mistry et al, 1991;Peerschke et al, 1980 (Clezardin et al, 1985;Landolfi et al, 1988;Mazzucato et al, 1989;Mistry et al, 1991 (ii) Synthetic peptides comprising short amino acid sequences which compete with fibrinogen for the binding sites on the GPIIb/IIIa complexes are another class of compounds with potential antithrombotic clinical application . The peptide glycineproline-arginine-proline was the first short chain peptide shown to inhibit platelet fibrinogen binding (Ruggeri et al, 1986).…”