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17 recordsLinked to original sources
PubMed1992

[The glycoprotein IIb/IIIa complex of the platelets. An activation-dependent integrin].

The glycoprotein (GP) IIb/IIIa complex is the most abundant platelet membrane receptor (approximately 80,000 copies/platelet). The GP IIb/IIIa complex is an adhesion receptor belonging to the integrin superfamily; it can bind five adhesive proteins containing the arginine-glycine-aspartic acid (RGD) sequence in their structure: fibrinogen (Fg), von Willebrand factor (vWf), thrombospondin (Tsp), fibronectin (Fn) and vitronectin (Vn). Fg mediates platelet aggregation; vWf, Tsp and Fn are large molecules that support platelet adhesion to vessel wall; Vn is a molecular connection among hemostasis and others physiological processes. The complex is presents at any time on the platelet surface, but macromolecular ligands cannot access to their receptor because of steric hindrances intrinsic to the complex itself or its microenvironment. Adhesive proteins can bind to the complex only after platelets become activated; following platelet stimulation and ligand binding a conformational change takes place, accompanied by expression of new epitopes termed LIBS (ligand-induced binding sites). The complex-bound fibrinogen undergoes to a progressive rearrangement which increases the adhesive function of the molecule. The RGD sequence present in adhesive proteins, in addition to its receptor role, may serve as a trigger sequence that induces a high affinity ligand-binding state in the GP IIb/IIIa complex. The different domains of adhesive proteins can bind to platelet surface receptors, other than GP IIb/IIIa, so realizing multiple ligand-receptor interactions.

Blood Platelets↗
PubMed1988

Assignment of human platelet GP2B (GPIIb) gene to chromosome 17, region q21.1-q21.3.

The platelet GPIIb-IIIa complex functions as a receptor for fibrinogen, fibronectin, and von Willebrand factor on activated platelets. This glycoprotein is a member of a broadly distributed family of structurally and immunologically related membrane receptors involved in cell-cell contact and cell-matrices interactions. GPIIb-IIIa is a heterodimer complex composed of GPIIb (the alpha subunit), which consists of two disulfide-linked heavy and light chains, and GPIIIa (the beta subunit), which is a single polypeptide chain. Congenital absence of platelet GPIIb-IIIa in Glanzmann's thrombasthenia results in a severe bleeding disorder characterized by defective platelet aggregation and failure of fibrinogen to bind to platelets. The gene coding for GPIIb was located on 17q21.1-17q21.3 as determined by in situ hybridization with a 2650-bp GP2B (GPIIb) cDNA probe prepared from human megakaryocytes.

Blood Platelets↗
PubMed1990

Shear-induced platelet aggregation.

Two platelet mechanisms contribute to haemostasis and thrombosis. (1) Compounds such as thrombin activate glycoprotein IIb/IIIa; fibrinogen is the ligand. The cyclooxygenase pathway is involved and so this process is aspirin sensitive. (2) Shearing forces alone activate a different domain on glycoprotein IIb/IIIa; von Willebrand's factor is the ligand. This process is probably non-enzymatic and is aspirin insensitive. The prevention of shear-induced platelet activation may prove to be more rewarding therapeutically than inhibition of aspirin sensitive pathways.

Blood Circulation↗
PubMed1988

Immunological characterization of a membrane glycoprotein of chromaffin granules: its presence in endocrine and exocrine tissues.

A glycoprotein was isolated from detergent solubilized membranes of bovine chromaffin granules by high-performance liquid chromatography. Specific antisera raised against this glycoprotein reacted in one- and two-dimensional immunoblots with a heterogeneous component with a pI of 4.2-4.7 and Mr 100,000. The antiserum against bovine glycoprotein II cross-reacted with an analogous component in several species. The specific localization of glycoprotein II in chromaffin granules was established by density gradient centrifugation followed by immunoblotting. The antiserum, as shown by one- and two-dimensional immunoblotting, reacted with an analogous antigen in the posterior pituitary, in endocrine (anterior pituitary, parathyroid gland) and exocrine (parotid gland, pancreas) organs. In the pancreas the protein reacting with the antiserum was found in the membranes of zymogen granules. The results demonstrate for the first time that secretory vesicles of endocrine and exocrine tissues have at least one common antigen, i.e. the glycoprotein II. It seems likely that this protein is involved in a basic function common to all secretory vesicles.

Adrenal Medulla↗
PubMed1991

Prospects for the use of antagonists to the platelet glycoprotein IIb/IIIa receptor to prevent post-angioplasty restenosis and thrombosis.

Despite many advances since its inception in humans in 1977, coronary angioplasty continues to be limited by the problems of abrupt arterial closure and late restenosis. Excessive platelet deposition at the site of angioplasty undoubtedly plays an important role in the pathophysiology of both of these problems. Monoclonal antibodies and snake venom-derived or synthetic peptides directed against a common protein recognition sequence on the platelet glycoprotein IIb/IIIa receptor are currently in the early stages of preclinical and clinical testing and hold promise of preventing abrupt closure and restenosis by inhibiting platelet function. Whether any of these agents will eventually be commonly used in clinical practice will depend on their effects on the complex pathophysiology of these problems and on their safety profile when administered to patients who are likely to receive other antithrombotic medications and who are instrumented for coronary angioplasty.

Angioplasty, Balloon, Coronary↗
PubMed1990

Glycoprotein II from adrenal chromaffin granules is also present in kidney lysosomes.

Glycoprotein II (GP II) is a protein found in the membranes of chromaffin granules from adrenal medulla. Immunoblotting (one- and two-dimensional) revealed that this antigen is also present in liver and in kidney. Subcellular fractionation of the latter organ indicated that GP II was present in lysosomes. This was confirmed by immunoelectron microscopy. The antiserum against GP II immunolabelled the membranes of organelles which could be identified as lysosomes by the labelling of their contents with an antiserum against cathepsin D. Thus GP II is an antigen common to secretory vesicles and lysosomes.

Adrenal Medulla↗
PubMed2025

Plasma Proteomic Profiling Reveals ITGA2B as A Key Regulator of Heart Health in High-altitude Settlers.

Myocardial injury is a common disease in the plateau, especially in the lowlanders who have migrated to the plateau, in which the pathogenesis is not well understood. Here, we established a cohort of lowlanders comprising individuals from both low-altitude and high-altitude areas and conducted plasma proteomic profiling. Proteomic data showed that there was a significant shift in energy metabolism and inflammatory response in individuals with myocardial abnormalities at high altitude. Notably, integrin alpha-Ⅱb (ITGA2B) emerged as a potential key player in this context. Functional studies demonstrated that ITGA2B upregulated the transcription and secretion of interleukin-6 (IL-6) through the integrin-linked kinase (ILK)/nuclear factor-κB (NF-κB) signaling axis under hypoxic conditions. Moreover, ITGA2B disrupted mitochondrial structure and function, increased glycolytic capacity, and aggravated energy reprogramming from oxidative phosphorylation to glycolysis. Leveraging the therapeutic potential of traditional Chinese medicine in cardiac diseases, we discovered that tanshinone ⅡA (TanⅡA) effectively alleviated the myocardial injury caused by the abnormally elevated expression of ITGA2B and hypobaric hypoxia exposure in mice, thus providing a novel candidate therapeutic strategy for the prevention and treatment of high-altitude myocardial injury.

Animals↗
PubMed1990

Induction of patching and its reversal on surface-activated human platelets.

Fibrinogen coupled to colloidal gold (Fgn/Au) has been used to follow GPIIb-IIIa receptors on surface-activated platelets and to evaluate the effects of the anti-actin agent, cytochalasin B (CB), on the movement of receptor-ligand complexes. Fgn/Au binds diffusely to spread platelets, but is translocated rapidly from the peripheral margin to cell centres and to channels of the open canalicular system (OCS). CB added after spreading and incubation with Fgn/Au reverses the centripetal movement of receptor-ligand complexes. Fgn/Au particles move back toward the margins of spread cells and form patches. The patches of receptor-ligand complexes overlie segments of the OCS filled with Fgn/Au. Washing out the CB reverses the process and receptor-ligand complexes are again translocated toward platelet centres.

Blood Platelets↗
PubMed1992

A new variant of Glanzmann's thrombasthenia (Strasbourg I). Platelets with functionally defective glycoprotein IIb-IIIa complexes and a glycoprotein IIIa 214Arg----214Trp mutation.

We describe a new variant of Glanzmann's thrombasthenia (variant Strasbourg I). The patient (M.S.) showed an absence of platelet aggregation to ADP, thrombin, and collagen, and a decreased clot retraction. Platelet fibrinogen was approximately 20% of normal levels. ADP-stimulated platelets bound markedly reduced amounts of soluble fibrinogen and platelet adhesion to surface-bound fibrinogen was defective. Normal to subnormal amounts of glycoprotein (GP) IIb-IIIa (alpha IIb beta 3) complexes, the platelet fibrinogen receptor, were revealed by SDS-PAGE, crossed immunoelectrophoresis, and antibody binding. However, the complexes were unusually sensitive to dissociation with EDTA at room temperature. Furthermore, flow cytometry showed that the platelets failed to bind the activation-dependent monoclonal antibody, PAC-1, after stimulation. In contrast, an RGDS-containing peptide induced significant binding of the anti-ligand-induced binding site antibody, D3GP3, suggesting the presence of a functional RGD binding domain on the patient's GPIIb-IIIa complex. Sequence analysis was performed after polymerase chain reaction amplification of selected patient's GPIIIa exons, and of the patient's platelet GPIIb and GPIIIa mRNAs. A point mutation (C to T) was localized in exon D (iv) of GPIIIa that resulted in an 214Arg to 214Trp amino acid substitution. The defect has been inherited from the parents who are heterozygous for the same mutation. This substitution points to an essential amino acid in a region of GPIIIa involved in the binding of fibrinogen and influencing the Ca(2+)-dependent stability of the GPIIb-IIIa complex.

Adult↗
PubMed1990

Sequence analysis of monoclonal antibodies derived from a patient with idiopathic thrombocytopenic purpura.

Autoantibodies directed at the platelet membrane glycoprotein Ib (GPIb) can mediate a severe form of idiopathic thrombocytopenic purpura (ITP). The platelet-specific antibody from plasma of one patient (DM) with this form of ITP displays a public idiotype termed DMId. The DMId idiotype has been found in the plasma of several patients with ITP, usually in association with GPIb-specific autoantibodies. As a step in the understanding of the molecular genetics of this form of ITP we have determined the nucleotide sequences of expressed V region genes selected from a panel of five human lymphoblastoid cell lines derived from patient DM. Two of the lines secreted antibodies that bound GPIb, and three of the lines secreted antibodies that expressed DMId. The H chain sequences of the DMId-positive antibodies and of one of the GPIb-binding antibodies belong to the VH4 family. The second GPIb-binding antibody belongs to the VH1 family. All have multiple substitutions from previously published sequences giving these antibodies the appearance of having been antigen driven. These results are consistent with the hypothesis that autoantibodies in ITP arise from a "normal" immune response inappropriately directed at platelet antigens. Further, our results suggest that VH4 gene segments may be recruited preferentially into the DMId-positive, GPIb-specific autoantibody response.

Amino Acid Sequence↗
PubMed1990

Mechanistic aspects of cellular interactions with artificial dialyzer membrane surfaces.

The platelet adhesion on adhesive protein-coated surfaces was significantly reduced by the addition of the synthetic tetrapeptide, RGDS (Arg-Gly-Asp-Ser), which was identified as the common amino acid sequence of adhesive site of adhesive proteins. The inhibitory effect was also observed for leukocyte(WBC) in complement-inactivated serum. No significant effect was observed for WBC in complement-activated serum. These indicate that the RGDS ligand-receptor mechanism operates on adhesive protein-adsorbed surfaces for both cellular systems and that activated complement factor (C3b)-membrane receptor (CR3) interaction operates for WBC as the complement is activated.

Amino Acid Sequence↗
PubMedDate not supplied

[Familial occurrence of Glanzmann thrombasthenia].

Glanzmann's thrombasthenia, known also as Glanzmann's disease, is an autosomally inherited hemorrhagic disease with unique abnormalities of platelet functions. Authors present a large family in which Glanzmann's disease was diagnosed in the father and two sons. An analysis of platelet membranes enabled diagnosis of Glanzmann's thrombasthenia type II. A decrease in clot contractibility, fibrinogen binding to blood platelets, and decreased glycoprotein IIb and IIIa levels with marked impairment of GP IIb and IIIa complexes formation were characteristic for affected family members. One daughter died 8 days after birth with the symptoms of hemorrhagic diathesis. Mother and remaining three sons are healthy without the signs of Glanzmann's disease.

Adolescent↗
PubMed1990

Identification of an abnormal gene for the GPIIIa subunit of the platelet fibrinogen receptor resulting in Glanzmann's thrombasthenia.

The platelet fibrinogen receptor, which is composed of glycoproteins IIb (GPIIb) and IIIa (GPIIIa), belongs to a large family of receptors that participate in a multitude of biologically important adhesive interactions. Platelets from most patients with the autosomal recessive bleeding disorder, Glanzmann's thrombasthenia, are deficient in GPIIb and GPIIIa. We have used cDNA probes to analyze the GPIIb and GPIIIa genes in four patients from three kindreds with Glanzmann's thrombasthenia. Southern analysis of their DNA was identical to that observed in normals when probed with a full-length GPIIb cDNA or a 3' GPIIIa cDNA. However, in one family, a 5' 2.0 kb GPIIIa cDNA identified abnormal DNA fragments in the father and two affected siblings' genes. A series of restriction digests resulting in small genomic fragments were probed with portions of the 5' 2.0 kb GPIIIa cDNA and indicated that the abnormal sequences are flanked by normal fragments of the GPIIIa gene. To analyze further the genetic defect in this family, RNA was prepared from their platelets. Northern analysis revealed normal levels of GPIIb mRNA compared to control platelets. We were unable to identify GPIIIa mRNA of any size in the clinically affected family members. We also identified an EcoRI restriction fragment length polymorphism (RFLP) that permitted carrier status determination in the clinically unaffected siblings. These studies indicate that Glanzmann's thrombasthenia can be caused by heterogeneous defects in the GPIIIa gene. Furthermore, we have shown that platelets can be used to characterize normal and abnormal GPIIIa and GPIIb mRNA, and RFLPs may be used to determine the carrier status in some families with Glanzmann's thrombasthenia. The specific gene abnormality in this family appears to represent an example of an insertional mutation resulting in a human disease.

Blood Platelet Disorders↗
PubMed1990

von Willebrand factor competes with fibrin for occupancy of GPIIb:IIIa on thrombin-stimulated platelets.

We have investigated two major questions related to the molecular basis of interactions between the three-dimensional fibrin network and thrombin-stimulated human platelets. First, what are the roles played by glycoproteins (GP) Ib and IIb:IIIa in linking the fibrin clot tightly to the platelet surface? Second, does von Willebrand factor (vWF) modulate the extent of platelet-fibrin interactions? Quantitative fluorescence microscopy (microfluorimetry) has been used to determine the quantity of fluorescein-labeled fibrin bound to the surface of thrombin-stimulated, gel-filtered platelets (the supernatants of which contained small quantities of vWF) in the presence/absence of receptor-specific and vWF-specific monoclonal antibodies (MoAbs), as well as exogenous vWF. A MoAb specific for the GPIIb:IIIa complex exhibited a concentration-dependent inhibition of fibrin binding, whereas a MoAb specific for GPIb was ineffective in this regard. Similarly, a MoAb that recognizes the N-terminal region of vWF involved in GPIb binding did not influence fibrin binding. In contrast, a MoAb that binds to a C-terminal region of vWF involved in GPIIb:IIIa recognition caused a specific, concentration-dependent increase in the quantity of platelet-bound fibrin. We also found that exogenous vWF caused a concentration-dependent decrease in fibrin binding. These results support the hypothesis that vWF and fibrin, both of which are multimeric adhesive ligands, compete for occupancy of the GPIIb:IIIa complex on thrombin-stimulated platelets.

Antibodies, Monoclonal↗
PubMed1990

Gova/b alloantigen system on human platelets.

In this report we describe a platelet alloantigen system that is carried on a novel platelet protein of 175 Kd. Antisera against the two alleles (Gova/Govb) were found in two patients who had received large numbers of platelet transfusions. The anti-Gov alloantibodies could not be detected using a whole platelet solid phase enzyme immunoassay, or by a platelet glycoprotein capture enzyme immunoassay using monoclonal antibodies against glycoproteins Ib/IX, Ia/IIa, and IIb/IIIa. Using radioimmunoprecipitation techniques, a protein was precipitated that migrated at 175 Kd (reduced). Under nonreduced conditions, a 150-Kd protein was detected with a minor component at 175Kd. The detection of the alloantigens was not activation-dependent. Using immunodepletion studies, we demonstrated that each alloantiserum recognized an epitope on a discrete population of the 175-Kd platelet protein. Family studies demonstrated that the alloantigens designated as Gova and Govb were inherited in an autosomal codominant fashion. The phenotypic frequencies were Gova/Gova, 26%; Gova/Govb, 55%; Govb/Govb, 19%; giving gene frequencies of 0.532 and 0.468 for Gova and Govb, respectively (n = 33).

Alleles↗
PubMed1989

[Microcytofluorometrical measurement of DNA content in immunologically identified micromegakaryocytes of human bone marrow].

We have developed a method to microfluorometrically determine the amount of DNA in immunologically identified micromegakaryocytes on bone marrow smears. Bone marrow smears were fixed with acetone-formalin buffer and immunostained with a monoclonal anti-GPIIb/IIIa antibody, followed by FITC conjugated anti-mouse IgG. After the smears were re-fixed with methanol, DAPI (4', 6-diamidino-2-phenylindole) staining was performed. Using an automatic Digital-Microfluorometer (Olympus MMSP-FR-II), megakaryocytes on the smears were identifies by the GPIIb/IIIa immunofluorescence and, after changing the barrier filters, their nuclear DNA content was measured by the intensity of DAPI fluorescence, which is proportional to the amount of DNA. Using this method, we found that the DNA histogram of the megakaryocytes from a patient with myelodysplastic syndrome showed a shift to small ploidy compared with normal controls. This method may be valuable in the measurement of the megakaryocyte DNA content.

Adult↗