scholarly journals Platelet vitronectin receptor expression differentiates Iraqi-Jewish from Arab patients with Glanzmann thrombasthenia in Israel

Blood ◽  
1991 ◽  
Vol 77 (1) ◽  
pp. 75-83 ◽  
Author(s):  
BS Coller ◽  
DA Cheresh ◽  
E Asch ◽  
U Seligsohn
Keyword(s):  
Receptor Expression ◽  
Platelet Glycoprotein ◽  
Adhesion Assay ◽  
Integrin Receptors ◽  
Arab Population ◽  
Vitronectin Receptor ◽  
Glanzmann Thrombasthenia ◽  
And Function ◽  
Alpha V Beta 3 ◽  
Inhibition Studies

Glanzmann thrombasthenia is a rare, inherited disorder of the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) complex. We previously identified two distinct populations with this disorder in Israel, Iraqi-Jews and Arabs. The groups are indistinguishable in hemorrhagic symptoms and platelet GP IIB/IIIa receptor deficiency, but they differ in their platelet immunodetectable GP IIIa (beta 3), with the Iraqi-Jewish population expressing no detectable GP IIIa and the Arab population expressing small amounts. We have now examined the platelets of these two populations as well as normal platelets for the alpha v beta 3 vitronectin receptor. Normal platelets contained between approximately 50 to 100 alpha v beta 3 vitronectin receptors as judged by the binding of antibodies to both alpha v (LM142) and the intact alpha v beta 3 vitronectin receptor complex (LM609). In addition, normal platelets bound to immobilized vitronectin in the presence of 1 mmol/LMnCl2; the adhesion was mediated predominantly through GP IIb/IIIa, but with a distinct contribution by the alpha v beta 3 vitronectin receptor, as determined by monoclonal antibody inhibition studies. Iraqi-Jewish patients' platelets had a profound decrease in immunodetectable alpha v beta 3 vitronectin receptors, and their platelets did not adhere well to vitronectin. In contrast, Arab patients' platelets had normal or increased numbers of platelet alpha v beta 3 vitronectin receptors, and these receptors functioned well in the vitronectin adhesion assay, taking over much of the adhesion mediated by GP IIb/IIIa in normal platelets. These studies define further the heterogeneity of the molecular basis of Glanzmann thrombasthenia; they also have more widespread implications for understanding the synthesis and function of the beta 3 family of integrin receptors.

scholarly journals Platelet vitronectin receptor expression differentiates Iraqi-Jewish from Arab patients with Glanzmann thrombasthenia in Israel

Blood ◽  
1991 ◽  
Vol 77 (1) ◽  
pp. 75-83 ◽  
Author(s):  
BS Coller ◽  
DA Cheresh ◽  
E Asch ◽  
U Seligsohn
Keyword(s):  
Receptor Expression ◽  
Platelet Glycoprotein ◽  
Adhesion Assay ◽  
Integrin Receptors ◽  
Arab Population ◽  
Vitronectin Receptor ◽  
Glanzmann Thrombasthenia ◽  
And Function ◽  
Alpha V Beta 3 ◽  
Inhibition Studies

Abstract Glanzmann thrombasthenia is a rare, inherited disorder of the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) complex. We previously identified two distinct populations with this disorder in Israel, Iraqi-Jews and Arabs. The groups are indistinguishable in hemorrhagic symptoms and platelet GP IIB/IIIa receptor deficiency, but they differ in their platelet immunodetectable GP IIIa (beta 3), with the Iraqi-Jewish population expressing no detectable GP IIIa and the Arab population expressing small amounts. We have now examined the platelets of these two populations as well as normal platelets for the alpha v beta 3 vitronectin receptor. Normal platelets contained between approximately 50 to 100 alpha v beta 3 vitronectin receptors as judged by the binding of antibodies to both alpha v (LM142) and the intact alpha v beta 3 vitronectin receptor complex (LM609). In addition, normal platelets bound to immobilized vitronectin in the presence of 1 mmol/LMnCl2; the adhesion was mediated predominantly through GP IIb/IIIa, but with a distinct contribution by the alpha v beta 3 vitronectin receptor, as determined by monoclonal antibody inhibition studies. Iraqi-Jewish patients' platelets had a profound decrease in immunodetectable alpha v beta 3 vitronectin receptors, and their platelets did not adhere well to vitronectin. In contrast, Arab patients' platelets had normal or increased numbers of platelet alpha v beta 3 vitronectin receptors, and these receptors functioned well in the vitronectin adhesion assay, taking over much of the adhesion mediated by GP IIb/IIIa in normal platelets. These studies define further the heterogeneity of the molecular basis of Glanzmann thrombasthenia; they also have more widespread implications for understanding the synthesis and function of the beta 3 family of integrin receptors.

scholarly journals Platelet fibrinogen and vitronectin in Glanzmann thrombasthenia: evidence consistent with specific roles for glycoprotein IIb/IIIA and alpha v beta 3 integrins in platelet protein trafficking [see comments]

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2603-2610 ◽  
Author(s):  
BS Coller ◽  
U Seligsohn ◽  
SM West ◽  
LE Scudder ◽  
KJ Norton
Keyword(s):  
Protein Trafficking ◽  
Extracellular Proteins ◽  
Platelet Glycoprotein ◽  
Integrin Receptors ◽  
Vitronectin Receptor ◽  
Glanzmann Thrombasthenia ◽  
Platelet Protein ◽  
Individual Contributions ◽  
The Individual ◽  
Alpha V Beta 3

Abstract To assess the individual contributions of the platelet glycoprotein (GP) IIb/IIIa receptor and the alpha v beta 3 vitronectin receptor to platelet levels of fibrinogen and vitronectin, we analyzed the platelets from two groups of Glanzmann thrombasthenic patients: Iraqi- Jews, whose platelets lack both receptors, and Arab patients in Israel, whose platelets lack GPIIb/IIIa, but have normal or increased numbers of alpha v beta 3 vitronectin receptors. The platelets from both thrombasthenic groups had profound deficiencies of fibrinogen, but the defect in the Iraqi-Jewish patients' platelets appeared to be slightly more severe. This finding indicates that GPIIb/IIIa is the major determinant of platelet fibrinogen, presumably acting by receptor- mediated uptake, and that the alpha v beta 3 vitronectin receptor plays little or no role. Arab patients' platelets have normal amounts of platelet vitronectin, whereas Iraqi-Jewish patients' platelets have nearly five times as much vitronectin as control or Arab patients' platelets. To account for these data, we propose a working hypothesis in which vitronectin is synthesized in megakaryocytes and the alpha v beta 3 vitronectin receptor is involved in transport of the protein out of megakaryocytes and/or platelets. Collectively, these observations suggest that in addition to their recognized roles in cell adhesion and in the interaction of cells with extracellular proteins, integrin receptors may be important in protein trafficking into, and perhaps out of, platelets.

scholarly journals Platelet fibrinogen and vitronectin in Glanzmann thrombasthenia: evidence consistent with specific roles for glycoprotein IIb/IIIA and alpha v beta 3 integrins in platelet protein trafficking [see comments]

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2603-2610 ◽  
Author(s):  
BS Coller ◽  
U Seligsohn ◽  
SM West ◽  
LE Scudder ◽  
KJ Norton
Keyword(s):  
Protein Trafficking ◽  
Extracellular Proteins ◽  
Platelet Glycoprotein ◽  
Integrin Receptors ◽  
Vitronectin Receptor ◽  
Glanzmann Thrombasthenia ◽  
Platelet Protein ◽  
Individual Contributions ◽  
The Individual ◽  
Alpha V Beta 3

To assess the individual contributions of the platelet glycoprotein (GP) IIb/IIIa receptor and the alpha v beta 3 vitronectin receptor to platelet levels of fibrinogen and vitronectin, we analyzed the platelets from two groups of Glanzmann thrombasthenic patients: Iraqi- Jews, whose platelets lack both receptors, and Arab patients in Israel, whose platelets lack GPIIb/IIIa, but have normal or increased numbers of alpha v beta 3 vitronectin receptors. The platelets from both thrombasthenic groups had profound deficiencies of fibrinogen, but the defect in the Iraqi-Jewish patients' platelets appeared to be slightly more severe. This finding indicates that GPIIb/IIIa is the major determinant of platelet fibrinogen, presumably acting by receptor- mediated uptake, and that the alpha v beta 3 vitronectin receptor plays little or no role. Arab patients' platelets have normal amounts of platelet vitronectin, whereas Iraqi-Jewish patients' platelets have nearly five times as much vitronectin as control or Arab patients' platelets. To account for these data, we propose a working hypothesis in which vitronectin is synthesized in megakaryocytes and the alpha v beta 3 vitronectin receptor is involved in transport of the protein out of megakaryocytes and/or platelets. Collectively, these observations suggest that in addition to their recognized roles in cell adhesion and in the interaction of cells with extracellular proteins, integrin receptors may be important in protein trafficking into, and perhaps out of, platelets.

scholarly journals Type I Glanzmann thrombasthenia patients from the Iraqi-Jewish and Arab populations in Israel can be differentiated by platelet glycoprotein IIIa immunoblot analysis

Blood ◽  
1987 ◽  
Vol 69 (6) ◽  
pp. 1696-1703 ◽  
Author(s):  
BS Coller ◽  
U Seligsohn ◽  
PA Little
Keyword(s):  
Jewish Population ◽  
Genetic Defect ◽  
Rabbit Antiserum ◽  
Immunoblot Analysis ◽  
Platelet Glycoprotein ◽  
Type I ◽  
Arab Population ◽  
Major Band ◽  
Glanzmann Thrombasthenia ◽  
Glycoprotein Iiia

Abstract A sensitive immunoblot technique for platelet glycoprotein IIIa (GPIIIa) was used to analyze the platelets of patients living in Israel who meet the diagnostic criteria for type I Glanzmann thrombasthenia. When reacted with solubilized normal platelets, a rabbit antiserum to GPIIIa identified a major band at molecular weight (mol wt) 90,000 and three additional minor bands at Mr 110,000, 81,000, and 64,000. The major band could not be detected, and the minor bands were either markedly reduced or absent in the platelet samples from 14 of the 15 patients from the Iraqi-Jewish population. In contrast, in all four Arab patients tested, the major band was detectable, although at markedly reduced levels, and the minor bands were either markedly reduced or absent; an additional minor band at mol wt 47,000 was also present in the platelets from these patients. One Iraqi-Jewish patient had a unique pattern in which two of the bands were present but reduced and two were undetectable. We conclude that the protein defect, and thus presumably the genetic defect, causing Glanzmann thrombasthenia in the majority of patients in the Iraqi-Jewish population differs from that in the Arab population, and we confirm that there is considerable biochemical heterogeneity among the patients who meet the criteria for type I Glanzmann thrombasthenia.

scholarly journals Integrin recognition of different cell-binding fragments of laminin (P1, E3, E8) and evidence that alpha 6 beta 1 but not alpha 6 beta 4 functions as a major receptor for fragment E8.

1990 ◽  
Vol 110 (6) ◽  
pp. 2145-2155 ◽  
Author(s):  
A Sonnenberg ◽  
C J Linders ◽  
P W Modderman ◽  
C H Damsky ◽  
M Aumailley ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Cell Types ◽  
Integrin Subunit ◽  
Integrin Receptors ◽  
Cell Binding ◽  
Vitronectin Receptor ◽  
Beta 1 Integrin ◽  
Integrin Alpha 6 ◽  
Alpha V Beta 3 ◽  
Integrin Family

The involvement of integrins in mediating interaction of cells to well-characterized proteolytic fragments (P1, E3, and E8) of laminin was assessed by antibody blocking studies. Cell adhesion to fragment P1 was affected by mAbs against the integrin beta 1 and beta 3 subunits and furthermore could be prevented completely by a synthetic peptide containing the Arg-Gly-Asp sequence. Because the beta 3 antibody-sensitive cell lines expressed the vitronectin receptor (alpha v beta 3) at high levels, the involvement of this receptor in cell adhesion to P1 is strongly suggested. Integrin-mediated cell adhesion to E3 is of low affinity and was inhibited by antibodies against the integrin beta 1 subunit. In contrast, adhesion of some cell types to E3 was not or only partially sensitive to inhibition by anti-integrin subunit antibodies. Cell adhesion to E8 was blocked completed by integrin alpha 6 or beta 1 antibodies. The alpha 6-specific antibody did not inhibit cell adhesion to E3 or P1. Furthermore, the antibody only blocked adhesion to laminin of those cells that adhered exclusively to the E8 fragment. In addition, expression of alpha 6 beta 1 was closely correlated with the ability of cells to bind to the E8 fragment of laminin. These results indicate that the alpha 6 beta 1 integrin is a specific receptor for the E8 fragment of laminin. Many cell types expressed, instead of or in addition to alpha 6 beta 1 the recently described integrin alpha 6 beta 4. Although the ligand of alpha 6 beta 4 was not identified, it must be different from that of alpha 6 beta 1, because cells that express alpha 6 beta 4, but not alpha 6 beta 1, do not adhere to E8, and cell adhesion to E8 was specifically blocked by beta 1 specific antibodies. In conclusion, the data indicate that distinct integrin receptors belonging to the beta 1 or beta 3 subfamily are involved in adhesion of cells to the various laminin fragments. Adhesion to E3 may also be brought about by other receptor molecules, possibly proteoglycans, not belonging to the integrin family.

Binding of Abciximab to αVβ3 and Activated αMβ2 Receptors: With a Review of Platelet-Leukocyte Interactions

1999 ◽  
Vol 82 (08) ◽  
pp. 326-336 ◽  
Author(s):  
Barry Coller
Keyword(s):  
Cardiovascular Disease ◽  
The Other ◽  
Platelet Glycoprotein ◽  
Inhibit Platelet Aggregation ◽  
Integrin Receptors ◽  
Antithrombotic Agent ◽  
Vitronectin Receptor ◽  
Pathologic Processes ◽  
Derivatives Of

IntroductionMurine monoclonal antibody 7E3, as well as the derivatives of 7E3 used in vivo [7E3-F(ab’)2, 7E3 Fab’, mouse/human chimeric 7E3 Fab (c7E3 Fab; abciximab; ReoPro™)], inhibit platelet aggregation induced by physiologic and pathologic agonists by binding to the platelet glycoprotein (GP) IIb/IIIa receptor.1,2 This biological activity formed the basis of its development as an antithrombotic agent to prevent and treat plateletmediated ischemic cardiovascular disease. During its development, 7E3 was reported to also react with two other integrin receptors, the αVβ3 “vitronectin” receptor (CD51/CD61)3,4 and at least one activation-dependent conformation of the αMβ2 or “Mac-1” receptor (CD11b/CD18).5 Whereas both αVβ3 and αMβ2 have been implicated in a number of different physiologic and pathologic processes, it is possible that some effects of abciximab are due to its reactivity with one or the other of these receptors. Moreover, the reactivity of abciximab with these receptors opens up the possibility that abciximab, or other agents that inhibit these receptors, may be useful in preventing or treating disorders in which these receptors play a role. This review will address these issues.

scholarly journals Type I Glanzmann thrombasthenia patients from the Iraqi-Jewish and Arab populations in Israel can be differentiated by platelet glycoprotein IIIa immunoblot analysis

Blood ◽  
1987 ◽  
Vol 69 (6) ◽  
pp. 1696-1703 ◽  
Author(s):  
BS Coller ◽  
U Seligsohn ◽  
PA Little
Keyword(s):  
Jewish Population ◽  
Genetic Defect ◽  
Rabbit Antiserum ◽  
Immunoblot Analysis ◽  
Platelet Glycoprotein ◽  
Type I ◽  
Arab Population ◽  
Major Band ◽  
Glanzmann Thrombasthenia ◽  
Glycoprotein Iiia

A sensitive immunoblot technique for platelet glycoprotein IIIa (GPIIIa) was used to analyze the platelets of patients living in Israel who meet the diagnostic criteria for type I Glanzmann thrombasthenia. When reacted with solubilized normal platelets, a rabbit antiserum to GPIIIa identified a major band at molecular weight (mol wt) 90,000 and three additional minor bands at Mr 110,000, 81,000, and 64,000. The major band could not be detected, and the minor bands were either markedly reduced or absent in the platelet samples from 14 of the 15 patients from the Iraqi-Jewish population. In contrast, in all four Arab patients tested, the major band was detectable, although at markedly reduced levels, and the minor bands were either markedly reduced or absent; an additional minor band at mol wt 47,000 was also present in the platelets from these patients. One Iraqi-Jewish patient had a unique pattern in which two of the bands were present but reduced and two were undetectable. We conclude that the protein defect, and thus presumably the genetic defect, causing Glanzmann thrombasthenia in the majority of patients in the Iraqi-Jewish population differs from that in the Arab population, and we confirm that there is considerable biochemical heterogeneity among the patients who meet the criteria for type I Glanzmann thrombasthenia.

Role of the 807 C/T Polymorphism of the α2 Gene in Platelet GP Ia Collagen Receptor Expression and Function

1999 ◽  
Vol 81 (06) ◽  
pp. 951-956 ◽  
Author(s):  
J. Corral ◽  
R. González-Conejero ◽  
J. Rivera ◽  
F. Ortuño ◽  
P. Aparicio ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Cell Types ◽  
Receptor Expression ◽  
Case Control Studies ◽  
Platelet Surface ◽  
Vitro Analysis ◽  
And Function ◽  
In Vitro Analysis

SummaryThe variability of the platelet GP Ia/IIa density has been associated with the 807 C/T polymorphism (Phe 224) of the GP Ia gene in American Caucasian population. We have investigated the genotype and allelic frequencies of this polymorphism in Spanish Caucasians. The T allele was found in 35% of the 284 blood donors analyzed. We confirmed in 159 healthy subjects a significant association between the 807 C/T polymorphism and the platelet GP Ia density. The T allele correlated with high number of GP Ia molecules on platelet surface. In addition, we observed a similar association of this polymorphism with the expression of this protein in other blood cell types. The platelet responsiveness to collagen was determined by “in vitro” analysis of the platelet activation and aggregation response. We found no significant differences in these functional platelet parameters according to the 807 C/T genotype. Finally, results from 3 case/control studies involving 302 consecutive patients (101 with coronary heart disease, 104 with cerebrovascular disease and 97 with deep venous thrombosis) determined that the 807 C/T polymorphism of the GP Ia gene does not represent a risk factor for arterial or venous thrombosis.

Clues for Understanding the Structure and Function of a Prototypic Human Integrin: The Platelet Glycoprotein IIb/IIIa Complex

1994 ◽  
Vol 72 (01) ◽  
pp. 001-015 ◽  
Author(s):  
Juan J Calvete
Keyword(s):  
Structure Function ◽  
Thrombus Formation ◽  
Platelet Glycoprotein ◽  
Primary Role ◽  
Clot Retraction ◽  
Inhibitory Peptide ◽  
Rgd Sequence ◽  
Platelet Receptor ◽  
Adhesive Proteins ◽  
And Function

SummaryThe glycoprotein (GP) IIb/IIIa, a Ca2+-dependent heterodimer, is the major integrin on the platelet plasma membrane. On resting platelets GPIIb/IIIa is maintained in an inactive conformation and serves as a low affinity adhesion receptor for surface-coated fibrinogen, whereas upon platelet activation signals within the cytoplasma alter the receptor function of GPIIb/IIIa (inside-out signalling), which undergoes a measurable conformational change within its exoplasmic domains, and becomes a competent receptor for soluble fibrinogen and some other RGD sequence-containing plasma adhesive proteins. Upon ligand binding, further structural alterations trigger the association of receptor-occupied GPIIb/IIIa complexes with themselves within the plane of the membrane. The simultaneous binding of dimeric fibrinogen molecules to GPIIb/IIIa clusters on adjacent platelets leads to platelet aggregation, which promotes attachment of fibrinogen-GPIIb/IIIa clusters to the cytoskeleton (outside-in signalling). This, in turn, provides the necessary physical link for clot retraction to occur, and generates a cascade of intracellular biochemical reactions which result in the formation of a multiprotein signalling complex at the cytoplasmic domains of GPIIb/IIIa. Glycoprotein IMIIa, also called αIIbβ3 in the integrin nomenclature, plays thus a primary role in both platelet adhesion and thrombus formation at the site of vascular injury. In addition, the human glycoprotein Ilb/IIIa complex is the most thoroughly studied integrin receptor, its molecular biology and major features of its primary structure having been elucidated mainly during the last six years. Furthermore, localization of functionally relevant monoclonal antibody epitopes, determination of the cross-linking sites of inhibitory peptide ligands, proteolytic dissection of the isolated integrin, and analysis of natural and artificial GPIIb/IIIa mutants have recently provided a wealth of information regarding structure-function relationships of human GPIIb/IIIa. The aim of this review is to summarize these many structural and functional data in the perspective of an emerging model. Although most of the interpretations based on structural elements of this initial biochemical model require independent confirmation, they may help us to understand the structure-function relationship of this major platelet receptor, and of other members of the integrin superfamily, as well as to perform further investigations in order to test current hypotheses.

P2 receptor expression signaling and function in osteoclasts

10.2741/s214 ◽  
2011 ◽  
Vol S3 (3) ◽  
pp. 1101-1118
Author(s):  
S. Jeffrey Dixon
Keyword(s):  
Receptor Expression ◽  
P2 Receptor ◽  
And Function
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