Anti-Glycoprotein Ib/IX and llb/llla Antibodies in Patients with Antiphospholipid Antibodies

1994 ◽  
Vol 71 (05) ◽  
pp. 571-575 ◽  
Author(s):  
Monica Galli ◽  
Maria Daldossi ◽  
Tiziano Barbui
Keyword(s):  
Antiphospholipid Antibodies ◽  
Cross Reactivity ◽  
Platelet Membrane ◽  
Platelet Glycoprotein ◽  
Platelet Destruction ◽  
Platelet Surface ◽  
Immune Mediated ◽  
Platelet Antigen ◽  
History Of ◽  
Associated Conditions

SummaryAntiphospholipid antibodies, namely lupus anticoagulant (LA), anticardiolipin (aCL) type A and type B antibodies, are frequently associated with immune-mediated thrombocytopenia. Antiphospholipid antibodies have been suggested to bind to the phospholipids of the platelet membrane, thus participating to the process of platelet destruction, which leads to thrombocytopenia. However, a clear antiphospholipid (aPL) demonstration of such a role has never been given for antibodies. Conversely, autoantibodies directed against membrane-associated glycoproteins (GP) have been shown to be pathogenet- ically linked to the development of thrombocytopenia in patients with idiopathic thrombocytopenic purpura. For this reason, we have measured anti-GPIb/IX and GPlIb/IIIa IgG in the plasma of 68 patients with aPL antibodies by ELISA. The monoclonal antibody-specific immobilization of platelet antigen (MAIPA) assay was used.Twenty-seven out of 68 patients with antiphospholipid antibodies (40%) had increased plasma levels of anti-GP antibodies. In particular, 7 of them had elevated anti-GPIIb/IIIa levels only, 6 had anti-GPIb/IX antibodies only, whereas in the remaining 14 cases both types of autoantibodies were found elevated. The level of anti-GP antibodies in plasma did not correlate with age, sex, clinical associated conditions, history of thrombosis, IgG aCL titer or the presence of a phospholipid- dependent inhibitor of coagulation. In contrast, a statistically significant association between thrombocytopenia and high anti-GP antibody titer was observed (p = 0.0458).To establish whether there was cross-reactivity between antiphospholipid and anti-GP antibodies, adsorption experiments were performed using eardiolipin-containing liposomes or washed, normal, resting platelets. When patients’ plasma was mixed with resting washed platelets, only anti-GP antibodies were adsorbed on platelet membrane and subsequently eluted from platelets. Conversely, binding to cardio- lipin-containing liposomes but not to platelet surface was demonstrated for antiphospholipid antibodies.In conclusion, our data indicate that high levels of anti-platelet glycoprotein antibodies are more frequently found in patients with antiphospholipid antibodies and thrombocytopenia and that they might be responsible, more than LA and/or aCL antibodies, for the development of thrombocytopenia.

Autoantibodies to αIIbβ3 in patients with chronic immune thrombocytopenic purpura bind primarily to epitopes on αIIb

Blood ◽  
2001 ◽  
Vol 97 (7) ◽  
pp. 2171-2172 ◽  
Author(s):  
Robert McMillan ◽  
Jennifer Lopez-Dee ◽  
Joseph C. Loftus
Keyword(s):  
Immune Thrombocytopenic Purpura ◽  
Cho Cells ◽  
Chinese Hamster ◽  
Surface Proteins ◽  
Platelet Glycoprotein ◽  
Beta Chain ◽  
Platelet Destruction ◽  
Thrombocytopenic Purpura ◽  
Platelet Surface ◽  
Chronic Immune Thrombocytopenic Purpura

Abstract Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disease caused by platelet destruction resulting from autoantibodies against platelet surface proteins, particularly platelet glycoprotein IIb/IIIa (αIIbβ3). To localize the auto-epitopes on platelet αIIbβ3, the binding of autoantibodies to Chinese hamster ovary (CHO) cells expressing either αIIbβ3 or αvβ3was studied. Thirteen of 14 ITP autoantibodies bound only to CHO cells expressing αIIbβ3. Because these 2 integrins have the same beta chain (β3), these results show that most epitopes in chronic ITP are dependent on the presence of glycoprotein αIIb.

scholarly journals Immune Thrombocytopenia

Hematology ◽  
2010 ◽  
Vol 2010 (1) ◽  
pp. 377-384 ◽  
Author(s):  
Adam Cuker ◽  
Douglas B. Cines
Keyword(s):  
Immune Thrombocytopenia ◽  
Therapeutic Decision ◽  
Platelet Destruction ◽  
Aggressive Therapy ◽  
Pulse Dose ◽  
Thrombopoietin Receptor ◽  
History Of ◽  
Associated Conditions ◽  
Therapeutic Decision Making

Abstract Immune thrombocytopenia (ITP) comprises a heterogeneous group of disorders characterized by autoimmune-mediated platelet destruction and impairment of thrombopoiesis. ITP may occur in the absence of an evident predisposing etiology (primary ITP) or secondary to a growing list of associated conditions (secondary ITP), and must be differentiated from other causes of thrombocytopenia. This review focuses on primary ITP in adults. The traditional goal of therapy in this population is to achieve a hemostatic platelet count of 30 × 109/L or above for most patients while minimizing treatment-related morbidity. This approach has been called into question by the recent advent of well-tolerated and effective agents for the management of ITP, including pulse-dose dexamethasone, rituximab, and the thrombopoietin receptor agonists. Recent studies suggest the potential for aggressive therapy at the time of diagnosis to alter the natural history of ITP and point to the importance of quality-of-life considerations in therapeutic decision making.

Immune Thrombocytopenia

Hematology ◽  
2010 ◽  
Vol 2010 (1) ◽  
pp. 377-384 ◽  
Author(s):  
Adam Cuker ◽  
Douglas B. Cines
Keyword(s):  
Immune Thrombocytopenia ◽  
Therapeutic Decision ◽  
Platelet Destruction ◽  
Aggressive Therapy ◽  
Pulse Dose ◽  
Thrombopoietin Receptor ◽  
History Of ◽  
Associated Conditions ◽  
Therapeutic Decision Making

Immune thrombocytopenia (ITP) comprises a heterogeneous group of disorders characterized by autoimmune-mediated platelet destruction and impairment of thrombopoiesis. ITP may occur in the absence of an evident predisposing etiology (primary ITP) or secondary to a growing list of associated conditions (secondary ITP), and must be differentiated from other causes of thrombocytopenia. This review focuses on primary ITP in adults. The traditional goal of therapy in this population is to achieve a hemostatic platelet count of 30 × 109/L or above for most patients while minimizing treatment-related morbidity. This approach has been called into question by the recent advent of well-tolerated and effective agents for the management of ITP, including pulse-dose dexamethasone, rituximab, and the thrombopoietin receptor agonists. Recent studies suggest the potential for aggressive therapy at the time of diagnosis to alter the natural history of ITP and point to the importance of quality-of-life considerations in therapeutic decision making.

scholarly journals Severe Menorrhagia and Thrombocytopenia in a Patient with Pseudohypoparathyroidism

2021 ◽  
Vol 5 (2) ◽  
pp. 01-04
Author(s):  
Lily Suh
Keyword(s):  
Intravenous Immunoglobulin ◽  
Platelet Transfusion ◽  
Severe Anemia ◽  
Platelet Dysfunction ◽  
Platelet Destruction ◽  
Platelet Counts ◽  
Immune Mediated ◽  
History Of ◽  
Pseudohypoparathyroidism Ia

A 15-year-old female with a history of hypothyroidism presented with severe anemia and thrombocytopenia in the setting of prolonged menses. After further evaluation, she was diagnosed with pseudohypoparathyroidism Ia (PHPIa). Her symptoms improved after starting medications and receiving a platelet transfusion, but a few weeks later she returned with complaints of bleeding and dizziness and was found to be thrombocytopenic once again. Her platelet counts improved after administration of intravenous immunoglobulin (IVIG), leading us to believe she has a combined immune mediated platelet destruction in addition to platelet dysfunction associated with her PHPIa.

scholarly journals Mechanisms of anti-GPIbα antibody–induced thrombocytopenia in mice

Blood ◽  
2020 ◽  
Vol 135 (25) ◽  
pp. 2292-2301
Author(s):  
Yosuke Morodomi ◽  
Sachiko Kanaji ◽  
Eric Won ◽  
Zaverio M. Ruggeri ◽  
Taisuke Kanaji
Keyword(s):  
Messenger Rna ◽  
Low Dose ◽  
Subcutaneous Administration ◽  
Chronic Phase ◽  
High Dose ◽  
Membrane Expression ◽  
Platelet Destruction ◽  
Platelet Surface ◽  
Platelet Size ◽  
Immune Mediated

Abstract Immune thrombocytopenia (ITP) is an acquired bleeding disorder characterized by antibody-mediated platelet destruction. Different mechanisms have been suggested to explain accelerated platelet clearance and impaired thrombopoiesis, but the pathophysiology of ITP has yet to be fully delineated. In this study, we tested 2 mouse models of immune-mediated thrombocytopenia using the rat anti-mouse GPIbα monoclonal antibody 5A7, generated in our laboratory. After a single IV administration of high-dose (2 mg/kg) 5A7, opsonized platelets were rapidly cleared from the circulation into the spleen and liver; this was associated with rapid upregulation of thrombopoietin (TPO) messenger RNA. In contrast, subcutaneous administration of low-dose 5A7 (0.08-0.16 mg/kg) every 3 days gradually lowered the platelet count; in this case, opsonized platelets were observed only in the spleen, and TPO levels remained unaltered. Interestingly, in both models, the 5A7 antibody was found on the surface of, as well as internalized to, bone marrow megakaryocytes. Consequently, platelets generated in the chronic phase of repeated subcutaneous 5A7 administration model showed reduced GPIbα membrane expression on their surface. Our findings indicate that evaluation of platelet surface GPIbα relative to platelet size may be a useful marker to support the diagnosis of anti-GPIbα antibody–induced ITP.

scholarly journals Immunolocalization of beta 1 integrins in platelets and platelet- derived microvesicles

Blood ◽  
1993 ◽  
Vol 82 (4) ◽  
pp. 1197-1203 ◽  
Author(s):  
JD Wencel-Drake ◽  
MG Dieter ◽  
SC Lam
Keyword(s):  
Cellular Localization ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Cross Reactivity ◽  
Fluorescent Labeling ◽  
Platelet Glycoprotein ◽  
Resting Cells ◽  
Intact Cells ◽  
Platelet Surface ◽  
Permeabilized Cells

Human platelets contain several adhesion receptors belonging to the integrin superfamily. At least three beta 1 integrins are present on platelets and have been shown to mediate platelet adhesion to collagen, fibronectin, and laminin. To study the cellular localization of the beta 1 integrins in platelets, we produced a polyclonal antibody by immunization of goat 172 with purified beta 1 subunit from HPB-ALL cells. Antibody 172 (Ab172) specifically immunoblotted a 135-Kd protein in a lysate of whole platelets. The reactivity of Ab172 with platelet membrane proteins was further determined by immunoprecipitation of lysates of surface-radioiodinated platelets. Ab172 immunoprecipitates, resolved by nonreducing/reducing two-dimensional sodium dodecyl sulfate- polyacrylamide gel electrophoresis consisted of three labeled proteins with migrational properties of platelet glycoprotein (GP)Ia, GPIc and GPIIa. Neither GPIIb/IIIa nor the vitronectin receptor were immunoprecipitated by Ab172, confirming a lack of cross-reactivity with the beta 3 integrins in platelets. Immunofluorescence studies using Ab172 were performed to investigate the cellular distribution of beta 1 integrins in platelets. Fluorescent labeling of intact cells demonstrated the presence of beta 1 antigen on the surface of resting cells. Permeabilization of platelets with Triton X-100 showed the presence of an intracellular pool of beta 1 antigen. Double-label experiments using Ab172 and AP-2 (anti-GPIIb/IIIa) showed identical labeling patterns, suggesting a similar subcellular distribution for these integrins. Following thrombin stimulation, permeabilized cells showed a centralized clearing of both beta 1 antigen and GPIIb/IIIa as well as an intensification of surface labeling for beta 1 antigen. These findings suggest the translocation of intracellular beta 1 antigen to the platelet surface as a result of thrombin stimulation. Because platelet-derived microvesicles have been reported to contain GPIIb/IIIa, we investigated the possible distribution of beta 1 integrins in these structures. Microvesicles, produced as a result of platelet activation, were labeled with Ab172, suggesting the distribution of beta 1 integrins in these structures as well as in intact cells.

scholarly journals Immunolocalization of beta 1 integrins in platelets and platelet- derived microvesicles

Blood ◽  
1993 ◽  
Vol 82 (4) ◽  
pp. 1197-1203 ◽  
Author(s):  
JD Wencel-Drake ◽  
MG Dieter ◽  
SC Lam
Keyword(s):  
Cellular Localization ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Cross Reactivity ◽  
Fluorescent Labeling ◽  
Platelet Glycoprotein ◽  
Resting Cells ◽  
Intact Cells ◽  
Platelet Surface ◽  
Permeabilized Cells

Abstract Human platelets contain several adhesion receptors belonging to the integrin superfamily. At least three beta 1 integrins are present on platelets and have been shown to mediate platelet adhesion to collagen, fibronectin, and laminin. To study the cellular localization of the beta 1 integrins in platelets, we produced a polyclonal antibody by immunization of goat 172 with purified beta 1 subunit from HPB-ALL cells. Antibody 172 (Ab172) specifically immunoblotted a 135-Kd protein in a lysate of whole platelets. The reactivity of Ab172 with platelet membrane proteins was further determined by immunoprecipitation of lysates of surface-radioiodinated platelets. Ab172 immunoprecipitates, resolved by nonreducing/reducing two-dimensional sodium dodecyl sulfate- polyacrylamide gel electrophoresis consisted of three labeled proteins with migrational properties of platelet glycoprotein (GP)Ia, GPIc and GPIIa. Neither GPIIb/IIIa nor the vitronectin receptor were immunoprecipitated by Ab172, confirming a lack of cross-reactivity with the beta 3 integrins in platelets. Immunofluorescence studies using Ab172 were performed to investigate the cellular distribution of beta 1 integrins in platelets. Fluorescent labeling of intact cells demonstrated the presence of beta 1 antigen on the surface of resting cells. Permeabilization of platelets with Triton X-100 showed the presence of an intracellular pool of beta 1 antigen. Double-label experiments using Ab172 and AP-2 (anti-GPIIb/IIIa) showed identical labeling patterns, suggesting a similar subcellular distribution for these integrins. Following thrombin stimulation, permeabilized cells showed a centralized clearing of both beta 1 antigen and GPIIb/IIIa as well as an intensification of surface labeling for beta 1 antigen. These findings suggest the translocation of intracellular beta 1 antigen to the platelet surface as a result of thrombin stimulation. Because platelet-derived microvesicles have been reported to contain GPIIb/IIIa, we investigated the possible distribution of beta 1 integrins in these structures. Microvesicles, produced as a result of platelet activation, were labeled with Ab172, suggesting the distribution of beta 1 integrins in these structures as well as in intact cells.

scholarly journals Levamisole-Adulterated Cocaine Induced Skin Necrosis of Nose, Ears, and Extremities: Case Report

2014 ◽  
Vol 5 (3) ◽  
pp. ar.2014.5.0101 ◽  
Author(s):  
Lauren A. Lawrence ◽  
Jose L. Jiron ◽  
Ho-Sheng Lin ◽  
Adam J. Folbe
Keyword(s):  
United States ◽  
Antiphospholipid Antibodies ◽  
Complete Resolution ◽  
Skin Necrosis ◽  
The United States ◽  
Antineutrophil Cytoplasmic Antibodies ◽  
Cocaine Use ◽  
Immune Mediated ◽  
The Face ◽  
History Of

Levamisole is an immunomodulatory and antihelminthic drug, previously removed from the United States market, and now estimated to be present in the vast majority of cocaine distributed in the United States. Levamisole-adulterated cocaine (LAC) exposure can result in neutropenia, thrombocytopenia, and vasculitis with a predilection for subsites of the face. The objective of this review is to increase awareness among otolaryngologists of the manifestations of LAC exposure. We present the case of a 33-year-old woman with a history of cocaine use, consulted for purpuric, necrotic lesions of the nose, cheeks, and ears, with accompanying leukopenia, thrombocytopenia, and positive antineutrophil cytoplasmic antibodies (ANCA). The effects of levamisole are immune mediated, with antibodies directed against neutrophils causing neutropenia, and vasculitis caused by antibody deposition or secondary to induction of antiphospholipid antibodies causing thrombosis. LAC exposure can be differentiated from other similar appearing pathologies by evaluating serology for specific ANCA. The most important treatment is cessation of cocaine use, which most often results in complete resolution of symptoms. Awareness of the presentation, complications, and treatment of LAC exposure may be especially important for otolaryngologists, who may be one of the firsts to evaluate an affected patient.

scholarly journals Thrombin-induced changes in platelet membrane glycoproteins Ib, IX, and IIb-IIIa complex

Blood ◽  
1987 ◽  
Vol 70 (5) ◽  
pp. 1673-1678 ◽  
Author(s):  
AD Michelson ◽  
MR Barnard
Keyword(s):  
Marked Decrease ◽  
Platelet Membrane ◽  
Platelet Glycoprotein ◽  
Membrane Glycoproteins ◽  
Surface Binding ◽  
Proteolytic Fragment ◽  
Platelet Surface ◽  
Platelet Release ◽  
Induced Changes ◽  
Damaged Vessel

Abstract Platelet membrane glycoprotein Ib (GPIb) and the GPIIb-IIIa complex have central roles in the interaction of platelets with the plasma coagulation system, damaged vessel walls, and other platelets. We investigated the effects of thrombin on these glycoproteins. Monoclonal antibodies were used to assess platelet surface glycoproteins by flow cytometry, total platelet glycoprotein content by immunoassay, and glycoproteins released from platelets, also by immunoassay. Five new observations were made with regard to thrombin-induced changes in platelet membrane glycoproteins: (a) The marked decrease in platelet surface binding of antibodies directed at GPIb was not confined to antibodies directed at the von Willebrand factor binding site. (b) There was a marked decrease in platelet surface binding of an antibody directed at GPIX, with maintenance of the 1:1 ratio of platelet surface binding of antibodies directed at GPIb and GPIX. (c) Changes in platelet surface binding of antibodies were not restricted to a distinct subpopulation of platelets. (d) There was no associated platelet release of glycocalicin (a proteolytic fragment of GPIb). (e) There was no associated platelet release of the GPIIb-IIIa complex. These thrombin-induced changes may be important in modulating the reactivity of platelets with the damaged vessel wall and with each other.

scholarly journals Thrombin-induced changes in platelet membrane glycoproteins Ib, IX, and IIb-IIIa complex

Blood ◽  
1987 ◽  
Vol 70 (5) ◽  
pp. 1673-1678
Author(s):  
AD Michelson ◽  
MR Barnard
Keyword(s):  
Marked Decrease ◽  
Platelet Membrane ◽  
Platelet Glycoprotein ◽  
Membrane Glycoproteins ◽  
Surface Binding ◽  
Proteolytic Fragment ◽  
Platelet Surface ◽  
Platelet Release ◽  
Induced Changes ◽  
Damaged Vessel

Platelet membrane glycoprotein Ib (GPIb) and the GPIIb-IIIa complex have central roles in the interaction of platelets with the plasma coagulation system, damaged vessel walls, and other platelets. We investigated the effects of thrombin on these glycoproteins. Monoclonal antibodies were used to assess platelet surface glycoproteins by flow cytometry, total platelet glycoprotein content by immunoassay, and glycoproteins released from platelets, also by immunoassay. Five new observations were made with regard to thrombin-induced changes in platelet membrane glycoproteins: (a) The marked decrease in platelet surface binding of antibodies directed at GPIb was not confined to antibodies directed at the von Willebrand factor binding site. (b) There was a marked decrease in platelet surface binding of an antibody directed at GPIX, with maintenance of the 1:1 ratio of platelet surface binding of antibodies directed at GPIb and GPIX. (c) Changes in platelet surface binding of antibodies were not restricted to a distinct subpopulation of platelets. (d) There was no associated platelet release of glycocalicin (a proteolytic fragment of GPIb). (e) There was no associated platelet release of the GPIIb-IIIa complex. These thrombin-induced changes may be important in modulating the reactivity of platelets with the damaged vessel wall and with each other.

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