Fab-mediated binding of drug-dependent antibodies to platelets in quinidine- and quinine-induced thrombocytopenia.
01 Jan 1985-Journal of Clinical Investigation (American Society for Clinical Investigation)-Vol. 75, Iss: 1, pp 310-314
TL;DR: Findings suggest that binding of drug-induced antibodies to platelets occurs at the Fab domains of the IgG molecule.
Abstract: Platelets coated with quinine- or quinidine-induced antibodies form rosettes around protein A-Sepharose beads and normal platelets form rosettes about protein A-Sepharose beads coated with these antibodies. These reactions occurred only in the presence of sensitizing drug. Platelets also formed rosettes about protein A-Sepharose beads coated with an anti-PIA1 antibody, but drug was not required. Formation of rosettes between antibody-coated platelets and protein A-Sepharose was inhibited by F(ab')2 fragments of goat antibody specific for the Fc portion of human IgG, while rosette formation between antibody-coated protein A-Sepharose and platelets was inhibited by F(ab')2 fragments directed against the F(ab')2 portion of the IgG molecule. Since binding of IgG to protein A is known to occur via the Fc region, these findings suggest that binding of drug-induced antibodies to platelets occurs at the Fab domains of the IgG molecule.
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TL;DR: Analysis of platelet antibodies provides valuable support for diagnosis and therapy of platelets-related bleeding disorders and posttransfusion purpura is a rare transfusion reaction affecting almost exclusively female patients.
Abstract: Analysis of platelet antibodies provides valuable support for diagnosis and therapy of platelet-related bleeding disorders. Platelet autoantibodies induce autoimmune thrombocytopenia and – in very rar
4 citations
TL;DR: It is concluded that these ITP patients produced antibodies specific for platelet GPIb/IX and/or GPIIb/IIIa, and that the autoantibody‐platelet interaction was mediated by the classic Fab binding.
Abstract: The antibody domain responsible for the interactions between platelet glycoproteins (GP) and serum IgG autoantibodies in patients with chronic idiopathic thrombocytopenic purpura (ITP) was studied. Sera from nine non-transfused ITP patients and 20 normal controls and a serum containing an anti-PlA1 antibody were employed. Serum, purified IgG and F(ab')2 fragments were prepared and their binding to platelet GPIb/IX and GPIIb/IIIa were analysed using a modified MAIPA assay and an antigen capture ELISA. In all experiments most of the autoantibodies studied behaved identically to the anti-PlA1 antibody in that the IgG-F(ab')2 fragments retained their ability to bind to the respective glycoprotein. Substituting the enzyme-conjugated secondary antibody (Fab specific), in the MAIPA assay, with an Fc specific antibody removed all reactivities observed against platelet GPs, produced by IgG-F(ab')2 fragments. Furthermore, in an antigen-capture ELISA, IgG autoantibodies against platelet GPIb/IX and/or GPIIb/IIIa were blocked preferentially by pre-incubating the ITP sera with a goat anti-human IgG (F(ab')2 specific) antibody, but not with an anti-Fc antibody. We conclude that these ITP patients produced antibodies specific for platelet GPIb/IX and/or GPIIb/IIIa, and that the autoantibody-platelet interaction was mediated by the classic Fab binding.
4 citations
01 Jan 1986
TL;DR: The intention of the present chapter is to provide succinct coverage of the clinical pharmacology of currently useful antimalarial drugs as well as some guidelines for their deployment in therapy.
Abstract: The history of antimalarial chemotherapy is discussed briefly in Chapter 1. A number of excellent reviews of the subject are available (Peters, 1970, 1974, 1980; Thompson and Werbel, 1972; WHO, 1973; Pratt, 1977; Rozman and Canfield, 1979; Richards, 1979; Bruce-Chwatt, 1980, 1981; Rollo, 1980; Dietrich and Kern, 1981; Wyler, 1983; Rieckmann, 1983; Ellis and Chiodini, 1984; Peters and Richards, 1984). The intention of the present chapter is to provide succinct coverage of the clinical pharmacology of currently useful antimalarial drugs as well as some guidelines for their deployment in therapy. Comprehensive descriptions of the disease can be found in any good medical or parasitological text.
3 citations
01 Jan 2005
TL;DR: It is probably more accurate to call the drug-induced variety a drug- induced lupus-like syndrome, because the pathogenic mechanisms of both are unknown, and even in idiopathic l upus the mechanisms may be significantly different in different patients.
Abstract: Systemic lupus erythematosus, often abbreviated SLE, is a serious autoimmune syndrome that usually affects young women. Most lupus is idiopathic, which means that its cause is unknown, but approximately 10% is associated with the use of specific drugs (Adams and Hess 1991). The diagnosis of drug-induced lupus is made on the same basis as idiopathic lupus; in addition, the symptoms must have begun after initiation of treatment with a drug and must resolve on discontinuation of that drug treatment. Although the signs and symptoms of drug-induced lupus overlap with those of idiopathic lupus and the two syndromes cannot be differentiated on the basis of differences in signs and symptoms, the usual clinical picture is somewhat different.A significant difference is that drug-induced lupus is usually milder, and the most serious manifestations of idiopathic lupus are usually absent in the drug-induced variety. Despite the overlap in symptoms between idiopathic and drug-induced lupus, the differences suggest that their pathogenic mechanisms are different. In addition, drugs associated with the induction of lupus do not usually exacerbate idiopathic lupus (Reza et al. 1975), and the genetically associated risk factors are different for the two syndromes, as described below. Therefore, it is probably more accurate to call the drug-induced variety a drug-induced lupus-like syndrome. However, the pathogenic mechanisms of both are unknown, and even in idiopathic lupus the mechanisms may be significantly different in different patients. Therefore, until we know more about the mechanism of both syndromes, it is reasonable to use the term “drug-induced lupus”.
3 citations
Cites background from "Fab-mediated binding of drug-depend..."
...Quinidine therapy is also associated with a relatively high incidence of an immune-mediated thrombocytopenia (Christie et al. 1985)....
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01 Jan 2017
TL;DR: This review will focus on the various cellular mechanisms that cause drug-induced immune thrombocytopenia and will also discuss its diagnosis and management.
Abstract: A large number of drugs have been reported to cause immune thrombocytopenia. Recent research has considerably increased our knowledge of the cellular mechanisms that drive this immune reaction to drugs. The diagnosis is usually made clinically after considering the causal relationship with the suspected drug and the occurrence of the thrombocytopenia. The mainstay of treatment is essentially cessation of the suspected drug or drugs. The platelet count usually returns to normal limits within 1–2 weeks. However, high-dose glucocorticosteroid and IVIg are often administered because of the high risk of bleeding associated with severe thrombocytopenia. This review will focus on the various cellular mechanisms that cause drug-induced immune thrombocytopenia and will also discuss its diagnosis and management.
3 citations
References
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TL;DR: It is concluded that, in PNH, platelets and granulocytes share the membrane defect characteristic of erythrocytes in this disorder, and these observations support the concept that PNH arises as the result of a somatic mutation in a primitive cell capable of differentiating into ery Throttleblast, myeloblast, and megakaryoblast lines.
Abstract: The tendency of platelets and leukocytes to lyse after their interaction with antibody and complement was studied by measuring the release of 51Cr from cells labeled with this isotope. Platelets from six patients with paroxysmal nocturnal hemoglobinuria (PNH) were 15-230 times more sensitive to antibodies and 10-32 times more sensitive to complement than normal platelets or platelets from patients with other types of thrombocytopenic or hemolytic disorders. Mixed white blood cell (WBC) preparations from patients with PNH were 3-20 times more sensitive to anti-WBC antibodies and 5-10 times more sensitive to C′ than were WBC preparations from normal subjects, but PNH lymphocytes showed normal immunologic reactivity. PNH platelets, like PNH erythrocytes, lysed more readily than normal platelets in acidified serum and in media of reduced ionic strength, but these characteristics were not demonstrable with PNH WBC's under the conditions of study. In PNH, platelets appear to comprise a single population with respect to their sensitivity to immune lysis, yet their survival time as measured with 51Cr falls within normal limits. PNH granulocytes likewise appear to consist of a single, uniformly sensitive population.
It is concluded that, in PNH, platelets and granulocytes share the membrane defect characteristic of erythrocytes in this disorder. These observations support the concept that PNH arises as the result of a somatic mutation in a primitive cell capable of differentiating into erythroblast, myeloblast, and megakaryoblast lines. PNH platelets or enzymatically treated normal platelets permit the detection of some types of platelet antibodies in dilutions up to 2000-fold greater than is possible with currently available methods, a finding suggesting that the immune lysis technique will prove useful for the study of platelet immunology.
198 citations
"Fab-mediated binding of drug-depend..." refers methods in this paper
...6 mMEDTA) by differential centrifugation as previously described (7)....
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TL;DR: Purpura occurring during convalescence can best be explained on the assumption of an allergic basis, similar perhaps to that to which nephritis following streptococcal infections has been attributed.
186 citations
"Fab-mediated binding of drug-depend..." refers background in this paper
...Ackroyd (13) proposed a mechanism for the drug-ddAbplatelet reaction in which drug, acting as a hapten, modified a platelet constituent to produce a hapten-carrier complex which induces antibody formation....
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TL;DR: Results of this study were consistent with the possibilities that the protein moiety of a haptenic antigen involved in development of an antibody which attaches to a cell is not necessarily a component of the cell, and that the cell reacts with the antibody by virtue of having a surface favorable for non-specific adsorption of certain haptene-antibody complexes.
Abstract: A steric and kinetic model for the sequence and mechanism of reactions leading to formation of a complex from an antibody, a haptene (quinidine), and a cell membrane (platelets), and to fixation of complement by the complex was deduced from the effects of varying the initial concentration of each component of the complex on the amount of complement fixed, from kinetic aspects of the sequential reactions, and from other chemical and physical properties of the various components involved. Theoretical results calculated using equations based on the model, which were derived by Dr. Terrell L. Hill, were similar in all respects to experimental results. Results of this study were consistent with the possibilities that the protein moiety of a haptenic antigen involved in development of an antibody which attaches to a cell is not necessarily a component of the cell, and that the cell reacts with the antibody by virtue of having a surface favorable for non-specific adsorption of certain haptene-antibody complexes.
153 citations
"Fab-mediated binding of drug-depend..." refers background in this paper
...Drugs like quinidine and quinine bind weakly to platelets in the absence of ddAb (2, 3); excess soluble drug is required for maximum ddAb binding to platelets (3); and excess soluble drug fails to displace platelet-bound ddAb (2, 3), but it is not yet certain whether ddAb interact with platelets via the Fab or the Fc portion of the antibody molecule....
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...Shulman (2) provided experimental support for the latter hypothesis by showing that quinidine binds only weakly to platelets and would, therefore, be unlikely to form complexes capable of inducing antibody, and that high concentrations of drug do not displace plateletbound ddAb, as would be expected in a conventional hapten inhibition reaction....
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TL;DR: It is demonstrated that incorporation of cholesterol into platelet membranes is associated with a diminished inhibitory effect of prostaglandin E, on platelet aggregation and therefore adenosine 3’:5’-monophosphate production in these platelets.
125 citations
"Fab-mediated binding of drug-depend..." refers background in this paper
...It is unlikely that this apparent platelet-platelet binding was due to aggregation, since it occurred in the presence of 8 mMEDTA and, in some experiments, 20 ng/ ml PGEI, which is a potent inhibitor of aggregation (10)....
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TL;DR: It is demonstrated that in quinine- and quinidine-induced thrombocytopenia, drug and antibody combine first in the soluble phase to form a complex, which then binds with high affinity to a receptor on the platelet surface (innocent bystander reaction), and that these antibodies are heterogeneous in respect to the amount of drug required to promote their binding to platelets, the number of platelet receptors they recognize, and their binding affinities.
Abstract: Binding of quinine- and quinidine-dependent antibodies to platelets was studied using an electroimmunoassay to measure platelet-bound IgG. Antibodies from four patients with drug-induced thrombocytopenia differed significantly in their interaction with platelets: association constants for binding to platelets at high drug concentrations ranged from 0.29 to 2.6 x 10(7) M(-1), the maximum number of antibody molecules bound ranged from 36,000 to 161,000/platelet, the amount of drug necessary to achieve half-maximum binding of antibodies to platelets ranged from 2 to 60 muM, and only one of the antibodies cross-reacted with the stereoisomer of the drug to which the patient was sensitized. Binding of the antibodies to platelets was enhanced at the highest achievable molar ratio of drug:antibody, 10,000:1, rather than being inhibited, as would be expected in a conventional, hapten-dependent reaction. The drug-antibody-platelet reaction was unaffected by Factor VIII/von Willebrand protein, nonspecifically aggregated IgG, or heat-labile complement components. After pretreatment with tritiated quinine, platelets retained several hundred thousand molecules of drug each, but failed to bind detectable amounts of antibody. However, platelets treated simultaneously with quinine-dependent antibody and tritiated quinine retained significantly more drug after repeated washes than platelets treated with drug and normal serum. These findings support the proposition that in quinine- and quinidine-induced thrombocytopenia, drug and antibody combine first in the soluble phase to form a complex, which then binds with high affinity to a receptor on the platelet surface (innocent bystander reaction), and demonstrate that these antibodies are heterogeneous in respect to the amount of drug required to promote their binding to platelets, the number of platelet receptors they recognize, and their binding affinities.
65 citations
"Fab-mediated binding of drug-depend..." refers background or methods in this paper
...These observations seem most consistent with the following model for drug-ddAb-platelet binding: platelets coated with drug express an unstable neoantigen which is stabilized upon interaction with the Fab domains of ddAb (3)....
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...Drugs like quinidine and quinine bind weakly to platelets in the absence of ddAb (2, 3); excess soluble drug is required for maximum ddAb binding to platelets (3); and excess soluble drug fails to displace platelet-bound ddAb (2, 3), but it is not yet certain whether ddAb interact with platelets via the Fab or the Fc portion of the antibody molecule....
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...Weconfirmed and extended these observations by showing that even platelets coated with a million molecules of drug do not express ddAb binding sites unless excess soluble drug is present (3)....
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...That is, platelets pretreated with drug and then washed do not express binding sites for ddAb, and bound ddAb can readily be removed from platelets by washing in the absence of drug (3)....
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...Mixtures were then centrifuged at 12,800 g for 2 min, and supernatants were analyzed for IgG content by electroimmunoassay (3)....
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