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Journal ArticleDOI

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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Citations
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Journal ArticleDOI
TL;DR: The current understanding of pathogenesis is summarized and a guide for diagnosis and management of thrombocytopenia is provided.
Abstract: Drug-induced thrombocytopenia should be suspected in any patient with acute thrombocytopenia of unknown cause Although the incidence is low, more than 100 drugs have been implicated in thrombocytopenia, including quinine, sulfonamides, abciximab, carbamazepine, and vancomycin, as well as herbal remedies and several nonprescription drugs This review summarizes the current understanding of pathogenesis and provides a guide for diagnosis and management of this potentially dangerous disorder

459 citations

Journal ArticleDOI
TL;DR: The most important aspects of patient management are a high index of suspicion and a careful history of drug exposure in an individual who presents with acute, often severe thrombocytopenia of unknown etiology.

280 citations

Journal ArticleDOI
TL;DR: The most common drugs to cause DIIHA are anti-microbials, which are associated with drug-dependent antibodies, and the most common drug to cause AIHA is fludarabine.

186 citations


Cites background from "Fab-mediated binding of drug-depend..."

  • ...In 1985, Aster's group showed that antibodies from patients with quinine and quinidine-induced thrombocytopenia bound to the platelets by their Fab portion, not their Fc portion, of the Ig molecule.(36) This did not support the “nonspecific” adsorption of drug–anti-drug complexes as suggested by Shulman, and even later suggestions that the attachment was to the Fc receptor on platelets....

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Journal ArticleDOI
01 Jul 1996-Blood
TL;DR: The experience suggests that MAIPA assays are useful in the laboratory assessment of thrombocytopenia, should be performed before therapy, and that some patients with 'nonimmune' thromBocy topenia may have genuine antiplatelet antibodies.

186 citations

References
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Journal ArticleDOI
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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Journal ArticleDOI
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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Journal ArticleDOI
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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Journal ArticleDOI
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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Journal ArticleDOI
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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