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: Drug-induced thrombocytopenia (DIT) is a relatively common clinical disorder that can be a consequence of decreased platelet production (bone marrow suppression) or accelerated platelet destruction (especially immune-mediated destruction).
Abstract: Drug-induced thrombocytopenia (DIT) is a relatively common clinical disorder. It is imperative to provide rapid identification and removal of the offending agent before clinically significant bleeding or, in the case of heparin, thrombosis occurs. DIT can be distinguished from idiopathic thrombocytopenic purpura, a bleeding disorder caused by thrombocytopenia not associated with a systemic disease, based on the history of drug ingestion or injection and laboratory findings. DIT disorders can be a consequence of decreased platelet production (bone marrow suppression) or accelerated platelet destruction (especially immune-mediated destruction).
159 citations
148 citations
TL;DR: Drug-induced immune cytopenias, although infrequently recognized, may cause significant morbidity and mortality as indicated by two reports of severe immune hemolytic anemia (IHA) caused by cefotetan, published in this issue of TRANSFUSION.
144 citations
TL;DR: Drug-induced immune thrombocytopenia can be treated by withholding the causative drug and, in severe cases associated with bleeding, by platelet transfusion, and is a relatively rare adverse drug reaction, its consequences may be severe.
Abstract: Thrombocytopenia can have several causes, including the use of certain drugs. The mechanism behind drug-induced thrombocytopenia is either a decrease in platelet production (bone marrow toxicity) or an increased destruction (immune-mediated thrombocytopenia). In addition, pseudothrombocytopenia, an in vitro effect, has to be distinguished from true drug-induced thrombocytopenia. This article reviews literature on drug-induced immune thrombocytopenia, with the exception of thrombo-haemorrhagic disorders such as thrombotic thrombocytopenic purpura and heparin-induced thrombocytopenia and thrombosis. A literature search in PubMed combined with a check of the reference lists of all the retrieved articles resulted in 108 articles relevant to the subject. The drug classes that are most often associated with drug-induced immune thrombocytopenia are cinchona alkaloid derivatives (quinine, quinidine), sulfonamides, NSAIDs, anticonvulsants, disease modifying antirheumatic drugs and diuretics. Several other drugs are occasionally described in case reports of thrombocytopenia; an updated review of these case reports can be found on the internet. A small number of epidemiological studies, differing largely in the methodology used, describe incidences in the magnitude of 10 cases per 1 000 000 inhabitants per year. No clear risk factors could be identified from these studies. The underlying mechanism of drug-induced immune thrombocytopenia is not completely clarified, but at least three different types of antibodies appear to play a role (hapten-dependent antibodies, drug-induced, platelet-reactive auto-antibodies and drug-dependent antibodies). Targets for drug-dependent antibodies are glycoproteins on the cell membrane of the platelets, such as glycoprotein (GP) Ib/IX and GPIIb/IIIa. Diagnosis of drug-induced immune thrombocytopenia may consist of identifying clinical symptoms (bruising, petechiae, bleeding), a careful evaluation of the causal relationship of the suspected causative drug, general laboratory investigation, such as total blood count and peripheral blood smear (to rule out pseudothrombocytopenia), and platelet serology tests. The sensitivity of these tests is dependent on factors such as the concentration of the drug in the test and the potential sensitisation of the patient by metabolites instead of the parent drug. Drug-induced immune thrombocytopenia can be treated by withholding the causative drug and, in severe cases associated with bleeding, by platelet transfusion. Although drug-induced thrombocytopenia is a relatively rare adverse drug reaction, its consequences may be severe. Therefore it is important to extend our knowledge on this subject. Future research should focus on the identification of potential risk factors, as well as the exact mechanism underlying drug-induced thrombocytopenia.
111 citations
TL;DR: Findings indicate that DDAb induced by SMX and SIX, in contrast to those induced by quinidine and quinine, are mainly specific for GPIIb/IIIa and react preferentially with calcium-dependent epitopes present only on the intact GP IIb/ IIIa heterodimer.
104 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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