Quinine-induced Thrombocytopenia Research Articles

Effect of quinine and artesunate combination therapy on platelet count of children with severe malaria

Background: There are several case reports of quinine-induced thrombocytopenia but no clinical trials to ascertain its incidence and significance in severe malaria.Objectives: The primary objective was to assess the effect of quinine on the platelet count in children with severe malaria and to compare it with artesunate combination therapy (ACT), and the secondary objective was to assess outcome of treatment with quinine and ACT.Methods: An open-labelled, randomised, controlled trial was undertaken in 100 children aged 6 months to 12 years who were diagnosed with malaria by microscopy and/or rapid diagnostic test kits with at least one WHO clinical or laboratory criterion for severe malaria. All subjects were commenced on either quinine or ACT. Clindamycin was added to artesunate as a combination drug (ACT). It was also given to patients on quinine to avoid its confounding effect on the results. Platelet counts were undertaken every 24 hours for 7 consecutive days, temperature and coma score (Blantyre coma score ≥3 in children <4 years or Glasgow coma score ≥13 in children >4 years) was recorded 6-hourly and peripheral smears were taken 12-hourly until two consecutively negative smears were obtained. The primary outcome was a fall in the platelet count by ≥20% from the time of drug initiation until day 7. The secondary outcome was comparison of the efficacy, parasite clearance time, fever clearance time, coma recovery time and adverse effects of quinine vs ACT.Results: 30.4% patients in the quinine group (n = 48) had ≥20% fall in platelet count and 10.8% of patients in the ACT group (n = 46) (P = 0.02). Despite the fall in platelet count, there was no bleeding. The efficacy of ACT was significantly better than quinine but the other treatment outcomes showed insignificant difference.Conclusion: Quinine should be used with caution in patients with severe malaria because of the potential risk of quinine-induced thrombocytopenia.

Structural Basis for Quinine-Dependent Antibody Binding to Platelet Integrin alphaIIbbeta3

Drug-induced immune thrombocytopenia (DITP) is caused by antibodies that react with specific platelet membrane glycoproteins when the provoking drug is present. More than 100 drugs including quinine have been implicated as causes of immune thrombocytopenia, a relatively common, sometimes life-threatening, disorder. The cause of DITP in most cases appears to be a drug-induced antibody that binds to a platelet membrane glycoprotein only when the drug is present. Quinine, originally used as a prophylactic against malaria, is used at lower concentrations to impart the bitter flavor to tonic water, and is still used occasionally for the prevention of nocturnal leg cramps. For unknown reasons, quinine is much more likely to cause DITP than other drugs, with the exception of heparin, which acts by a distinctly different mechanism. The hallmark of DITP caused by drugs other than heparin is an antibody that is non-reactive in the absence of the sensitizing drug but binds tightly to a platelet glycoprotein, usually integrin αIIbβ3 (GPIIb/IIIa) when the drug is present. In contrast to drugs that act as a hapten to induce hypersensitivity, drugs that cause DITP appear not to bind covalently to the target antigen and do not inhibit antibody binding at high concentration. Nor has it been possible to show that drug binds noncovalently to an autologous target and somehow primes it for antibody binding. A mechanism recently proposed to explain drug-dependent antibody binding in DITP proposes that DDAbs are derived from a pool of naturally-occurring immunoglobulins that react weakly with autologous targets and that drug reacts at the antibody-antigen interface to increase the Ka for binding ("sandwich model"). Studies to define the mechanism(s) responsible for drug-dependent antibody (DDAb) binding to platelets have been handicapped by the requirement to use human antibodies, which are polyclonal and often in short supply. Recently developed murine monoclonal antibodies 314.1 and 314.3, which are specific for the β-propeller domain of αIIb integrin and closely mimic the behavior of antibodies found in patients with quinine-induced thrombocytopenia in vitro and in vivo, have provided new tools for characterizing this interaction at a molecular level. In this report, we demonstrate specific, high-affinity binding of quinine to the complementarity-determining regions (CDR) of these antibodies and define in crystal structures the changes induced in the CDR by this interaction. Since in previous studies, no detectable binding of quinine to the target integrin could be demonstrated, the findings indicate that a hybrid paratope consisting of quinine and reconfigured antibody CDR plays a critical role in recognition of its target epitope by antibody and suggest that, in this type of drug-induced immunologic injury, the primary reaction involves binding of drug to antibody CDR, causing it to acquire specificity for a site on a platelet integrin. This previously undescribed mechanism for drug-dependent antibody-target interaction could have implications for other types of drug sensitivity. DisclosuresAster:BLOODCENTER OF WISCONSIN: Patents & Royalties: A patent application has been filed based partly on these findings (Method of detecting platelet activating antibodies that cause heparin-induced thrombocytopenia/thrombosis; PCT/US14/62591).

Structural basis for quinine-dependent antibody binding to platelet integrin αIIbβ3

AbstractDrug-induced immune thrombocytopenia (DITP) is caused by antibodies that react with specific platelet-membrane glycoproteins when the provoking drug is present. More than 100 drugs have been implicated as triggers for this condition, quinine being one of the most common. The cause of DITP in most cases appears to be a drug-induced antibody that binds to a platelet membrane glycoprotein only when the drug is present. How a soluble drug promotes binding of an otherwise nonreactive immunoglobulin to its target, leading to platelet destruction, is uncertain, in part because of the difficulties of working with polyclonal human antibodies usually available only in small quantities. Recently, quinine-dependent murine monoclonal antibodies were developed that recognize a defined epitope on the β-propeller domain of the platelet integrin αIIb subunit (GPIIb) only when the drug is present and closely mimic the behavior of antibodies found in human patients with quinine-induced thrombocytopenia in vitro and in vivo. Here, we demonstrate specific, high-affinity binding of quinine to the complementarity-determining regions (CDRs) of these antibodies and define in crystal structures the changes induced in the CDR by this interaction. Because no detectable binding of quinine to the target integrin could be demonstrated in previous studies, the findings indicate that a hybrid paratope consisting of quinine and reconfigured antibody CDR plays a critical role in recognition of its target epitope by an antibody and suggest that, in this type of drug-induced immunologic injury, the primary reaction involves binding of the drug to antibody CDRs, causing it to acquire specificity for a site on a platelet integrin.

Quinine-Induced Thrombocytopenia in a Patient With Myocardial Infarction

Quinine-induced thrombocytopenia is a relatively rare phenomenon likely mediated by both quinine-induced production of anti-platelet antibodies as well as the production of antibodies leading to apoptosis of megakaryocytes. We report the case of a gentleman who presented with evidence of acute inferior myocardial infarction in the setting of quinine-induced thrombocytopenia. We discuss the history and pathogenesis of quinine-induced thrombocytopenia as well as the relationship between platelet count and risk and outcome of myocardial infarction. The patient successfully underwent percutaneous coronary intervention and the placement of a bare metal stent, chosen in preference to a drug-eluting stent due to the wish to minimize the duration of dual anti-platelet therapy in the setting of thrombocytopenia. His platelets increased significantly with no intervention other than holding tonic water, and he suffered no bleeding complications related to catheterization. We conclude that cardiac catheterization can be successfully performed in the setting of quinine-induced thrombocytopenia and believe that this is one of the first reported cases of quinine-induced thrombocytopenia in the setting of myocardial infarction. J Hematol. 2015;4(1):137-140 doi: http://dx.doi.org/10.14740/jh92w

Update of drug-induced immune thrombocytopenia

Immune thrombocytopenia is a common adverse effect of many drugs including heparin, quinine, GPIIb/IIIa inhibitors, antibiotics, ranitidine and rifampicin. Quinine-induced thrombocytopenia (QIT) is often considered a prototype of drug-induced immune thrombocytopenia (DIT). In DIT, the thrombocytopenia is severe (platelet count 9 /L) and has an abrupt onset. Bleeding is common. In QIT, the anti-platelet antibodies have specificity for platelet membrane proteins (GPIb-IX, GPIIb/IIIa, and occasionally GP V or PECAM-1) of which GPIb-IX is the major autoantigen. The antibody binds to platelets and causes premature platelet clearance by the reticuloendothelial system. We have located the antibody epitopestoresidues 283–293ofGPIba 1 andresiduesR110 to Q115 of GPIX. 2 Interestingly the epitope of three other DIT antibodies, namely quinidine-, ranitidine- and rifampicin-induced antibodies, have been mapped to the same region on GPIX as that of the antibody in QIT. This is probably because this region of GPIX is hyperflexible and is able to bind many drugs with diverse chemical structures to form drug/antigen complexes. We recently showed that the QIT antibodies also bound megakar-yocytes (MKs) via GPIb-IX, caused MK apoptosis and inhibited proplatelet and platelet formation. 3 These data suggest that there is a previously unrecognised mechanism of thrombocytopenia in DIT, mediated by antibody-induced decrease in platelet production. The management of DIT is cessation of the offending drug. Other therapeutic measures include the administration of glucocorticos-teroid and/or intravenous immunoglobulin.

Quinine-induced thrombocytopenia: drug-dependent GPIb/IX antibodies inhibit megakaryocyte and proplatelet production in vitro

AbstractThe development of immune cytopenias is a well-recognized side effect of many drugs. Quinine- and quinidine-dependent antibodies are classic examples of drug-induced effects that cause severe, life-threatening thrombocytopenia. Whereas the effects of drug-dependent antibodies on platelets have been well documented, their effects on megakaryocyte (Mk) biology are still unclear. We analyzed sera from several quinine-induced thrombocytopenia (QITP) patients on highly pure Mks (98% glycoprotein IIb-positive [GPIIb+]; 92% GPIX+) derived from human CD34+ cells cultured with human thrombopoietin. We demonstrate by flow cytometry and confocal microscopy that QITP IgGs bind Mks efficiently in the presence of quinine. Incubation of day-4 Mks with QITP sera or purified IgG resulted in induction of apoptosis, a significant decrease in cell viability, and an increase in cell death. Furthermore, QITP sera preferentially reduced the number of late GPIX+/GPIbα+ Mks and the number of receptors per cell in the surviving population. Ploidy distribution, lobularity, and average cell size of Mks remained unchanged after treatment. In addition, treated Mks showed a marked decrease in their proplatelet production capacity, suggesting that drug-dependent antibodies hinder platelet production. Therefore, QITP antibodies considerably reduce the proplatelet production capabilities of Mks despite undetectable effects on DNA content, morphology, and cell size.

Drug-induced thrombocytopenia: development of a novel NOD/SCID mouse model to evaluate clearance of circulating platelets by drug-dependent antibodies and the efficacy of IVIG

AbstractDrug-induced immune thrombocytopenia (DITP) is an adverse drug effect mediated by drug-dependent antibodies. Intravenous immunoglobulin (IVIG) is frequently used to treat DITP and primary immune thrombocytopenia (ITP). Despite IVIG's proven beneficial effects in ITP, its efficacy in DITP is unclear. We have established a nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse model of DITP in which human platelets survive for more than 24 hours, allowing platelet clearance by DITP/ITP antibodies to be studied. Rapid human platelet clearance was uniformly observed with all quinine-induced thrombocytopenia (QITP) patient sera studied (mean platelet lifespans: QITP 1.5 ± 0.3 hours vs controls 16.5 ± 4.3 hours), consistent with the clinical presentation of DITP. In contrast, clearance rates with ITP antibodies were more variable. IVIG treatment partially prevented platelet clearance by DITP and ITP antibodies. Our results suggest that the NOD/SCID mouse model is useful for investigating the efficacy of current and future DITP therapies, an area in which there is little experimental evidence to guide treatment.

Drug-induced thrombocytopenia: localization of the binding site of GPIX-specific quinine-dependent antibodies

AbstractImmune thrombocytopenia is a common complication of therapy with a large number of drugs. The most widely studied drug-induced immune thrombocytopenia (DIT) is caused by quinine. In most cases of DIT, antibodies bind to the platelet membrane glycoprotein (GP) Ib-IX complex in a drug-dependent fashion and bring about increased platelet clearance by the reticuloendothelial system resulting in thrombocytopenia. Here, we report the characterization of the quinine-dependent antibody activity of sera from 13 patients with quinine-induced thrombocytopenia. In our series of patients, GPIX was the most prevalent target of quinine-dependent antibodies. To identify the structural determinants of GPIX recognized by quinine-dependent antibodies, 4 chimeric mouse/human GPIX constructs and stable Chinese hamster ovary (CHO) cell lines that expressed the chimeras in association with GPIbα and GPIbβ were produced. The analysis of 6 patient sera with the chimeric cell lines provided evidence for localization of the anti-GPIX quinine-dependent antibody binding site to the C-ext region (amino acid [aa] 64-135) of human GPIX. Further characterization of the C-ext region of the GPIX indicated that replacement of the Arg110 and Gln115 of the human GPIX with the corresponding residues from mouse (Gln and Glu, respectively) resulted in a significant reduction in the binding of GPIX antibodies in our series of patients, with Arg110Gln, giving a more pronounced effect than Gln115Glu. Hence, these 2 residues, particularly Arg110, play an important role in the structure of the antigenic site on GPIX recognized by anti-GPIX antibodies.

Synercid-Induced Myalgias; Another Allergic Reaction to Methylprednisolone; More on Heparin Flush–Induced Thrombocytopenia; Hiccups and Steroid Injections; Topical Tricyclic Toxicity?; Priapism with OTC Hormonal Agent; Quinine-induced Thrombocytopenia and Neutropenia; Hyperventilation and Quetiapine

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), to discuss methods of prevention, and to promote reporting of ADRs to the FDA's medWatch program (1-800-FDA-1088). If you have reported an interesting preventable ADR to medWatch, please consider sharing the account with our readers.

A case of quinine‐induced thrombocytopenia and neutropenia

Australian and New Zealand Journal of MedicineVolume 30, Issue 1 p. 96-96 A case of quinine-induced thrombocytopenia and neutropenia T. L. CHUAH, T. L. CHUAH Resident Medical OfficerSearch for more papers by this authorC. DENARO, C. DENARO Director of Internal Medicine, Department of Internal Medicine, Royal Brisbane Hospital and the University of Queensland, Brisbane, Qld.Search for more papers by this author T. L. CHUAH, T. L. CHUAH Resident Medical OfficerSearch for more papers by this authorC. DENARO, C. DENARO Director of Internal Medicine, Department of Internal Medicine, Royal Brisbane Hospital and the University of Queensland, Brisbane, Qld.Search for more papers by this author First published: 25 March 2008 https://doi.org/10.1111/j.1445-5994.2000.tb01068.xCitations: 4AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume30, Issue1February 2000Pages 96-96 RelatedInformation

Quinine-Dependent Antibodies Bind a Restricted Set of Epitopes on the Glycoprotein Ib-IX Complex: Characterization of the Epitopes

Severe immune thrombocytopenia is an idiosyncratic complication of quinine therapy. Although in most cases the responsible antibody is directed against platelet membrane glycoprotein (GP) Ib-IX, specificity for GPIIb-IIIa or both epitopes has also been reported. The objective of this study was to characterize the binding site of GPIb-IX–specific quinine-dependent antibodies. Antibody binding to Chinese hamster ovary cells or mouse L cells stably transfected with various combinations of the three genes (Ibα, Ibβ, or IX) that encode this complex was detected using flow cytometry, monoclonal antibody–specific immobilization of platelet antigens assay, and differential adsorption studies. IgG in sera from 15 patients with quinine-induced thrombocytopenia binding to the cells, in the presence of quinine, showed three distinct patterns. Group 1 sera contained at least two antibody populations, one which binds to GPIbα and another which recognizes GPIX. Group 2 sera contained an antibody which binds drug dependently to GPIX, and Group 3 sera contained an antibody which recognizes a quinine-dependent epitope on GPIbα. Thus, the quinine-dependent antibodies fall into two distinct populations that bind to GPIbα and GPIX independently. Using proteases which cleave GPIbα at specific sites, we have shown that the GPIbα-specific antibody binds to an 11–amino acid (283 to 293) region. Peptide inhibition studies provide confirmatory evidence that this region contains the epitope for the GPIbα-specific quinine-dependent antibody.

Quinine-Dependent Antibodies Bind a Restricted Set of Epitopes on the Glycoprotein Ib-IX Complex: Characterization of the Epitopes

Severe immune thrombocytopenia is an idiosyncratic complication of quinine therapy. Although in most cases the responsible antibody is directed against platelet membrane glycoprotein (GP) Ib-IX, specificity for GPIIb-IIIa or both epitopes has also been reported. The objective of this study was to characterize the binding site of GPIb-IX–specific quinine-dependent antibodies. Antibody binding to Chinese hamster ovary cells or mouse L cells stably transfected with various combinations of the three genes (Ibα, Ibβ, or IX) that encode this complex was detected using flow cytometry, monoclonal antibody–specific immobilization of platelet antigens assay, and differential adsorption studies. IgG in sera from 15 patients with quinine-induced thrombocytopenia binding to the cells, in the presence of quinine, showed three distinct patterns. Group 1 sera contained at least two antibody populations, one which binds to GPIbα and another which recognizes GPIX. Group 2 sera contained an antibody which binds drug dependently to GPIX, and Group 3 sera contained an antibody which recognizes a quinine-dependent epitope on GPIbα. Thus, the quinine-dependent antibodies fall into two distinct populations that bind to GPIbα and GPIX independently. Using proteases which cleave GPIbα at specific sites, we have shown that the GPIbα-specific antibody binds to an 11–amino acid (283 to 293) region. Peptide inhibition studies provide confirmatory evidence that this region contains the epitope for the GPIbα-specific quinine-dependent antibody.

Fatal Quinine-Induced Thrombocytopenia

Letters and Corrections15 February 1990Fatal Quinine-Induced ThrombocytopeniaJoel P. Freiman, MD, MPHJoel P. Freiman, MD, MPHSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-112-4-308 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the Editor: Quinine sulfate is widely used for the treatment of nocturnal leg cramps, although studies (1-3) have shown it to be of minimal benefit. One of the most serious and well-recognized side effects of quinine sulfate is thrombocytopenia. The mechanism of this reaction appears to be the formation of drug antibody complexes with an affinity for some component of the platelet membrane (4). The Food and Drug Administration (FDA) has received two reports of fatal quinine-induced thrombocytopenia.Patient 1, a 41-year-old woman, initially presented with sudden onset of severe abdominal pain radiating to her back. She had marked...

Quinine-induced thrombocytopenia. A case report.

Quinine-induced thrombocytopenia. A case report.

Fab-mediated binding of drug-dependent antibodies to platelets in quinidine- and quinine-induced thrombocytopenia.

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.

Quinine-Induced Thrombocytopenia Following Intravenous Use of Heroin

Profound thrombocytopenia developed in a 22-year-old man after intravenous use of heroin. A high-titer, quinine-dependent, platelet-specific antibody was detected in his serum using lysis of normal platelets labeled with chromium 51 and an electroimmunoassay for measurement of platelet-associated IgG. The antibody was specific for quinine and failed to react with platelets in the presence of quinidine hydrochloride or two structural analogues of heroin. Quinine, a common adulterant found in heroin, was detected in the patient's blood and urine. On the basis of these observations, the patient was judged to have quinine-induced immunologic thrombocytopenia. To our knowledge, this report is the first to confirm that quinine used as an adulterant can induce immunologic thrombocytopenia following an injection of heroin.

Quinine-induced thrombocytopenia following intravenous use of heroin

Quinine-induced thrombocytopenia following intravenous use of heroin

Thrombocytopenia induced by quinine

Occasional cases of quinine-induced thrombocytopenia have been reported in the dental literature. A case of quinine-induced thrombocytopenia, seen first in a dental surgery office, is reported, and the procedure leading to a definitive demonstration of the role of quinine in the induction of thrombocytopenia is described.

Quinine-induced purpura. Observation on antibody titers

THE STUDY of patients with purpura caused by quinine has been important in the understanding of drug-induced thrombocytopenia. Vipan¹attributed skin and mucous membrane purpura of four patients to quinine. Peshkin and Miller²described positive direct and passive transfer skin tests with quinine in a patient with suspected quinine-related thrombocytopenic purpura and, recalling that thrombocytopenia could be a part of the anaphylactic reaction, considered drug purpura as allergic. Quinine-induced thrombocytopenia has been extensively studied and several in vitro tests have been described. The mechanism of drug-induced thrombocytopenic purpura will be reviewed after an illustrative case report. <h3>Report of a Case</h3> For six months a 20-year-old white girl has taken quinine sulfate intermittently for nocturnal leg cramping. On the morning of Oct 18, 1963, she awoke with purpura of the lower lip and during the day noted numerous petechiae of the legs. She had not taken quinine during the

Quinine-Induced Purpura

THE STUDY of patients with purpura caused by quinine has been important in the understanding of drug-induced thrombocytopenia. Vipan¹attributed skin and mucous membrane purpura of four patients to quinine. Peshkin and Miller²described positive direct and passive transfer skin tests with quinine in a patient with suspected quinine-related thrombocytopenic purpura and, recalling that thrombocytopenia could be a part of the anaphylactic reaction, considered drug purpura as allergic. Quinine-induced thrombocytopenia has been extensively studied and several in vitro tests have been described. The mechanism of drug-induced thrombocytopenic purpura will be reviewed after an illustrative case report. <h3>Report of a Case</h3> For six months a 20-year-old white girl has taken quinine sulfate intermittently for nocturnal leg cramping. On the morning of Oct 18, 1963, she awoke with purpura of the lower lip and during the day noted numerous petechiae of the legs. She had not taken quinine during the