An Unusual Case of Drug-Induced Thrombocytopenia

Drug-induced thrombocytopenia (DIT) is a differential diagnosis for consideration when acute thrombocytopenia is encountered in the outpatient or inpatient setting. The mechanism of thrombocytopenia induced by different antiplatelet therapies varies. DIT may occur due to antibody formation following the exposure to a drug, or naturally occurring preexisting antibodies may produce rapid-onset thrombocytopenia when a drug molecule binds to a platelet receptor inducing a conformational change thus rendering it to be an antigen target for naturally occurring antibodies. A 66-year-old female with history of hypertension presented with non-ST elevation myocardial infarction, had drug eluting stent placed in first obtuse marginal artery of left circumflex coronary artery. Started on antiplatelet medications aspirin 81 mg, ticagrelor 90 mg (which was later transitioned to clopidogrel 75 mg), as well as tirofiban 12.5 mg (for 12 hours only). Tirofiban is a GP IIb/IIIa antagonist, other drugs in this class have been documented to induce thrombocytopenia as well, but rates for tirofiban appear to be the highest, the reason is unclear. These antibodies are thought to be either naturally occurring or induced from conformational changes to GP IIb/IIIa binding site after binding to the GP IIb/IIIa receptor, binding of these drugs to the receptor precipitates an epitope much more specific for platelet surface antigens. Tirofiban and clopidogrel/ticagrelor can cause thrombocytopenia, but onset in this case is unusual: acute antibody reaction would be expected within hours, not delayed 30 hours after starting antiplatelet medication, and nonacute reaction would present 1 to 2 weeks out.

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The platelet P2Y12 receptor for adenosine diphosphate: congenital and drug-induced defects

Blood ◽

10.1182/blood-2010-08-263111 ◽

2011 ◽

Vol 117 (7) ◽

pp. 2102-2112 ◽

Cited By ~ 119

Author(s):

Marco Cattaneo

Keyword(s):

Platelet Function ◽

Cardiovascular Events ◽

Thrombus Formation ◽

Adenosine Diphosphate ◽

New Drugs ◽

Drug Induced ◽

P2y12 Inhibitors ◽

Major Cardiovascular Events ◽

Platelet Receptor ◽

Net Clinical Benefit

Abstract P2Y12, the Gi-coupled platelet receptor for adenosine diphosphate (ADP), plays a central role in platelet function. Patients with congenital P2Y12 defects display a mild to moderate bleeding diathesis, characterized by mucocutaneous bleedings and excessive post-surgical and post-traumatic blood loss. Defects of P2Y12 should be suspected when ADP, even at high concentrations (≥ 10μM), is unable to induce full, irreversible platelet aggregation. Tests that evaluate the degree of inhibition of adenylyl cyclase by ADP should be used to confirm the diagnosis. Drugs that inhibit P2Y12 are potent antithrombotic drugs, attesting the central role played by P2Y12 in platelet thrombus formation. Clopidogrel, the most widely used drug that inhibits P2Y12, is effective both in monotherapy and in combination with acetylsalicylic acid. The most important drawback of clopidogrel is its inability to inhibit adequately P2Y12-dependent platelet function in approximately one-third of patients who are therefore not protected from major cardiovascular events. New drugs, such as prasugrel and ticagrelor, which effectively inhibit P2Y12 in the majority of patients, proved to be more efficacious than clopdidogrel in preventing major cardiovascular events. Although they increase the incidence of major bleedings, the net clinical benefit is in favor of the new P2Y12 inhibitors.

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Drug-Induced Conformational Changes in Multidrug Efflux Transporter AcrB from Haemophilus influenzae

Journal of Bacteriology ◽

10.1128/jb.00471-07 ◽

2007 ◽

Vol 189 (15) ◽

pp. 5550-5558 ◽

Cited By ~ 17

Author(s):

Vishakha Dastidar ◽

Weimin Mao ◽

Olga Lomovskaya ◽

Helen I. Zgurskaya

Keyword(s):

Multidrug Resistance ◽

Haemophilus Influenzae ◽

Conformational Changes ◽

Efflux Transporter ◽

Multidrug Efflux ◽

Drug Induced ◽

Gram Negative ◽

Membrane Fusion Protein ◽

Outer Membrane Channel

ABSTRACT In gram-negative bacteria, transporters belonging to the resistance-nodulation-cell division (RND) superfamily of proteins are responsible for intrinsic multidrug resistance. Haemophilus influenzae, a gram-negative pathogen causing respiratory diseases in humans and animals, constitutively produces the multidrug efflux transporter AcrB (AcrBHI). Similar to other RND transporters AcrBHI associates with AcrAHI, the periplasmic membrane fusion protein, and the outer membrane channel TolCHI. Here, we report that AcrABHI confers multidrug resistance when expressed in Escherichia coli and requires for its activity the E. coli TolC (TolCEC) protein. To investigate the intracellular dynamics of AcrABHI, single cysteine mutations were constructed in AcrBHI in positions previously identified as important for substrate recognition. The accessibility of these strategically positioned cysteines to the hydrophilic thiol-reactive fluorophore fluorescein-5-maleimide (FM) was studied in vivo in the presence of various substrates of AcrABHI and in the presence or absence of AcrAHI and TolCEC. We report that the reactivity of specific cysteines with FM is affected by the presence of some but not all substrates. Our results suggest that substrates induce conformational changes in AcrBHI.

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Characterisation of the conformational changes in platelet factor 4 induced by polyanions: towards in vitro prediction of antigenicity

Thrombosis and Haemostasis ◽

10.1160/th13-08-0634 ◽

2014 ◽

Vol 112 (07) ◽

pp. 53-64 ◽

Cited By ~ 42

Author(s):

Sven Brandt ◽

Krystin Krauel ◽

Kay E. Gottschalk ◽

Thomas Renné ◽

Christiane A. Helm ◽

...

Keyword(s):

Conformational Changes ◽

Structural Changes ◽

Cd Spectroscopy ◽

Platelet Factor 4 ◽

Drug Induced ◽

Platelet Factor ◽

Preclinical Drug Development ◽

Varying Length ◽

Endogenous Proteins

SummaryHeparin-induced thrombocytopenia (HIT) is the most frequent drug-induced immune reaction affecting blood cells. Its antigen is formed when the chemokine platelet factor 4 (PF4) complexes with polyanions. By assessing polyanions of varying length and degree of sulfation using immunoassay and circular dichroism (CD)-spectroscopy, we show that PF4 structural changes resulting in antiparallel β-sheet content >30% make PF4/polyanion complexes antigenic. Further, we found that polyphosphates (polyP-55) induce antigenic changes on PF4, whereas fondaparinux does not. We provide a model suggesting that conformational changes exposing antigens on PF4/polyanion complexes occur in the hairpin involving AA 32–38, which form together with C-terminal AA (66–70) of the adjacent PF4 monomer a continuous patch on the PF4 tetramer surface, explaining why only tetrameric PF4 molecules express “HIT antigens”. The correlation of antibody binding in immunoassays with PF4 structural changes provides the intriguing possibility that CD-spectroscopy could become the first antibody-independent, in vitro method to predict potential immunogenicity of drugs. CD-spectroscopy could identify compounds during preclinical drug development that induce PF4 structural changes correlated with antigenicity. The clinical relevance can then be specifically addressed during clinical trials. Whether these findings can be transferred to other endogenous proteins requires further studies.

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Processing of RNA Containing 8-Oxo-7,8-Dihydroguanosine (8-oxoG) by the Exoribonuclease Xrn-1

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.780315 ◽

2021 ◽

Vol 8 ◽

Author(s):

Cheyenne N. Phillips ◽

Shawn Schowe ◽

Conner J. Langeberg ◽

Namoos Siddique ◽

Erich G. Chapman ◽

...

Keyword(s):

Secondary Structure ◽

Conformational Changes ◽

Solid Phase Synthesis ◽

Solid Phase ◽

Spatial Constraints ◽

Phase Synthesis ◽

Naturally Occurring ◽

Processive Enzyme ◽

Moving Band ◽

Hydrolysis Of

Understanding how oxidatively damaged RNA is handled intracellularly is of relevance due to the link between oxidized RNA and the progression/development of some diseases as well as aging. Among the ribonucleases responsible for the decay of modified (chemically or naturally) RNA is the exonuclease Xrn-1, a processive enzyme that catalyzes the hydrolysis of 5′-phosphorylated RNA in a 5′→3′ direction. We set out to explore the reactivity of this exonuclease towards oligonucleotides (ONs, 20-nt to 30-nt long) of RNA containing 8-oxo-7,8-dihydroguanosine (8-oxoG), obtained via solid-phase synthesis. The results show that Xrn-1 stalled at sites containing 8-oxoG, evidenced by the presence of a slower moving band (via electrophoretic analyses) than that observed for the canonical analogue. The observed fragment(s) were characterized via PAGE and MALDI-TOF to confirm that the oligonucleotide fragment(s) contained a 5′-phosphorylated 8-oxoG. Furthermore, the yields for this stalling varied from app. 5–30% with 8-oxoG located at different positions and in different sequences. To gain a better understanding of the decreased nuclease efficiency, we probed: 1) H-bonding and spatial constraints; 2) anti-syn conformational changes; 3) concentration of divalent cation; and 4) secondary structure. This was carried out by introducing methylated or brominated purines (m1G, m6,6A, or 8-BrG), probing varying [Mg2+], and using circular dichroism (CD) to explore the formation of structured RNA. It was determined that spatial constraints imposed by conformational changes around the glycosidic bond may be partially responsible for stalling, however, the results do not fully explain some of the observed higher stalling yields. We hypothesize that altered π-π stacking along with induced H-bonding interactions between 8-oxoG and residues within the binding site may also play a role in the decreased Xrn-1 efficiency. Overall, these observations suggest that other factors, yet to be discovered/established, are likely to contribute to the decay of oxidized RNA. In addition, Xrn-1 degraded RNA containing m1G, and stalled mildly at sites where it encountered m6,6A, or 8-BrG, which is of particular interest given that the former two are naturally occurring modifications.

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An intronic polymorphism in the PAR-1 gene is associated with platelet receptor density and the response to SFLLRN

Blood ◽

10.1182/blood-2002-07-2149 ◽

2003 ◽

Vol 101 (5) ◽

pp. 1833-1840 ◽

Cited By ~ 79

Author(s):

Annabelle Dupont ◽

Pierre Fontana ◽

Christilla Bachelot-Loza ◽

Jean-Luc Reny ◽

Ivan Bièche ◽

...

Keyword(s):

Allelic Frequency ◽

Interindividual Variation ◽

Expression Data ◽

Receptor Density ◽

Platelet Response ◽

Platelet Surface ◽

Mrna Expression Data ◽

Intronic Polymorphism ◽

Platelet Receptor ◽

Protease Activated Receptor 1

Protease-activated receptor 1 (PAR-1), the main thrombin receptor on vascular cells, plays a key role in platelet activation. We examined the range of PAR-1 expression on platelets, obtained twice, 1 week apart, from 100 healthy subjects and found a 2-fold interindividual variation in receptor numbers (95% CI = 858-1700). Because PAR-1 density was stable with time (r2 = 76%,P < .001), we sought a genetic explanation for the observed variability. To validate this approach, we also analyzed the α2β1 genotype according to receptor density and platelet mRNA expression data. We found that the number of PAR-1 receptors on the platelet surface is associated with the intervening sequence IVSn−14 A/T intronic variation. The number of receptors was also found to govern the platelet response to the SFLLRN agonist, in terms of aggregation and P-selectin expression. The T allele (allelic frequency, 0.14) can be considered as an allele with decreased expression, because it was associated with lower PAR-1 expression on the platelet surface and with a lower response to SFLLRN. The IVSn−14 A/T intronic variation may therefore be clinically relevant.

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Adverse reactions to medication

Oxford Textbook of Inpatient Psychiatry ◽

10.1093/med/9780198794257.003.0012 ◽

2019 ◽

pp. 103-114

Author(s):

Tomasz Bajorek ◽

Jonathan Hafferty

Keyword(s):

Adverse Effect ◽

Adverse Effects ◽

Adverse Reactions ◽

Bleeding Risk ◽

Inpatient Setting ◽

Extrapyramidal Side Effects ◽

Inpatient Psychiatry ◽

Drug Induced ◽

Threatening Condition ◽

Life Threatening

Adverse reactions to medication represent a major issue in inpatient psychiatry. This chapter systematically explores the most relevant, concerning, and problematic adverse effects routinely encountered in an inpatient setting. It describes the typical presentation, pathophysiology, incidence, and practical management of these problems. Extrapyramidal side effects including acute dystonia, drug-induced parkinsonism, akathisia, and tardive dyskinesia are considered before the chapter explores the rare but potentially life-threatening condition of neuroleptic malignant syndrome. Other adverse effects common to antipsychotics that are described include hyperprolactinaemia and psychotropic-induced arrhythmias including QTc prolongation. Sexual dysfunction is an under-recognized and undertreated adverse effect common to several classes of psychotropic medication and is also considered. Focusing on antidepressants, the chapter reviews the frequently encountered issue of hyponatraemia as well as serotonin syndrome and selective serotonin reuptake inhibitor-induced bleeding risk. Finally, the chapter addresses perinatal considerations for psychotropic drugs.

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Bleomycin-induced lung injury treated with venovenous extracorporeal membrane oxygenation (ECMO) and ultra-protective ventilator settings

BMJ Case Reports ◽

10.1136/bcr-2020-236474 ◽

2020 ◽

Vol 13 (11) ◽

pp. e236474

Author(s):

Mazen Faris Odish ◽

William Cameron McGuire ◽

Patricia Thistlethwaite ◽

Laura E Crotty Alexander

Keyword(s):

Lung Injury ◽

Extracorporeal Membrane Oxygenation ◽

Case Reports ◽

Rapid Onset ◽

High Dose ◽

Drug Induced ◽

Membrane Oxygenation ◽

Hypoxic Respiratory Failure ◽

Venovenous Extracorporeal Membrane Oxygenation ◽

Vv Ecmo

Bleomycin treats malignancies, such as germ cell tumours and Hodgkin lymphoma. While efficacious, it can cause severe drug-induced lung injury. We present a 42-year-old patient with stage IIB seminoma treated with radical orchiectomy followed by adjuvant chemotherapy with bleomycin, etoposide and cisplatin. His postbleomycin course was complicated by the rapid onset of hypoxic respiratory failure, progressing to acute respiratory distress syndrome and requiring venovenous extracorporeal membrane oxygenation (VV-ECMO) support. Although the patient was treated with high dose systemic steroids and ultra-protective ventilator strategies to minimise ventilator-induced lung injury while on VV-ECMO, his lung injury failed to improve. Care was withdrawn 29 days later. Lung autopsy revealed diffuse organising pneumonia. We found six case reports (including this one) of bleomycin-induced lung injury requiring VV-ECMO with a cumulative survival of 33% (2/6). While VV-ECMO may be used to bridge patients to recovery or lung transplant, the mortality is high.

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Dynamic Debonding Force Measurements of Ligand (RGD)-Platelet Receptor (GP Ilb/IIIa) System under Physiological Conditions

Microscopy and Microanalysis ◽

10.1017/s1431927600037363 ◽

2000 ◽

Vol 6 (S2) ◽

pp. 974-975

Author(s):

ImShik Lee ◽

Roger E. Marchant

Keyword(s):

Thrombus Formation ◽

Peptide Sequence ◽

Chain Extension ◽

Force Measurements ◽

Platelet Surface ◽

Force Microscopy ◽

Atomic Force ◽

Direct Measurements ◽

Platelet Receptor ◽

Physical Absorption

ABSTRACTBinding formation between a peptide sequence (GSSSGRGDSPA) which contains the cell adhesion sequence –RGD-found in fibrinogen, vWF, fibrinonectin, and vitronectin and human platelet intergrin GP Ilb/IIIa plays an important role in thrombus formation. Using atomic force microscopy (AFM), we visualized the detailed structures of membrane and submembrane of the cell, and measured the interaction forces between a peptide modified cantilever probe tip and platelet surface from pN to nN levels under physiological buffer. Direct measurements of the debonding force for the RGD ligand - GP Ilb/IIIa system are presented. To eliminate the possible measurement of the hgand-receptor pair, or of the ligand and AFM tip, following desorption of the ligand; the cantilever tip surface was modified with covalent coupling chemistry rather than physical absorption. Our results showed that the single molecular rupturing force was 93.3 ± 10.41 pN with considerable chain extension in the receptor. The rupturing forces showed a logarithmic dependence of the rate of loading

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Short- and Midterm Adherence to Platelet P2Y12 Receptor Inhibitors After Percutaneous Coronary Intervention With Drug-Eluting Stents

Journal of Cardiovascular Pharmacology and Therapeutics ◽

10.1177/1074248420926667 ◽

2020 ◽

Vol 25 (5) ◽

pp. 466-471

Author(s):

Fernando Morita ◽

Mauricio Wajngarten ◽

Marcelo Katz ◽

Miguel Morita Fernandes-Silva ◽

Adriano Caixeta ◽

...

Keyword(s):

Cardiovascular Disease ◽

Percutaneous Coronary Intervention ◽

Antiplatelet Agents ◽

Coronary Intervention ◽

P2y12 Receptor ◽

Drug Eluting Stent ◽

P2y12 Inhibitors ◽

Platelet Receptor ◽

Percutaneous Coronary ◽

Drug Eluting

Introduction/Objectives: In patients who have undergone recent percutaneous coronary intervention (PCI), poor adhesion to antiplatelet agents may increase the risk of stent thrombosis and death. We aimed to investigate the adherence to different P2Y12 receptor inhibitors after PCI with drug-eluting stent in stable and unstable patients and to evaluate the factors associated with low adherence. Method: In a prospective study conducted between 2014 and 2018, the 8-item Morisky scale was applied at 30 days and 6 months post-PCI to measure P2Y12 receptor inhibitors adherence. Also, we describe the characteristics of patients using different platelet receptor P2Y12 inhibitors. Regression models were used to identify predictors of poor adherence. Results: A total of 214 patients were included (65 ± 12 years, 81% man, 61% acute coronary syndromes). Patients in the clopidogrel group were older than those in the prasugrel (68 ± 12 vs 59 ± 11 years, P < .01, respectively) or ticagrelor group (68 ± 12 vs 62 ± 12 years, P < .01). Patients with low/moderate adherence at 30 days and 6 months represented, respectively, 19.8% and 27.5% of our sample. Current smokers and preexisting cardiovascular disease at presentation were associated with lower adherence at 30 days. Conclusions: We found substantial rates of moderate and low adherence to P2Y12 receptor inhibitors early after PCI. Current smokers and preexisting cardiovascular disease at presentation were associated with a lower likelihood of adherence. These results highlight the need of monitoring adherence to medical treatment after PCI.

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Antibodies causing thrombocytopenia in patients treated with RGD-mimetic platelet inhibitors recognize ligand-specific conformers of αIIb/β3 integrin

Blood ◽

10.1182/blood-2012-01-406322 ◽

2012 ◽

Vol 119 (26) ◽

pp. 6317-6325 ◽

Cited By ~ 27

Author(s):

Daniel W. Bougie ◽

Mark Rasmussen ◽

Jieqing Zhu ◽

Richard H. Aster

Keyword(s):

Binding Sites ◽

Structural Changes ◽

Recognition Site ◽

Platelet Inhibitors ◽

Head Region ◽

Drug Induced ◽

Naturally Occurring ◽

Β3 Integrin ◽

Effect Of Treatment ◽

Arginine Glycine Aspartic Acid

Arginine-glycine-aspartic acid (RGD)–mimetic platelet inhibitors act by occupying the RGD recognition site of αIIb/β3 integrin (GPIIb/IIIa), thereby preventing the activated integrin from reacting with fibrinogen. Thrombocytopenia is a well-known side effect of treatment with this class of drugs and is caused by Abs, often naturally occurring, that recognize αIIb/β3 in a complex with the drug being administered. RGD peptide and RGD-mimetic drugs are known to induce epitopes (ligand-induced binding sites [LIBS]) in αIIb/β3 that are recognized by certain mAbs. It has been speculated, but not shown experimentally, that Abs from patients who develop thrombocytopenia when treated with an RGD-mimetic inhibitor similarly recognize LIBS determinants. We addressed this question by comparing the reactions of patient Abs and LIBS-specific mAbs against αIIb/β3 in a complex with RGD and RGD-mimetic drugs, and by examining the ability of selected non-LIBS mAbs to block binding of patient Abs to the liganded integrin. Findings made provide evidence that the patient Abs recognize subtle, drug-induced structural changes in the integrin head region that are clustered about the RGD recognition site. The target epitopes differ from classic LIBS determinants, however, both in their location and by virtue of being largely drug-specific.

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