scholarly journals An Antibody From a Patient With Ranitidine-Induced Thrombocytopenia Recognizes a Site on Glycoprotein IX That Is a Favored Target for Drug-Induced Antibodies

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2359-2365 ◽  
Author(s):  
G. Gentilini ◽  
B.R. Curtis ◽  
R.H. Aster
Keyword(s):  
Tight Binding ◽  
Chinese Hamster ◽  
Severe Thrombocytopenia ◽  
H2 Receptor Antagonist ◽  
Drug Induced ◽  
Histamine H2 Receptor ◽  
H2 Receptor ◽  
Drug Dependent ◽  
A Site ◽  
Common Target

Abstract Although thrombocytopenia associated with the use of histamine H2 receptor (H2R) antagonists has been described, a drug-dependent, platelet-reactive antibody has not previously been identified in such cases. We studied serum from a patient who developed acute, severe thrombocytopenia after exposure to the H2 receptor antagonist, ranitidine, and identified an antibody that reacted with normal platelets in the presence of this drug at pharmacologic concentrations. In flow cytometric and immunoprecipitation studies, the antibody was shown to be specific for the glycoprotein Ib/IX complex (GPIb/IX). From the pattern of monoclonal antibody (MoAb) inhibition and the reactions of antibody with Chinese hamster ovary (CHO) cells transfected with GPIX and GPIbβ, we found that the patient's antibody is specific for an epitope on GPIX close to, or identical with a site recognized by the MoAb SZ1 that is a common target for antibodies induced by quinine and quinidine, drugs structurally unrelated to ranitidine. These findings provide evidence that immune thrombocytopenia can be caused by sensitivity to an H2 R antagonist and suggest that the SZ1 binding site on GPIX may be a common target for drug-induced antibodies. Further studies of the epitope for which SZ1 is specific may provide clues to the mechanism(s) by which drugs promote tight binding of antibody to a membrane glycoprotein and cause platelet destruction in patients with drug sensitivity.

scholarly journals An Antibody From a Patient With Ranitidine-Induced Thrombocytopenia Recognizes a Site on Glycoprotein IX That Is a Favored Target for Drug-Induced Antibodies

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2359-2365 ◽  
Author(s):  
G. Gentilini ◽  
B.R. Curtis ◽  
R.H. Aster
Keyword(s):  
Tight Binding ◽  
Chinese Hamster ◽  
Severe Thrombocytopenia ◽  
H2 Receptor Antagonist ◽  
Drug Induced ◽  
Histamine H2 Receptor ◽  
H2 Receptor ◽  
Drug Dependent ◽  
A Site ◽  
Common Target

Although thrombocytopenia associated with the use of histamine H2 receptor (H2R) antagonists has been described, a drug-dependent, platelet-reactive antibody has not previously been identified in such cases. We studied serum from a patient who developed acute, severe thrombocytopenia after exposure to the H2 receptor antagonist, ranitidine, and identified an antibody that reacted with normal platelets in the presence of this drug at pharmacologic concentrations. In flow cytometric and immunoprecipitation studies, the antibody was shown to be specific for the glycoprotein Ib/IX complex (GPIb/IX). From the pattern of monoclonal antibody (MoAb) inhibition and the reactions of antibody with Chinese hamster ovary (CHO) cells transfected with GPIX and GPIbβ, we found that the patient's antibody is specific for an epitope on GPIX close to, or identical with a site recognized by the MoAb SZ1 that is a common target for antibodies induced by quinine and quinidine, drugs structurally unrelated to ranitidine. These findings provide evidence that immune thrombocytopenia can be caused by sensitivity to an H2 R antagonist and suggest that the SZ1 binding site on GPIX may be a common target for drug-induced antibodies. Further studies of the epitope for which SZ1 is specific may provide clues to the mechanism(s) by which drugs promote tight binding of antibody to a membrane glycoprotein and cause platelet destruction in patients with drug sensitivity.

A site involving the “hybrid” and PSI homology domains of GPIIIa (β3-integrin subunit) is a common target for antibodies associated with quinine-induced immune thrombocytopenia

Blood ◽  
2003 ◽  
Vol 101 (3) ◽  
pp. 937-942 ◽  
Author(s):  
Julie A. Peterson ◽  
Contessa E. Nyree ◽  
Peter J. Newman ◽  
Richard H. Aster
Keyword(s):  
Disulfide Bonds ◽  
Tight Binding ◽  
Integrin Subunit ◽  
Target Epitope ◽  
Glycoprotein Iiia ◽  
Β3 Integrin ◽  
Drug Dependent ◽  
A Site ◽  
Common Target ◽  
Homology Domains

Abstract Drug-dependent antibodies (DDAbs) can cause the precipitous destruction of platelets if a patient is exposed to the drug for which the antibodies are specific. The molecular character of the epitopes recognized is poorly understood, and the mechanism by which drugs promote tight binding of these antibodies to platelet glycoproteins without linking covalently to protein or antibody is not yet known. We studied a group of quinine-dependent antibodies that react with human glycoprotein IIIa (GPIIIa; β3-integrin subunit) but fail to recognize rat GPIIIa, despite close homology between the 2 proteins. By characterizing reactions of these antibodies with human/rat GPIIIa chimeras and selected GPIIIa mutants, we found that each of 3 quinine-dependent antibodies requires a 17-amino acid sequence in the newly recognized “hybrid” and PSI homology domains of GPIIIa for drug-dependent binding. Disulfide bonds are required to stabilize the target epitope. Monoclonal antibody AP3, which blocks the binding of these DDAbs to GPIIIa, was found to require a more limited stretch of the same peptide for its reaction with the glycoprotein. The findings suggest this region of GPIIIa may be a favored target for quinine-dependent antibodies and may provide a basis for further studies to elucidate the molecular basis of glycoprotein–drug–antibody interaction.

scholarly journals Interaction between the two signal transduction systems of the histamine H2 receptor: desensitizing and sensitizing effects of histamine stimulation on histamine-dependent cAMP production in Chinese hamster ovary cells

1996 ◽  
Vol 320 (1) ◽  
pp. 27-32 ◽  
Author(s):  
Yasushi FUKUSHIMA ◽  
Tomoichiro ASANO ◽  
Hideki KATAGIRI ◽  
Makoto AIHARA ◽  
Toshihito SAITOH ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Chinese Hamster Ovary ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Camp Production ◽  
Histamine H2 Receptor ◽  
H2 Receptor ◽  
H2 Receptors ◽  
Sensitizing Effect ◽  
Pkc Activation

The histamine H2 receptor is a member of the family of G-protein-coupled receptors and is linked to the activation of adenylate cyclase phospholipase C (PLC). In this study we examined the effects of protein kinase C (PKC) activation in Chinese hamster ovary (CHO) cells stably expressing canine histamine H2 receptors. Pretreatment with 100 nM phorbol 12-myristate 13-acetate at 37 °C for 15 min led to significant potentiation of histamine-dependent and forskolin-dependent cAMP production, whereas the biologically inactive phorbol ester, 4α-phorbol 12,13-didecanoate, was without effect. These potentiating effects were abolished by preincubation with 0.5 µM bisindolylmaleimide, a PKC inhibitor. Thus the activation of PKCs seems to be involved in the potentiation of cAMP production by acting on a post-receptor mechanism. Preincubation of a CHO cell line, CHO-H2R, with 10 µM histamine for 30 min had two effects. Maximal histamine-dependent cAMP production and forskolin-dependent cAMP production were potentiated by 36% and 105.2% respectively. The other effect was a desensitization of the histamine-dependent adenylate cyclase response as demonstrated by a three-fold increase in EC50. Administration of 0.5 µM bisindolylmaleimide before preincubation of CHO-H2R with 10 µM histamine did not alter the desensitizing effect on cAMP production, but did abolish the sensitizing effect. Preincubation of CHO-H2R cells with 10 nM histamine resulted in moderate potentiation, which was also abolished by bisindolylmaleimide, but not in desensitization of the histamine-dependent cAMP production. Thus these results suggest that preincubation with histamine had a sensitizing effect on cAMP production mediated by PLC and PKC activation, as well as a desensitizing effect on the H2 receptor. The former effect is dependent on the intensity of PLC and PKC signals delivered by H2 receptors. The latter effect requires a higher concentration of histamine.

The metabolism in animals and man of oxmetidine—A new histamine H2-receptor antagonist

Xenobiotica ◽  
1984 ◽  
Vol 14 (7) ◽  
pp. 509-514 ◽  
Author(s):  
P. J. Cox ◽  
W. M. H. Heijbroek ◽  
D. C. Taylor ◽  
P. J. Wood ◽  
P. R. Cresswell ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
H2 Receptor Antagonist ◽  
Histamine H2 Receptor ◽  
H2 Receptor ◽  
Histamine H2 Receptor Antagonist

scholarly journals Drug-induced thrombocytopenia: pathogenesis, evaluation, and management

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 153-158 ◽  
Author(s):  
James N. George ◽  
Richard H. Aster
Keyword(s):  
Single Dose ◽  
Causal Relation ◽  
Severe Thrombocytopenia ◽  
Antithrombotic Agents ◽  
Drug Induced ◽  
Level Of Evidence ◽  
Common Cause ◽  
Fibrinogen Binding ◽  
Immune Mediated ◽  
Drug Dependent

AbstractAlthough drugs are a common cause of acute immune-mediated thrombocytopenia in adults, the drug etiology is often initially unrecognized. Most cases of drug-induced thrombocytopenia (DITP) are caused by drug-dependent antibodies that are specific for the drug structure and bind tightly to platelets by their Fab regions but only in the presence of the drug. A comprehensive database of 1301 published reports describing 317 drugs, available at www.ouhsc.edu/platelets, provides information on the level of evidence for a causal relation to thrombocytopenia. Typically, DITP occurs 1 to 2 weeks after beginning a new drug or suddenly after a single dose when a drug has previously been taken intermittently. However, severe thrombocytopenia can occur immediately after the first administration of antithrombotic agents that block fibrinogen binding to platelet GP IIb-IIIa, such as abciximab, tirofiban, and eptifibatide. Recovery from DITP usually begins within 1 to 2 days of stopping the drug and is typically complete within a week. Drug-dependent antibodies can persist for many years; therefore, it is important that the drug etiology be confirmed and the drug be avoided thereafter.

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