Evidence that thrombocytopenia observed in humans treated with orally bioavailable glycoprotein IIb/IIIa antagonists is immune mediated

Blood ◽  
2002 ◽  
Vol 99 (10) ◽  
pp. 3540-3546 ◽  
Author(s):  
Jeffrey T. Billheimer ◽  
Ira B. Dicker ◽  
Richard Wynn ◽  
Jodi D. Bradley ◽  
Debra A. Cromley ◽  
...  
Keyword(s):  
Chemical Structure ◽  
Blood Donors ◽  
Solid Phase ◽  
Enzyme Linked Immunosorbent Assay ◽  
Drug Induced ◽  
Immune Mediated ◽  
Antagonist Binding ◽  
Orally Bioavailable ◽  
Drug Dependent ◽  
High Level

Glycoprotein (GP) IIb/IIIa antagonists are effective therapeutic agents, but elicit thrombocytopenia with a frequency that approaches 2%. Here, we provide evidence that thrombocytopenia in humans treated with the GP IIb/IIIa antagonist roxifiban is immune mediated. Two patients underwent conversion to a highly positive drug-dependent antibody (DDAB) status temporally associated with thrombocytopenia. Despite the continued presence of DDABs, the fall in platelet count was reversed by discontinuation of drug treatment, pointing to the exquisite drug dependency of the immune response. DDABs appear to bind to neoepitopes in GP IIb/IIIa elicited on antagonist binding. This information was used to develop an enzyme-linked immunosorbent assay (ELISA) for DDAB using solid-phase GP IIb/IIIa. A high level of specificity is indicated by the observation that DDAB binding is dependent on the chemical structure of the GP IIb/IIIa antagonist and that only 2% to 5% of human blood donors and 5% of chimpanzees present with pre-existing DDABs. Furthermore, none of 108 nonthrombocytopenic patients from the phase II roxifiban study showed an increase in antibody titer. Absorption of thrombocytopenia plasma with platelets reduced the DDAB ELISA signal, indicating that the test detects physiologically relevant antibodies. Screening patients for pre-existing or increasing DDAB titer during treatment with GP IIb/IIIa antagonists may reduce the incidence of drug-induced thrombocytopenia.

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.

scholarly journals Acute Immune-Mediated Thrombocytopenia due to Oxaliplatin and Irinotecan Therapy

2019 ◽  
Vol 2019 ◽  
pp. 1-5 ◽  
Author(s):  
Eric L. Tam ◽  
Padma L. Draksharam ◽  
Jennifer A. Park ◽  
Gurinder S. Sidhu
Keyword(s):  
Colon Cancer ◽  
Flow Cytometry ◽  
Severe Thrombocytopenia ◽  
Flow Cytometry Assay ◽  
Drug Induced ◽  
Advanced Colon Cancer ◽  
Platelet Antibodies ◽  
Immune Mediated ◽  
Drug Dependent ◽  
Underlying Mechanisms

We describe a case of a 63-year-old woman with advanced colon cancer and liver metastases who was treated with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and cetuximab chemotherapy. She tolerated 13 cycles of chemotherapy without any significant hematological side effects, but after the 14th cycle, she developed melena and was admitted for severe thrombocytopenia. After supportive care, the platelet counts rapidly improved to 76,000/μL. Upon initiation of FOLFIRI and cetuximab chemotherapy, she again developed rectal bleeding and severe thrombocytopenia with a platelet count of 6000/μL. Lab testing was positive for oxaliplatin and irinotecan drug-dependent platelet antibodies on flow cytometry assay. Drug-induced thrombocytopenia (DITP) is associated with several classes of drugs with several proposed underlying mechanisms. Prospective studies are needed to further address different mechanisms of drug-induced thrombocytopenia.

Rifampicin-dependent antibodies bind a similar or identical epitope to glycoprotein IX–specific quinine-dependent antibodies

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 1988-1992 ◽  
Author(s):  
Janette K. Burgess ◽  
Jose A. Lopez ◽  
Leonie E. Gaudry ◽  
Beng H. Chong
Keyword(s):  
Flow Cytometric Analysis ◽  
Antibody Binding ◽  
Enzyme Linked Immunosorbent Assay ◽  
Drug Induced ◽  
Complementary Dna ◽  
Glycoprotein Complex ◽  
Flow Cytometric ◽  
Antibody Binding Site ◽  
Close Proximity ◽  
Drug Dependent

Abstract The drug-dependent antibody of a patient with rifampicin-induced thrombocytopenia was characterized using the antigen-capture enzyme-linked immunosorbent assay (MAIPA assay), flow cytometry, and immunoprecipitation. The antibody was found to bind glycoprotein (GP) Ib-IX but not GPIIb-IIIa because (1) it immunoprecipitated drug-dependently the former but not the latter glycoprotein complex and (2) the MAIPA assay showed strong rifampicin-dependent antibody binding when anti-GPIb-IX monoclonal antibodies (mAbs) (AK2 and FMC25) but not anti-GPIIb-IIIa mAbs (AP2, SZ21, and SZ22) were used to capture the antigen. The antibody binding site was further localized to the GPIX subunit of the GPIb-IX complex because flow cytometric analysis revealed drug-dependent antibody binding to L cells transfected with human GPIbβ and GPIX complementary DNA (L βIX cells) but not with human GPIb and GPIbβ complementary DNA (L β cells). Finally, in the MAIPA assay, the rifampicin-dependent antibody almost completely cross-blocked the binding of the anti-GPIX mAb (SZ1) to platelets. Similar cross-blocking of SZ1binding to platelets by the quinine-dependent antibodies was also observed. This finding not only confirms that the epitope of the rifampicin-dependent antibody is on GPIX but it is also identical to or located in close proximity to that of the quinine-dependent antibody and SZ1. Further characterization of the epitopes of these antibodies may have important implications for a general understanding of the mechanism of drug-induced thrombocytopenia.

Tamoxifen-Induced Immune-Mediated Platelet Destruction. A Case Report

1993 ◽  
Vol 79 (3) ◽  
pp. 231-234 ◽  
Author(s):  
Alfonso Candido ◽  
Stefano Bussa ◽  
Raffaele Tartaglione ◽  
Rosalba Mancini ◽  
Carlo Rumi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Severe Thrombocytopenia ◽  
Platelet Destruction ◽  
Drug Induced ◽  
New Era ◽  
Elderly Female ◽  
Immune Mediated ◽  
Drug Dependent ◽  
Reliable Methods

Drug-induced immunologic thrombocytopenia, a fairly common disorder, is characterized by drug-dependent antiplatelet antibodies that destroy circulating platelets in the presence of the provoking drug or its metabolites. The development of reliable methods for the detection of platelet-bound immunoglobulins causing in vivo platelet destruction, such as the use of monoclonal antibodies tagged with fluorescein and flow cytofluorimetric analysis, has ushered in a new era to differentiate between immune and non-immune thrombocytopenias. A severe thrombocytopenia developed in an elderly female patient treated with tamoxifen, a non-steroidal antiestrogen drug, after surgery for breast cancer. A tamoxifen-dependent platelet antibody was detected in the patient's serum and linked on the platelet membranes. This antibody reacted only in the presence of the offending drug and showed platelet specificity. Withdrawal of drug restored platelet count to normal levels.

Immune-Mediated Thrombocytopenia in Patients Treated with Vancomycin.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1238-1238
Author(s):  
Annette von Drygalski ◽  
Brian Curtis ◽  
Dan Bougie ◽  
Scott Ahl ◽  
Kelty Baker ◽  
...  
Keyword(s):  
Solid Phase ◽  
Case Reports ◽  
Fatal Outcome ◽  
Normal Subjects ◽  
Soluble Form ◽  
Flow Cytometric ◽  
Immune Mediated ◽  
Normal Individuals ◽  
Life Threatening ◽  
Drug Dependent

Abstract Numerous drugs are known to cause immune thrombocytopenia (TP) mediated by antibodies (abs) that bind to platelets only when the sensitizing drug is present in soluble form. The widely used antibiotic, vancomycin, has been implicated as a cause of TP only in 8 case reports and little is known about antibodies possibly responsible for this complication. We characterized clinical and serologic aspects of TP occurring in 39 patients during treatment with vancomycin. In this group, TP developed after 1–27 days of treatment (median 6 days) and plt nadirs ranged from 1,000 to 60,000 plts/uL (median 14,000 plts/uL). Bleeding occurred in 14 patients and contributed to a fatal outcome in 3. TP persisted for 1–17 days after discontinuing vancomycin (median 7 days). Platelets eventually returned to baseline in all surviving patients. Serum obtained after the onset of TP was studied for vancomycin-dependent, platelet-reactive abs by flow cytometry and by solid phase ELISA using immobilized plt glycoproteins (GP) as targets. Vancomycin-dependent antibodies detected in patients and normal subjects IgG only IgM only IgG + IgM No antibody Total Patients with TP 21 (54%) 5 (13%) 13 (33%) (0)%) 39 Normal individuals 58 (21%) 4 (1%) 1 (0%) 210 (77%) 273 Results of flow cytometric studies are summarized above. All patients had IgG and/or IgM abs that reacted with normal plts in the presence, but not in the absence of vancomycin. The IgG mean fluorescence intensity (MFI) signal in the presence of drug was 1.6 to 32.0 times stronger (mean ratio 5.7) than that obtained in the absence of drug. Vancomycin-dependent IgG abs were also identified in 59 of 273 normal individuals but were much weaker than abs detected in patients (p = 0.004). IgM abs (mean ratio 5.7, range 1.6 – 34) were found in 18 of 39 patients (46%). Weaker IgM abs were found in only 5 of 273 normal subjects (1.8%) (p = 0.001). Two patient abs studied in ELISA reacted preferentially with GPIIb/IIIa. Studies to determine the frequency of abs in patients given vancomycin who do not develop TP are in progress. These findings provide evidence that TP in patients given vancomycin can be caused by drug-dependent abs specific for GPIIb/IIIa that are stimulated by vancomycin exposure. IgG and IgM abs in patients with TP are generally much stronger than drug-dependent, platelet-reactive immunoglobulins found in some normal subjects. The significance of the latter abs is presently unknown. Drug-dependent IgM abs are found almost exclusively in patients with vancomycin-associated TP and may be diagnostic. Patients treated with vancomycin often have life-threatening bacterial sepsis and may have various reasons for developing TP. Serologic testing for drug-dependent, platelet-reactive IgG and IgM abs may provide a means of identifying those in whom vancomycin should be discontinued.

scholarly journals Drug-dependent and non-drug-dependent antiplatelet antibody in drug- induced immunologic thrombocytopenic purpura

Blood ◽  
1985 ◽  
Vol 66 (2) ◽  
pp. 306-311 ◽  
Author(s):  
W Lerner ◽  
R Caruso ◽  
D Faig ◽  
S Karpatkin
Keyword(s):  
Solid Phase ◽  
Protein A ◽  
Staphylococcal Protein A ◽  
Antiplatelet Antibody ◽  
Drug Induced ◽  
Thrombocytopenic Purpura ◽  
Autoimmune Thrombocytopenic Purpura ◽  
History Of ◽  
Solid Phase Radioimmunoassay ◽  
Drug Dependent

Abstract The mechanism of drug-dependent immunologic thrombocytopenic purpura (DITP) was investigated by studying the sera of four patients with classic DITP (two with quinidine-, one with acetaminophen-, and one with phenazopyridine-dependent antiplatelet antibody) using a solid- phase radioimmunoassay with 125I-staphylococcal protein A. Two forms of antiplatelet antibody could be demonstrated: one that required drug to bind to platelets and one that bound to platelets in the absence of drug. Drug-dependent antiplatelet antibody required the simultaneous addition of drug and the Fc domain of the drug-dependent IgG molecule for binding to platelets. It did not require serum complement or factor VIII-related antigen for binding to platelets. Drug-dependent binding of antibody to platelets was saturation-dependent. Non-drug-dependent antiplatelet antibody of two patients (one with quinidine-induced thrombocytopenia and the other with acetaminophen-induced thrombocytopenia) reacted with autologous platelets as well as with homologous platelets, indicating that they were autoantibodies. Both autoantibodies had disappeared when their sera were tested 23 and 138 days, respectively, after withdrawal of their initial positive sera. Non-drug-dependent antiplatelet antibody binding could be demonstrated with the F(ab')2 fragment of the purified IgG of the serum of the second patient with quinidine DITP, who did not have detectable alloantibodies against HLA. None of the four patients with non-drug- dependent antiplatelet antibody had a past or present history of autoimmune thrombocytopenic purpura.

Levofloxacin-Induced Acute Immune-Mediated Thrombocytopenia of Rapid-Onset

2017 ◽  
Vol 31 (2) ◽  
pp. 234-237 ◽  
Author(s):  
Andrew W. Shih ◽  
Andy S. Lam ◽  
Theodore E. Warkentin
Keyword(s):  
Platelet Count ◽  
Drug Exposure ◽  
Rapid Onset ◽  
Chronic Obstructive ◽  
Drug Induced ◽  
Obstructive Pulmonary Disease ◽  
Immune Mediated ◽  
Drug Dependent ◽  
Low Sensitivity ◽  
Count Recovery

Drug-induced immune thrombocytopenia (D-ITP) typically occurs after the patient has been receiving the implicated drug for at least 1 week, due to newly forming drug-dependent antibodies (“typical-onset” D-ITP). A “rapid-onset” form of D-ITP can occur when previous sensitization has occurred, where antibodies have thus already been formed, and a precipitous platelet count fall occurs upon reexposure. Typical-onset D-ITP has been reported after levofloxacin, but the rapid-onset form with a well-documented previous exposure has not been described. We report a 76-year-old male treated with levofloxacin for acute exacerbation of chronic obstructive pulmonary disease. After a single 750 mg oral dose of levofloxacin, his platelet count fell from 187 to 5 × 109/L (nadir) over 4 days. Other causes of thrombocytopenia were ruled out. He had received a previous course of levofloxacin 6 months earlier. Discontinuation of levofloxacin and treatment with intravenous immunoglobulin and dexamethasone resulted in platelet count recovery. Levofloxacin-dependent antibodies were not detectable, consistent with the known low sensitivity of laboratory tests for drug-dependent antibodies, presumably indicating antibodies against levofloxacin metabolites, as is indirectly supported by the abrupt but relatively slow platelet count decline observed. This case illustrates a rapid-onset presentation of levofloxacin-induced D-ITP in the setting of previous drug exposure.

scholarly journals Drug-dependent and non-drug-dependent antiplatelet antibody in drug- induced immunologic thrombocytopenic purpura

Blood ◽  
1985 ◽  
Vol 66 (2) ◽  
pp. 306-311
Author(s):  
W Lerner ◽  
R Caruso ◽  
D Faig ◽  
S Karpatkin
Keyword(s):  
Solid Phase ◽  
Protein A ◽  
Staphylococcal Protein A ◽  
Antiplatelet Antibody ◽  
Drug Induced ◽  
Thrombocytopenic Purpura ◽  
Autoimmune Thrombocytopenic Purpura ◽  
History Of ◽  
Solid Phase Radioimmunoassay ◽  
Drug Dependent

The mechanism of drug-dependent immunologic thrombocytopenic purpura (DITP) was investigated by studying the sera of four patients with classic DITP (two with quinidine-, one with acetaminophen-, and one with phenazopyridine-dependent antiplatelet antibody) using a solid- phase radioimmunoassay with 125I-staphylococcal protein A. Two forms of antiplatelet antibody could be demonstrated: one that required drug to bind to platelets and one that bound to platelets in the absence of drug. Drug-dependent antiplatelet antibody required the simultaneous addition of drug and the Fc domain of the drug-dependent IgG molecule for binding to platelets. It did not require serum complement or factor VIII-related antigen for binding to platelets. Drug-dependent binding of antibody to platelets was saturation-dependent. Non-drug-dependent antiplatelet antibody of two patients (one with quinidine-induced thrombocytopenia and the other with acetaminophen-induced thrombocytopenia) reacted with autologous platelets as well as with homologous platelets, indicating that they were autoantibodies. Both autoantibodies had disappeared when their sera were tested 23 and 138 days, respectively, after withdrawal of their initial positive sera. Non-drug-dependent antiplatelet antibody binding could be demonstrated with the F(ab')2 fragment of the purified IgG of the serum of the second patient with quinidine DITP, who did not have detectable alloantibodies against HLA. None of the four patients with non-drug- dependent antiplatelet antibody had a past or present history of autoimmune thrombocytopenic purpura.

The Interaction of β2 Glycoprotein-I and Heparin and Its Effect on β2 Glycoprotein-I Antiphospholipid Antibody Cofactor Function in Plasma

1994 ◽  
Vol 72 (04) ◽  
pp. 578-581 ◽  
Author(s):  
T McNally ◽  
S E Cotterell ◽  
I J Mackie ◽  
D A Isenberg ◽  
S J Machin
Keyword(s):  
Solid Phase ◽  
Pharmaceutical Preparations ◽  
Enzyme Linked Immunosorbent Assay ◽  
Antiphospholipid Antibody ◽  
Biological Functions ◽  
Dermatan Sulphate ◽  
Glycoprotein I ◽  
Crossed Immunoelectrophoresis ◽  
Calcium Heparin ◽  
Cofactor Activity

Summaryβ2 glycoprotein-I (β2GPI), a cofactor for antiphospholipid antibody (aPA) binding, binds to many anionic macromolecules including heparin. The nature of this interaction with heparin is not well understood and its effect on the purported biological functions of β2GPI is unknown.We have examined the interactions of dermatan sulphate (DS) and different pharmaceutical preparations of heparin with β2GPI by crossed immunoelectrophoresis (CIE) and investigated the effect of these agents on plasma levels of p2GPI antigen (β2GPI: Ag) by a standardised enzyme linked immunosorbent assay (ELISA). P2GPI aPA cofactor activity (β2GPI:Cof) was also measured using a modified solid phase an-ti-phosphatidylserine (aPS) ELISA. CIE results confirmed a heparin-β2GPI interaction with unfractionated (UF) heparin. β2GPI:Ag levels were unaffected by any of the preparations investigated. There were no significant differences in β2GPI:Cof activities of the samples containing LMW heparins or DS but levels of β2GPI:Cof were increased in samples containing UF sodium and calcium heparin preparations (0.5 IU/ml Monoparin, p <0.05, and 10 IU/ml Liquemin and Calcipa-rine, p <0.05).

An Enzyme Immunoassay (ELISA) for the Quantitation of Human Factor VII

1986 ◽  
Vol 56 (03) ◽  
pp. 250-255 ◽  
Author(s):  
C Boyer ◽  
M Wolf ◽  
C Rothschild ◽  
M Migaud ◽  
J Amiral ◽  
...  
Keyword(s):  
Human Factor ◽  
Solid Phase ◽  
Factor Vii ◽  
Enzyme Linked Immunosorbent Assay ◽  
Poor Correlation ◽  
Vein Thrombosis ◽  
Coagulant Activity ◽  
Significant Difference ◽  
Large Populations ◽  
Deep Vein

SummaryA new solid phase enzyme-linked immunosorbent assay (ELISA) was developed for the quantitation of human Factor VII antigen (F VII Ag), using a monospecific rabbit anti-F VII antiserum. Anti-F VII F(ab′)2 fragments were adsorbed to polystyrene plates. The binding of serial dilutions of control or test plasma, containing F VII, was detected by incubation with peroxidase-labeled anti- FV II IgG followed by the addition of hydrogen peroxyde and O-phenylenediamine. This ELISA is specific, sensitive (detection limit: 0.05%) and accurate (coefficient of variation: 1.5-4% for within- and 1.6-9% for between-assays). F VII coagulant activity (F VII C) and F VII Ag were determined in large populations of controls and patients. In normal plasma (n = 38), F VII Ag ranged from 83 to 117% and the correlation coefficient between F VII Ag and F VII C was 0.94. In patients with severe (F VII C inf. 1%) congenital F VII deficiency (n = 5), F VII Ag was undetectable in two cases (inf. 0.05%) and markedly reduced (0.35 to 5.6%) in the three other cases. In patients with liver cirrhosis (n = 15), F VII Ag ranged from 21 to 59% and was in good correlation with F VII C (r = 0.84). In dicoumarol treated patients (n = 15), the levels of F VII Ag ranged from 51% to 79% and a poor correlation (r = 0.52) with F VIIC was observed. In “compensated” DIC (n = 5), levels of F VII Ag varied from 60 to 186%, with significantly higher F VII C levels (from 143 to 189%). In contrast, in “decompensated” DIC (n = 7), low F VII Ag and F VII C levels were observed (from 7 to 27%). In patients with deep-vein thrombosis (n = 25), high levels of F VII Ag (from 102 to 136%) and F VII C (from 110 to 150%) were demonstrated. In surgical patients, no significant difference was observed before and one day after intervention.

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