Acute Thrombocytopenia in Patients Treated with the Oral Glycoprotein IIb/IIIa Inhibitors Xemilofiban and Orbofiban: Evidence for an Immune Etiology

2002 ◽  
Vol 88 (12) ◽  
pp. 892-897 ◽  
Author(s):  
Jacqueline Brassard ◽  
Brian Curtis ◽  
Richard Cooper ◽  
John Ferguson ◽  
Wendy Komocsar ◽  
...  
Keyword(s):  
At Risk ◽  
Drug Exposure ◽  
Clinical Findings ◽  
Severe Thrombocytopenia ◽  
Serum Samples ◽  
Review Panel ◽  
Patients At Risk ◽  
Drug Dependent

SummaryThrombocytopenic episodes occurring in 18,845 patients treated with the GPIIb/IIIa inhibitors xemilofiban and orbofiban (“fibans”) were analyzed by a blinded review panel and 73 patients were classified as having “possible fiban-induced thrombocytopenia”. When the treatment codes were broken, a significant association between drug exposure and assignment to this group was found (p <0.001). Twenty-eight (82%) of 34 archived serum samples from these patients contained fiban-dependent antibodies specific for GPIIb/IIIa, but no such antibodies were found in 61 drug treated patients not classified as having “possible fiban-induced thrombocytopenia” (p <0.001). We conclude that fiban-dependent antibodies were the major cause of acute, severe thrombocytopenia in patients judged on the basis of clinical findings to have thrombocytopenia “possibly-induced” by xemilofiban and orbofiban. Measurement of drug-dependent antibodies may be helpful in determining the basis for acute thrombocytopenia in fiban-treated patients and possibly for identification of patients at risk to develop thrombocytopenia.

Drug-Induced Thrombocytopenia

2009 ◽  
Vol 133 (2) ◽  
pp. 309-314
Author(s):  
Barton Kenney ◽  
Gary Stack
Keyword(s):  
At Risk ◽  
19Th Century ◽  
Clinical Management ◽  
Drug Induced ◽  
Medication Withdrawal ◽  
Platelet Antibodies ◽  
Patients At Risk ◽  
Drug Dependent ◽  
The 19Th Century ◽  
Prompt Diagnosis

Abstract Drug-induced thrombocytopenia was first described in the 19th century, yet our understanding of its pathogenesis continues to evolve. The list of drugs implicated in drug-induced thrombocytopenia is extensive and growing. Many, if not most, of these medications induce thrombocytopenia by immune mechanisms. Because the degree of thrombocytopenia can put patients at risk for serious bleeding, a prompt diagnosis is key to clinical management. The laboratory approach to diagnosing drug-induced thrombocytopenia is 2-pronged. First, nondrug causes of thrombocytopenia must be ruled out. Second, testing for drug-dependent platelet antibodies, available at specialized reference laboratories, often can identify the offending medication, although usually not in time for initial clinical management. Once a medication is suspected of causing thrombocytopenia, it must be discontinued promptly, and the patient should be monitored closely. Thrombocytopenia generally resolves quickly after offending medication withdrawal, and the prognosis of drug-induced thrombocytopenia is then excellent.

scholarly journals Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2071-2076 ◽  
Author(s):  
Daniel W. Bougie ◽  
Peter R. Wilker ◽  
Elizabeth D. Wuitschick ◽  
Brian R. Curtis ◽  
Mohammad Malik ◽  
...  
Keyword(s):  
High Titer ◽  
Drug Binding ◽  
Prior Exposure ◽  
Severe Thrombocytopenia ◽  
Serum Samples ◽  
Igg Antibody ◽  
Drug Binding Site ◽  
Naturally Occurring ◽  
Previously Treated ◽  
Drug Dependent

Abstract Acute thrombocytopenia is a recognized complication of treatment with GPIIb/IIIa inhibitors whose cause is not yet known. We studied 9 patients who developed severe thrombocytopenia (platelets less than 25 × 109/L) within several hours of treatment with the GPIIb/IIIa inhibitors tirofiban (4 patients) and eptifibatide (5 patients). In each patient, acute-phase serum contained a high titer (range, 1:80-1:20 000) IgG antibody that reacted with the glycoprotein IIb/IIIa complex only in the presence of the drug used in treatment. Four patients had been previously treated with the same drug, but 5 had no known prior exposure. Pretreatment serum samples from 2 of the latter patients contained drug-dependent antibodies similar to those identified after treatment. No tirofiban- or eptifibatide-dependent antibodies were found in any of 100 randomly selected healthy blood donors, and only 2 of 23 patients receiving tirofiban or eptifibatide who did not experience significant thrombocytopenia had extremely weak (titer, 1:2) tirofiban-dependent antibodies. In preliminary studies, evidence was obtained that the 9 antibodies recognize multiple target epitopes on GPIIb/IIIa complexed with the inhibitor to which the patient was sensitive, indicating that they cannot all be specific for the drug-binding site. The findings indicate that acute thrombocytopenia after the administration of tirofiban or eptifibatide can be caused by drug-dependent antibodies that are “naturally occurring” or are induced by prior exposure to drug. These antibodies may be human analogs of mouse monoclonal antibodies that recognize ligand-induced binding sites (LIBS) induced in the GPIIb/IIIa heterodimer when it reacts with a ligand-mimetic drug.

Clinical significance of qualitative human cytomegalovirus (HCMV) detection in cell-free serum samples in HIV-infected patients at risk for HCMV disease

AIDS ◽  
1997 ◽  
Vol 11 (9) ◽  
pp. 1195-1196
Author(s):  
T. Laue ◽  
T. Mertenskötter ◽  
T. Grewing ◽  
O. Degen ◽  
J. van Lunzen ◽  
...  
Keyword(s):  
At Risk ◽  
Clinical Significance ◽  
Human Cytomegalovirus ◽  
Serum Samples ◽  
Hcmv Disease ◽  
Patients At Risk ◽  
Free Serum

P093 IDENTIFICATION OF PATIENTS AT RISK OF SUBTHERAPEUTIC DRUG EXPOSURE PRIOR TO INITIATION OF CERTOLIZUMAB PEGOL THERAPY FOR THE TREATMENT OF CROHN’S DISEASE

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S69-S70
Author(s):  
Pavine Lefevre ◽  
Leonardo Guizzetti ◽  
Brian Feagan ◽  
Anca Pop ◽  
Mohamed Yassine ◽  
...  
Keyword(s):  
At Risk ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Drug Exposure ◽  
Certolizumab Pegol ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Clinical Variables ◽  
Therapy Initiation ◽  
Patients At Risk

Abstract Background Certolizumab pegol (CZP) is effective treatment for moderately-to-severely active Crohn’s disease (CD)1, 2 at approved subcutaneous doses of 400 mg on weeks 0, 2 and 4 (induction) and every 4 weeks thereafter (maintenance). Prior research has demonstrated a relationship between CZP drug exposure and outcomes, with higher plasma CZP concentrations during induction and maintenance therapy associated with more favorable clinical, endoscopic and biologic (C-reactive protein [CRP], fecal calprotectin [FC]) disease outcomes.3 Increased drug clearance is the driver of subtherapeutic CZP concentrations, although the identification of patients at risk for accelerated clearance prior to therapy initiation has not previously been possible. Methods A population pharmacokinetic model4 was used to estimate baseline CZP clearance (i.e., at the time of therapy initiation) using baseline clinical variables (i.e., gender, body weight, albumin and CRP concentration) available from patients with CD previously included in nine randomized, controlled, phase 2 and 3 trials (N=2157). Baseline CZP clearance was compared between patients who achieved observed Week 6 CZP plasma concentrations previously associated with meaningful clinical (&gt;36 μg/mL for Crohn’s Disease Activity Index [CDAI] ≤ 150), biologic (&gt;44 μg/mL for FC ≤ 250 μg/g) and composite clinical and biologic (&gt;48 μg/mL for CDAI ≤ 150 and FC ≤ 250 μg/g) outcomes at Week 6. Receiver operating characteristic curve analysis identified baseline CZP clearance thresholds associated with effective CZP concentrations at Week 6. Results Baseline CZP clearance was significantly higher in patients not achieving effective Week 6 CZP plasma concentration thresholds of 36 μg/mL, 44 μg/mL and 48 μg/mL compared to patients who achieved these thresholds (Figure 1; p&lt;0.0001 for all comparisons). Baseline CZP CL of ≥ 0.5 L/day was associated with subtherapeutic observed Week 6 CZP plasma concentrations. The sensitivity, specificity, likelihood ratios and area under the concentration curves for the association between baseline CZP clearance and observed Week 6 CZP concentration thresholds are shown in Table 1. Conclusion Patients with CD who have accelerated baseline CZP clearance are at risk of subtherapeutic CZP concentrations. Clearance can be calculated using baseline clinical variables and would allow for identification of patients for whom therapeutic CZP concentrations may be achieved with current approved dosing. Implementing therapeutic drug monitoring may increase the likelihood of achieving therapeutic drug exposure during induction as well as treatment success. References

scholarly journals Simple and Rapid Detection of Candida albicans DNA in Serum by PCR for Diagnosis of Invasive Candidiasis

2000 ◽  
Vol 38 (8) ◽  
pp. 3016-3021 ◽  
Author(s):  
Retno Wahyuningsih ◽  
Hans-Joachim Freisleben ◽  
Hans-Günther Sonntag ◽  
Paul Schnitzler
Keyword(s):  
At Risk ◽  
Candida Albicans ◽  
Invasive Candidiasis ◽  
Blood Cultures ◽  
Systemic Candidiasis ◽  
Pcr Assay ◽  
Serum Samples ◽  
Simple Method ◽  
Patients At Risk ◽  
Dna Enzyme Immunoassay

A rapid and sensitive PCR assay for the detection of Candida albicans DNA in serum was established. DNA from human serum samples was purified using the QIAamp blood kit, which proved to be a fast and simple method for isolating minute amounts ofCandida DNA from clinical specimens for diagnosis of invasive candidiasis. Universal primer sequences used in the PCR assay are derived from the internal transcribed spacer rRNA gene of fungi, whereas the biotinylated hybridization probe used in a DNA enzyme immunoassay (DEIA) binds specifically to C. albicans DNA. The sensitivity of this PCR-DEIA method is very high; the detection limit for genomic Candida DNA is one C. albicans genome per assay. Blood from uninfected and infected persons, ranging from healthy volunteers, patients with mucocutaneous infections, and patients at risk to develop a systemicCandida infection to patients with an established systemic candidiasis, was analyzed for the presence of C. albicansto diagnose fungal infection. Candida DNA could not be detected in sera of 16 culture-negative controls and from 11 nonsystemic candidal infections by PCR or DEIA. Blood cultures from patients at risk were all negative for Candida, whereas all blood cultures from systemic candidiasis patients were positive. However, Candida DNA could be detected by PCR and DEIA in the serum from three out of nine patients who were at risk for a systemic infection and in the serum of all seven patients who had already developed an invasive Candida infection. PCR is more sensitive than blood culture, since some of the patients at risk for invasive yeast infection, whose blood cultures were all negative for Candida, tested positive in the PCR amplification. These results indicate the potential value of PCR for detectingC. albicans in serum samples and for identifying patients at risk for invasive candidiasis.

scholarly journals Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2071-2076 ◽  
Author(s):  
Daniel W. Bougie ◽  
Peter R. Wilker ◽  
Elizabeth D. Wuitschick ◽  
Brian R. Curtis ◽  
Mohammad Malik ◽  
...  
Keyword(s):  
High Titer ◽  
Drug Binding ◽  
Prior Exposure ◽  
Severe Thrombocytopenia ◽  
Serum Samples ◽  
Igg Antibody ◽  
Drug Binding Site ◽  
Naturally Occurring ◽  
Previously Treated ◽  
Drug Dependent

Acute thrombocytopenia is a recognized complication of treatment with GPIIb/IIIa inhibitors whose cause is not yet known. We studied 9 patients who developed severe thrombocytopenia (platelets less than 25 × 109/L) within several hours of treatment with the GPIIb/IIIa inhibitors tirofiban (4 patients) and eptifibatide (5 patients). In each patient, acute-phase serum contained a high titer (range, 1:80-1:20 000) IgG antibody that reacted with the glycoprotein IIb/IIIa complex only in the presence of the drug used in treatment. Four patients had been previously treated with the same drug, but 5 had no known prior exposure. Pretreatment serum samples from 2 of the latter patients contained drug-dependent antibodies similar to those identified after treatment. No tirofiban- or eptifibatide-dependent antibodies were found in any of 100 randomly selected healthy blood donors, and only 2 of 23 patients receiving tirofiban or eptifibatide who did not experience significant thrombocytopenia had extremely weak (titer, 1:2) tirofiban-dependent antibodies. In preliminary studies, evidence was obtained that the 9 antibodies recognize multiple target epitopes on GPIIb/IIIa complexed with the inhibitor to which the patient was sensitive, indicating that they cannot all be specific for the drug-binding site. The findings indicate that acute thrombocytopenia after the administration of tirofiban or eptifibatide can be caused by drug-dependent antibodies that are “naturally occurring” or are induced by prior exposure to drug. These antibodies may be human analogs of mouse monoclonal antibodies that recognize ligand-induced binding sites (LIBS) induced in the GPIIb/IIIa heterodimer when it reacts with a ligand-mimetic drug.

P093 IDENTIFICATION OF PATIENTS AT RISK OF SUBTHERAPEUTIC DRUG EXPOSURE PRIOR TO INITIATION OF CERTOLIZUMAB PEGOL THERAPY FOR THE TREATMENT OF CROHN'S DISEASE

2020 ◽  
Vol 158 (3) ◽  
pp. S113-S114
Author(s):  
Pavine Lefevre ◽  
Leonardo Guizzetti ◽  
Brian Feagan ◽  
Anca Pop ◽  
Mohamed Yassine ◽  
...  
Keyword(s):  
At Risk ◽  
Crohn’S Disease ◽  
Crohn's Disease ◽  
Drug Exposure ◽  
Certolizumab Pegol ◽  
Patients At Risk

scholarly journals Autopsy-Controlled Prospective Evaluation of Serial Screening for Circulating Galactomannan by a Sandwich Enzyme-Linked Immunosorbent Assay for Hematological Patients at Risk for Invasive Aspergillosis

1999 ◽  
Vol 37 (10) ◽  
pp. 3223-3228 ◽  
Author(s):  
Johan Maertens ◽  
Jan Verhaegen ◽  
Hilde Demuynck ◽  
Penelope Brock ◽  
Gregor Verhoef ◽  
...  
Keyword(s):  
At Risk ◽  
Invasive Aspergillosis ◽  
Immunosorbent Assay ◽  
Predictive Value ◽  
Sandwich Elisa ◽  
Enzyme Linked Immunosorbent Assay ◽  
Serum Samples ◽  
Hematological Patients ◽  
Increased Risk ◽  
Patients At Risk

Efforts to improve the diagnosis of invasive aspergillosis (IA) have been directed towards the detection of fungal antigens, including galactomannan (GM). However, previous evaluations of GM detection have been hampered by a lack of proven cases of IA and by a nonserial study design. This prospective study assessed the diagnostic value of serial screening for circulating GM by using a recently developed sandwich enzyme-linked immunosorbent assay (ELISA) for prolonged-neutropenic and/or steroid-treated patients with hematological disorders. Serum GM levels were monitored twice weekly for 186 consecutive patients at increased risk for IA. The patients were stratified according to the likelihood of IA (proven, probable, possible, and no evidence of IA) by using stringent criteria. Proven IA was defined by characteristic histopathological findings together with a positive culture forAspergillus species. Autopsy and culture from autopsy specimens was used to verify both positive and negative test results. A total of 2,172 serum samples were tested from 243 episodes (mean, 9 samples/episode). Based on the analysis of 71 patients with confirmed disease status (culture and histology), the sensitivity and specificity of serial GM monitoring were 92.6 and 95.4%, respectively. The positive predictive value was almost 93%, the negative predictive value was 95%, and the efficacy was 94%. False-positive reactions occurred at a rate of nearly 8%, although this figure might have been overestimated. Less than 1% of all tested sera were considered inconclusive. In more than half of the cases, antigenemia was detected before clinical suspicion of IA (median, 6 days before). Serial determination of serum GM by the sandwich ELISA technique is a sensitive tool for the diagnosis of IA in hematological patients at risk. This approach may substantially influence clinical management with regard to preemptive and empirical antifungal therapy.

1678: Identifying Patients at Risk for Benign Versus Life Shortening Postoperative Prostate-Specific Antigen Failure

2005 ◽  
Vol 173 (4S) ◽  
pp. 455-455
Author(s):  
Anthony V. D’Amico ◽  
Ming-Hui Chen ◽  
Kimberly A. Roehl ◽  
William J. Catalona
Keyword(s):  
At Risk ◽  
Prostate Specific Antigen ◽  
Specific Antigen ◽  
Patients At Risk
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