En février 2018, il est déclaré aux CRPV d’Angers le cas n°AN20180251 d’un homme de 70 ans sans antécédent chez qui est réalisée une coronarographie et pour lequel une sténose significative de l'ostium de l'artère interventriculaire antérieure proximale d'aspect thrombotique est diagnostiquée. Suite à l’intervention, le patient a présenté une thrombocytopénie grade IV, 5 jours après une administration d’ABX. Dans ce cas deux traitements avaient été suspectés, l’ABX et le lansoprazole codés en C2-S1-B3-I1. Du Lovenox® avait été administré, mais non suspecté, car la recherche des anticorps antiPF4 était négative. Les thrombopénies étaient alors bien décrites dans le RCP mais il n’y était pas mentionné le caractère retardé. C’est sur ce motif que ce cas a été transmis à l'ANSM en mars 2018 selon la procédure des cas marquants. Or, l’ABX, est au centre d’une réévaluation européenne réalisée tous les 5 ans dont la dernière s’étendant de novembre 2012 à novembre 2017. Le bilan des effets indésirables couvert par la période avait été réalisé par le laboratoire et soumis le 15 mars 2018. Le laboratoire concluait qu'il n'y avait pas de nouvelle information de sécurité, la thrombocytopénie étant déjà un risque important identifié, sans
mentionner le caractère retardé. Afin que ce cas marquant soit pris en compte dans la procédure de réévaluation, une analyse des données de la littérature et des cas graves de thrombopénies retardées issus de la base nationale de pharmacovigilance couvrant la période (novembre 2012 - novembre 2017), avec comme seul suspect l'ABX, a été demandée au CRPV d'Angers. Ce rapport complet a été transmis à l’ANSM puis à l'EMA le 13 juin 2018. Suite à ce rapport, l’EMA a demandé au laboratoire, le 25 juin 2018, de réaliser une revue cumulative des cas issus des essais cliniques, de leur base de pharmacovigilance et de la littérature sous 3 mois. Enfin suite à cette procédure, l’ajout de la mention des thrombopénies retardées sous ABX a été réalisé le 24 octobre 2019 dans la rubrique 4.4 (cf RCP en annexe 1).
Ainsi l’objectif principal de ce travail est de décrire les thrombopénies retardées graves sous ABX en termes de gravité, d’évolution et de prise en charge, en ajoutant les données de la base internationale de pharmacovigilance et ainsi de montrer l’intérêt de la pharmacovigilance allant de la déclaration d’un cas par un service de cardiologie jusqu’ à la modification du RCP d’un médicament.
Article
DELAYED THROMBOCYTOPENIA FOLLOWING ADMINISTRATION OF ABCIXIMAB Louis Vincent*1, Delphine Bourneau-Martin*1, Anaïs Maurier1, Marina Babin1, Stéphane Delepine2, Dominique Helley3, Aurélie Grandvuillemin4, Laurence Lagarce1, Agnès Lillo-Le Louët5, Marie Briet1,6,7
1- Department of Pharmacology, Toxicology and Pharmacovigilance, Angers University Hospital, Angers, France
2- Cardiology Department, Angers University Hospital, Angers, France
3- Department of biological Haematology, George Pompidou European Hospital, Paris, France
4- Regional Pharmacovigilance Centre, Dijon University Hospital, Dijon, France 5- Regional Pharmacovigilance Centre, George Pompidou European Hospital, Paris,
France
6- University of Angers, Angers, France
7- MitoVasc Laboratory, UMR CNRS 6214 INSERM 1083
*These authors contributed equally to this work
Running title: Delayed thrombocytopenia and abciximab Corresponding author
Dr Bourneau-Martin Delphine
Department of Pharmacology, Toxicology and Pharmacovigilance Angers University Hospital
Abstract
Background: Abciximab (ABX) is used for acute coronary syndrome and unstable angina. Thrombocytopenia is a frequent adverse effect described as occurring in the first 24 hours. The aim of this study was to evaluate the occurrence of delayed thrombocytopenia following ABX infusion in pharmacovigilance database reports and in the literature.
Methods: Individual case safety reports (ICSRs) of delayed thrombocytopenia – between 3 and 30 days - with ABX presented as a single suspect were selected in VigiBase®, the WHO global database of ICSRs. The French cases were then extracted from the French National Pharmacovigilance Database. In addition, a literature review of published cases was performed using PubMed.
Results: Among the 84 ICSRs selected from VigiBase®, 43 were also reported in the FPVD. Mean age was 60.1±12.3 years with a majority of male patients (77.4%). The average time to onset (TTO) was 8.9±5.2 days. Thrombocytopenia regressed in 5.1±2.7 days. Haemorrhagic complications were reported in 15% of ICSRs. In the French cases, the median nadir of platelet count was 28 x 109/L (range 1-110) with a majority of grade 4 thrombocytopenia (39.5%). The literature review identified 42 cases and provides additional information on administered therapies, which include platelet units, corticosteroids, and IV immunoglobulins. GPIIb/IIIa-ABX complex antibodies were described in 26 published cases.
Conclusion: Delayed thrombocytopenia, probably due to immune reaction, is a possible life-threatening adverse effect of ABX with a mean TTO of 9 days, supporting the recommendation of a platelet count monitoring during at least two weeks.
Introduction
Abciximab (ABX) is the Fab fragment of the chimeric human-murine monoclonal antibody 7E3 that binds the platelet receptor glycoprotein IIb/IIIa (GPIIb/IIIa). ABX exerts an antiaggregant effect by preventing the binding of fibrinogen and Von Willebrand Factor to GPIIb/IIIa receptor on activated platelets 1. The blockade of GPIIb/IIIa was greater than 90% two hours after ABX infusion. The inhibition of platelet function gradually decreases. The reversibility of the inhibition is illustrated by partial recovery of platelet function within 48 hours after the end of the infusion 2. ABX is used as an antithrombotic therapy during percutaneous coronary intervention (PCI) to prevent ischemic complications of percutaneous coronary revascularisation. It is also indicated for patients with unstable angina who are not responding to conventional medical therapy when PCI is planned within 24 hours 1.
The most common adverse effects of ABX are bleeding and acute thrombocytopenia.
Haemorrhage incidence varies from 0.8% to 16.8% and acute thrombocytopenia incidence from 2.5% to 5.2% 1. Thrombocytopenia is described as occurring within a few hours after ABX infusion, but cases of delayed thrombocytopenia, occurring 3 days after the infusion are also reported 3–18. The objective of this study was to review the reports of delayed thrombocytopenia after ABX administration in VigiBase®, the WHO global database of ICSRs, the French National Pharmacovigilance Databases (FPVD) and the literature.
Methods
We selected all individual cases safety reports (ICSRs) from 19 September 1995 - the commercialisation date of ABX - to 5 December 2018 using the Medical Dictionary for Regulatory Activities (MedDRA) term “thrombocytopenia” (HLT medDRA term) and
“abciximab” (for substance) as suspected medication in the international pharmacovigilance database VigiBase®, with a time to onset (TTO) between 3 and 30 days. The cut-off of 3 days was chosen since thrombocytopenia was already described within the first 48 hours and 30 days considering the half-life of immunoglobulin. We excluded cases with no information about TTO or no possibility to calculate it, cases with multiple TTO reported, cases with pre-existing thrombocytopenia with no information about the date of aggravation and cases where ABX was not the single suspect. For each observation, the following data were collected: age, gender, complications, severity criteria, TTO, evolution and indications. Among the cases selected in VigiBase®, the French cases were identified and extracted from the French
National Pharmacovigilance Database in order to have access to more detailed information. The following additional information was collected: platelet count and immunological investigations. Thrombocytopenia was graded according to the WHO scale: grade 4, defined by platelet count under 25 G/L; grade 3 between 25 and 49 G/L; grade 2 between 50 and 74 G/L, grade 1 between 75 and 99 G/L platelets and grade 0 defined by platelet count superior to 100 G/L.
For the literature review, we performed a search on PubMed website with the MESH terms “abciximab” and “thrombocytopenia”. The cases with TTO between 3 and 30 days were included in the present study. Cases of pseudothrombocytopenia related to EDTA-dependent aggregation were excluded.
Results
Description of the reports of delayed thrombocytopenia in the pharmacovigilance databases
Among the 1,989 ICSRs of thrombocytopenia associated with ABX administration registered in VigiBase®, 432 concerned acute thrombocytopenia and 84 ICSRs reported delayed thrombocytopenia, both with ABX as single suspected (Figure 1).
Delayed thrombocytopenia ICRS represented 16% of thrombocytopenia ICRS with ABX as single suspect in VigiBase®. The characteristics of the 84 cases of delayed thrombocytopenia following ABX administration are described in Table 1. Most of the reported cases were considered as serious. The mean age was 60.1±12.3 years and 77% of the patients were male. The TTO average was 8.9±5.2 days. Hemorrhagic complications were reported in 15% of patients. Thrombocytopenia had completely regressed in 5.1±2.7 days. Platelet count returned to normal in 68% of cases at the reporting date.
Among the 84 ICSRs, 43 were also reported in the French National Pharmacovigilance Database, where more detailed information is available. The median nadir of platelet count was 28 x 109/L (range 1-110). Grade 4 thrombocytopenia was described in 17 cases (39,5%), grade 3 in 13 cases (30%) and grade 2 in 5 cases (11,5%), and grade 1 in 8 cases (18%). Hemorrhagic complications were reported in 5% of the French cases (epistaxis and purpura with bleeding gums). Immunological investigations were performed for 9 patients and all showed the presence of an anti-abciximab antibody and 2 present anti-GPIIb/IIIa-ABX complex antibody. Heparin-induced thrombocytopenia was investigated in 23 cases with agglomeration tests and antibodies anti-PF4/heparin quantification and was negative for 22 cases. The test
were not in favor of an acute heparin-induced thrombocytopenia 19. Platelet transfusions were required for 6 patients (14%) who showed a median platelet count at 5 x 109/L [range 1-11G/L]. Among the 6 French ICSRs with information about symptomatic treatment, all received platelet units. One of them gets red blood cells in addition and one other received corticosteroid.
Review of the published cases of delayed thrombocytopenia following ABX administration
In the literature, 42 cases of ABX-induced delayed thrombocytopenia were published
3–18 and summarised in Table 2. Mean age was 61.8±10.7 years and 66.6% of patients were male. The TTO average was 7.5±3 days and the average time of improvement was 4 days (range: 2-12 days). The mean nadir of platelet count was close to the one calculated from the reports of the French National Pharmacovigilance Database (19.2±23.7 versus 25.4±13 x 109/L). Haemorrhagic complications were described in 43% of cases with bleeding at the injection site, bruising, mucocutaneous haematomas, petechiae, bleeding gums, haematuria, digestive bleeding and cerebral haemorrhage. It is worth noting that one case was fatal due to cerebral haemorrhage.
In this case, the co-prescription of two antiplatelet drugs (acetylsalicylic acid 300 mg and clopidogrel 75 mg) may have contributed to the cerebral haemorrhagic complication. In the cases reported in the literature, patients were treated with platelet units (n=14, 33%), corticosteroids (n=6, 14%), and intravenous immunoglobulin (n=5, 12%). No treatment was specifically administrated for thrombocytopenia in 10 cases (24%) and no information was available in 10 cases (24%). An anti-GPIIb/IIIa-ABX complex antibody was searched for in 62% of the cases and all searches were positive. Heparin-induced thrombocytopenia was investigated in 29 cases and the results of this were negative for 28 patients. Only one patient had anti-PF4/heparin and anti-GPIIb/IIIa-ABX complex antibodies.
Discussion
The data obtained from the international and national databases confirmed that ABX administration could be complicated by delayed thrombocytopenia with a median TTO of around 8 days. Thrombocytopenia was severe in a large part of the reported cases and haemorrhagic complications could be observed. Whenever it was searched for, an anti-GPIIb/IIIa-ABX complex antibody was found.
Considering the presence of anti-ABX/platelet antibodies in published cases and FPVD cases, immune-mediated thrombocytopenia is the most likely hypothesis, even if the pathophysiological mechanism is not clearly established. Indeed, in vitro, Curtis et al.
3 demonstrated in 13 patients, all of whom presented delayed thrombocytopenia with ABX, the presence of antibodies (IgG antibodies in 13 patients and IgM in 11 patients) binding the Fab fragment of ABX (murine sequence) (Figure 2). The platelets sensitised by the attachment of an anti-ABX antibody/platelet were then destroyed. In addition, Nurden et al. showed that the ABX-dependent antibodies found in the plasma of patients who presented delayed thrombocytopenia had the ability to activate and aggregate normal platelets 16. Antibodies that recognise the cleavage site caused by papain (papain is used to prepare Fabs from IgG) located in the C-terminal region of Fabs (normal ab binding in Figure 1 below) have been also reported. The pathogenicity of these antibodies is discussed. They may be responsible for immediate thrombocytopenia on ABX.16,20
After a first exposure to ABX, approximatively 6% of patients develop human anti-chimeric antibodies 1. The risk of sensitisation to murine sequences is increased by the fact that ABX remains bound to circulating platelets in detectable quantities for up to two weeks after treatment 21,22. This immunological mechanism supports the recommendation that ABX should not be administered again after an episode of ABX-induced thrombocytopenia. Two second-line drugs, tirofiban and eptifibatide, which are two other GPIIb/IIIa inhibitors, can be used in this situation.
Management of drug-induced immune thrombocytopenia is usually based on platelet unit transfusion and corticosteroids after stopping use of the drug 23,24. The treatments for the delayed thrombocytopenia after ABX administration reported in published cases and in reports from the French National Pharmacovigilance Database are consistent with these recommendations. The use of intravenous immunoglobulins has also been reported 24.
However, this work provides a synthesis of the cases of delayed-thrombocytopenia after ABX administration. The physician’s attention should be alerted to the possibility of delayed thrombocytopenia that is probably caused by immunological mechanisms following ABX treatment. Close and prolonged monitoring of platelet count after ABX administration should be recommended, even if the patient has returned home.
Acknowledgements
The authors would like to thank the Uppsala Monitoring Centre (UMC), which provided and gave permission to use the data analysed in this study. The authors are indebted to the National Pharmacovigilance Centres that contributed to the data. The opinions and conclusions in this study are not necessarily those of the various centres or of the UMC or the WHO. Information from VigiBase® comes from a variety of sources, and the probability that the suspected adverse effect is drug-related is not the same in all cases. GPIIb/IIIa platelet receptor blocker in refractory unstable angina. European Cooperative Study Group. Circulation. 1994;89(2):596-603.
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Table 1. Main characteristics of the 84 reports of delayed thrombocytopenia included Socio-demographic characteristics
Age, years (mean ± SD) (n=79) 60.1±12.3
Gender, M/F (n=84) 65/19
Time to onset, days (mean ± SD) (n=84) 8.9±5.2 Treatment duration, days (median [range]) (n=74) 1 [0-22]
Regression time, days (median [range]) (n=62) 5 [1-14]
Evolution
Myocardial infarction, n (%) 18 (21.4)
Angioplasty, n (%) 10 (14.3)
Acute coronary syndrome, n (%) 7 (9.5)
Thrombosis, n (%) 3.6 (3.6)
Percutaneous coronary intervention, n (%) 1 (1.2)
Angiography, n (%) 1 (1.2)
Anaemia and haemoglobin decrease, n (%) 3 (3.6)
Purpura, n (%) 2 (2.4)
Disseminated intravascular coagulation, n (%) 1 (1.2)
Table 2. Summary of the 42 cases of delayed thrombocytopenia following abciximab administration in the literature Socio-demographic characteristics
Age (mean ± SD) (n=29) 61.8±10.7
Gender (M/F) (n=30) 20/10
Time to onset, days (mean ± SD) (n=39) 7,5±3 Regression time (median [range]) (n=30) 4 [2-12]
Evolution
Treatment administrated in case management
Platelets units, n (%) 14 (33)
No treatment, n (%) 10 (24)
Corticosteroids, n (%) 6 (14)
Intravenous immunoglobulin, n (%) 5 (12)
Red blood cells, n (%) 4 (9.5) intervention; ACS: Acute coronary syndrome, IV Ig: intravenous immunoglobulin.
Figure 1. Pharmacovigilance report selection flowchart (VigiBase® and French Pharmacovigilance database).
Figure 2. Schematic representation of the apparent binding sites on platelet-associated abciximab for antibodies that cause thrombocytopenia in patients given abciximab (patient ab) and antibodies found commonly in normal persons (normal ab). Figure adapted from Curtis et al.3
Discussion
Les données obtenues à partir des bases de données internationales et nationales ont confirmé que l’administration d’ABX pouvait être compliquée d’une thrombopénie retardée avec un délai d’apparition médian d’environ 9 jours. La thrombopénie était grave dans une grande partie des cas signalés et des complications hémorragiques ont pu être observées. Les patients présentant ce type d’effet étaient dans 3/4 des cas des hommes. Malgré une résolution des effets indésirables, il est à noter la présence de 5 décès parmi les cas des bases de pharmacovigilance et de deux décès dans les cas de la littérature. C’est pourquoi le suivi des patients durant les deux semaines après l’administration de l’ABX est crucial. En effet, ces thrombopénies retardées sont survenues alors que les patients étaient sortis d’hospitalisation.
L’impact d’une thrombopénie grave à domicile n’est donc pas à négliger, surtout que celles-ci peuvent être le plus fréquemment de grade 4 d’après les cas retrouvés dans la littérature (38 %) ainsi que dans les cas des bases de pharmacovigilance (39,5 %).
D'après les données de la littérature, les prises en charge de ces thrombopénies consistaient en une administration de concentrés plaquettaire dans 14 cas, d’une injection de corticostéroïdes dans 6 cas et dans 10 cas aucun traitement symptomatique n’a été administré.
Un autre point intéressant relevé lors de l’analyse de la littérature est l’augmentation du risque d’apparition d’une thrombopénie retardée lors d’une réadministration d’ABX [27]. Il semble donc prudent d’éviter toute nouvelle injection d’ABX chez un patient ayant présenté une thrombopénie aiguë ou retardée secondaire à cette administration.
De plus lors de l’apparition d’une thrombopénie chez un patient, l’enquête pharmacologique devrait prendre en compte les administrations antérieures d’ABX. En effet, il est important de ne pas se restreindre aux seuls traitements en cours ou très récemment arrêtés. Malheureusement l’amalgame reste facile et la connaissance de l’administration d’ABX par le service prenant en charge le patient reste difficile puisque ce traitement est administré dans la majorité des cas en service de cardiologie alors que lors d’un épisode de thrombopénie, le patient sera pris en charge dans d’autres services ou d’autres structures.
L’origine immunomédiée de ces thrombopénies retardées est actuellement l’hypothèse la plus probable, même si les mécanismes exacts ne sont toujours pas connus. La
d’ailleurs été démontrée in vitro dans un travail de Curtis et al [28]. Les anticorps
d’ailleurs été démontrée in vitro dans un travail de Curtis et al [28]. Les anticorps