Longitudinal profile of estrogen-related thrombotic biomarkers after cessation of combined hormonal contraceptives.

ABSTRACT: The persistence of risk of venous thromboembolism (VTE) due to combined hormonal contraceptives (CHCs), after their cessation, is unknown but important to guide clinical practice. The objective of this prospective cohort study was to define the time until normalization of estrogen-related thrombotic biomarkers after CHC cessation. We enrolled women aged 18 to 50 years who had decided to stop their CHC, excluding those with a personal history of VTE, anticoagulation, or pregnancy. The study started before cessation of CHC, with 6 visits afterwards (at 1, 2, 4, 6, and 12 weeks after cessation). Primary outcomes were normalized sensitivity ratios to activated protein C (nAPCsr) and to thrombomodulin (nTMsr), with sex hormone-binding globulin (SHBG) as a secondary end point. We also included control women without CHC. Among 66 CHC users, from baseline until 12 weeks, average levels of nAPCsr, nTMsr, and SHBG decreased from 4.11 (standard deviation [SD], 2.06), 2.53 (SD, 1.03), and 167 nmol/L (SD, 103) to 1.27 (SD, 0.82), 1.11 (SD, 0.58), and 55.4 nmol/L (SD, 26.7), respectively. On a relative scale, 85.8%, 81.3%, and 76.2% of the decrease from baseline until 12 weeks was achieved at 2 weeks and 86.7%, 85.5%, and 87.8% at 4 weeks after CHC cessation, respectively. Levels were not meaningfully modified throughout the study period among 28 control women. In conclusion, CHC cessation is followed by a rapid decrease in estrogen-related thrombotic biomarkers. Two to 4 weeks of cessation before planned major surgery or withdrawal of anticoagulants in patients with VTE appears sufficient for the majority of women. The trial is registered at www.clinicaltrials.gov as #NCT03949985.

[Angiology and hemostasis: what's new in 2023]. / Angiologie et hémostase: ce qui a changé en 2023.

We discuss four topics among the angiology and hemostasis studies of importance in 2023. The BASIL-2 study provides new data for the management of chronic limb-threatening ischemia by comparing surgical and endovascular treatment. The new classification of antiphospholipid antibody (aPL) syndrome integrates new clinical elements and gives a different weight among the isotype and titer of aPL. Concizumab, an antibody targeting the tissue factor pathway inhibitor, broadens the therapeutic arsenal for hemophilia A and B as evidenced by the results of the EXPLORER 7 study. The PREVENT-CLOT and CASTING study focus on the prevention of thrombosis after trauma, by testing the role of aspirin or the lack of thromboprophylaxis, respectively.

Parmi les sujets d'angiologie et d'hémostase qui ont marqué l'année 2023, quatre ont retenu notre attention. L'étude BASIL-2 apporte de nouvelles données pour la prise en charge de l'ischémie critique des membres inférieurs en comparant les traitements chirurgical et endovasculaire. La nouvelle classification du syndrome des anticorps antiphospholipides (aPL) intègre de nouveaux items cliniques et donne un poids différent aux isotypes et titres des aPL. Le concizumab, un anticorps ciblant l'inhibiteur de la voie du facteur tissulaire, vient élargir l'arsenal thérapeutique pour les hémophilies A et B comme en témoignent les résultats de l'étude EXPLORER 7. Les études PREVENT-CLOT et CASTING s'intéressent à la prévention de la thrombose après traumatisme, en testant la place de l'aspirine ou l'absence de thromboprophylaxie.

Applicability of the European Society of Cardiology Guidelines on the management of acute coronary syndromes to older people with haemophilia A - A modified Delphi consensus by the ADVANCE Working Group.

INTRODUCTION: As people with haemophilia (PWH) receive better treatment and live longer they are more likely to encounter cardiovascular disease (CVD) and other comorbidities. ESC guidelines for the acute management of patients presenting with acute coronary syndrome (ACS) are based on the non-haemophilia population. AIM: To review the guidelines and propose relevant adaptations for PWHA without inhibitors who are treated with prophylaxis and present with ACS. METHODS: As part of the ADVANCE Group, 20 European haemophilia experts used a modified Delphi approach to develop and gain consensus on proposed adaptations of the ESC guidelines for PWHA without inhibitors. RESULTS: Of the 32 Class I recommendations across both guidelines, adaptions were considered necessary and proposed for 15. The adaptions highlight the need to provide sufficient FVIII trough levels at the time of antithrombotic treatment in people with haemophilia A (HA) without inhibitors. Patients receiving emicizumab prophylaxis and requiring oral anticoagulation therapy or combined single antiplatelet plus oral anticoagulation therapy will require additional FVIII replacement therapy. CONCLUSION: In the absence of high-quality clinical evidence, the combined expert opinion used to develop these adaptions to the current ESC guidelines may help to guide clinicians in their treatment decisions when a PWHA presents with ACS.

Clinicians' adherence to guidelines for the preoperative management of direct oral anticoagulants in a tertiary hospital: a retrospective study.

INTRODUCTION: Despite clear, relatively easy-to-use guidance, many clinicians find the preoperative management of direct oral anticoagulants (DOACs) challenging. Inappropriate management can delay procedures and lead to haemorrhagic or thromboembolic complications. We aimed to describe preoperative management practices regarding DOACs in a tertiary hospital and clinicians' adherence to in-house recommendations. METHOD: We included all patients being treated with DOACs who underwent elective surgery in 2019 and 2020 (n = 337). In-house recommendations for perioperative management were largely comparable to the 2022 American College of Chest Physicians guidelines. RESULTS: Typical patients were older adults with multiple comorbidities and high thrombotic risk stratification scores, and 65.6% (n = 221) had not undergone recommended preoperative anticoagulation management protocols. Patients operated on using local anaesthesia (adjusted OR = 0.30, 95%CI 0.14-0.66; p < 0.01) were less likely to have been treated following institutional recommendations, but no association between their procedure's bleeding risk and adherence was found. Clinicians' failures to adhere to recommendations mostly involved late or non-indicated interruptions of anticoagulation treatment (n = 89, 26.4%) or inappropriate heparin bridging (n = 54, 16.0%). Forty-five (13.3%) procedures had to be postponed. Incorrect preoperative anticoagulation management was directly responsible for 12/45 postponements (26.7% of postponements). CONCLUSION: This study highlights clinicians' low adherence rates to institutional recommendations for patients treated with DOACs scheduled for elective surgery in a tertiary hospital centre. To the best of our knowledge, this is the first clinical study addressing the issue of clinicians' adherence to guidelines for the preoperative management of DOACs. Going beyond the issue of whether clinicians are knowledgeable about guidelines or have them available, this study questions how generalisable guidelines are in a tertiary hospital managing many highly polymorbid patients. Further studies should identify the causes of poor adherence.

[Angiology and hemostasis : what's new in 2022]. / Angiologie et hémostase : ce qui a changé en 2022.

In this article, we have selected four topics that particularly caught our attention during the year 2022, and which are related to anticoagulation, its bleeding complications, and hemophilia. Thus, we discuss the issue of the treatment with rivaroxaban of atrial fibrillation associated with rheumatic valvulopathy, which has been studied in a randomized trial, the intensity of thromboprophylaxis in COVID outpatients and inpatients, and the bleeding risk of anticoagulation in patients with cerebral tumors. Finally, recent data on gene therapy in severe hemophilia A, an upcoming treatment, are discussed.

Dans cet article, nous avons sélectionné 4 sujets qui ont particulièrement retenu notre attention durant l'année 2022, en lien avec l'anticoagulation, ses complications hémorragiques et l'hémophilie. Ainsi, nous abordons le traitement par rivaroxaban de la fibrillation atriale associée à une valvulopathie rhumatismale qui a fait l'objet d'une étude randomisée, l'intensité de la thromboprophylaxie chez les patients hospitalisés ou traités en ambulatoire avec un Covid dont les données se sont bien étoffées, le risque associé à l'anticoagulation chez les patients avec une néoplasie cérébrale et, finalement, la thérapie génique dans l'hémophilie A sévère qui devrait apparaître sur le marché très prochainement.

[Direct oral anticoagulant for venous thrombosis in unusual sites]. / Place des anticoagulants oraux directs dans le traitement des thromboses veineuses de localisation inhabituelle.

Thrombosis in unusual sites account for approximately 4% of venous thromboembolic events. The safety of direct oral anticoagulants (DOACs) has led to the widespread use of these treatments. However, they have mainly been studied in deep vein thrombosis of the lower limbs and in pulmonary embolism. This review of the literature assesses the current knowledge of the use of DOACs for venous thrombosis in unusual sites (splanchnic, cerebral, ovarian, upper-extremity deep vein thrombosis). Numerous case reports or observational studies have been published, but very few randomized trials. Nevertheless, experts-based guidelines suggest that these anticoagulants may be considered in specific cases.

La maladie thromboembolique veineuse de localisation atypique (MTEV-LA) représente environ 4 % des événements thromboemboliques veineux. Les anticoagulants oraux directs (ACOD), faciles d'utilisation et sécuritaires, ont essentiellement été étudiés dans la MTEV classique (thrombose veineuse profonde des membres inférieurs et embolie pulmonaire). Dans cette revue de la littérature, nous dressons un état des lieux sur les connaissances actuelles concernant l'utilisation des ACOD dans la MTEV-LA, notamment les thromboses splanchnique, cérébrale, ovarienne et des membres supérieurs. De nombreuses descriptions de cas et études observationnelles ont été publiées mais très peu d'essais randomisés l'ont été. Malgré cela, plusieurs sociétés savantes proposent la prescription d'ACOD dans certains cas spécifiques de MTEV-LA.

[Bleeding of unknown cause: diagnostic and therapeutic approach]. / Saignements d'origine indéterminée : approche diagnostique et thérapeutique.

A bleeding tendency is a frequent cause of hematological consultation. However, despite extensive biological investigations, no hemostasis abnormality is identified in the majority of patients, leading to the diagnosis of bleeding of unknown cause (BUC). Overall, the pathogenesis of BUC is most likely of multifactorial etiology and the accumulation of minor alterations in fibrin clot structure, fibrinolysis, platelet function and thrombin generation can tip the balance of hemostasis towards the bleeding side. In recent years, unconventional biological explorations have found new hemorrhagic abnormalities. Therapeutic options are limited but are usually effective to prevent bleeding.

Une tendance hémorragique est une cause fréquente de consultation hématologique. Toutefois, malgré des investigations biologiques étendues, aucune anomalie de l'hémostase n'est identifiée dans la majorité des cas. Il s'agit donc de saignements d'origine indéterminée. Dans l'ensemble, ceux-ci sont le plus vraisemblablement d'étiologie multifactorielle, et l'accumulation d'altérations mineures au niveau de la structure du caillot de fibrine, de la fibrinolyse, de la fonction plaquettaire et de la génération de thrombine peut faire basculer l'équilibre de l'hémostase du côté hémorragique. Ces dernières années, des explorations biologiques non conventionnelles ont permis de mettre en évidence de nouvelles anomalies hémorragipares. Les possibilités thérapeutiques sont peu nombreuses mais s'avèrent efficaces.

[Selected highlights in angiology and haemostasis for the year 2021]. / Angiologie-hémostase - Année 2021 : morceaux choisis.

Several topics among those that marked the year 2021 are discussed in this article. Factor XI represents an original target for new anticoagulants, and the first results of a phase 2 study of prophylaxis after knee replacement surgery are very promising. A real-life study confirms that the pulmonary embolism exclusion strategy using an age-adjusted D-dimer cut-off is safe and increases the diagnostic yield. Several studies of tranexamic acid provide further insight into the indications for its use and highlight some potential risks. Finally, the concerns regarding a potential risk of increased mortality related to paclitaxel-eluting technology used in lower limb revascularisation are questioned by the results of the latest trials.

Plusieurs sujets parmi ceux qui ont marqué l'année 2021 sont abordés dans cet article. Le facteur XI représente une cible originale pour de nouveaux anticoagulants et les premiers résultats d'une étude de phase 2 dans la prophylaxie après chirurgie du genou sont très prometteurs. Une étude de vie réelle confirme que la stratégie d'exclusion de l'embolie pulmonaire en utilisant un seuil de D-dimères adapté à l'âge est sûre et augmente le rendement diagnostique. Plusieurs études concernant l'acide tranexamique permettent de mieux cerner les indications de son utilisation et soulignent quelques risques potentiels. Finalement, les données récentes remettent en cause le risque de surmortalité liée à la technologie à élution au paclitaxel utilisée dans les interventions endovasculaires des membres inférieurs rapporté précédemment.

A universal anti-Xa assay for rivaroxaban, apixaban, and edoxaban measurements: method validation, diagnostic accuracy and external validation.

A universal anti-Xa assay for the determination of rivaroxaban, apixaban and edoxaban drug concentrations would simplify laboratory procedures and facilitate widespread implementation. Following two pilot studies analysing spiked samples and material from 698 patients, we conducted a prospective multicentre cross-sectional study, including 867 patients treated with rivaroxaban, apixaban or edoxaban in clinical practice to comprehensively evaluate a simple, readily available anti-Xa assay that would accurately measure drug concentrations and correctly predict relevant levels in clinical practice. Anti-Xa activity was measured by an assay calibrated with low-molecular-weight heparin (LMWH) in addition to ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). As an external validation, LMWH-calibrated anti-Xa activity was also determined in nine external laboratories. The LMWH-calibrated anti-Xa activity correlated strongly with rivaroxaban, apixaban or edoxaban drug levels [rs  = 0·98, 95% confidence interval (CI) 0·98-0·98]. The sensitivity for the clinically relevant cut-off levels of 30, 50 and 100 µg/l was 96·2% (95% CI 94·4-97·4), 96·4% (95% CI 94·4-97·7) and 96·7% (95% CI 94·3-98·1) respectively. Concordant results were obtained in the external validation study. In conclusion, a universal, LMWH-calibrated anti-Xa assay accurately measured rivaroxaban, apixaban and edoxaban concentrations and correctly predicted relevant drug concentrations in clinical practice.

A Unique Case of Acquired Hemophilia A Presenting with Transient Ischemic Attack.

Acquired hemophilia A (AHA) is a rare but serious condition, usually associated with significant spontaneous or traumatic bleeding and a high mortality rate. In this report, we describe the case of an elderly patient presenting a transient ischemic attack concurrently with AHA. A thrombotic event in AHA is occasionally associated with the use of bypassing agents for treatment, but a spontaneous thrombotic event has not ever been described.

[Towards new indications for direct oral anticoagulants]. / Angiologie-hémostase - Vers de nouvelles indications des anticoagulants oraux directs.

Direct oral anticoagulants (DOAC) represent commonly prescribed drugs in everyday clinical practice for indications such as atrial fibrillation, prevention of venous thromboembolic disease (VTE) after major orthopaedic surgery, treatment of deep vein thrombosis and pulmonary embolism, and long term prevention of VTE recurrence. More recently, the efficacy of DOAC has been demonstrated in new clinical situations, such as heparin-induced thrombocytopenia, cancer-associated VTE and secondary prevention of cardiovascular events in patients with atherothrombotic arterial disease. This article's aims is to present the recent data on which these new indications are based.

Les anticoagulants oraux directs (ACOD) font actuellement partie des médicaments couramment prescrits en pratique clinique dans les indications telles que la fibrillation atriale, la prévention de la maladie thromboembolique veineuse (MTEV) après chirurgie orthopédique majeure, le traitement de la thrombose veineuse profonde et embolie pulmonaire et la prévention de la récidive de MTEV au long cours. Se sont récemment rajoutées de nouvelles situations cliniques dans lesquelles les ACOD ont fait la preuve de leur efficacité, telles que la thrombopénie induite par l'héparine, le traitement de la MTEV liée au cancer et la prévention secondaire des événements cardiovasculaires chez les patients avec maladie athéromateuse. Cet article a pour but de présenter les données récentes sur lesquelles sont basées ces nouvelles indications.

MicroRNA-126 is a regulator of platelet-supported thrombin generation.

Circulating microRNA (miRNA) expression profiles correlate with platelet reactivity. MiR-126 is a promising candidates in this regard. We generated a transgenic zebrafish line with thrombocyte-specific overexpression of miR-126. Laser injury of the posterior cardinal vein of 5 day-old larvae was performed with or without antithrombotic pre-treatment. Platelet-like structures (PLS) derived from human megakaryocytes transfected with miR-126 were also evaluated for procoagulant activity. Finally, we studied the correlation between miR-126 level and thrombin generation markers in a cohort of stable cardiovascular patients. Control zebrafish developed small thrombocyte-rich thrombi at the site of vessel injury, without vessel occlusion. The miR-126 transgenic line developed an occluding thrombus in 75% (95% CI: 51-91%) of larvae. Pre-treatment with the direct thrombin inhibitor argatroban, but not aspirin, prevented vessel occlusion in the transgenic line (0% occlusion, 95%CI: 0-18%). Upon activation, human PLS showed an increased procoagulant profile after miR-126 transfection compared to control. Finally, the plasma levels of miR-126, but not a control platelet-derived miRNA, correlated with markers of in vivo thrombin generation in a cohort of 185 cardiovascular patients. Our results from three complementary approaches support a key role for miR-126 in platelet-supported thrombin generation and open new avenues in the tailoring of antithrombotic treatment.

An unusual thrombus location in a Heartmate 3TM device with fatal outcome.

Even if the HeartMate 3TM left ventricular assist device is associated with excellent outcomes, complications, such as pump thrombosis continue to affect patients on hemodynamic support. We report the history of a 68-year-old man who underwent implantation of an HeartMate 3TM as a bridge to transplantation. Nineteen months later, he developed signs of heart failure leading to cardiogenic shock. Neither clinical examination nor parameters from the device allowed a clear-cut diagnosis. Only surgical exploration revealed the presence of clots between the polyethylene terephthalate (Dacron®) and polytetrafluoroethylene tubes. This constitutes a weakness of this device for which we propose to the manufacturer for minimal modifications to overcome the problem.

[Contraception and venous thromboembolism]. / Contraception et maladie thromboembolique veineuse.

Combined oral contraceptives remain in 2020 the most used contraceptive method in Switzerland and Europe, and are found in about half of venous thromboembolism (VTE) occurring in women aged up to 50 years. In this narrative review, we describe the determinants of the VTE risk, related to the types of oral contraceptives and to genetic or acquired risk factors of users, while summarizing several current recommendations of prescription for contraceptives. The complex management of contraception at the time of VTE should be discussed with patients, in order to minimize the risks of undesired pregnancy, abnormal uterine bleeding and recurrent VTE.

En 2020, la contraception orale combinée reste la méthode contraceptive la plus utilisée en Suisse et en Europe, et son usage est retrouvé dans environ la moitié des événements de maladie thromboembolique veineuse (MTEV) des femmes de moins de 50 ans. Dans cette revue narrative, nous décrivons les déterminants du risque de MTEV en fonction du type de contraceptif et des facteurs de risque acquis ou génétiques des utilisatrices, en se basant sur les recommandations actuelles de prescription. La gestion de la contraception lors d'un événement de MTEV reste complexe et doit alors être discutée avec la patiente, afin de minimiser les problèmes de grossesse non désirée, de ménorragies et de récidive thromboembolique.

[Venous thrombotic risk related to SARS-CoV-2†: prevalence, recommendations and perspectives]. / Risque thrombotique veineux induit par le SARS-CoV-2†: prévalence, recommandations et perspectives.

Since the SARS-CoV-2 pandemic outbreak, growing evidence suggests that patients suffering from COVID-19 are at increased risk of thrombotic events. The sepsis-related activation of the coagulation combined with a high prevalence of common thrombotic risk factors could contribute to this prothrombotic state. Coagulation biomarkers could help in the identification of patients at risk of complications and mortality. The incidence of venous thromboembolic events appears to be increased, especially in severe COVID-19 patients. Based on that knowledge, several societies have provided recommendation on the prevention of venous thromboembolism. In this narrative review, we summarize available epidemiologic data on venous thromboembolism and recommendations on thromboprophylaxis in COVID-19.

Depuis le début de l'épidémie de SARS-CoV-2, des faisceaux d'évidences suggèrent que les patients souffrant de COVID-19 sont à risque augmenté d'événements thrombotiques. L'activation de la coagulation secondaire au sepsis associée à des facteurs de risques thrombotiques classiques pourrait contribuer à cet état prothrombotique. Les marqueurs de la coagulation semblent stratifier le risque de détérioration clinique et de mortalité. Le risque de la maladie thromboembolique veineuse (MTEV) semble très élevé, notamment chez les patients sévèrement atteints. Dans ce contexte, de nombreuses sociétés savantes ont émis des recommandations pour la prévention de la MTEV. Nous proposons une mise à jour des connaissances actuelles sur les données épidémiologiques disponibles et sur les recommandations pour la prévention de la MTEV dans le COVID-19.

Obstetrical and postpartum complications in women with hereditary fibrinogen disorders: A systematic literature review.

INTRODUCTION: Hereditary fibrinogen disorders (HFD) are rare quantitative or qualitative fibrinogen anomalies, including afibrinogenaemia (A), hypofibrinogenaemia (H), dysfibrinogenaemia (D) and hypodysfibrinogenaemia (HD). As fibrinogen plays an essential role in pregnancy, we addressed the issue of obstetrical and postpartum complications in women with HFD. METHODS: A systematic literature review, restricted to English manuscripts, was conducted according to the PRISMA guidelines. We searched through the MEDLINE database for English articles, published from January 1985 until November 2018, focusing on pregnancy in A, H, D and HD. A total of 198 articles were identified, 15 articles were added from other sources. Overall, 213 articles were screened and 54 were included in the final analysis. RESULTS: A total of 188 pregnancies from 70 women were analysed. About half of pregnancies resulted in miscarriage; more specifically in 15 (42.9%), 36 (46.8%), 27 (42.9%) and 4 (30.8%) of A, H, D and HD patients, respectively. Preterm complications were also frequent (33.5%). Metrorrhagia, mainly in the first trimester, was observed in 21.7% of the pregnancies. Placenta abruption was reported in 5 (14.3%), 4 (5.2%), 5 (7.9%) and 1 (7.7%) of A, H, D and HD, respectively. A total of 24 (12.7%) deliveries were complicated by postpartum thrombotic events (3.2%) or postpartum haemorrhage (9.6%). A fibrinogen replacement therapy was introduced in 30% of pregnancies, as prophylaxis (81.1%) or on demand (18.9%). CONCLUSION: These results suggest that women with HFD are at high risk of obstetrical and postpartum complications. Prospective international registries may allow to identify more precisely the incidence of obstetrical and postpartum adverse outcomes and their management.

Management of bleeding and invasive procedures in haemophilia A patients with inhibitor treated with emicizumab (Hemlibra® ): Proposals from the French network on inherited bleeding disorders (MHEMO), the French Reference Centre on Haemophilia, in collaboration with the French Working Group on Perioperative Haemostasis (GIHP).

INTRODUCTION: Emicizumab (Hemlibra® ) recently became available and requires an adaptation for managing bleeding, suspected bleeding and emergency or scheduled invasive procedures in haemophilia A patients with inhibitor. This implicates a multidisciplinary approach and redaction of recommendations for care that must be regularly adapted to the available data. AIM: The following text aims to provide a guide for the management of people with haemophilia A with inhibitor treated with emicizumab in case of bleeding or invasives procedures. METHODS: The French network on inherited bleeding disorders (MHEMO), the French Reference Centre on Haemophilia (CRH), in collaboration with the French Working Group on Perioperative Haemostasis (GIHP) have been working together to make proposals for the management of these situations. RESULTS: Haemostatic treatment and other medications should be given stepwise, according to the severity and location of the bleeding or the risk of bleeding of the procedure as well as the haemostatic response obtained at each step in order to ensure an optimal benefit/risk ratio. CONCLUSION: The lack of data means that it is only possible to issue proposals rather than recommendations.

Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points-Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC).

RATIONALE: The P2Y12 receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Platelet inhibition by clopidogrel shows wide interpatient variability, and high on-treatment platelet reactivity is a risk factor for atherothrombotic events, particularly in high-risk populations. CYP2C19 polymorphism plays an important role in this variability, but heritability estimates suggest that additional genetic variants remain unidentified. The aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify genetic determinants of clopidogrel pharmacodynamics and clinical response. STUDY DESIGN: Based on the data published on www.clinicaltrials.gov, clopidogrel intervention studies containing genetic and platelet function data were identified for participation. Lead investigators were invited to share DNA samples, platelet function test results, patient characteristics, and cardiovascular outcomes to perform candidate gene and genome-wide studies. RESULTS: In total, 17 study sites from 13 countries participate in the ICPC, contributing individual patient data from 8,829 patients. Available adenosine diphosphate-stimulated platelet function tests included vasodilator-stimulated phosphoprotein assay, light transmittance aggregometry, and the VerifyNow P2Y12 assay. A proof-of-principle analysis based on genotype data provided by each group showed a strong and consistent association between CYP2C19*2 and platelet reactivity (P value=5.1 × 10-40). CONCLUSION: The ICPC aims to identify new loci influencing clopidogrel efficacy by using state-of-the-art genetic approaches in a large cohort of clopidogrel-treated patients to better understand the genetic basis of on-treatment response variability.