Search

International audience; The primary hemostatic function of platelets has been recognized for more than a century, but increasing experimental and clinical evidences suggest that platelets are also important mediators of cancer. Cancer indeed influences platelet physiology, and activated platelets participate in each step of cancer development by promoting tumor growth, angiogenesis, metastasis, and cancer-associated thrombosis. Based on both the results of numerous experimental models addressing the involvement of platelets in cancer progression and the results of epidemiologic studies on the use of anti-platelet drugs to prevent cancer, platelets have been proposed as a potential target to reduce the short-term risk of cancer, cancer dissemination and cancer mortality. However, the cancer-associated thrombosis and the risk of bleeding due to anti-platelet drugs are not enough evaluated in experimental models. Therefore, the interesting contribution of platelets to cancer and cancer-associated thrombosis requires the standardization of preclinical and clinical models.

Guidelines recommend a ticagrelor loading dose (LD) before PCI or a prasugrel LD at the time of percutaneous coronary intervention (PCI) in intermediate and high-risk non–ST-elevation acute coronary syndrome (NSTE-ACS). However, achieving an optimal PR inhibition at the time of PCI is critical to prevent adverse events and depends on the timing of LD intake in relation to PCI. We aimed to compare the rate of myonecrosis related to PCI in patients with NSTE-ACS receiving ticagrelor pretreatment versus prasugrel at the time of intervention. We prospectively randomized 213 patients with NSTE-ACS to a 180 mg of ticagrelor LD given as soon as possible after admission and before PCI or to a 60 mg LD of prasugrel given at the time of PCI. The primary end point was the rate of periprocedural myonecrosis as defined by an increase of >5 times the ninety-ninth percentiles in troponin-negative patients or a 20% increase in troponin-positive patients. The 2 groups were similar regarding baseline characteristics including clinical setting (p = 0.2). Procedural characteristics were also identical including the number of treated vessels and stenting procedures. Patients in the prasugrel group more often required emergent PCI (p = 0.001). Patients in the ticagrelor group had less periprocedural myonecrosis compared with those in the prasugrel group (19.8% vs 38.3%; p = 0.03). The rate of major adverse cardiovascular events and Bleeding Academic Research Consortium ≥2 at 1-month follow-up was low and similar between the 2 groups. In conclusion, a ticagrelor LD as soon as possible before PCI is superior to prasugrel at the time of PCI to prevent periprocedural myonecrosis in NSTE-ACS.

ObjectivesWe analyzed the benefit of a 600-mg clopidogrel loading dose on platelet reactivity and clinical outcomes after stenting for non–ST-segment elevation acute coronary syndrome (NSTE ACS).BackgroundHigh post-treatment platelet reactivity (HPPR = adenosine diphosphate 10 μmol·l−1[ADP]–induced platelet aggregation >70%) is a marker for low responders to dual antiplatelet therapy with increased risk of recurrent cardiovascular (CV) events after stenting for NSTE ACS.MethodsA total of 292 consecutive NSTE ACS patients undergoing coronary stenting were included and randomly received a 300-mg (n = 146) or 600-mg (n = 146) loading dose of clopidogrel at least 12 h before percutaneous coronary intervention. A single post-treatment blood sample was obtained before percutaneous coronary intervention to analyze maximal intensity of ADP-induced platelet aggregation and platelet surface expression of P-selectin. One-month follow-up CV events were recorded.ResultsThe ADP-induced platelet aggregation and expression of P-selectin were significantly lower in patients receiving 600 mg than in those receiving 300 mg (mean ± SD: 50 ± 19% vs. 61± 16%, p < 0.0001 and 0.38 ± 0.24 arbitrary units vs. 0.60 ± 0.40 arbitrary units; p < 0.0001 respectively). Persistence of HPPR was less common in patients receiving 600 mg than in those receiving 300 mg (15 vs. 25%, p = 0.03). During the 1-month follow-up, 18 CV events (12%) occurred in the 300-mg group versus 7 (5%) in the 600-mg group (p = 0.02); this difference was not affected by adjustment for conventional CV risk factors (p = 0.035).ConclusionsIn NSTE ACS patients undergoing coronary stenting, a 600-mg loading dose of clopidogrel shows its benefit on platelet reactivity and clinical prognosis.

Summary. Background and objectives: Low response toantiplatelet therapy may be a risk factor for the developmentof ischemic complications in patients with non-ST segmentelevation acute coronary syndrome (NSTE ACS) undergoingcoronary stenting. Methods: We prospectively studied theplatelet response to both clopidogrel and aspirin in 106 NSTEACS consecutive patients undergoing percutaneous coronaryintervention(PCI) with stenting. A single post-treatment bloodsample was obtained just before PCI and analyzed by plateletaggregometry using both ADP and arachidonic acid (AA) asagonists to explore the responses to clopidogrel and aspirin,respectively. Patients were divided into quartiles according tothe ADP or AA induced maximal intensity of plateletaggregation. Patients of the highest quartile (quartile 4) weredefined as the low-responders. Results: Twelve recurrentcardiovascular (CV) events occurred during the 1-monthfollow-up. Clinical outcome was significantly associated withplateletresponsetoclopidogrel[Quartile4vs.1,2,3:OR(95%CI) 22.4 (4.6–109)]. Low platelet response to aspirin wassignificantly correlated with clopidogrel low response ( P ¼0.003) but contributed less to CV events [OR (95%CI): 5.76(1.54–35.61)]. Conclusions: A post-treatment ADP-inducedplatelet aggregation performed just before PCI identifies lowresponderstodualantiplatelettherapywithanincreasedriskofrecurrent CV events.Keywords: acute coronary syndrome, aspirin, clopidogrel, non-responders, recurrent cardiovascular event, stenting.IntroductionIn combination with aspirin, clopidogrel is now the treatmentof choice to prevent stent thrombosis in patients undergoingpercutaneous coronary intervention (PCI) [1] and to reducemajor adverse cardiovascular (CV) events in patients withnon-ST segment elevation acute coronary syndrome (NSTEACS) [2,3].Nevertheless, numerous studies have reported inter-individ-ual variability in platelet response to clopidogrel [4–10] andaspirin [11], and identified patientswho didnotachieveplateletinhibition as low-responders or resistants.The concept of clopidogrel resistance has increasinglyemerged in the literature but its clinical relevance, as a riskfactor for thrombotic events, has been explored in only twosmall studies [12,13]. In these studies, response to clopidogrelwas defined as the difference between baseline and post-treatment maximal intensity of platelet aggregation [4–10].Several issues can be raised regarding this approach: first it didnot take into account the absolute level of pre and post-treatment platelet activity and second it is not suitable for dailyclinical practice as the majority of ACS patients are urgently-treated and many others are already on chronic clopidogrel oraspirin therapy at the admission to the hospital. In addition,recent studies support that post-platelet reactivity is a betterestimate of thrombotic risk rather than clopidogrel responsive-ness [5,14]Accordingly, we analyzed the inter-individual variabilityin platelet response to clopidogrel and aspirin based on a

Background The clinical benefit of ticagrelor compared to clopidogrel in ACS patients suggested off-target property. Such pleiotropic effect could be mediated by circulating endothelial progenitor cells (EPC) which are critical for vascular healing. We aimed to investigate the impact of ticagrelor on EPC in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). Methods We prospectively randomized 106 ACS patients to ticagrelor or clopidogrel. Sub-populations of CD34+ circulating progenitor cells (PC) were analyzed by flow cytometry allowing one to determine the levels of CD34+ PC, CD34+CD45+ Hematopoietic PC, CD34+133+ immature PC and CD34+KDR+ EPC on admission and at 1month. Changes in PC level were calculated as the difference between 1month and baseline value. Results The 2 groups were similar regarding baseline characteristics including PC numbers on admission. The 2 groups had similar change in overall CD34+ PC and hematopoietic CD34+45+ PC level (p=0.2). On the contrary, when considering CD34+133+ PC and CD34+KDR+ EPC, we observed that patients treated by ticagrelor had a significantly higher increase in levels of these PC subtypes compared to those treated by clopidogrel (0.23 (−0.33; 0.79) vs 0.00 (−0.5; 0.34); p=0.04 and 0.01 (−0.04; 0.05) vs −0.01 (−0.06; 0.03); p=0.02). Changes in the level of CD34+CD133+ PC correlated with platelet activity measured by the VASP index (r=−0.30; p=0.008). By contrast the increase in the level of CD34+KDR+ EPC in the ticagrelor group was independent of platelet activity. Conclusions Ticagrelor increases the number of EPC in ACS patients suggesting a benefit on endothelial regeneration that may participate in the pleiotropic property of the drug.

Summary. Objectives: To evaluate the association of thrombin-activatable fibrinolysis inhibitor (TAFI) gene polymorphisms with the risk of coronary heart disease (CHD) and with TAFI levels measured by a newly developed enzyme-linked immunosorbent assay (ELISA) (TAFI-1B1), shown to be a reliable method for detecting quantitative variations in circulating TAFI. Patients/Methods: Six polymorphisms (C-2599G, G-438A, Ala147Thr, Thr325Ile, C + 1542G and T + 1583A) were genotyped and baseline plasma concentrations of TAFI were measured in a nested case–control design as part of the Prospective Epidemiological Study of Myocardial Infarction (PRIME) Study. Participants from France and Northern Ireland who had developed a CHD event during a 5-year follow-up (n = 321) were compared with 645 population- and age-matched control subjects. Results: In France, the Thr147 allele was more frequent in cases than in controls (0.41 vs. 0.32; P = 0.02), whereas the reverse was observed in Northern Ireland (0.33 vs. 0.38; P = 0.19) (P = 0.01 for interaction). No other polymorphism was associated with CHD risk. Consistent with the results derived from the single-locus analysis, haplotype analysis revealed that the haplotype carrying the Thr147 allele was associated with increased risk of CHD in France while the reverse tended to hold in the Northern Ireland population. Single-locus and haplotype analyses revealed that two polymorphisms, C-2599G and Ala147Thr (or T + 1583A that is in nearly complete association with it), had additive effects on TAFI levels and explained >18% of TAFI variability. This effect was homogeneous in France and Northern Ireland, and in cases and controls who exhibited similar TAFI levels. Conclusions: Thrombin-activatable fibrinolysis inhibitor gene polymorphisms are strongly associated to plasma TAFI levels, but the relation to CHD risk is less clear.

Points essentials ● L’obesite est associee a un risque accru de complications cardio-vasculaires. ● Les molecules biologiquement actives produites par le tissu adipeux seraient un des maillons essentiels de la chaine liant l’obesite a l’atherothrombose. ● Le tissu adipeux est reconnu comme un organe endocrine qui controle le metabolisme energetique. C’est une source d’hormones susceptibles de modifier certaines reponses vasculaires et de proteines anti-fibrinolytiques comme l’inhibiteur des activateurs du plasminogene de type 1, capable de favoriser l’accumulation de fibrine, de cytokines pro-inflammatoires qui vont, a distance, faciliter la reponse inflammatoire. ● Cet article a pour objectif d’aider a mieux comprendre les liens qui unissent l’activite endocrine du tissu adipeux et le risque vasculaire.

SummaryReports have reappraised the genotype-dependent variation of Thrombin Activatable Fibrinolysis Inhibitor (TAFI), demonstrating that, in some enzyme-linked immunosorbent assays (ELISA), decreased antibody reactivity towards the TAFI 325 Ile isoform led to erroneous TAFI levels. Assays free of this artefact are required to evaluate the contribution of theTAFI gene polymorphisms toTAFI level variability.TAFI levels were measured in 209 individuals with both immunological and functional assays. Each assay was characterized, in particular for its reactivity towards the 325 Thr and Ile isoforms. Two ELISAs were found to have a lower reactivity towards the Ile isoform, leading to an overesti-mate of the magnitude of variation between two different genotypes. In contrast, one ELISA, as well as functional assays, was found to be free of genotype-dependent artefact constituting a reliable method to detect true quantitative variations of TAFI levels. Using these reliable methods, univariate and haplotype analyses revealed that TAFI gene polymorphisms explain 25% of TAFI level variability. This effect seems to be the consequence of the joint independent action of two polymorphisms, one in the 5’ (G-1102T) and the other in the 3’ region (T+1583A) of the TAFI gene.

The mechanisms underlying the variability of factor VIII (FVIII) levels are still poorly understood. The only receptor of FVIII identified so far is the lipoprotein receptor-related protein (LRP), which is thought to be involved in FVIII degradation. We aimed to characterize biological and genetic factors related to FVIII variability, focusing on coding polymorphisms of the LRP gene and polymorphisms potentially detected by molecular screening of the LRP-binding domains of the FVIII gene. Plasma FVIII coagulant activity (FVIII:C) and von Willebrand factor (VWF:Ag) antigen levels were measured in a sample of 100 healthy nuclear families (200 parents and 224 offspring). The ABO blood group and the three coding polymorphisms of the LRP gene (A217V, D2080N and C766T) were genotyped. Lipids and anthropometric factors poorly contributed to the variability of FVIII:C (

Over the past 20 years, venous thromboembolism (VTE) has become the second cause of death in cancer patients, where it accounts for increased morbidity, mortality, and health-care costs. Incidental VTE is increasingly diagnosed on systematic computed tomography scan evaluations, raising new questions in daily oncology practice. The exact mechanisms underlying the increase in cancer-related VTE are not fully understood. Risk factors include patient-related, cancer-related, and treatment-related parameters which vary for a single patient throughout cancer disease and which require repeated individual risk assessments. Cumulative results from studies in cancer patients with versus without VTE suggest that anticoagulation therapy prevents morbidity and may reduce mortality. However, despite the availability of effective and safe therapeutic options, VTE is often underrecognized and sub-optimally managed. Clinical practice guidelines addressing the management of VTE in cancer patients are heterogeneous and require adequate educational and active implementation strategies. This review, resulting from an extensive literature search, aims to summarize the recently published evidence-based guidelines for treatment and prophylaxis of cancer-related VTE, as well as the place of new oral anticoagulants in the treatment strategies. Adherence to guidelines could substantially decrease the burden of VTE and increase survival in cancer patients.

We read with great interest the paper by Stratz et al. [(1)][1] on a new automated method to quantify reticulated platelets through several markers, including the immature platelet count (IPC), to predict platelet reactivity (PR). In this well-designed study, the authors observed, using a validated

Cancer is an independent and major risk factor for venous thromboembolism (VTE), defined by symptomatic or asymptomatic DVT, including catheter-related thrombosis (CRT), and/or pulmonary embolism (PE). Over the past 20 years, VTE has become the second cause of death in cancer patients, where it accounts for increased morbidity, mortality, and healthcare costs. Incidental VTE is increasingly diagnosed on systematic computed tomography in cancer patients, raising new questions in daily oncology practice. Risk factors for VTE in cancer include patient-, cancer-, and treatment-related parameters, which vary for a single patient throughout the course of cancer disease and necessitate repeated individual risk assessments. The use of biomarkers and risk assessment models allow identification of cancer patients at high risk for VTE. Anticoagulant therapy for the prophylaxis and the treatment of established VTE is efficient and relatively safe when contraindications are respected, but the variety of risk factors and the number of comorbidities remain major challenges for adequate VTE treatment in cancer patients. Several national guidelines for primary prevention and treatment of VTE in cancer patients were issued in the past 10 years. To homogeneize existing Clinical Practice Guidelines (CPGs), an international consensus working group released specific guidelines for the treatment and prophylaxis of VTE in cancer patients in 2013, so as to make each CPG easier to use at the national level. In cancer patients treated for VTE, the use of low-molecular-weight heparins (LMWHs) is preferred over other anticoagulants in most cases, and LMWHs were shown to be superior to vitamin K antagonists (VKAs). For the prophylaxis of VTE, LMWHs have been validated in surgical patients. For medical cancer patients, ongoing or recent clinical trials will inform our practice. However, several questions remain unanswered due to the number of comorbities in a single patient and expert opinion regarding special situations is required. Better adherence worldwide to CPGs necessitates adequate educational and active implementation strategies, which could substantially decrease the burden of VTE and increase survival in cancer patients.

In clinical studies, thromboprophylaxis with low-molecular-weight heparins (LMWHs) has been demonstrated to reduce the risk of venous thromboembolism and to improve outcomes in cancer patients. Moreover, preclinical models have previously suggested that LMWHs may also offer additional benefits through direct antitumor properties. However, the optimal doses of LMWHs that may prevent both cancer-related thrombosis and tumor development are yet unknown., The goal of this study was to determine the optimal doses of tinzaparin that may prevent both cancer-related thrombosis and tumor development in a syngeneic ectopic model of pancreatic cancer., The optimal doses of tinzaparin to generate a plasma anti-Xa activity >0.2IU/mL were determined in vivo following injection into wild type mice.The syngeneic ectopic model of cancer was induced in wild-type mice using the mouse pancreatic cancer cell line Panc02. Mice were injected daily with 200, 300IU/kg or 400IU/kg, or placebo from day 8 to 25 following tumor induction. Kinetics of thrombus formation and fibrin generation were determined in real time by digital real time intravital microscopy in mice bearing a tumor treated with tinzaparin or placebo. The growth of the tumor and the bleeding times were measured and compared in the different groups of mice., Plasma anti-Xa levels 0.2IU/mL were obtained with >200IU/kg tinzaparin doses. At day 25 following tumor induction, the kinetics of thrombosis were not affected in mice treated with daily 200IU/kg tinzaparin compared to controls whereas it was strongly affected in mice treated with daily 300 and 400IU/kg tinzaparin. Interestingly, a significant decrease in tumor growth was observed in mice treated with 200, 300 and 400IU/kg tinzaparin in comparison to controls, with no significant difference between these groups. Bleeding times were similar to control mice in mice treated with 200IU/kg tinzaparin, but significantly increased in mice treated with 300IU/kg and 400IU/kg tinzaparin., At the dose of 200IU/kg, tinzaparin treatment significantly inhibits tumor growth but did not affect the thrombotic phenotype in mice developing a cancer. When 300 and 400IU/kg dose are used, tinzaparin treatment decreases both cancer-related thrombotic phenotype and tumor growth, but at the price of a significant increase in the bleeding time.

Background: Symptomatic Catheter Related Thrombosis (CRT) occurs in 3-5% of cancer patients with Central Venous Catheters (CVC) and, overall, the incidence of CRT could reach 30% when including asymptomatic cases (1). In women with Breast Cancer (BC), the most frequent cancer in females world-wide, the high risk of Venous Thromboembolism (VTE) during chemotherapy may be related in part to CRT (2). We therefore designed the CAVECCAS (Cathéter VEineux Central et CAncer du Sein) study to analyze CRT incidence and CRT risk factors in BC patients with CVC receiving (neo)adjuvant chemotherapy (NAC). Methods: CAVECCAS is a prospective, multicenter cohort study of patients with non metastatic invasive BC undergoing insertion of a single lumen CVC for at least 3 months of NAC. All included patients with signed informed consent between September 2008 and December 2011 underwent repeated double-blind Doppler US evaluation before (D0) and at 7, 30 and 90 days (D) after CVC insertion. In case of VTE symptoms, diagnosis was confirmed by venography, ultrasonography and/or computed tomography. Venous blood samples were systematically drawn before and 2 days after CVC insertion to determine D-Dimers levels (VIDAS® D-Dimer Exclusion™), Platelet-derived MPs (Pd-MPs) and Pd-MPs expressing phosphatidyl serin (Pd-MP/PS+) levels (3), thrombin generation (Calibrated Automated Thrombogram assay®, Stago) and endogenous thrombin potential (ETP). After completing recruitment and follow-up (D90), a nested case-control study analyzed additional individual thrombophilic risk factors (Antithrombin, Protein C and Protein S levels, presence of Factor V and Factor II Leiden mutations, presence of antiphospholipid, anticardiolipin and antiβ2GP1 antibodies) using two controls without CRT from the CAVECCAS cohort matched for TNM status with each symptomatic or asymptomatic CRT patient. Statistical analysis used Fisher or Wilcoxon tests for univariate analysis; step down selection procedure with p-values < 0.10 for multivariate models; conditional logistic model to study the occurrence of CRT based on thrombophilia testing (open-source software R Version 2.15.2 (2012-10-26). Results(expressed as median and inter-quartile range [IQR] for quantitative data and numbers and percentages for categorical data). 524 patients with non metastatic BC (85% ductal carcinoma, 12.2% Lobular carcinoma, 2.8% other) with respective T0/T1/T2/T3/T4 staging (0.5%/47.6%/43.3%/8.0%/0.7%), SBR 1/2/3 grading (11.2%/53%/35.8%), 49.2 % having node involvement and 79.5% steroid hormone receptors, were analyzed. During follow-up, the overall CRT incidence rate was 2.18 cases/100 patient-months, with 14 symptomatic and 46 asymptomatic patients, 27, 10 and 9 of the asymptomatic CRT being respectively diagnosed on D8, 30 and day 90 US. In univariate analysis, increased age (>50 years) (OR, 1.80; 95% CI, 1.01-3.22; p=0.048), BMI> 30 kg/m² (OR, 2.64; 95% CI, 1.46-4.76; p=0.001) and comorbidities (OR, 2.05; 95% CI, 1.18-3.56; p=0.011) were associated with CRT. CRT was less frequent in ductal (OR, 0.55; 95% CI, 0.28-1.07; p=0.078) versus lobular carcinoma (OR, 2.53; 95% CI, 1.32-4.85; p= 0.005). In multivariate analysis, BMI>30 kg/m² (OR, 2.66: 99%CI, 1.46-4.84, p=0.001) and lobular carcinoma histology (OR, 2.56; 95%CI, .32-4.96, p=0.005) remained CRT risk factors. Pd-MPs (981.5 [518-2147] vs 758.5 [416.5-373] /mL; p Conclusion: In this large sample size study with serial measurements of clinical parameters and biomarkers for thrombosis, only obesity and lobular carcinoma histology appeared strong risk factors for CRT in non metastatic BC treated with NAC. Further studies will elucidate how individual stratification of BC patients may identify those who may benefit from CRT prophylaxis. 1) Debourdeau P and Farge D et al. J Thromb Haemost 2013; 11:71-80 2) Walker AJ et al. Blood 2016;127(7):849-57 3) Robert S et al J Thromb Haemost 2009;7:190-7 Disclosures No relevant conflicts of interest to declare.

Thrombin, the major enzyme of the hemostatic system, is involved in biological processes associated with several human diseases. The capacity of a given individual to generate thrombin, called the thrombin generation potential (TGP), can be robustly measured in plasma and was shown to associate with thrombotic disorders. To investigate the genetic architecture underlying the interindividual TGP variability, we conducted a genome-wide association study in 2 discovery samples (N = 1967) phenotyped for 3 TGP biomarkers, the endogenous thrombin potential, the peak height, and the lag time, and replicated the main findings in 2 independent studies (N = 1254). We identified the ORM1 gene, coding for orosomucoid, as a novel locus associated with lag time variability, reflecting the initiation process of thrombin generation with a combined P value of P = 7.1 × 10(-15) for the lead single nucleotide polymorphism (SNP) (rs150611042). This SNP was also observed to associate with ORM1 expression in monocytes (P = 8.7 × 10(-10)) and macrophages (P = 3.2 × 10(-3)). In vitro functional experiments further demonstrated that supplementing normal plasma with increasing orosomucoid concentrations was associated with impaired thrombin generation. These results pave the way for novel mechanistic pathways and therapeutic perspectives in the etiology of thrombin-related disorders.

Introduction Les patients presentant une insuffisance renale chronique ont un risque thrombotique augmente. Les anticorps IgA anti-β2 GPI ont une frequence augmentee chez les patients en hemodialyse et s’accompagnent d’une augmentation du risque de deces en particulier par maladie cardiovasculaire (CV). Cette etude prospective observationnelle a pour but de determiner si la presence d’anticorps antiphospholipides (APL) est associee a une augmentation du risque de deces et de thromboses. Patients et methodes Nous avons inclus, entre octobre et novembre 2012, 192 patients en hemodialyse chronique, d’âge moyen 66 ans, 55 % sont des hommes, 38 % sont diabetiques et 87 % hypertendus. Nous avons dose, par les methodes de reference, les APL suivants : IgA anti-β2 glycoproteine I (IgA-aβ2GPI), IgG anti-β2 glycoproteine I, IgM anti-β2 glycoproteine I, IgG anti-cardiolipine, IgM anti-cardiolipine, IgG anti-phosphatidylethanolamine, IgM anti-phosphatidylethanolamine et anticoagulants circulants (ACC). Tous les evenements ont ete recueillis prospectivement. Apres l’inclusion, les patients ont ete suivis 20 mois. Resultats Quarante pour cent des patients presentent au moins un APL, le plus frequent est l’anticorps IgA-aβ2GPI avec 26 % des patients porteurs. Nous avons analyse 179 patients (1 perdu de vue et 12 transplantes). Soixante-neuf patients sont decedes dont 40 % des cas de cause CV. Les facteurs de risque de deces sont, en analyse multivariee, la presence d’une insuffisance cardiaque (HR : 2,3, valeur de p : 0,0004), une augmentation de l’hemoglobine (HR : 1,3 par g, valeur de p : 0,024). Les facteurs protecteurs sont une augmentation de l’albumine (HR : 0,8 par g, valeur de p : p : 0,003). La presence d’un APL n’a pas d’impact sur la survenue d’un evenement thrombotique. Discussion Nous n’avons pas retrouve l’effet deletere des IgA-aβ2GPI, a l’inverse, il s’agirait d’un marqueur de bon pronostic. Nous avons etudie l’ensemble des APL et n’avons pas trouve d’impact sur la survenue des thromboses, en particulier d’abord vasculaire. Conclusion La recherche des APL chez les patients en hemodialyse chronique n’est pas utile pour identifier les patients a risque de deces ou de thrombose.

Contexte Nous rapportons la demarche diagnostique d’un syndrome hemorragique chez une fille âgee de 6 ans. Observation Une fillette de 6 ans est hospitalisee pour volumineux hematome traumatique (torsion de l’avant bras par jeu). Elle n’a pas d’antecedent hemorragique, mais l’anamnese ne revele aucune situation a haut risque. Elle est la 3eme enfant d’une fratrie de 3 et n’a pas d’antecedent hemorragique familial. Il n’y a pas de notion de consanguinite. Les parents separes de l’enfant sont en conflit ouvert et le pere gardait sa fille les jours precedant l’hospitalisation. La mere a un comportement difficile vis-a-vis du personnel. Elle s’oppose a toute intervention de la psychologue aupres de son enfant agitee. L’examen clinique est normal en dehors de l’hematome. Il n’y a ni syndrome tumoral, ni symptomatologie infectieuse. Quels examens de depart ? Plaquettes a 386 G/L ; Hb a 112 g/L ; Leucocytes a 10,6 G/L sans cellule pathologique ; TP a 36 % ; TCA et TCK > 150s ; TT > 60s ; fibrinogene a 2,56 g/l ; taux de facteurs II, VII et X diminues respectivement a 48 %, 54 % et 21 % avec FV et bilan hepatique normaux ; taux de FVIII normal (126 %), taux de FIX, FXI et FXII diminues respectivement a 35 %, 55 % et 28 % ; monomeres de fibrine et D-Dimeres negatifs. L’hypothese de CIVD est eliminee Quelles hypotheses, donnees complementaires d’interrogatoire et explorations ? Il n’y pas de notion de prise medicamenteuse (ni AVK, ni nouvel anticoagulant oral, ni heparine) ; pas de prise de substance heparine-like, pas de morsure ou piqure d’insecte. L’activite anti-Xa (heparine) est fortement positive a 1,54 UI/ml, mais l’ajout de sulfate de protamine in vivo et in vitro est sans effet. La supplementation en vitamine K per os puis IV ne modifie pas les resultats obtenus. Les hypotheses d’intoxication, empoisonnement ou envenimation sont eliminees. Quelles autres hypotheses ? On suppose la presence d’un anticoagulant circulant (ACC) puissant. Cependant, la recherche d’ACC est negative en dRVVT. Le TT sur melange reste allonge. Le diagnostic ? La generation de thrombine est a peine detectable. L’hypothese d’un inhibiteur puissant dirige contre la thrombine est evoquee devant la perturbation majeure de tous les temps de la coagulation qui detectent la formation de thrombine (TP, TCA, TT). Les 2 grandes hypotheses sont alors une cause constitutionnelle avec l’existence d’un variant antithrombine (variant Pittsburgh de l’alpha 1 antitrypsine) ou une cause acquise avec presence d’un anticorps puissant. Dans le serum, l’electrophorese des proteines revele un pic supplementaire en zone des α2-globulines, et l’immunofixation avec anticorps anti-α1-AT montre la presence de deux bandes distinctes. Le sequencage direct du gene de l’α1-AT retrouve la mutation Met 382 > Arg, en position c.1145T > G du gene, a l’etat heterozygote (ancienne nomenclature : Met358 > Arg). Ainsi le diagnostic d’une maladie hemorragique constitutionnelle rare est retenu. Conclusion Le variant Pittsburgh de l’α1-antitrypsine (α1-AT) ou « antithrombine Pittsburgh » resulte d’une substitution Met 358 > Arg sur le site reactif de l’α1-AT, lui conferant une activite antithrombine drastique. Ce variant rare, rapporte dans la litterature chez 4 patients, s’accompagne d’un syndrome hemorragique d’intensite variable.

Platelet activity is critical in coronary artery disease patients to prevent acute thrombotic complications [(1)][1]. Indeed, an extensive literature has clearly demonstrated that the level of platelet reactivity (PR) inhibition correlated with the clinical outcome including cardiovascular death

The level of platelet reactivity (PR) inhibition obtained after P2Y12-ADP receptor antagonist loading dose (LD) is associated with the ischemic and bleeding risk following percutaneous coronary intervention (PCI) in acute coronary syndromes (ACS).We aimed to evaluate the level of PR inhibition achieved by a 180 mg LD of ticagrelor and the rate of high on-treatment platelet reactivity (HTPR) in ACS patients undergoing PCI.We performed a multicentre prospective observational study enrolling ACS patients undergoing PCI. Patients were included if they were admitted for ST-elevation myocardial infarction or non ST-elevation ACS. To assess PR, a VASP index was measured at least 6 and within 24 hours following a 180 mg LD of ticagrelor. HTPR was defined as a VASP index ≥50%.One hundred and fifteen patients were included: 31.3% of STEMI, 49.6% of NSTEMI and 19.1% of unstable angina. Following ticagrelor LD the mean VASP index was 17±14%. However the response to ticagrelor was not uniform with a small inter-individual variability: inter quartile range: 7.6-22.8% and a rate of HTPR of 3.5%. A high number of patients, 65.6%, had a VASP index16%. None of the baseline characteristics of the study population was associated with PR. In addition, PR was similar in STEMI, NSTEMI and unstable angina (p=0.9).In ACS patients the level of PR inhibition achieved by a 180 mg loading dose of ticagrelor is not uniform and the rate of HTPR is 3.5%. A high proportion of patients exhibited a VASP index16%.

Objectifs La survenue d’une maladie thromboembolique veineuse chez les patients cancereux est un evenement frequent rapporte chez 15 a 20 % des patients. Differentes etudes ont rapporte une augmentation des concentrations en microparticules circulantes procoagulantes chez des patients souffrant d’un cancer, en particulier digestif. L’objectif de cette etude est de determiner le role des microparticules dans la survenue de thromboses associees au cancer. Materiel et methode Afin de caracteriser les microparticules circulantes, nous avons developpe differents modeles murins de cancer du pancreas, de cancer du poumon et de cancer colorectal. La microscopie intravitale en temps reel nous a permis de determiner in vivo les mecanismes impliques dans la genese d’un etat thrombotique lie au cancer, le role des microparticules ainsi que leur origine cellulaire. La caracterisation des microparticules plasmatiques a ete effectuee a partir d’une cohorte de malades souffrant d’un cancer du pancreas ou d’un cancer colorectal. Resultats Dans nos modeles murins de cancer, des microparticules d’origine cancereuse sont presentes dans la circulation sanguine et participent a la formation de thromboses. Contrairement aux microparticules circulantes endotheliales, leucocytaires, plaquettaires et erythrocytaires, elles expriment a leur surface des monomeres de fibrine. La presence de microparticules circulantes portant de la fibrine a ete confirmee chez des patients souffrant d’un cancer du pancreas. Ces microparticules interagissent avec l’endothelium et les plaquettes sanguines via l’expression du ligand de la selectine-P, le PSGL-1, de differentes integrines et de fibrine. Elles activent la cascade de coagulation en exprimant du facteur tissulaire a leur surface. L’inhibition des interactions entre les microparticules d’origine cancereuse, les plaquettes sanguines et l’endothelium diminue significativement la thrombose associee au cancer et le developpement de metastases. Conclusion Les microparticules d’origine cancereuse procoagulantes semblent jouer un role important dans la thrombose associee au cancer et dans le developpement de metastases. Ces microparticules qui expriment de la fibrine a leur surface peuvent etre identifiees a partir de prelevements sanguins. L’inhibition de leur interaction avec les plaquettes et l’endothelium pourrait constituer une strategie efficace afin de reduire la thrombose et egalement de limiter la progression du cancer.

Prasugrel is a new-generation thienopyridine that exhibits a more potent, less variable, and faster platelet blockade of the purinergic receptor P2Y, G-protein coupled, 12 (P2Y12) -adenosine diphosphate (ADP) receptor compared with clopidogrel, as demonstrated by the results of early phase studies

SummaryPlatelet response to clopidogrel shows inter-individual variability that is partially explained by genetic polymorphisms. This variability affects clinical outcome when clopidogrel is administered in patients with acute coronary syndrome (ACS). Catecholamines, released during ACS, contribute to platelet aggregation through platelet α2A- (α2A-AR) and β2-adrenergic receptor (β2-AR) stimulation. It was the objective of this study to assess the potential influence of α2A-AR and β2-AR gene polymorphisms on platelet reactivity after dual antiplatelet therapy with aspirin and clopidogrel in ACS. We screened 641 ACS patients for 6.3/6.7 kb α2A-AR polymorphism, and for Arg16Gly and Gln27Glu β2-AR polymorphism. After 600 mg clopidogrel, we assessed ADP 10 μmol-induced platelet aggregation (ADP-Ag) and vasoactive stimulated phosphoprotein (VASP). All single nucleotide polymorphisms were in Hardy-Weinberg equilibrium. A slight though negligible association was found between 6.3 kb allele of α2A-AR with platelet reactivity ADPAg induced (beta: –2.91 [-5.68;-0.14], p=0.04). A borderline not significant reduction in PRI VASP was observed in 6.3 kb α2A-AR carriers (beta: –3.81 [-0.09;7.72], p=0.06). No significant effect on platelet parameters was observed for the other tested polymorphisms. Common α2A- and β2-adrenergic receptor polymorphisms do not show any major impact on residual platelet reactivity in non-ST-elevation ACS when a dual antiplatelet therapy with 250 mg aspirin and 600 mg clopidogrel is administered.

A low response to clopidogrel has been associated with an increased risk of stent thrombosis. However, the definition of a nonresponse to clopidogrel remains controversial, and different tests have been used to assess the clopidogrel response. The present study was designed to assess the predictive value of adenosine diphosphate (ADP)-induced platelet aggregation (ADP-Ag) and the Platelet Reactivity Index of vasodilator-stimulated phosphoprotein for the occurrence of stent thrombosis in patients admitted for non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention. A total of 598 consecutive patients with non-ST-elevation acute coronary syndrome undergoing coronary stenting were prospectively included. They received 600 mg of clopidogrelor=12 hours before percutaneous coronary intervention. Acute or subacute definite or probable stent thrombosis occurred in 11 patients (1.8%). These patients had significantly greater ADP-Ag compared to patients free of stent thrombosis (68 +/- 14% vs 56 +/- 19%, p = 0.002) but only a trend toward a greater Platelet Reactivity Index of vasodilator-stimulated phosphoprotein (62 +/- 14% vs 53 +/- 23%, p = 0.19). The construction of receiver operating characteristic curves to examine the most predictive value of ADP-Ag for stent thrombosis gave a threshold of ADP-Ag of67% to identify low responders. These patients were at a greater risk of stent thrombosis than the clopidogrel responders (4.3% vs 0.8%, odds ratio 5.8, 95% confidence interval 1.9 to 24.6, p = 0.003). In conclusion, in patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention, ADP-Ag is a good parameter to identify clopidogrel nonresponders who are at increased risk of stent thrombosis, with a cutoff value of ADP-Ag of67%.

This study sought to compare the effect of 2 proton pump inhibitors (PPIs) on platelet response to clopidogrel after coronary stenting for non-ST-segment elevation acute coronary syndrome (NSTE ACS).Use of omeprazole has been reported to significantly decrease the clopidogrel antiplatelet effect because of cytochrome P450 interaction. Because all PPIs are metabolized by CYP2C19, but to a varying degree, we hypothesized that the reported negative omeprazole-clopidogrel drug interaction may not be caused by a class effect.A total of 104 patients undergoing coronary stenting for NSTE ACS were prospectively included and randomized to omeprazole or pantoprazole 20 mg. They received at discharge 75-mg aspirin and 150-mg clopidogrel. Platelet reactivity index (PRI) vasoactive stimulated phosphoprotein (VASP) was used to assess clopidogrel response and adenosine diphosphate (ADP)-induced aggregation for platelet reactivity (ADP-Ag).After 1 month, patients receiving pantoprazole had a significantly better platelet response to clopidogrel as assessed with the PRI VASP: 36 +/- 20% versus 48 +/- 17% (p = 0.007). We identified more clopidogrel nonresponders in the omeprazole group than in the pantoprazole group: 44% versus 23% (p = 0.04), odds ratio: 2.6 (95% confidence interval: 1.2 to 6.2). Conversely, we did not observe any significant difference in platelet reactivity with ADP-Ag between the omeprazole and pantoprazole groups: 52 +/- 15% and 50 +/- 18%, respectively (p = 0.29).The present findings suggest the preferential use of pantoprazole compared with omeprazole in patients receiving clopidogrel to avoid any potential negative interaction with CYP2C19.

Objectives We have prospectively investigated the association between aspirin and clopidogrel responses and the clinical predictors of non response. Methods 635 Non ST Elevation Acute Coronary Syndrome (NSTE ACS) patients were included and received loading doses of 250 mg aspirin and 600 mg clopidogrel. We analyzed post-treatment maximal intensity of arachidonic acid and ADP-induced platelet aggregation (AA-Ag and ADP-Ag) and Platelet Reactivity Index of VAsodilator-Stimulated Phosphoprotein (PRI VASP). Aspirin and clopidogrel non responses were defined respectively by AA-Ag > 30% and ADP-Ag > 70%. Results Aspirin non responders patients had significantly higher ADP-Ag and PRI VASP than aspirin responders: 63.7 ± 15.9% vs 55 ± 19% (p = 0.0001) and 73.6 ± 13.3% vs 53 ±23% (p = 0.0001) respectively and the rate of clopidogrel non responders was higher among aspirin non responders than aspirin responders: 36.7% vs 22.7% (p = 0.003). In addition, clopidogrel non responders had significantly higher AA-Ag and rate of aspirin non responders than clopidogrel responders: 21.6 ± 24% vs 10.3 ± 19% (p = 0.0001) and 22.8% vs 12.9% (p = 0.003) respectively. Age and Body Mass Index (BMI) were significantly associated with non response to Clopidogrel (p = 0.035 and 0.02 respectively) and diabetes mellitus by trend (p = 0.07). Conclusion We observed a relationship between aspirin and clopidogrel non responses and an association between age, BMI and diabetes mellitus and clopidogrel response.

Thrombin Activatable Fibrinolytic Inhibitor (TAFI) is a plasma protein, which inhibits fibrinolysis by removing carboxyterminal lysine residues from partially degraded fibrin thereby decreasing plasminogen binding on its surface. In this study we have investigated the antigenic level variability (Inter and Intraindividual) of Thrombin Activatable Fibrinolysis Inhibitor in 120 healthy Asian Indians since no data on this is available regarding this population. TAFI antigen levels did not show a normal distribution in our population (p0.001). Median TAFI antigen levels were found to be 11.683 microg/ml. It ranged from 33.9-202.5%of normal pool plasma (3.9-23.5 microg/ml). TAFI antigenic level showed high level of variability in the Indian population (coefficient of variation: 37.4%). TAFI antigenic levels were stable intraindividually (p=0.218).

Genetic polymorphisms of cytochrome P450 (CYP) isoforms may promote variability in platelet response to clopidogrel. This study was conducted to analyze, in 603 patients with non-ST elevation acute coronary syndromes, the effect of CYP3A4, CYP3A5, and CYP2C19 gene polymorphisms on clopidogrel response and post-treatment platelet reactivity assessed by adenosine diphosphate (ADP)-induced platelet aggregation, vasodilator-stimulated phosphoprotein phosphorylation index, and ADP-induced P-selectin expression. The CYP2C19*2 polymorphism was significantly associated with ADP-induced platelet aggregation, vasodilator-stimulated phosphoprotein phosphorylation index, and ADP-induced P-selectin expression in recessive (p0.01, p0.007, and p0.06, respectively) and codominant (p0.08, p0.0001, and p0.009, respectively) models, but the CYP3A4*1B and CYP3A5*3 polymorphisms were not. The CYP2C19*2 allele carriers exhibited the highest platelet index levels in multivariate analysis (p = 0.03). After covariate adjustment, the CYP2C19*2 allele was more frequent in clopidogrel nonresponders, defined by persistent high post-treatment platelet reactivity (ADP-induced platelet aggregation70%; p = 0.03). In conclusion, the present data suggest that the CYPC19*2 allele influences post-treatment platelet reactivity and clopidogrel response in patients with non-ST elevation acute coronary syndromes.

Introduction En chirurgie bariatrique (CB), les accidents thromboemboliques, mais aussi les accidents hemorragiques, sont des complications post-operatoires potentiellement graves et redoutees par toutes les equipes. Actuellement, les recommandations concernant la thromboprophylaxie peri-operatoire sont de bas grade. L’objectif de cette etude etait d’evaluer les pratiques dans les centres specialises d’obesite (CSO). Methodes Un questionnaire portant sur la thromboprophylaxie veineuse encadrant la CB comportant 25 questions a ete envoye par courriel aux 37 CSO. L’heure et le jour de debut de l’anticoagulation, la dose, l’adaptation au poids, la duree, et la surveillance ont ete evaluees. Resultats 92 % des CSO ont repondu. L’anticoagulant le plus utilise etait l’enoxaparine (89 %), en 2 injections/j (71 %), debutee pour la majorite 6 h apres l’intervention (74 %). Les doses variaient selon les equipes (de 4 000 a 12 000 unites/J), de meme que la duree de l’anticoagulation (7j, 9 % ; 21j, 4 7 %). La moitie des equipes realisait une adaptation posologique au poids. Une surveillance biologique etait effectuee dans 5 9 % des c as ; une seule equipe dosait l’activite anti-Xa (4 %). Une prophylaxie mecanique intermittente etait associee dans 40 % des cas. Conclusion Cette enquete montre une grande heterogeneite des pratiques dans les CSO, notamment pour l’adaptation posologique et la duree du traitement prophylactique, soulignant la necessite d’etablir des recommandations specifiques. Declaration d’interet Les auteurs n’ont pas transmis de conflits d’interets.

Background Variability in platelet response to clopidogrel and its clinical relevance have been well described. However, the underlying mechanisms remain unclear. Recently, the T744C polymorphism of the P2Y12 receptor gene has been associated with enhanced platelet aggregation in healthy volunteers, suggesting a possible mechanism for modulation of clopidogrel response. Aim of this study To assess whether the clopidogrel response may be influenced by the T744C P2Y12 gene polymorphism in patients with non ST elevation acute coronary syndrome (NSTE ACS). Methods 597 NSTE ACS patients were included in our study and were divided into 3 groups: CC homozygotes, CT heterozygotes ad TT homozygotes. All patients received loading doses of 600 mg clopidogrel and 250 mg aspirin at least 12 hours before blood samples. Clopidogrel response was assessed by post-treatment ADP 10 μmol/L-induced platelet aggregation (ADP-Ag), VASP phosphorylation (PRI VASP) and P-selectin expression (PS). Clopidogrel resistance was defined by persistence of High Post-treatment Platelet Reactivity (HPPR = ADP-Ag > 70%). Results Significant variability in the distribution of platelet parameters was observed in the overall study population. No significant difference in platelet parameter profiles was observed within patients having the same genotype, for ADP-Ag (p = 0.39), PRI VASP (p = 0.97) and PS (p = 0.62). The genotype frequencies of the T744C polymorphism of the P2Y12 gene were similar in responders and non responders defining by HPPR (p = 0.75). Conclusion Our study did not show any influence of the T744C polymorphism of the P2Y12 receptor gene on clopidogrel response assessed by ADP-Ag, PRI VASP or P-selectin expression in NSTE ACS patients.

Recent studies revisiting the association between plasma thrombin-activatable fibrinolysis inhibitor (TAFI) Ag levels and polymorphisms of the CPB2 gene (coding for TAFI) suggested that TAFI Ag levels were influenced by 2 major quantitative trait nucleotides (QTNs) in European whites. However, the strong linkage disequilibrium (LD) between CPB2 polymorphisms in European whites did not allow one to distinguish which polymorphisms could be the putative QTNs. To get a better insight into the identification of QTNs, a transethnic haplotype analysis contrasting 2 populations of African and European subjects was performed using 13 CPB2 polymorphisms. Results of the haplotype analyses suggested that 3 QTNs had independent effects and explained about 15% of the TAFI variability, consistently in the 2 populations. The lower LD observed in the African population enabled us to identify the 1583T>A SNP located in 3′UTR as one of these QTNs, whereas the -2599C>G and -2345--2344insG SNPs located in the 5′ region might be the 2 other QTNs. A phylogenetic study suggested that these 3 polymorphisms occurred before the period of migration “out of Africa.” Although this transethnic comparison contributed to better map the putative CPB2 QTNs, further studies are required to clarify the role of the promoter region.

Antithrombin (AT) is a major physiological inhibitor of hemostasis. We report 22 novel antithrombin gene (SERPINC1) mutations associated with antithrombin deficiency in 17 French and five German families. They were all present at the heterozygous state. Nine missense mutations accounted for type I deficiency, defined by equally low antithrombin activity and antigen level. Most of them (7/9) affected highly conserved serpin residues and were associated with venous thrombosis occuring at a young age (before age 32). One splice site, one nonsense mutation, three small deletions and one insertion were also identified as a cause for type I antithrombin deficiency. Seven other missense mutations were identified in type II or unclassified AT deficiency; g.5270C>T (p.T147I, T115I) and g.5281A>T (p.I151F, I119F) change residues in the heparin binding region, g.13267C>G (p.P439A, P407A) and g.13271T>C (p.F440S, F408S) affect amino acids in the pleiotropic region, g.2372G>A (p.G25D, G-8D) changes a signal peptide amino acid, g.2456G>C (p.C53S, C21S) affects one of the three disulfide bonds of the protein, and g.7585A>T (p.M347K, M315K) changes a nonconserved residue on strand 2C. © 2006 Wiley-Liss, Inc.

Platelets have recently been shown to accumulate in brain microvessels of patients with cerebral malaria and to modulate the binding of Plasmodium falciparum-infected red cells to human brain endothelium in vitro. In the present study we used a platelet-endothelial cell coculture model to investigate the mechanisms by which platelets modify the function of human brain microvascular endothelial cells (HBEC). Platelets were found to have a proapoptotic effect on TNF-activated HBEC, and this was contact-dependent, as inhibiting platelet binding prevented endothelial cell killing. We also showed that the supernatants of thrombin-activated platelets killed TNF-stimulated HBEC and that TGF-β1 was the main molecule involved in endothelial cell death, because its inhibition completely abrogated the activated-platelet supernatant effect. Our data illustrate another aspect of the duality of TGF-β1 in malaria and may provide new insights into the pathogenesis of cerebral malaria.

Increased plasma thrombin-activatable fibrinolysis inhibitor (TAFI) levels were recently shown to be a part of the insulin resistance syndrome. We investigated the relationship between plasma TAFI antigen levels and insulin resistance markers and compared these results with those obtained for PAI-1 and fibrinogen which are known to be closely related to insulin resistance syndrome and fat mass, respectively. Eighty-nine obese females had 1.3-, 1.2-, and 3-fold higher circulating TAFI, fibrinogen and PAI-1, respectively, compared with 64 lean females. Univariate analysis showed that the significance level for association between TAFI or fibrinogen concentrations and insulin resistance markers was lower than the significance level for association between PAI-1 and insulin resistance markers. Nevertheless, TAFI, fibrinogen, and PAI-1 plasma levels were significantly associated to each other. In linear stepwise ascendant analysis, insulin resistance markers accounted for 50% of the interindividual variability of plasma PAI-1 and only for 10% of plasma TAFI and 13% of fibrinogen variability. The contribution of insulin resistance markers to plasma TAFI antigen levels variability disappeared when PAI-1 or fibrinogen was entered in the statistical model. TAFI mRNA was detected in the liver but not in adipose tissue and endothelial cells. No TAFI mRNA was detected in normal or atherosclerotic vessels either. These results suggest that elevated TAFI antigen levels found in obese subjects are not independently associated with the metabolic markers of the insulin resistance syndrome. Increased plasma TAFI antigen levels in obesity might reflect a specific pathway of regulation at the liver level.

International audience

Plasma TAFI antigen (Ag) levels are almost entirely under the control of the TAFI gene.[1-3][1] Several polymorphisms found to be associated with TAFI Ag levels have been already described,[1-4][1] but a recently performed segregation-linkage analysis indicates that the TAFI-linked quantitative

Aims Premature discontinuation of antiplatelet therapy has been identified as a major risk factor for stent thrombosis and prior aspirin withdrawal has been associated with poor prognosis after acute coronary syndrome. We investigated the hypothesis that biological aspirin “resistance” may often be related to non compliance in patients undergoing coronary stenting. Methods and Results We prospectively investigated the occurrence of aspirin non compliance in 136 consecutive patients undergoing coronary stenting receiving aspirin 75 mg daily. We analyzed post-treatment maximal intensity of arachidonic acid-induced platelet aggregation (AA-Ag) during hospitalization after controlled intake of aspirin and one month after hospital discharge. After one month, all non responders received controlled aspirin 75 mg and assessment of response was repeated. Aspirin non response was defined by AA-Ag>30%. During in-hospital period, the range of AA-Ag varied from 0 to 34% with a mean value of 7.5±10% and 4 patients (3%) were classified as non responders. One month after discharge, AA-Ag of the population was significantly higher than during the hospital phase (15.3±23 vs 7.5±10%, p=0.0004) and 19 patients (14%) were identified as non responders. After controlled administration of aspirin, all but one of these “non responders” became responders and were identified as patients with non compliance rather than biological resistance. Conclusion Aspirin resistance is rare in compliant patients using methods that directly indicate the degree of platelet cyclooxygenase inhibition. More than 10% of patients receiving aspirin for coronary stenting are non compliant for aspirin therapy during the first month after stenting. These results suggest a need for improved education of these patients.

A 64 year old woman with previous history of coronary stenting five days before was admitted in our institution for intracranial bleeding while receiving aspirin and clopidogrel. At hospital discharge, platelet testing showed hyper response to antiplatelet therapy with very low post treatment platelet reactivity.

A congenital FXIII A subunit deficiency was diagnosed in a male child because of umbilical bleeding at birth. Venous infusion was difficult and prophylactic FXIII infusion was delayed. At age 1, he suffered a spontaneous intracranial haemorrhage. Substitutive FXIII was initiated, and at age 12, no other significant bleeding event had occurred. His 5 years younger brother also bears the same FXIII deficiency. The younger brother's treatment was initiated at birth and never discontinued, and no bleeding occurred. Mutation gene analysis found a homozygous four bases insertion predicting a stop codon seven residues after PRO675. Antigen assay indicated that the mutant molecule is secreted. This case highlights the importance of prophylactic FXIII infusion.

Background La thrombose et l’inflammation sont impliquees dans l’initiation et la progression de la lesion atheromateuse. Ainsi, de nombreuses cellules du compartiment vasculaire jouent un role cle dans la pathogenese de la maladie coronarienne et ses complications. Determiner precisement l’etat d’activation de ces differents types cellulaires pourrait contribuer a identifier les patients coronariens a haut risque d’evenements recurrents. Les microparticules (MP) sont des fragments de membrane desormais reconnus comme marqueurs fiables de l’activation et de l’apoptose cellulaires. Objectif Notre objectif a ete de determiner si les taux de MP issues de differents types cellulaires etaient associes a la severite des lesions atheromateuses et a la recurrence d’evenements cardiovasculaires chez des patients coronariens. Methodes et Resultats Les taux plasmatiques de MP ont ete mesures par cytometrie en flux chez 172 patients en attente de coronarographie a l’hopital de la Timone. 77 patients (46 %) ont beneficie d’une pose de stent et ont ete suivis durant 1 mois. 12 evenements recurrents ont ete rapportes pendant la periode de suivi. Dans la cohorte totale, les taux de MP positives pour le marqueur d’activation leucocytaire CD11b (MPCD11b+) etaient significativement plus eleves chez les patients traites par des statines (p = 0,001) et chez les patients ayant une fraction d’ejection preservee (p = 0,02). Les taux de MPCD11b+ etaient significativement mais negativement associes a l’etendue des lesions atheromateuses coronaires evaluee par les donnees angiographiques et par le Syntax Score, ceci meme apres ajustement sur le traitement par les statines et sur la fraction d’ejection (p = 0,005). Au sein de la population stentee, les taux de MPCD11b+ etaient significativement inferieurs chez les patients ayant presente un evenement recurrent (p = 0,0001). Cette difference restait significative apres ajustement sur le Syntax Score, sur la fraction d’ejection et sur le traitement par des statines (p = 0,03). Conclusion Les MPCD11b+ sont un marqueur biologique qui permet d’identifier les patients coronariens a haut risque de recurrence independamment de la severite des lesions observees lors de la coronarographie.