Platelet transmission electron microscopy for the assessment of poor biological response to antiplatelet agent: pilot descriptive and prospective study - ELECTROSTROKE.

INTRODUCTION: Ischaemic stroke is the leading cause of adult disability. Thus, a strategy based on an efficient antiplatelet therapy has been developed. The monitoring of antiplatelet therapy is now limited to high risk and poor prognosis patients. Indeed, the biological monitoring of the antiplatelet therapy with available platelet function assays do not provide a global integrative approach. Platelet transmission electron microscopy, recently validated for assessing distinct ultrastructural abnormalities is a reliable morphological platelet structural analysis tool which could be used to collect all the ultrastructural platelet characteristics and assess the degree of activation of platelets. METHODS AND ANALYSIS: Our pilot prospective and descriptive study will include 50 consecutive patients hospitalized for an ischaemic stroke. We expect to identify ultrastructural characteristics that will be correlated with the degree of platelet activation to guide clinicians in decision making regarding the antiplatelet therapy strategy. ETHICS AND DISSEMINATION: The French Ethics Committee (comité de protection des personnes d'Ile-de-France VII) approved the information notice that will be given to participants and the protocol of this trial (protocol No 21-031).The results of the trial will be disseminated through scientific publications. TRIAL REGISTRATION NUMBER: NCT05004233.

Monitoring of biological response to clopidogrel after treatment for non-cardioembolic ischemic stroke or transient ischemic attack.

BACKGROUND AND PURPOSE: Biological response to clopidogrel prescribed after a non-cardioembolic ischemic stroke or transient ischemic attack (TIA) has been little studied. The aim of our study (AAPIX) was to assess this response and investigate the agreement between different biological assays in revealing poor responders. METHODS: Patients hospitalized following a non-cardioembolic ischemic stroke or transient ischemic attack (TIA) and prescribed clopidogrel were consecutively included from September 2013 to November 2015 in the Stroke Center of Saint-Etienne Hospital. Blood was drawn after 5 to 8 days of standard-dose clopidogrel. Light transmission aggregometry (LTA) and flow cytometric assays, using vasodilator-stimulated phosphoprotein [VASP] and CD62P, were accomplished for all patients. Transmission electron microscopy (TEM) was performed for a poor clopidogrel-responder and for a patient with discordant platelet assay results (platelet reactivity index (PRI) >50% and maximum platelet aggregation <70%), after activation with adenosine diphosphate (ADP) 10 µM. RESULTS: 72 patients were included. According to LTA, VASP assay and CD62P test results, 65%, 71% and 0% of patients, respectively, had a low response to clopidogrel, indicating poor agreement between these assays. Images of ADP-activated platelet samples from a patient manifesting a low response to clopidogrel and from a patient with discordant platelet assay results showed an ultrastructural pattern typical of activation and a state of slight activation, respectively. CONCLUSIONS: Platelet function results obtained using different assays for patients having experienced a non-cardioembolic ischemic stroke or TIA were discordant. Transmission electron microscopy could be useful in certain clinical contexts when platelet function assay results disagree.

Direct Oral Anticoagulants for the Treatment of Cerebral Venous Thrombosis.

BACKGROUND: Cerebral venous thrombosis (CVT) is an uncommon neurological condition usually treated with heparin followed by oral vitamin K antagonists (VKAs). In patients with venous thromboembolism (VTE), compared to VKAs, direct oral anticoagulants (DOACs) offer several advantages. However, there is little data concerning their use in managing CVT. AIMS: This retrospective observational study pursued 2 objectives: (1) to investigate clinical characteristics of CVT patients treated with heparin + DOACs vs. heparin + standard treatment; (2) to compare clinical outcomes. METHODS: Consecutive CVT patients recruited from January 2016 to March 2018 in 2 French university hospitals (Lyon, Saint-Etienne), and treated with DOACs or VKAs were identified. Radiological evolution, VTE, hemorrhagic events, and antithrombotic medication were recorded. Functional outcome was assessed by the modified Rankin scale score and venous recanalization was assessed by magnetic resonance imaging. RESULTS: Overall, 41 patients were included: 25 (61%) received VKAs and 16 (39%) DOACs. We identified no clinical or radiological features explaining the physicians' preference for a specific anticoagulation treatment, and age, initial clinical presentation, radiological severity, and individual risk factors thus unlikely guided the choice of anticoagulant. No DOAC patient exhibited clinical or radiological thrombosis aggravation, and the thrombosis completely vanished in 6 (40%). Two of the VKA-treated patients (28.6%) demonstrated complete venous recanalization, whereas 3 others experienced clinical or radiological aggravation versus baseline. There was no major bleeding leading to hospitalization in both groups. CONCLUSION: The collected data on DOAC efficacy and safety in CVT management appear encouraging, yet needs to be confirmed by larger prospective randomized clinical trials.

Role of platelet α2-adrenoreceptor in biological low response to Clopidogrel for patients with non cardioembolic ischemic stroke or transient ischemic attack.

BACKGROUND AND PURPOSE: Low biological response to Clopidogrel prescribed after non cardioembolic ischemic stroke or transient ischemic attack (TIA) is a major clinical problem and could explain the recurrence of vascular events. Platelet α2-adrenoreceptors are involved in the high residual platelet reactivity in stable coronary artery disease patients on dual antiplatelet therapy. In the present study we investigated the impact of platelet α2-adrenoreceptors on ADP-induced platelet aggregation and on ADP-induced platelet membrane CD62P (P-selectin) expression, a marker of platelet activation on blood samples from patients hospitalized at the acute phase of a non cardioembolic ischemic stroke or TIA. METHODS: 72 consecutive patients were prospectively recruited over the course of two years in a monocentric study. Patients received a daily 75 mg-dose of Clopidogrel. ADP-induced platelet aggregation was measured alone, with low dose epinephrine or with atipamezole, a selective α blocker of α2-adrenoreceptors, by Light Transmittance Aggregometry (LTA). Platelet membrane expression of P-selectin was measured by flow cytometry with either ADP alone or combined with epinephrine. RESULTS: Epinephrine at low dose stimulated ADP-induced platelet membrane expression of CD62P whereas Atipamezole significantly inhibited 10 µM ADP-induced platelet aggregation. CONCLUSIONS: Our study showed the role of platelet α2-adrenoreceptors in biological low response to Clopidogrel for patients hospitalized for a non-cardioembolic ischemic stroke or TIA. Atipamezole could improve the status of biological response to Clopidogrel.

Brain magnetic resonance imaging findings in cryptogenic stroke patients under 60 years with patent foramen ovale.

PURPOSE: To compare magnetic resonance imaging (MRI) brain feature in cryptogenic stroke patients with patent foramen ovale (PFO), cryptogenic stroke patients without PFO and patients with cardioembolic stroke. MATERIALS AND METHODS: The ethics committee required neither institutional review board approval nor informed patient consent for retrospective analyses of the patients' medical records and imaging data. The patients' medical files were retrospectively reviewed in accordance with human subject research protocols. Ninety-two patients under 60 years of age were included: 15 with cardioembolic stroke, 32 with cryptogenic stroke with PFO and 45 with cryptogenic stroke without PFO. Diffusion-weighted imaging of brain MRI was performed by a radiologist blinded to clinical data. Univariate, Fischer's exact test for qualitative data and non-parametric Wilcoxon test for quantitative data were used. RESULTS: There was no statistically significant difference found between MRI features of patients with PFO and those with cardioembolic stroke (p<.05). Patients without PFO present more corticosubcortical single lesions (p<.05) than patients with PFO. Patients with PFO have more often subcortical single lesions larger than 15mm, involvement of posterior cerebral arterial territory and intracranial occlusion (p<.05) than patients with cryptogenic stroke without PFO. CONCLUSION: Our study suggests a cardioembolic mechanism in ischemic stroke with PFO.

[New oral anticoagulants in nonvalvular atrial fibrillation]. / Nouveaux anticoagulants oraux dans la fibrillation atriale non valvulaire.

Vitamin K antagonists (VKA) had several decades of proven efficacy in AF-related stroke prevention but the drug's numerous limitations make its implementation difficult for practitioners and patients. The drawbacks of VKA have prompted the development of new oral anticoagulants (NOAC) that are at least as efficacious and safe as warfarin in phase III trials. Dabigatran (220 and 300mg/day), rivaroxaban (20mg/day) and apixaban (10mg/day) were proved to be non-inferior compared with warfarin in the prevention of bleeding, stroke and systemic embolism. Dabigatran 300mg/day and apixaban were found to be statistically superior to warfarin in stroke reduction. All these drugs reduced the risk of intracranial bleeding compared to warfarin. Dabigatran 220mg/day and apixaban decreased the risk of major bleeding. The limitation of NOAC was an increase of gastrointestinal bleeding by dabigatran 300mg/j and rivaroxaban and myocardial infarction by dabigatran. Practitioners must also be aware of the disadvantages of these new drugs when choosing NOAC for their patients with unstable INR.

[Intracranial hemorrhages: epidemiology and implication of antithrombotic therapy]. / Hémorragies intracrâniennes : épidémiologie et implication des traitements antithrombotiques.

OBJECTIVE: Intracranial hemorrhage (ICH) is an antithrombotic treatment complication. Our study's goal is to assess the proportion of ICH occurring while the patient is on antithrombotic treatment. The secondary goal is to assess the proportion of "avoidable" ICH (anticoagulant overdosage, debatables indications). METHODS: We conducted a descriptive epidemiological single-center study of ICH during 2 years. We analyzed the type of ICH, the type of antithrombotic treatment, the level of anticoagulation and the relevance of antithrombotic treatment indication. RESULTS: Of the 400 patients admitted for an ICH, 131 (33%) were treated by antithrombotic therapy: oral anti-vitamin K anticoagulants (VKA) in 14.1% of cases and antiplatelet agents in 15.1%. Of VKA patients, overdosage rate was 30.2%. The indication of antithrombotic therapy was debatable in 18.3% of cases. CONCLUSION: Our study highlights the frequency of ICH occurring on antithrombotic therapy and the significant proportion of "avoidable" ICH.

A prospective long-term study of 220 patients with a retrievable vena cava filter for secondary prevention of venous thromboembolism.

BACKGROUND: The immediate and long-term clinical events associated with the placement and removal of a retrievable filter (ALN filter; ALN Implants Chirurgicaux; Ghisonaccia, France) remain largely unknown. METHODS: This was a prospective cohort study with an 18-month follow-up. All consecutive patients scheduled for placement of an ALN filter between April 1999 and June 2005 in the Radiology Department of our hospital were included. RESULTS: During the study period, placement of an ALN filter was indicated in 220 patients (mean age, 70.8 years), who were followed up for a median duration of 338.5 days (range, 1 to 561 days); 148 patients (67.3%) completed the 18-month follow-up. No patients were unavailable for follow-up. All patients had an acute or past venous thromboembolism. Main indications were recurrent venous thromboembolism despite adequate anticoagulation therapy (10.9%), transient bleeding event (21.8%), definitive contraindication for anticoagulant therapy (26.8%), or obligation to stop anticoagulant therapy due to major surgery, major trauma, or invasive procedure (37.7%). Filter insertion was successful in 98.6% of patients and resulted in an immediate complication in 11.8%. The median duration of filter implantation was 166 days (first to third quartiles, 34 to 478 days). Meanwhile, 17.0% (37 of 217 patients) had at least one venous thromboembolic event. Filter retrieval was attempted in 25.3% of patients after a median of 51 days (range, 6 to 352 days); removal was successful at the first attempt in 92.7% of patients. CONCLUSIONS: The filter could be easily inserted and successfully removed up to 1 year after insertion. Its safety and efficacy in preventing pulmonary embolism should be properly assessed in a randomized study.

Factors predictive of venous thrombotic complications in patients with isolated superficial vein thrombosis.

OBJECTIVE: Superficial vein thrombosis may be complicated with venous thromboembolism. We examined factors predictive of venous thromboembolism in superficial vein thrombosis, which, to our knowledge, had not been prospectively studied before. DESIGN AND METHODS: We performed post hoc analysis of the STENOX trial, a prospective randomized controlled trial that investigated various antithrombotic therapies in 427 hospitalized patients with objectively confirmed symptomatic isolated superficial vein thrombosis. The value of various baseline characteristics as predictive factors of venous thrombotic complications at 3 months was studied with logistic regression. Venous thrombotic complications were defined as deep vein thrombosis or pulmonary embolism, or recurrence or proximal extension of superficial vein thrombosis. RESULTS: Venous thrombotic complications occurred in 78 patients. Independent predictive factors for complications were superficial vein thrombosis of recent onset (odds ratio [OR], 3.01; 95% confidence interval [CI], 1.44-6.27), severe chronic venous insufficiency (OR, 2.75; CI, 1.10-6.89), male gender (OR, 2.17; CI, 1.28-3.68), and history of venous thromboembolism (OR, 2.07; CI 1.06-4.04). Deep vein thrombosis or pulmonary embolism occurred in 19 patients. Only severe chronic venous insufficiency was an independent predictor of this complication (OR, 4.50; CI, 1.30-15.61). CONCLUSIONS: After symptomatic isolated superficial vein thrombosis, venous thrombotic complications are relatively frequent, and are more likely to occur in men, in patients with a history of venous thromboembolism or with severe chronic venous insufficiency, or in whom superficial vein thrombosis is recent. Knowledge of such predictive factors may be useful for determining appropriate treatment in patients with superficial vein thrombosis and for designing future phase III clinical trials.

Superficial vein thrombosis: risk factors, diagnosis, and treatment.

Superficial vein thrombosis (SVT) risk factors are close to those of venous thromboembolism (VTE). Diagnosis is made in a clinical setting but ultrasonography is useful to eliminate concomitant deep vein thrombosis (DVT). For SVT of the lower limbs, which is the main location, varicose veins represent the principal cause but underlying conditions (e.g.: autoimmune diseases, malignancy or thrombophilia) must be sought in idiopathic, migrant or recurrent SVT and in the absence of varicose veins. Concomitant DVT and pulmonary embolism can occur in approximately 15% and 5% respectively. Historical treatments consist of anti-inflammatory agents plus elastic stockings and, in case of varicose veins, thrombectomy and stripping. Other treatments (anticoagulants, vein ligation) were assessed to limit the VTE risk. A one-month prophylactic dose of low molecular weight heparin plus elastic stockings could be the appropriate strategy in most cases. Other studies are needed before definitive conclusions can be drawn.