Direct oral anticoagulant use in patients with thrombophilia, antiphospholipid syndrome or venous thrombosis of unusual sites: A narrative review.

Direct oral anticoagulants (DOACs) are indicated in the treatment and prevention of venous thromboembolism (VTE). However, the use of DOACs in unusual VTE, including cerebral venous thrombosis (CVT) and splanchnic venous thrombosis (SVT), and in patients with biological thrombophilia including minor thrombophilia (Factor V Leiden and prothrombin G20210A), major innate thrombophilia (protein C and S deficiency, and antithrombin) and major acquired thrombophilia (antiphospholipid syndrome [APS]), remains controversial due to the paucity of available data. There are some reports of DOACs use in the initial treatment or long-term maintenance of patients with either CVT or SVT, but their efficacy remains unclear. The efficacy of DOACs may be suitable in patients with biological minor or major thrombophilia. The use of DOACs for the long-term maintenance of patients with APS is more contentious. Randomized clinical trials, which are currently underway, should offer definitive insight into the efficacy and safety profiles of DOACs in these patient populations.

Dosing issues with non-vitamin K antagonist oral anticoagulants for the treatment of non-valvular atrial fibrillation: Why we should not underdose our patients.

Non-vitamin K antagonist oral anticoagulants (NOACs) - dabigatran, rivaroxaban, apixaban and edoxaban - are well established in terms of preventing stroke or systemic embolism in patients with non-valvular atrial fibrillation and high thromboembolism risk. When prescribed incorrectly, NOACs are associated with an increased risk of ischaemic events and bleeding. Current NOAC labels explicitly address dose adjustments according to age, body weight, renal function and concomitant treatment with P-glycoprotein inhibitors. The required dose adjustments vary significantly from molecule to molecule, thereby creating a complex dose adjustment environment. Furthermore, recommendations support assessment of individual risk using thromboembolic and bleeding risk scores. Evidence-based medicine also provides data about specific patient profiles. In particular, some patients who are at higher risk of bleeding, such as patients on polymedication, are often at higher risk of stroke. More and more patients are being treated with NOACs. The question of appropriate dosing has become important, as studies are starting to show that reduced doses are being prescribed at very high rates. Although these data have not been evaluated in light of individual risk assessments, in everyday practice, physicians are often more concerned about drug-related bleeding than about the spontaneous evolution of the disease (stroke/systemic embolism), leading to high rates of prescription of inadequately low doses. Recent results have shown that only certain risk criteria justify dose reduction. Thus, the right dose needs to be prescribed for the right patient in order to obtain, in real-life practice, the benefits of NOACs that have been demonstrated in randomized clinical trials.

Aortitis and aortic occlusion in Crohn disease.

Patients with Crohn disease (CD) or ulcerative colitis are known to be at increased risk of arterial thromboembolic complications. We report the case of a 33-year-old woman suffering from CD for 19 years who presented lower limb claudication. Computed tomography scan revealed an aortoiliac occlusion extending from the level of the inferior mesenteric artery to both iliac bifurcations. Endovascular recanalization was attempted as a first option but failed. We then performed an aortobi-femoral bypass through a left retroperitoneal approach that allowed a total relief of the symptoms. Histologic study of the aorta demonstrated a nonspecific aortitis with lymphohistiocytic cell infiltration in the media and adventitia tunica. There was no signs of associated vasculitis. At the light of a literature review, we discussed our surgical strategy and the inflammation of the aortic wall as local factor of thrombosis that has never been previously described.

Platelet antiaggregation therapy and subinguinal endovascular revascularization.

BACKGROUND: Platelet antiaggregation therapy (PAT) is widely acknowledged to be a positive prognostic factor after revascularization, either at the coronary or the peripheral level. This study evaluated the results of infrainguinal endovascular procedures performed for critical ischemia, in accordance with patient compliance to clopidogrel treatment. MATERIALS AND METHODS: This retrospective study included patients who underwent infrainguinal endovascular therapy for critical ischemia between January 2003 and December 2009. For 1 month, patients received the same postoperative PAT protocol: aspirin associated with clopidogrel, and then clopidogrel in the long term. Patient follow-up was set at 3 months, 6 months, 1 year, and then yearly thereafter. Survival rates, primary patency (PP), and limb salvage (LS) were studied in accordance with therapy compliance. Patients were classified into 2 groups: group 1 for compliant patients and group 2 for noncompliant patients in the long term. From January 2003 to December 2009, 153 infrainguinal endovascular procedures were performed on 150 patients experiencing critical ischemia who had benefited from the authors' postoperative PAT protocol. RESULTS: Both groups were comparable in terms of comorbidity. Of the procedures performed in groups 1 (N = 105) and 2 (N = 45), 62.8% (n = 66) and 44.4% (n = 20), respectively, were femoral, 14.3% (n = 15) and 22.2% (n = 10), respectively, were infrapopliteal, and 22.9% (n = 24) and 33.4% (n = 15), respectively, were mixed. Mean follow-up time was 30.3 ± 20.2 months (range, 1-70 months). The survival rate was comparable between the groups (P = 0.46). PP and LS rates were significantly higher in group 1 than in group 2 (PP: 84% vs. 80%, respectively, at 1 year, 79% vs. 50%, respectively, at 2 years, 65% vs. 30%, respectively, at 3 years, and 60% vs. 18%, respectively, at 4 years; P = 0.02; LS: 92% vs. 78%, respectively, at 1 year, 86% vs. 62%, respectively, at 2 years, 80% vs. 55%, respectively, at 3 years, and 77% vs. 36%, respectively, at 4 years; P = 0.04). CONCLUSIONS: This study shows that in common practice, 31% of patients stop their clopidogrel therapy, with a negative impact on PP and LS. These results indicate that medical follow-up after endovascular surgery must be reinforced.

Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: results from the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) randomized study.

OBJECTIVES: We investigated whether maintenance therapy with clopidogrel 150 mg/day produces greater platelet inhibition than the standard 75-mg/day dose and whether the higher maintenance dose increases platelet inhibition in low responders to clopidogrel 75 mg/day. BACKGROUND: Patients show interindividual variability in their platelet response to clopidogrel. Low responders could potentially obtain greater clinical benefit from greater doses of clopidogrel. METHODS: One hundred fifty-three elective percutaneous coronary intervention patients were randomized to clopidogrel 150 mg/day (n = 58) or 75 mg/day (n = 95) for 4 weeks, with vasodilator-stimulated phosphoprotein assay-guided switching to clopidogrel 150 mg/day after 2 weeks in low responders (platelet reactivity index >or=69%). All patients received aspirin 75 mg/day. RESULTS: After 2 weeks, clopidogrel 150 mg/day produced a significantly lower platelet reactivity index than clopidogrel 75 mg/day (43.9 +/- 17.3% vs. 58.6 +/- 17.7%; p < 0.0001). The proportion of low responders was significantly lower in patients randomized to clopidogrel 150 mg/day than in those randomized to clopidogrel 75 mg/day (8.6% vs. 33.7%; p = 0.0004). In the clopidogrel 75 mg/day group, 64.5% (20 of 31) of low responders became responders after switching to clopidogrel 150 mg/day for 2 weeks. No major bleeds occurred during the study; the incidence of minor bleeds was similar in each treatment group. CONCLUSIONS: In elective percutaneous coronary intervention patients, a 150-mg/day clopidogrel maintenance dose produces greater inhibition of platelet function than clopidogrel 75 mg/day. In low responders to clopidogrel 75 mg/day, switching to clopidogrel 150 mg/day overcomes low responsiveness in a majority of patients. These findings warrant further clinical evaluation. (VASP-02; EudraCT number: 2004-005230-40).

Megakaryocyte-restricted MYH9 inactivation dramatically affects hemostasis while preserving platelet aggregation and secretion.

Mutations in the MYH9 gene encoding the nonmuscle myosin heavy chain IIA result in bleeding disorders characterized by a macrothrombocytopenia. To understand the role of myosin in normal platelet functions and in pathology, we generated mice with disruption of MYH9 in megakaryocytes. MYH9Delta mice displayed macrothrombocytopenia with a strong increase in bleeding time and absence of clot retraction. However, platelet aggregation and secretion in response to any agonist were near normal despite absence of initial platelet contraction. By contrast, integrin outside-in signaling was impaired, as observed by a decrease in integrin beta3 phosphorylation and PtdIns(3,4)P(2) accumulation following stimulation. Upon adhesion on a fibrinogen-coated surface, MYH9Delta platelets were still able to extend lamellipodia but without stress fiber-like formation. As a consequence, thrombus growth and organization, investigated under flow by perfusing whole blood over collagen, were strongly impaired. Thrombus stability was also decreased in vivo in a model of FeCl(3)-induced injury of carotid arteries. Overall, these results demonstrate that while myosin seems dispensable for aggregation and secretion in suspension, it plays a key role in platelet contractile phenomena and outside-in signaling. These roles of myosin in platelet functions, in addition to thrombocytopenia, account for the strong hemostatic defects observed in MYH9Delta mice.

Plasma glycoprotein V levels in the general population: normal distribution, associated parameters and implications for clinical studies.

Soluble glycoprotein V (sGPV) is a new plasma marker of thrombosis released from the platelet surface by thrombin. sGPV levels are increased in patients with atherothrombotic diseases, but the determinants of sGPV levels are unknown in the general population. Identification of these potential confounding factors is needed for correct design and analysis of clinical studies on cardiovascular diseases. The aim of this study was to determine the normal range of plasma values and the factors controlling sGPV levels in a population of normal individuals. Three hundred blood donors were recruited at the Etablissement Français du Sang-Alsace for the measurement of plasma levels of sGPV, platelet factor 4 (PF4), thrombin-antithrombin complexes (TAT) and D-dimers. The plasma level of sGPV was (median [interquartile range]) 27.5 [23.5-34.4] microg/l and displayed a Gaussian distribution. sGPV had a lower interindividual coefficient of variation (33%) than PF4 (176%), TAT (87%) or D-dimers (82%). sGPV levels were independent of age and sex but sensitive to red cell (r = 0.412; p < 0.0001) and platelet counts (r = 0.267; p = 0.001), total cholesterol (r = -0.313; p < 0.0001), food intake (r = 0.184; p = 0.0014) and smoking (r = -0.154; p = 0.039). Contrary to PF4 and TAT, sGPV did not differ between venous and arterial blood samples of 12 healthy individuals. Red cell and platelet counts, total cholesterol, current smoking and recent food intake are important determinants of sGPV levels and must be taken into account in clinical studies using sGPV as a thrombosis marker. Normal distribution of sGPV levels in the general population supports its use in clinical applications.

Platelet-derived serotonin mediates liver regeneration.

The liver can regenerate its volume after major tissue loss. In a mouse model of liver regeneration, thrombocytopenia, or impaired platelet activity resulted in the failure to initiate cellular proliferation in the liver. Platelets are major carriers of serotonin in the blood. In thrombocytopenic mice, a serotonin agonist reconstituted liver proliferation. The expression of 5-HT2A and 2B subtype serotonin receptors in the liver increased after hepatectomy. Antagonists of 5-HT2A and 2B receptors inhibited liver regeneration. Liver regeneration was also blunted in mice lacking tryptophan hydroxylase 1, which is the rate-limiting enzyme for the synthesis of peripheral serotonin. This failure of regeneration was rescued by reloading serotonin-free platelets with a serotonin precursor molecule. These results suggest that platelet-derived serotonin is involved in the initiation of liver regeneration.

[Atherothrombosis: transposition of the models to the clinic and reciprocally]. / Athérothrombose: transposition des modèles a la clinique et réciproquement.

The transposition of experimental models to clinical situations in the atherothrombosis field will be illustrated by two examples: in one hand, the steps of the discovery of drugs such as ticlopidine and clopidogrel, the identification of their molecular targets on blood platelets and the pharmacological consequences of these developments; on the other hand, the setting up of a model of localized arterial thrombosis in mice, with two degrees of severity which react differentially to antithrombotic drugs. The main features of these models will be compared to clinical situations such as unstable angina and myocardial infarction.

Soluble platelet glycoprotein V is a marker of thrombosis in patients with ischemic stroke.

BACKGROUND AND PURPOSE: The diagnosis and management of patients with acute ischemic stroke still lack an informative biochemical test. Soluble glycoprotein V (sGPV) is a new plasmatic marker of thrombosis released from the platelet surface by thrombin. The objective of this prospective study was to compare the levels of sGPV in stroke and control patients. METHODS: Consecutive patients with acute ischemic stroke (n=159) and controls (n=70) were recruited for sGPV measurement. RESULTS: Plasmatic levels of sGPV were significantly increased in ischemic stroke compared with control patients (median [interquartile range] 39.4 [31.8 to 52.9] versus 28.1 [24.0 to 37.9] ng/mL; P<0.0001). In multivariate analysis, ischemic stroke was the major determinant of the sGPV increase (odds ratio [95% CI], 5.87 [2.62 to 13.12]; P<0.0001). CONCLUSIONS: sGPV is a new marker of arterial thrombosis and represents a tool to study the mechanisms involved in ischemic stroke. The increase in plasmatic sGPV observed in stroke patients supports a role of platelets and thrombin in the events leading to ischemic stroke.