Elevated factor XI is associated with increased risk of recurrent cerebral venous sinus thrombosis: a cohort study.

Cerebral venous sinus thrombosis (CVST) has no identified cause in 15% of cases. Elevated factors (F) VIII and FXI have been associated with thromboembolism, but data on CVST are limited. We hypothesized that elevated plasma FVIII and FXI predispose to first and recurrent CVST. In 50 CVST survivors aged < 60 years, following anticoagulant cessation and in 50 controls, we determined plasma FVIII and FXI, along with fibrin clot properties: lysis time, permeability, maximum D-dimer (D-Dmax), and maximum rate of D-dimer increase (D-Drate). We recorded CVST recurrence during a follow-up of 58.5 (55.0-60.0) months. Plasma FVIII was 22.7% higher in CVST than in controls, with elevated FVIII > 150% in 13 (26%) vs. 4 (8%) patients, respectively (p = 0.02). Median FXI tended to be higher in CVST vs. controls (110.5 [99.0-117-0]% vs. 104.5 [97.0-116.0]%, p = 0.07), while FXI > 120% was observed more commonly in the former group (12 [24%] vs. 4 [8%], respectively, p = 0.03). Patients with FVIII > 150% were less likely to achieve complete recanalization compared with the remainder (2 [15.4%] vs. 28 [75.7%], respectively; p < 0.001). Eight patients (16%) experienced CVST recurrence. They had higher baseline FXI, but not FVIII, as compared with the remainder (125.5 [114.5-140.0]% vs. 107.5 [102.0-117.0]%, respectively, p = 0.01). Patients with FXI > 120% were four times more likely to have recurrent CVST (5 [62.5%] vs. 7 [16.7%], respectively; p = 0.01). Plasma FXI > 120% could represent a novel risk factor for first and recurrent CVST. Given advances in anti-FXI agents, CVST might be another indication for this emerging treatment.

Elevated plasma factor XI predicts cardiovascular events in patients with type 2 diabetes: a long-term observational study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) patients are at high risk of cardiovascular (CV) events. Factor XI (FXI) is associated with arterial thromboembolism, including myocardial infarction (MI), stroke, and CV mortality. The role of FXI in T2DM is unknown. We investigated whether plasma FXI is associated with CV events in T2DM patients in long-term observation. METHODS: In 133 T2DM patients (aged 66 ± 8 years, 40.6% women, median T2DM duration 5 [2-10] years) we assessed plasma FXI levels, along with fibrin clot properties, thrombin generation, and fibrinolysis proteins. A composite endpoint of MI, stroke, or CV death, as well as CV mortality alone were assessed during a median follow-up of 72 months. RESULTS: Plasma FXI above the 120% upper normal limit was detected in 25 (18.8%) patients and showed positive association with LDL cholesterol and thrombin activatable fibrinolysis inhibitor, but not glycated hemoglobin, inflammatory markers or thrombin generation. The composite endpoint (n = 21, 15.8%) and CV death alone (n = 16, 12%) were more common in patients with elevated FXI (hazard ratio [HR] 10.94, 95% confidence interval [CI] 4.46-26.87, p < 0.001 and HR 7.11, 95% CI 2.61-19.31, p < 0.001, respectively). On multivariable analysis, FXI remained an independent predictor of the composite endpoint and CV death, regardless of concomitant coronary artery disease. CONCLUSIONS: To our knowledge, this study is the first to show that in T2DM patients, elevated FXI could predict major CV events, including mortality, which suggest that anti-FXI agents might be a potential novel antithrombotic option in this disease.

Elevated factor XIa as a modulator of plasma fibrin clot properties in coronary artery disease.

INTRODUCTION: Patients with coronary artery disease (CAD) display a prothrombotic fibrin clot phenotype, involving low permeability and resistance to lysis. The determinants of this phenotype remain elusive. Circulating tissue factor (TF) and activated factor XI (FXIa) are linked to arterial thromboembolism. We investigated whether detectable active TF and FXIa influence fibrin clot properties in CAD. METHODS: In 118 CAD patients (median age 65 years, 78% men), we assessed Ks, an indicator of clot permeability, and clot lysis time (CLT) in plasma-based assays, along with the presence of active TF and FXIa. We also analysed proteins involved in clotting and thrombolysis, including fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and thrombin activatable thrombolysis inhibitor (TAFI). During a median 106 month (interquartile range 95-119) follow-up, myocardial infarction (MI), stroke, systemic thromboembolism (SE) and cardiovascular (CV) death were recorded. RESULTS: Circulating TF and FXIa, detected in 20.3% and 39.8% of patients, respectively, were associated with low Ks and prolonged CLT. Solely FXIa remained an independent predictor of low Ks and high CLT on multivariable analysis. Additionally, fibrinogen and PAI-1 were associated with low Ks, while PAI-1 and TAFI-with prolonged CLT. During follow-up low Ks and prolonged CLT increased the risk of MI and the latter also a composite endpoint of MI, stroke/SE or CV death. CONCLUSIONS: To our knowledge, this study is the first to show that circulating FXIa is associated with prothrombotic fibrin clot properties in CAD, suggesting additional mechanisms through which FXIa inhibitors could act as novel antithrombotic agents in CAD.

Cardiac Magnetic Resonance Shows Improved Outcomes in Patients with an ST-Segment Elevation Myocardial Infarction and a High Thrombus Burden Treated with Adjuvant Aspiration Thrombectomy.

There is a discrepancy between epicardial vessel patency and microcirculation perfusion in a third of patients treated with percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). Optimization with aspiration thrombectomy (AT) may reduce distal embolization and microvascular obstruction. The effect of AT in the treatment of STEMI is debatable. The purpose of this study was to use cardiac magnetic resonance (CMR) to determine whether AT influences microvascular obstruction (MVO), infarct size and left ventricular (LV) remodelling in STEMI patients. Sixty STEMI patients with a thrombus-occluded coronary artery were randomized in a 2:1 fashion to receive PCI proceeded by AT (AT + PCI group), or PCI only. MVO, myocardial infarct size and LV remodelling were assessed by CMR during the index hospitalization and 6 months thereafter. The majority of patients had a large thrombus burden (TIMI thrombus grade 5 in over 70% of patients). PCI and AT were effective in all cases. There were no periprocedural strokes. CMR showed that the addition of AT to standard PCI was associated with lesser MVO when indexed to the infarct size and larger infarct size reduction. There were less patients with left ventricle remodelling in the AT + PCI vs. the PCI only group. To conclude, in STEMI patients with a high thrombus burden, AT added to PCI is effective in reducing infarct size, MVO and LV remodelling.

Activated factor XI is associated with increased factor VIIa - Antithrombin complexes in stable coronary artery disease: Impact on cardiovascular outcomes.

BACKGROUND: Coronary artery disease (CAD) is associated with a prothrombotic tendency including increased factor (F) VIIa-antithrombin (FVIIa-AT) complexes, a measure of tissue factor (TF) exposure, and activated FXI (FXIa). We investigated whether increased FVIIa-AT complexes are associated with FXIa and active TF and if major adverse clinical outcomes are predicted by the complexes in CAD. METHODS: In 120 CAD patients, we assessed FVIIa-AT complex concentrations and the presence of circulating FXIa and active TF. Levels of 8-iso-prostaglandin F2α (8-iso-PGF2α), interleukin-6, high-sensitivity C reactive protein, prothrombin fragment 1 + 2, and free Tissue Factor Pathway Inhibitor were determined. Myocardial infarction (MI), ischemic stroke, systemic thromboembolism (SE), and cardiovascular (CV) death were recorded separately and as a composite endpoint, during follow-up. RESULTS: FVIIa-AT complexes were positively associated with current smoking and multivessel CAD. Elevated FVIIa-AT complexes characterized patients with circulating FXIa and/or active TF in association with increased plasma isoprostanes but not with thrombin generation or inflammatory markers. During a median follow-up of 106 months (interquartile range 95-119), high baseline levels of FVIIa-AT complexes predicted ischemic stroke/SE (HR 4.61 [95% CI 1.48-18.42]) and a composite endpoint of MI, stroke/SE, and CV death (HR 7.47 [95% CI 2.81-19.87]). CONCLUSIONS: This study is the first to show that high FVIIa-AT complexes characterize advanced CAD patients with detectable FXIa and active TF, which is, in part, driven by oxidative stress. High FVIIa-AT complexes were associated with the risk of ischemic stroke/SE during long-term follow-up, highlighting the need for effective antithrombotic agents in CAD.

Paraoxonase 2 C311S single nucleotide polymorphism is associated with type C lesions in coronary atherosclerosis.

BACKGROUND: Paraoxonases (PON) 1-3 are lactonases with antioxidant and atheroprotective properties. The best known single nucleotide polymorphisms (SNPs) within the PON family, include: Q192R (rs662), L55M (rs854560) in the PON1 gene and C311S (rs7493) in the PON2 gene. Their influence on the occurrence and course of coronary artery disease (CAD) is unclear. The aim of this study was to assess the association between the most common PON1 and PON2 genetic variants with the presence of CAD, as well as their relation to coronary lesion complexity in accordance with the ACC/AHA standard. METHODS: We included 1027 individuals: 367 CAD patients qualified for coronary angiography and 660 healthy volunteers as controls. We extracted DNA from circulating blood leukocytes, amplified the PON1 and PON2 genetic sequence and used restriction enzymes to identify the SNPs. Patients with CAD underwent coronary angiography and were assigned to two groups based on lesion severity: patients with at least one type C lesion and without a type C lesion. The former where categorized into those with a significant narrowing (≥50% diameter stenosis) and those without one. RESULTS: We found no association between the analyzed SNPs and symptomatic CAD. However, in patients with diagnosed CAD, the PON311S allele was independently associated with the risk of the most complex type C coronary lesion occurrence. CONCLUSIONS: Our study is the first report of an association between PON2 311S SNP and the type of coronary atherosclerotic lesions in humans.

Active factor XI is associated with the risk of cardiovascular events in stable coronary artery disease patients.

BACKGROUND AND AIMS: Tissue factor (TF) and activated factor XI (FXIa) have been associated with acute coronary syndrome, ischemic stroke and venous thromboembolism. Their predictive value in stable coronary artery disease (CAD) is unclear. We investigated whether active TF and FXIa were associated with clinical outcomes in CAD patients in long-term observation. METHODS: In 124 stable patients with multivessel CAD, we assessed the presence of circulating, active TF and FXIa by measuring a response of thrombin generation to respective inhibitory antibodies. We recorded the composite endpoint of myocardial infarction (MI), stroke, systemic thromboembolism and cardiovascular death during follow-up (median 106 months, interquartile range 95-119). RESULTS: Circulating FXIa and active TF were detected in 40% and 20.8% of the 120 patients (aged 65.0 [57.0-70.3] years, men, 78.3%), who completed follow-up. The composite endpoint occurred more frequently in patients with detectable active TF and FXIa present at baseline (hazard ratio [HR] 4.02, 95% confidence interval [CI] 2.26-7.17, p < 0.001 and HR 6.21, 95% CI 3.40-11.40, p < 0.001, respectively). On multivariate analysis FXIa, but not active TF, was an independent predictor of the composite endpoint, as well as MI, stroke/systemic thromboembolism, and cardiovascular death, when analyzed separately. CONCLUSIONS: To our knowledge, this study is the first to show that circulating FXIa predicts arterial thromboembolic events in advanced CAD, supporting a growing interest in FXIa inhibitors as novel antithrombotic agents.

Profilin 1 and Mitochondria-Partners in the Pathogenesis of Coronary Artery Disease?

Atherosclerosis remains a large health and economic burden. Even though it has been studied for more than a century, its complex pathophysiology has not been elucidated. The relatively well-established contributors include: chronic inflammation in response to oxidized cholesterol, reactive oxygen species-induced damage and apoptosis. Recently, profilin 1, a regulator of actin dynamics emerged as a potential new player in the field. Profilin is abundant in stable atherosclerotic plaques and in thrombi extracted from infarct-related arteries in patients with acute myocardial infarction. The exact role of profilin in atherosclerosis and its complications, as well as its mechanisms of action, remain unknown. Here, we summarize several pathways in which profilin may act through mitochondria in a number of processes implicated in atherosclerosis.

Role of the Wnt signalling pathway in the development of endothelial disorders in response to hyperglycaemia.

INTRODUCTION: Diabetes mellitus (DM) is the most common metabolic disease. A WHO report from 2016 indicates that 422 million people worldwide suffer from DM or hyperglycaemia because of impaired glucose metabolism. Chronic hyperglycaemia leads to micro- and macrovessel damage, which may result in life-threatening complications. The Wnt pathway regulates cell proliferation and survival by modulating the expression of genes that control cell differentiation. Three linked Wnt pathways have been discovered thus far: a ß-catenin-dependent pathway and two pathways independent of ß-catenin - the planar cell polarity pathway and calcium-dependent pathway. The Wnt pathway regulates genes associated with inflammation, cell cycle, angiogenesis, fibrinolysis and other molecular processes. AREAS COVERED: This review presents the current state of knowledge regarding the contribution of the Wnt pathway to endothelial ageing under hyperglycaemic conditions and provides new insights into the molecular basis of diabetic endothelial dysfunction. CONCLUSION: The ß-catenin-dependent pathway is a potential target in the prophylaxis and treatment of early-stage diabetes-related vascular complications. However, the underlying molecular mechanisms remain largely undetermined and require further investigation.

Percutaneous management of long and diffused coronary lesions using newer generation drug-eluting stents in routine clinical practice: long-term outcomes and complication predictors.

INTRODUCTION: Long and diffuse coronary lesions (LDCLs) are routinely subjected to percutaneous management, but long­term clinical outcomes and complication predictors with the use of contemporary stents and techniques remain undetermined. OBJECTIVES: The aim of the study was to address long­term effects of percutaneous management of LDCLs, using contemporary devices and optimization techniques. PATIENTS AND METHODS: Long and diffuse coronary lesion was defined as a lesion requiring an implantation of 30 mm or longer total stent(s) length (TSL) into one coronary artery (bailouts excluded). There were 290 LDCL interventions with the use of newer generation drug­eluting stents (DESs; cobalt chromium everolimus- or zotarolimus-eluting stents) performed between January 2013 and January 2016. RESULTS: The mean (SD) TSL was 55.5 (16.8) mm. The use of intravascular ultrasound / optical coherence tomography was 17.1%, rotablation, 6.9%, and noncompliant balloon, 88.9%. The median (range) follow­up duration was 831 (390-1373) days. All­cause mortality and cardiac death rates were 11.7% and 6.9%, respectively. The myocardial infarction (MI) rate was 6.6%, including target­vessel MI in 4.1%. The rate of clinically­driven repeat revascularization was 13.8%, and of definite or probable LDCL stent thrombosis, 7.2%. Overall patient­oriented adverse event rate (any death, MI, or repeat revascularization) was 25.5%, and device­oriented rate (cardiac death, target vessel­MI, or target lesion restenosis), 13.4%. Adverse outcome predictors were chronic kidney disease, acute coronary syndrome as an indication for the procedure, chronic heart failure with reduced left ventricular ejection fraction, multivessel disease, and coexisting peripheral artery disease, but not lesion­related factors, such as bifurcation, calcification, chronic total occlusion, or TSL. CONCLUSIONS: Adverse outcomes following contemporary LDCL management using newer generation DESs in routine clinical practice are associated with clinical patient characteristics rather than lesion characteristics or TSL. We identified high­risk patient cohorts that may benefit from enhanced surveillance.

Adaptation of global hemostasis to therapeutic hypothermia in patients with out-of-hospital cardiac arrest: Thromboelastography study.

BACKGROUND: The use of mild therapeutic hypothermia (MTH) in patients after out-of-hospital cardiac arrest (OHCA) who are undergoing primary percutaneous coronary intervention (pPCI) can protect patients from thromboembolic complications. The aim of the study was to evaluate the adaptive mecha- nisms of the coagulation system in MTH-treated comatose OHCA survivors. METHODS: Twenty one comatose OHCA survivors with acute coronary syndrome undergoing imme- diate pPCI were treated with MTH. Quantitative and qualitative analyses of physical clot properties were performed using thromboelastography (TEG). Two analysis time points were proposed: 1) during MTH with in vitro rewarming conditions (37°C) and 2) after restoration of normothermia (NT) under normal (37°C) and in vitro cooling conditions (32°C). RESULTS: During MTH compared to NT, reaction time (R) was lengthened, clot kinetic parameter (a) was significantly reduced, but no effect on clot strength (MA) was observed. Finally, the coagulation index (CI) was significantly reduced with clot fibrinolysis attenuated during MTH. The clot lysis time (CLT) was shortened, and clot stability (LY60) was lower compared with those values during NT. In vitro cooling generally influenced clot kinetics and reduced clot stability after treatment. CONCLUSIONS: Thromboelastography is a useful method for evaluation of coagulation system dysfunc- tion in OHCA survivors undergoing MTH. Coagulation impairment in hypothermia was associated with a reduced rate of clot formation, increased weakness of clot strength, and disturbances of fibrinoly- sis. Blood sample analyses performed at 32°C during MTH, instead of the standard 37°C, seems to enhance the accuracy of the evaluation of coagulation impairment in hypothermia.

Antiplatelet and anticoagulant agents for primary prevention of thrombosis in individuals with antiphospholipid antibodies.

BACKGROUND: Antiphospholipid syndrome (APS) is an autoimmune disease characterised by the presence of antiphospholipid (aPL) antibodies that have prothrombotic activity. Antiphospholipid antibodies are associated with an increased risk of pregnancy complications (recurrent miscarriage, premature birth, intrauterine growth retardation) and thrombotic events (both arterial and venous). The most common thrombotic events include brain ischaemia (stroke or transient ischaemic attack) and deep vein thrombosis. To diagnose APS, the presence of aPL antibodies in two measurements and at least one thrombotic event or pregnancy complication are required. It is unclear if people with positive aPL antibodies but without any previous thrombotic events should receive primary antithrombotic prophylaxis. OBJECTIVES: To assess the effects of antiplatelet or anticoagulant agents versus placebo or no intervention or other intervention on the development of thrombosis in people with aPL antibodies who have not had a thrombotic event. We did not address obstetric outcomes in this review as these have been thoroughly addressed by other Cochrane Reviews. SEARCH METHODS: We searched the Cochrane Vascular Specialised Register (4 December 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) (last search 29 November 2017), MEDLINE Ovid, Embase Ovid, CINAHL, and AMED (searched 4 December 2017), and trials registries (searched 29 November 2017). We also checked reference lists of included studies, systematic reviews, and practice guidelines, and contacted experts in the field. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared any antiplatelet or anticoagulant agents, or their combinations, at any dose and mode of delivery with placebo, no intervention, or other intervention. We also included RCTs that compared antiplatelet or anticoagulant agents with each other or that compared two different doses of the same drug. We included studies performed in people of any age and with no history of thrombosis (as defined by APS Sapporo classification criteria or updated Sydney classification criteria), but with aPL antibodies confirmed on at last two separate measurements. The studies included both pregnant women who tested positive for aPL antibodies and had a history of recurrent obstetric complications, as well as non-pregnancy related cases with positive screening for antibodies, in accordance with the criteria mentioned above. DATA COLLECTION AND ANALYSIS: Pairs of authors independently selected studies for inclusion, extracted data, and assessed the risk of bias for the included studies and quality of evidence using GRADE. Any discrepancies were resolved through discussion or by consulting a third review author when necessary. In addition, one review author checked all the extracted numerical data. MAIN RESULTS: We included nine studies involving 1044 randomised participants. The studies took place in several countries and had different funding sources. No study was at low risk of bias in all domains. We classified all included studies as at unclear or high risk of bias in two or more domains. Seven included studies focused mainly on obstetric outcomes. One study included non-pregnancy-related cases, and one study included both pregnancy-related cases and other patients with positive results for aPL antibodies. The remaining studies concerned women with aPL antibodies and a history of pregnancy failure. Four studies compared anticoagulant with or without acetylsalicylic acid (ASA) versus ASA only and observed no clear difference in thrombosis risk (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.25 to 3.77; 4 studies; 493 participants; low-quality evidence). No major bleeding was reported, but minor bleeding risk (nasal bleeding, menorrhagia) was higher in the anticoagulant with ASA group as compared with ASA alone in one study (RR 22.45, 95% CI 1.34 to 374.81; 1 study; 164 participants; low-quality evidence). In one study ASA was compared with placebo, and there were no clear differences in thrombosis (RR 5.21, 95% CI 0.63 to 42.97; 1 study; 98 participants; low-quality evidence) or minor bleeding risk between the groups (RR 3.13, 95% CI 0.34 to 29.01; 1 study; 98 participants; low-quality evidence), and no major bleeding was observed. Two studies compared ASA with low molecular weight heparin (LMWH) versus placebo or intravenous immunoglobulin (IVIG), and no thrombotic events were observed in any of the groups. Moreover, there were no clear differences in the risk of bleeding requiring transfusion (RR 9.0, 95% CI 0.49 to 164.76; 1 study; 180 participants; moderate-quality evidence) or postpartum bleeding (RR 1.30, 95% CI 0.60 to 2.81; 1 study; 180 participants; moderate-quality evidence) between the groups. Two studies compared ASA with high-dose LMWH versus ASA with low-dose LMWF or unfractionated heparin (UFH); no thrombotic events or major bleeding was reported. Mortality and quality of life data were not reported for any of the comparisons. AUTHORS' CONCLUSIONS: There is insufficient evidence to demonstrate benefit or harm of using anticoagulants with or without ASA versus ASA alone in people with aPL antibodies and a history of recurrent pregnancy loss and with no such history; ASA versus placebo in people with aPL antibodies; and ASA with LMWH versus placebo or IVIG, and ASA with high-dose LMWH versus ASA with low-dose LMWH or UFH, in women with aPL antibodies and a history of recurrent pregnancy loss, for the primary prevention of thrombotic events. In a mixed population of people with a history of previous pregnancy loss and without such a history treated with anticoagulant combined with ASA, the incidence of minor bleeding (nasal bleeding, menorrhagia) was increased when compared with ASA alone. Studies that are adequately powered and that focus mainly on thrombotic events are needed to draw any firm conclusions on the primary prevention of thrombotic events in people with antiphospholipid antibodies.

Zinc oxide nanoparticles impair the integrity of human umbilical vein endothelial cell monolayer in vitro.

Disruption of the intercellular interactions between endothelial cells leads to endothelial dysfunction. The role of nanoparticles in plasma membrane stability, actin cytoskeleton organization and intercellular junctions is unclear. Human umbilical vein endothelial cells were treated with zinc oxide NPs in vitro. Cell shape, adhesiveness and plasma membrane integrity were analyzed by means of optical fluorescence microscopy, scanning electron microscopy and flow cytometry methods. Additionally, lactate dehydrogenase activity assay and annexin V staining were performed. The scanning electron microscopy analysis showed changes in morphology and surface topography. The F-actin organization was typical for migrating cells. Cell membrane damage (significant increase in lactate dehydrogenase release and annexin V staining) was observed in the concentration of ZnO nanoparticles above 30 microg/ml. The relationship between ZnO nanoparticles and endothelial dysfunction was clearly established and the importance of cytoskeleton reorganization and loosening of the continuous endothelial monolayer after nanoparticles exposure has been documented.