Combination oral antiplatelet therapy may increase the risk of hemorrhagic complications in patients with acute ischemic stroke caused by large artery disease

Introduction

The association between the frequency or severity of bleeding complications and combination antiplatelet therapy for acute stroke treatment is not understood in detail. This retrospective study investigated whether combination oral antiplatelet therapy for cases with acute ischemic stroke due to large artery disease increased the incidence of hemorrhagic complications.

Materials and Methods

We reviewed 1335 consecutive patients who were admitted to our department within 7 days of the onset of an ischemic stroke or transient ischemic attack between April 2005 and November 2009. We enrolled 167 patients with > 50% stenosis or occlusion in culprit major vessels and who were administered oral antiplatelet agents within 48 hours of admission. Hemorrhagic complications were classified according to the bleeding severity index. We studied the association between the incidence and severity of hemorrhagic complications during hospitalization and the clinical characteristics, including antiplatelet therapy.

Results

Fifty-nine and 108 patients were treated with only 1 antiplatelet agent and combination antiplatelet agents, respectively. Fourteen patients developed bleeds (3 major and 11 minor), and all of the major bleeds occurred in those given combination agents. The proportion of patients receiving combination agents was significantly higher in those with significant bleeds. Multivariate logistic regression analysis revealed that being older and receiving combination agents were independent predictors for significant bleeds during hospitalization.

Conclusions

Despite the retrospective nature of this study, our findings suggest that the incidence of hemorrhagic complications increases in patients with acute ischemic stroke treated with combination antiplatelet agents.     

Lipoprotein lipase Ser447Ter polymorphism associated with the risk of ischemic stroke: a meta-analysis

Introduction

Previous studies suggested lipoprotein lipase (LPL) Ser447Ter and Asn291Ser polymorphisms were associated with the risk of ischemic heart disease, however, their effects on ischemic stroke were controversial. A meta-analysis was performed to assess the associations between these two LPL polymorphisms and the risk of ischemic stroke.

Methods

The electronic databases PubMed and Embase were used to identify relevant studies by two interviews independently. The pooled odds ratios (ORs) and weighted mean differences (WMD) with 95% confidence interval (CI) were estimated for the risk of ischemic stroke and the plasma lipids in various Ser447Ter genotypes respectively. A fixed or random effect model was selected for pooling data based on homogeneity test.

Results

13 studies including 4,681 ischemic stroke cases and 8,516 controls were involved in this meta-analysis. Overall, LPL Ter447 variant was associated with a significantly reduced risk for ischemic stroke (OR = 0.79, 95% CI: 0.68-0.93) both in Caucasian (OR = 0.87, 95% CI: 0.77-0.97) and East-Asian (OR = 0.65, 95% CI: 0.43-0.99), whereas no significant association of Ser291 variant was observed (OR = 1.25, 95% CI: 0.96-1.63). The Ser447Ter polymorphism may be more important in association with the decreased risk of atherosclerotic stroke (OR = 0.44, 95% CI: 0.32-0.62) which derived from significantly increased high density lipoprotein cholesterol, decreased triglyceride and total cholesterol in Ter447 carriers compared with non-carriers.

Conclusions

This meta-analysis indicated that LPL Ser447Ter polymorphism was associated with a significant reduction in the risk of ischemic stroke, especially atherosclerotic stroke subtype in both Caucasian and East-Asian.     

Evaluation of a rapid qualitative immuno-chromatography D-dimer assay (Simplify D-dimer) for the exclusion of pulmonary embolism in symptomatic outpatients with a low and intermediate pretest probability. Comparison with two automated quantitative assays

The performance of a rapid qualitative solid-phase immuno-chromatography-based D-dimer assay (Simplify D-dimer) for diagnosing pulmonary embolism (PE) was evaluated in 469 outpatients with a low or intermediate pretest probability. They were referred to the emergency department of a university hospital during a 4-month period. Test results were compared to those of two automated quantitative assays. Simplify D-dimer assay result was positive in all 47 patients in whom the diagnosis of PE was retained and in 219 of the 422 patients without PE (51.2%), leading to a sensitivity of 100% (95%CI, 92.5 to 100%), a specificity of 48.8% (95%CI, 44.0 to 53.6%) and a negative predictive value (NPV) of 100% (95%CI, 98.2 to 100%). These results compared favorably with those of the Vidas D-dimer New assay [sensitivity = 100% (95%CI, 92.5 to 100), specificity = 49.8% (95%CI, 45.0 to 54.6%) and NPV = 100% (95%CI, 98.3 to 100%)] and the STA^®-Liatest^® D-DI assay [sensitivity = 100% (95%CI, 92.5 to 100%), specificity = 48.1% (95%CI, 43.3 to 52.9%) and NPV = 100% (95%CI, 98.2 to 100%)]. The inter-observer (n = 2) variability was very good with 1.7% discordant readings and a kappa coefficient (K) value = 0.97 (95%CI, 0.93 to 1.00). In conclusion, the Simplify D-dimer assay could be a valuable tool for ruling out PE in out-patients but a specific learning course of those having to work with is required in order to minimize the number of ambiguous reading and to overcome the inter-observer variability.     

Non-clinical pharmacokinetics and pharmacodynamics of rVIII-SingleChain,a novel recombinant single-chain factor VIII

Introduction

rVIII-SingleChain (CSL627), a novel recombinant coagulation factor VIII (FVIII), is under investigation in a phase I/III clinical programme (AFFINITY) for the treatment of haemophilia A. Non-clinical studies were conducted to investigate the pharmacokinetic/pharmacodynamic profile of rVIII-SingleChain in comparison with full-length recombinant FVIII.

Materials and Methods

Binding affinity of rVIII-SingleChain for von Willebrand factor was investigated by surface plasmon resonance analysis. The pharmacokinetic profile of rVIII-SingleChain was compared with a marketed full-length recombinant FVIII concentrate (Advate^®) in haemophilia A mice, von Willebrand factor knock-out mice, Crl:CD (SD) rats, rabbits and cynomolgus monkeys. Systemic FVIII activity or antigen levels were recorded. Procoagulant activity was measured in an FeCl₃-induced arterial occlusion model and by recording thrombin generation activity (ex vivo) after administration of 200–250 IU/kg rVIII-SingleChain or full-length FVIII to haemophilia A mice.

Results

rVIII-SingleChain displayed a high affinity for von Willebrand factor (K_D = 44 pM vs. 139 pM for full-length recombinant FVIII). In all animal species tested, rVIII-SingleChain had more favourable pharmacokinetic properties than full-length recombinant FVIII: clearance was decreased and area under the curve and terminal half-life were enhanced vs. full-length recombinant FVIII, while in vivo recovery and volume of distribution were equivalent. rVIII-SingleChain showed a prolonged thrombin generation potential and prolonged procoagulant activity vs. full-length recombinant FVIII in an FeCl₃-induced arterial occlusion model.

Conclusions

rVIII-SingleChain had a higher affinity for von Willebrand factor than full-length recombinant FVIII and displayed favourable pharmacokinetic/pharmacodynamic properties in non-clinical models.     

Patients with primary antiphospholipid antibody syndrome and without associated vascular risk factors present a normal endothelial function

Introduction

Primary antiphospholipid antibody syndrome (PAPS) is characterized by venous or arterial thrombosis and positive antiphospholipid antibodies. It is controversial whether PAPS patients have early atherosclerosis. Endothelial dysfunction is an early event in the natural history of atherosclerosis. Aim of our study was to compare endothelial function of patients with PAPS and no associated risk factors with that of age- and sex-matched controls.

Materials and Methods

Patients with PAPS, carefully selected to exclude all known risk factors for cardiovascular diseases, estrogen therapy, pregnancy, intake of drugs affecting endothelial function, vitamins or antioxidants, were included in a case-control study. Controls were age- (± 5 years) and sex-matched subjects with the same exclusion criteria but without PAPS. Flow-mediated dilation of the brachial artery and some plasmatic markers of endothelial and platelet activation were measured. Measures are expressed as mean±SEM.

Results

Twenty cases (mean age 42 ± 4.0 years, 11 females) and 39 controls (mean age 41 ± 2.9, 22 females) were studied. FMD was 5.7 ± 0.8% in cases (95% CI: 4.1 to 7.3) and 6.8 ± 0.5% (5.7 to 7.9) in controls (p = NS). Plasma von Willebrand factor was 128 ± 11.3% and 134.2 ± 16.1% in cases and controls, respectively (p = NS). Soluble P-selectin and soluble CD40L were 94.1 ± 4.9 ng/ml and 0.7 ± 0.1 ng/ml in cases and 87.7 ± 4.0 ng/ml and 1.0 ± 0.2 in controls, respectively (p = NS). In a substudy, circulating progenitor and mature endothelial cells were comparable between the two groups.

Conclusions

Endothelial function in patients with PAPS and no associated risk factors is similar to that of age- and sex- matched controls. These data suggest that the alterations leading to thrombosis in PAPS concern primarily the clotting system.     

Preclinical efficacy and safety of rVIII-SingleChain (CSL627), a novel recombinant single-chain factor VIII

Introduction

The preclinical efficacy and safety of rVIII-SingleChain (CSL627), a novel recombinant single-chain factor VIII, was assessed in a series of animal studies.

Materials and Methods

In the tail-clip bleeding model, hemophilia A mice were injected with escalating doses (1–150 IU/kg) of rVIII-SingleChain, B-domain deleted (BDD) rFVIII (ReFacto AF^®), or full-length rFVIII products (Advate^®, Helixate^®). Total blood loss and the percentage of animals in which hemostasis occurred were assessed in this observer-blinded, randomized study. In a second non-randomized study in hemophilia A mice, thromboelastographic analysis, thrombin generation, and activated partial thromboplastin time assays were performed. General safety and toxicity were assessed in three animal species, including determination of the prothrombotic potential of rVIII-SingleChain in a rabbit venous thrombosis model.

Results

Under acute bleeding conditions, the effect of rVIII-SingleChain on total blood loss and hemostasis was indistinguishable from BDD and full-length rFVIII. rVIII-SingleChain and full-length rFVIII (both 20 IU/kg) corrected thromboelastographic parameters, activated partial thromboplastin time, and thrombin generation to a similar degree in hemophilia A mice. In a thrombosis model, the effect of rVIII-SingleChain on thrombus incidence was non-significant and comparable to BDD rFVIII at doses up to 500 IU/kg. Treatment with rVIII-SingleChain did not cause anaphylactic reaction or local intolerance in safety and toxicity studies, and demonstrated an excellent overall safety profile.

Conclusions

rVIII-SingleChain showed convincing hemostatic efficacy and excellent tolerability in animal studies, warranting continued investigation in human Phase I/III trials (AFFINITY).     

Plasma factor and inhibitor composition contributes to thrombin generation dynamics in patients with acute or previous cerebrovascular events

Introduction

More than 80% of cerebrovascular events are ischemic and largely thromboembolic by nature. We evaluated whether plasma factor composition and thrombin generation dynamics might be a contributor to the thrombotic phenotype of ischemic cerebrovascular events.

Materials and Methods

We studied (1) 100 patients with acute ischemic stroke (n = 50) or transient ischemic attack (TIA) (n = 50) within the first 24 hours from symptom onset, and (2) 100 individuals 1 to 4 years following ischemic stroke (n = 50) or TIA (n = 50). The tissue factor pathway to thrombin generation was simulated with a mathematical model using plasma levels of clotting factors (F)II, V, VII, VIII, IX, X, antithrombin and free tissue factor pathway inhibitor (TFPI).

Results

The plasma levels of free TFPI, FII, FVIII, and FX were higher, while antithrombin was lower, in the acute patients compared to the previous event group (all p ≤ 0.02). Thrombin generation during acute events was enhanced, with an 11% faster maximum rate, a 15% higher maximum level and a 26% larger total production (all p < 0.01). The increased thrombin generation in acute patients was determined by higher FII and lower antithrombin, while increased free TFPI mediated this effect. When the groups are classified by etiology, all stroke sub-types except cardioembolic have increased TFPI and decreased AT and total thrombin produced.

Conclusion

Augmented thrombin generation in acute stroke/TIA is to some extent determined by altered plasma levels of coagulation factors.     

Superficial vein thrombosis,thrombin generation and activated protein C resistance as predictors of thromboembolic events in lupus and antiphospholipid patients. A prospective cohort study

Introduction

Predicting thrombosis in patients with systemic lupus erythematosus (SLE) and/or antiphospholipid antibodies (aPL) is still challenging. Our objective was to determine risk factors for thrombotic events including activated protein C (APC) resistance proven by a thrombin generation (TG) assay in patients with SLE and/or aPL.

Materials and methods

We performed a prospective cohort study in a French University Hospital and tertiary care center. Ninety-two consecutive patients with SLE and/or aPL without ongoing anticoagulant treatment were enrolled. The outcome was time to thrombotic event. We evaluated clinical and laboratory variables including APC sensitivity ratio (APCsr) determined by TG. An APCsr > 90th percentile of a control population indicated APC resistance.

Results

Patients were followed-up for a median duration of 35 months (inter-quartile range: 26 to 62; 320 patient-years). Thrombosis during follow-up occurred in 18 patients. In univariate analysis, together with history of hypertension, superficial vein thrombosis (SVT) and arterial thrombosis, patients with both aPL and APC resistance had an increased risk for incident thromboembolic events (HR, 3.67[95% confidence interval, 1.31 to 10.31]). In multivariate analysis, only history of hypertension (HR, 10.77 [95% confidence interval, 3.15 to 36.83]), SVT (HR, 7.45 [95% confidence interval, 2.25 to 24.66]) and arterial thrombosis (HR, 3.31 [95% confidence interval, 1.14 to 9.55]) remained independent risk factors.

Conclusions

History of thrombosis including seemingly benign SVT have a higher predictive value for incident thrombotic events in SLE or aPL patients than APC resistance proven by TG.     

The role of IL-6, IL-8 and MCP-1 and their promoter polymorphisms IL-6 -174GC, IL-8 -251AT and MCP-1 -2518AG in the risk of venous thromboembolism: a case-control study

Introduction

Cytokines increased the risk of venous thromboembolism (VTE) in some case-control studies, but not in a prospective study. Data concerning the role of cytokines in the risk of VTE are limited. We examined in a case-control study the association of VTE and levels of interleukin (IL)-6, IL-8 and monocyte chemotactic protein-1 (MCP-1) and assessed whether promoter polymorphisms (IL-6 -174GC, IL-8 -251AT, MCP-1 -2518AG) would affect the thrombotic risk and cytokine levels.

Materials and methods

The study included 119 patients (94 women) with a first event of VTE aged between 18-60 years, and 126 healthy controls (100 women) matched for age (± 5 years). Blood was collected > 7 months after the thrombotic event. Odds ratios (ORs) were calculated per increase of cytokines levels by 1 pg/mL.

Results

ORs adjusted for age and sex were 1.520 [95% Confidence Interval (CI) 1.177 - 1.962] for IL-6, 1.095 (95% CI 1.002 - 1.196) for IL-8 and 1.000 (0.988 - 1.012) for MCP-1. With additional adjustment for ethnic composition, body mass index (BMI) and high sensitive C-reactive protein (hs-CRP), risk estimates remained significant for IL-6 and became of borderline statistical significance for IL-8. Polymorphisms did not influence the thrombotic risk and the cytokine levels in study participants.

Conclusion

VTE was associated with IL-6 and IL-8 levels, and for IL-6 this association was independent of BMI and hs-CRP. Thus far, a causal relationship between inflammation and VTE remains to be clarified and more prospective data are warranted.     

Anti-phospholipid antibodies contribute to arteriosclerosis in patients with systemic lupus erythematosus through induction of tissue factor expression and cytokine production from peripheral blood mononuclear cells

Introduction

In systemic lupus erythematosus (SLE) patients, the prevalence of arteriosclerosis obliterans (ASO) is high despite a lack of common risk factors for ASO. The main objective of this study was to investigate a possible direct role of anti-phospholipid antibodies (aPLs), which are frequently detected in SLE patients, in the pathogenesis of ASO.

Materials and Methods

We examined tissue factor (TF) expression on the monocyte surface by flow cytometric analysis in 89 SLE patients with or without ASO and/or aPLs and studied the in vitro effect of purified IgG fractions from plasma of SLE patients or normal healthy volunteers (aPLs(+) IgG, n = 8; aPLs(−) IgG, n = 6; Normal IgG, n = 6) on the expression of TF and production of TNF-α and IL-1β in healthy peripheral blood mononuclear cells (PBMCs) or isolated monocytes.

Results

We confirmed that high expression of monocyte TF was strongly associated with the prevalence of ASO and the presence of aPLs. Treatments of PBMCs with aPLs(−) IgG or normal IgG did not significantly increase expression of TF, TNF-α, and IL-1β messenger RNA (mRNA) and the production of TNF-α and IL-1β. However, stimulation of PBMCs with aPLs(+) IgG caused significant increase in expression of TF, TNF-α, and IL-1β mRNA. Moreover, aPLs(+) IgG stimulated PBMCs and significantly enhanced the production of TNF-α and IL-1β.

Conclusion

These results suggest that IgG-aPLs cause persistently high TF expression and inflammatory cytokine production by interacting with peripheral blood monocytes and lymphocytes, which may be an important mechanism in the pathogenesis of ASO peculiar to SLE patients.     

Managing pulmonary embolism from presentation to extended treatment

Pulmonary embolism (PE) remains a major healthcare problem. PE presents with a variety of non-specific symptoms, and confirmation of diagnosis involves the use of clinical risk scores, scanning techniques and laboratory tests. Treatment choice is informed by the risk of sudden death, with high-risk patients recommended to receive thrombolytic therapy or thrombectomy. Patients with less severe presentations are given anticoagulant therapy, traditionally with parenteral heparins in the acute phase of treatment, transitioning to oral vitamin K antagonists (VKAs). The limitations of these agents and the introduction of non-VKA oral anticoagulants challenge this paradigm. To date, clinical studies of four non-VKA oral anticoagulants to treat acute thrombosis have been published, and rivaroxaban is now approved for treatment and prevention of PE (and deep vein thrombosis). Rivaroxaban and apixaban alone, and dabigatran and edoxaban after parenteral anticoagulant induction, were non-inferior to enoxaparin/VKA for the prevention of recurrent venous thromboembolism; the risk of major bleeding was similar with dabigatran and edoxaban and significantly reduced with rivaroxaban and apixaban. Patients with an initial PE are recommended to receive continued anticoagulation for 3 months or longer, depending on individual risk factors, and studies of non-VKA oral anticoagulants have shown a continued benefit for up to 2 years, without a significantly increased risk of major bleeding. Given that the non-VKA oral anticoagulants are given at fixed doses without the need for routine coagulation monitoring, their adoption is likely to ease the burden on both PE patients and healthcare practitioners when longer-term or extended anticoagulation is warranted.     

Benefits and risks of oral anticoagulation for stroke prevention in nonvalvular atrial fibrillation

Nonvalvular atrial fibrillation is the most common clinically significant cardiac arrhythmia in the United States. It increases both the risk for and the severity of strokes and is associated with substantial morbidity, mortality, decreased quality of life, and related health care costs. Guidelines recommend anticoagulation therapy for the majority of patients with atrial fibrillation. Clinical trials have established that vitamin K antagonists are effective for stroke prevention for patients with atrial fibrillation for whom anticoagulation is recommended. However, vitamin K antagonists remain underutilized for a variety of reasons, including drug, physician, and patient factors. While vitamin K antagonists considerably reduce the risk of stroke, the absolute risk reduction varies according to individual patient risk factors. Accurately assessing each patient's true risk of stroke and bleeding is essential when determining which (if any) antithrombotic strategy should be used. Several stroke risk stratification schemes exist; of these, CHADS₂ is widely employed and simple. New, more sophisticated schemes may generate more precise risk estimates and better identify those patients for whom anticoagulant therapy offers a net clinical benefit. More studies are needed to determine the utility of bleeding risk stratification systems, as well as the role of surgical and interventional alternatives to anticoagulation treatment. Several novel oral anticoagulants are in (or have completed) phase 3 clinical trials. Dabigatran etexilate, approved in the United States in October 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, now offers the first oral alternative to warfarin for patients with atrial fibrillation.     

A clinical-laboratory approach contributing to a rapid and reliable diagnosis of heparin-induced thrombocytopenia

Introduction

Heparin-induced thrombocytopenia (HIT) remains a very challenging diagnosis. The first objective of this study was to compare the performance of the ID-H/PF4 PaGIA^® with the Asserachrom^® HPIA ELISA. The main purpose was to evaluate the diagnostic utility of the combination of the H/PF4 PaGIA^® with the clinical “4T's” score as a screening strategy.

Materials and Methods

102 patients with clinical suspicion of HIT were classified into risk groups using the 4T's score. The presence of HIT antibodies was assessed by two immunoassays and confirmed by a functional flow cytometric assay.

Results

Comparison of the ID-H/PF4 PaGIA^® with the Asserachrom^® HPIA ELISA demonstrated a comparable technical performance, being an excellent screening test to rule out HIT (negative predictive value or NPV = 100%). According to the 4T's score, HIT was excluded in all low risk patients (NPV = 100%). ELISA optical density levels were significantly different between all risk groups (P-values < 0.01). In contrast, due to the low positive predictive value (22%) and weak positive likelihood ratio (2.6), a positive ID-H/PF4 PaGIA^® result did not considerably increase the probability of HIT.

Conclusion

Our study confirms the combination of the 4T's score with the ID-H/PF4 PaGIA^® as a reliable strategy to rule out HIT. Yet, confirming positive ID-H/PF4 PaGIA^® results by flow cytometry within 1-2 h after blood sampling remains necessary. This novel clinical-laboratory approach can contribute in a rapid and reliable way to the definite diagnosis of HIT.