Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: A pooled analysis of three trials

Background

Three randomized, double-blind trials compared dabigatran, an oral direct thrombin inhibitor, with enoxaparin for the primary prevention of venous thromboembolism (VTE) in patients undergoing elective total hip and knee arthroplasty.

Objectives and Methods

We conducted a pre-specified pooled analysis of these trials. 8,210 patients were randomized, of whom 8,135 were treated (evaluable for safety) with dabigatran 220 mg or 150 mg once-daily, or subcutaneous enoxaparin (40 mg once-daily or 30 mg twice-daily). Efficacy analyses were based on the modified intention-to-treat population of 6,200 patients with an evaluable outcome. The common risk difference (RD) of treatment effect between each dabigatran dose and enoxaparin was estimated using fixed-effects models, and statistical heterogeneity was estimated using the I² statistic.

Results

The composite outcome of major VTE (proximal deep vein thrombosis and/or pulmonary embolism) and VTE-related mortality occurred in 3.3% of the enoxaparin group versus 3.0% of the dabigatran 220 mg group (RD vs. enoxaparin -0.2%, 95% CI -1.3% to 0.9%, I² = 37%) and 3.8% of the 150 mg group (RD vs. enoxaparin 0.5%, -0.6% to 1.6%, I² = 0%). Major bleeding occurred in 1.4% of the enoxaparin group versus 1.4% of the dabigatran 220 mg group (RD vs. enoxaparin -0.2%, -0.8% to 0.5%, I² = 40%) and 1.1% of the 150 mg group (RD vs. enoxaparin -0.4%, -1.0% to 0.2%, I² = 0%).

Conclusions

Oral dabigatran was as effective as subcutaneous enoxaparin in reducing the risk of major VTE and VTE-related mortality after hip or knee arthroplasty and has a similar bleeding profile.     

Platelet protease-activated receptor 1 and membrane expression of P-selectin in pulmonary arterial hypertension

Introduction

Pulmonary arterial hypertension (PAH) is frequently associated with thrombotic events, particularly involving the pulmonary microcirculation at sites of vascular injury. We therefore decided to analyse protease-activated receptor 1 (PAR1), a key element in the activation of human platelets by thrombin, in PAH patients in stable clinical condition.

Methods

Using flow cytometry, we analyzed platelet PAR1 density, PAR1-mediated exposure of P-selectin and the formation of platelet-leukocyte aggregates in 30 PAH patients aged 11 to 78 years (median 50.5 years). The control group consisted of 25 healthy subjects with the same age range as patients.

Results

In patients, total platelet PAR1 density and uncleaved PAR1 density correlated negatively with platelet count (r² = 0.33 and r² = 0.34 respectively, p < 0.0015). In patients with a low platelet count (< 150 × 10⁹ platelets/L), both densities were increased relative to controls (82% and 33% respectively, p < 0.05). Thrombin peptide-induced platelet exposure of P-selectin was directly related to total and uncleaved PAR1 density (respectively, r² = 0.33 and r² = 0.29, p < 0.0025) and increased in subjects with low platelet count (46% versus those with normal platelet count, p < 0.05). Patients with low platelet count had decreased in vitro thrombin-induced formation of platelet-leukocyte aggregates (57% decrease versus controls, p < 0.05).

Conclusions

There seems to be a subpopulation of PAH patients with increased propensity to thrombotic events as suggested by increased platelet PAR1 expression and PAR-mediated surface exposure of P-selectin associated with decreased platelet count.     

Systemic and local factors associated with coronary plaque disruption

Introduction

Yellow plaques are regarded vulnerable; and disrupted yellow plaques are the major cause of acute coronary syndrome. We examined the factors associated with the disruption of yellow plaques among patients and lesion characteristics.

Materials and Methods

Consecutive 161 patients with ischemic heart diseases who received coronary angioscopic examination were analyzed. Yellow plaques in the segments to which intervention had never been performed were included, and their yellow color grade and presence/ absence of disruption were examined. Associated factors for plaque disruption were examined among patients and lesion characteristics.

Results

In 161 patients, 392 yellow plaques were included for analysis and 70 of them were disrupted. Frequency of plaque disruption (= disrupted / all yellow plaques) was significantly higher at the segments of severer stenosis (stenosis≥75% vs. 75-25% vs. < 25%: 34% vs. 21% vs. 14%, p = 0.006). Multivariate analysis revealed angiographic stenosis (odds ratio [OR], 1.014; 95% confidence interval [CI], 1.005-1.023; p = 0.003), yellow color grade (OR, 3.297; 95% CI, 2.062-5.273, p < 0.001), LDL-cholesterol (OR, 1.012; 95% CI, 1.004-1.020, p = 0.003), male gender (OR, 3.608; 95% CI, 1.538-8.465; p = 0.003), and hypertension (OR, 2.552; 95% CI, 1.094-5.953; p = 0.030) as significant associated factors for plaque disruption.

Conclusion

Angiographic stenosis, yellow color grade, LDL-cholesterol, male gender, and hypertension were significantly associated with the disruption of yellow plaques.     

Efficacy and safety of enoxaparin in Japanese patients undergoing curative abdominal or pelvic cancer surgery: Results from a multicenter, randomized, open-label study

Background

Enoxaparin sodium (enoxaparin) is used worldwide for the prevention of venous thromboembolism (VTE). Registration trials of enoxaparin have been conducted primarily in Caucasian populations, and its preventive use in Japanese patients has yet to be established. To address this, we evaluated the efficacy and safety of postoperative enoxaparin in Japanese patients undergoing surgery for abdominal cancer.

Methods

This multicenter, open-label study randomized 151 Japanese patients undergoing curative surgery for abdominal cancer to enoxaparin 20 mg twice daily for 14 days, started 24-36 hours after surgery (n = 113) or intermittent pneumatic compression (IPC) as a reference (n = 38). IPC was performed at least once in both groups between randomization and surgery. The primary efficacy endpoint was the incidence of VTE in the modified intention-to-treat (mITT) population. The primary safety outcome was the incidence of any bleeding during treatment and follow-up.

Results

Incidence of VTE was 1.2% (95% CI, 0.03-6.53%) (1/83 patients) in the enoxaparin group and 19.4% (95% CI, 7.45-37.47%) (6/31 patients) in the IPC group. In the safety population, 10/109 patients in the enoxaparin group (9.2%; 95% CI, 4.49-16.23%) and 3/38 patients in the IPC group (7.9%; 95% CI, 1.66-21.38%) experienced a bleeding event. There were no cases of fatal bleeding or bleeding into any critical organ.

Conclusions

These favorable efficacy and safety data support the use of enoxaparin (20 mg twice daily for 14 days started 24-36 hours after surgery) in Japanese patients undergoing abdominal or pelvic cancer surgery.     

Lack of P-selectin glycoprotein ligand-1 protects mice from thrombosis after collagen/epinephrine challenge

Introduction

In thrombotic processes, during the association of leukocytes with platelets and endothelial cells, P-selectin glycoprotein ligand-1 (PSGL-1) binds to P-selectin, expressed on activated platelets and endothelial cells. Our aim was to establish the role of PSGL-1 in thrombus formation by evaluating the response to thrombotic stimuli in wild type and PSGL-1 knockout mice.

Materials and methods

Mice were challenged by tail vein injection of (i) 15 μg collagen plus 3 μg epinephrine (coll/epi) (ii) 7.5 μg collagen plus 1.5 μg epinephrine or (iii) saline. Retro-orbital blood samples were collected in ACD anticoagulaed tubes and platelet and leukocyte counts were measured. In addition, kidneys, liver, spleen and lungs were investigated for fibrin deposition by immunohistochemistry and Western-blotting. Frozen sections were analysed for double labeling for platelet and leukocyte presence.

Results

After coll/epi challenge, the number of platelets and leukocytes decreased significantly in both genotypes. Lower agonist concentration resulted in an attenuated platelet decrease in PSGL-1 knockout mice compared to the controls, however changes in leukocyte and neutrophil counts were not significantly different in the two strains. In knockout mice considerably less fibrin deposition has been observed in the lungs by Western-blotting and immunohistochemistry. After coll/epi challenge the lungs of the PSGL-1 knockout animals contained both platelets and leukocytes but less thrombi has been detected than in wild-type mice.

Conclusions

Our results indicate that the deficiency of PSGL-1 results in milder thrombocytopenia, less fibrin deposition and lower number of thrombosed blood vessels, suggesting that this molecule is essential for multicellular interactions during thrombus formation.     

Genome-wide association study of blood pressure response to methylphenidate treatment of attention-deficit/hyperactivity disorder

Objective

We conducted a genome-wide association study of blood pressure in an open-label study of the methylphenidate transdermal system (MTS) for the treatment of attention-deficit/hyperactivity disorder (ADHD).

Method

Genotyping was conducted with the Affymetrix Genome-Wide Human SNP Array 6.0. Multivariate association analyses were conducted using the software package PLINK. After data cleaning and quality control we tested 316,934 SNPs in 140 children with ADHD.

Results

We observed no genome-wide statistically significant findings, but a SNP in a K⁺-dependent Na⁺/Ca²⁺ exchanger expressed in vascular smooth muscle (SLC24A3) was included in our top associations at p < 1E-04. Genetic enrichment analyses of genes with ≥ 1 SNP significant at p < 0.01, implicated several functional categories (FERM domain, p = 5.0E-07; immunoglobulin domain, p = 8.1E-06; the transmembrane region, p = 4.4E-05; channel activity, p = 2.0E-04; and type-III fibronectins, p = 2.7E-05) harboring genes previously associated with related cardiovascular phenotypes.

Conclusions

The hypothesis generating results from this study suggests that polymorphisms in several genes consistently associated with cardiovascular diseases may impact changes in blood pressure observed with methylphenidate pharmacotherapy in children with ADHD.     

Efficacy of postoperative anticoagulation therapy with enoxaparin for portal vein thrombosis after hepatic resection in patients with liver cancer

Backgrounds

Enoxaparin, low-molecular-weight heparin, has become a routine thromboprophylaxis in general surgery.

Study design

A retrospective cohort study was performed in 281 patients who underwent hepatic resections for liver cancers from 2011 to 2013. These patients were divided into two groups; an enoxaparin (-) group (n = 228) and an enoxaparin (+) group (n = 53). Short-term surgical results including venous thromboembolism (VTE) and portal vein thrombosis (PVT) were compared.

Results

In the enoxaparin (+) group, the patients’ age (65 vs. 69 years; p = 0.01) and BMI (22.9 vs. 24.4; p < 0.01) were significantly higher. According to the symptomatic VTE, symptomatic pulmonary embolism occurred in one patient (0.4%) in the enoxaparin (-) group, but the complication rate was not significantly different (p = 0.63). The complication rate of PVT was significantly lower in the enoxaparin (+) group (10 vs. 2%; p = 0.04). The independent risk factors for PVT were an operation time ≥ 300 minutes (Odds ratio 6.66) and non-treatment with enoxaparin (Odds ratio 2.49).

Conclusions

Postoperative anticoagulant therapy with enoxaparin could prevent PVT in patients who underwent hepatic resection for liver cancers.     

Safety of coronary artery bypass surgery during therapeutic oral anticoagulation

Introduction

Therapeutic (international normalized ratio, INR 2.0-3.5) oral anticoagulation (TOAC) is assumed to increase perioperative bleeding complications and a standard recommendation is to discontinue warfarin before coronary bypass grafting (CABG).

Materials and Methods

To assess the safety of TOAC we retrospectively analyzed consecutive patients (n = 270) with long-term warfarin therapy referred for CABG in two centers where TOAC strategy is employed. The main in-hospital outcomes of interest were death, stroke, acute myocardial infarction, new onset renal failure, resternotomy, and their composite. In the TOAC group of 103 patients CABG was performed during therapeutic oral anticoagulation and in the control group (81 patients) preoperative INR was lowered to a subtherapeutic (≤ 1.5) level.

Results

The patients in TOAC group were more often operated on an emergency basis (p = 0.02) and their EuroSCORE was higher (p = 0.02). There were no significant differences in the major outcome events or their composite (17.5 vs. 11.1%, p = 0.30) between the groups. Patients in the TOAC group had more postoperative blood loss (941 ± 615 vs. 754 ± 610 ml, p < 0.01) and received more fresh frozen plasma (2.8 ± 3.0 vs. 1.3 ± 2.4 units, p < 0.001), but transfused red blood cells (2.1 ± 2.8 vs. 2.1 ± 3.4 units) were comparable in the groups. Preoperative clopidogrel (OR 4.8, 95% CI 1.4-16.2, p = 0.01) and enoxaparin therapy (OR 2.6, 95% CI 1.1-6.5, p = 0.04) were the only significant independent predictors for any major adverse event.

Conclusions

Our study suggests that CABG is a safe procedure during TOAC with no excess bleeding or major complications. Prospective trials are needed to confirm this observation.     

Association of elevated soluble P-selectin levels with fetal loss in women with a history of venous thromboembolism

Introduction

An association between pregnancy complications such as fetal loss with inherited and acquired thrombophilic defects has frequently been reported. Recently, the cell adhesion molecule P-selectin has been identified to be a strong risk factor for venous thromboembolism (VTE).

Patients and Methods

The aim of our study was to investigate whether soluble P-selectin (sP-selectin) is also associated with fetal loss (e.g. miscarriage or stillbirth) in 304 women (median age [25th-75th percentile]: 45 [37-54] years) with a history of VTE, in whom data on pregnancy-associated complications had been evaluated. At the time of sP-selectin measurement none of the women was pregnant or had an acute VTE.

Results

The prevalence of miscarriage was 21.4% and that of stillbirth was 4.6%. The median sP-selectin level of the total study population was 38.0 [31.7-44.4] ng/mL. In subjects with elevated sP-selectin levels (defined as sP-selectin ≥ 44.4 ng/mL, representing the 75th percentile of levels in the study population) the prevalence of stillbirth was significantly higher compared to those with lower levels (10.5% vs. 2.6%, p = 0.008), whereas no statistically significant difference in the prevalence of miscarriage was observed between women with and without elevated sP-selectin (17.1% vs. 22.9%, p = 0.303). The odds ratio [95% CI] of elevated sP-selectin was 4.2 [1.5-12.7] for stillbirth and 0.7 [0.4-1.3] for miscarriage.

Conclusions

Elevated sP-selectin plasma levels were associated with a 4.2-fold risk for stillbirth in women with a history of VTE. Our data support a possible role of P-selectin in late pregnancy loss.     

Different effects of enoxaparin and unfractionated heparin on some thrombogenesis markers during hemodialysis: a cross-over study

Background

Unfractionated heparin (UFH) and low molecular weight heparin constitute fundamental anticoagulants during hemodialysis (HD). We aimed to investigate the effect of UFH and enoxaparin on plasma levels of prothrombin fragment 1 + 2 (PF 1 + 2) and thrombin/antithrombin complex (TAT) as markers of intravascular thrombogenesis during HD.

Methods

We enrolled 22 chronic HD patients, who were randomly assigned to either iv enoxaparin (n = 11) or UFH (n = 11) anticoagulation, and followed prospectively for 12 weeks before crossing over to the alternate therapy for further 12 weeks. Plasma levels of PF 1 + 2 and TAT were measured by immunoassay at the start, at 10 and 180 min of HD session after each period of evaluation.

Results

The baseline PF 1 + 2 and TAT levels were comparable under enoxaparin and UFH treatment. PF 1 + 2 significantly decreased during both UFH (χ² ANOVA = 9.82, P = 0.007) and enoxaparin (χ² ANOVA = 29.40, P < 10^− 6) anticoagulated HD, while over-HD TAT levels changes differed depending on the type of heparin. The switch from enoxaparin to UFH treatment was connected with a significantly higher PF 1 + 2 after 10 and 180 min as well as higher TAT concentration after 180 min of HD. Only during enoxaparin anticoagulated HD 34% PF 1 + 2 decrease and TAT levels after 180 min of HD was closely associated with heparin dosage.

Conclusion

Single bolus of enoxaparin ensures efficient and convenient anti-thrombotic protection during HD procedure. Enoxaparin mean dose of 0.67 mg/kg, which is generally lower than manufacturer's instructions, can be recommended for over-dialytic regular use.     

Interleukin-10 promoter microsatellite polymorphisms influence the immune response to heparin and the risk of heparin-induced thrombocytopenia

Introduction

Heparin-induced thrombocytopenia (HIT) results from an atypical immune response with synthesis of IgG antibodies (Abs) to platelet factor 4/heparin complexes (PF4/H), and probably involves both B and T cells. We investigated whether 3 single nucleotide polymorphisms (SNPs), rs1800896 (− 1082G/A), rs1800871 (− 819C/T) and rs1800872 (− 592C/A) and the polymorphic CA repeat microsatellites IL10R [5325CA(11_15)] and IL10G [8134CA(14_29)] are associated with the synthesis of Abs to PF4/heparin and HIT.

Materials and methods

Eighty-two patients with definite HIT and two control groups were studied. The first control group (Ab^neg) consisted of 85 patients without Abs to PF4/heparin after cardiopulmonary bypass (CPB). The second control group (Ab^pos) consisted of 84 patients who had developed significant levels of PF4-specific antibodies after CPB, but without HIT.

Results

Allele frequencies of the 3 SNPs were similar in HIT patients and controls. Fourteen alleles in IL10G (G16 to G29) and 3 alleles in IL10R (R13 to R15) were defined. The short G20 allele of IL10G was more frequent in Ab^neg patients (8.2%) than in Ab^pos (2.9%) and HIT patients (3%). It thereby appeared to protect against developing Abs to PF4/heparin (OR 0.29; 95% CI [0.12-0.70], p = 0.006). Combined haplotypes cH1/cH8 comprising the short G20 + R13 alleles were less frequent in HIT (OR 0.33; 95% CI [0.11-0.97], p = 0.036), and levels of Abs to PF4 in Ab^pos patients were lower in cH1/cH8 subjects (p = 0.019).

Conclusion

These results suggest that IL10 promoter microsatellite polymorphisms might influence the immune response against PF4/heparin and the risk of HIT.     

The relationship between aortic aneurysm sac thrombus volume on coagulation, fibrinolysis and platelet activity

Aim

Abdominal aortic aneurysm (AAA) is associated with chronic mural inflammation and a pro-thrombotic diathesis. It has been suggested that both may be related to biologically active intra-sac thrombus. The aim of this study was to examine the relationship between thrombin generation, fibrinolysis, platelet activity and AAA sac thrombus volume.

Methods

30 patients (29 men) of median (IQR) age 75 (71-82) years with an infra-renal AAA > 5.5 cm in antero-posterior diameter were prospectively studied. AAA, lumen and thrombus volumes were calculated using a CT workstation (Vitrea). Plasma thrombin-antithrombin (TAT), plasminogen activator inhibitor (PAI)-1, and soluble (s) P-selectin were measured as biomarkers of coagulation, fibrinolysis and platelet activity, respectively

Results

Median (IQR) AAA total, lumen and thrombus volumes were 188 (147-247) cm³, 80 (54.3-107) cm³ and 97.6 (63-127) cm³ respectively.TAT levels were significantly higher (median, QR, 7.15 [4.7-31.3] μg/L, p = < 0.001) and sP-selectin levels significantly lower (median, IQR, 80.5 [68-128] ng/ml, p = < 0.0001) than the normal range. PAI-1 levels (median, IQR, 20.9 [8.4-50.7] ng/ml) were normal. There was no correlation between AAA thrombus volume and PAI-1 (r = − 0.25, p = 0.47), sP-Selectin (r = 0.26, p = 0.43) or TAT plasma levels (r = − 0.21, p = 0.54).

Conclusion

The present study confirms that patients with AAA demonstrate haemostatic derangement, but the extent of the haemostatic derangement does not correlate with AAA sac thrombus volume.     

Shared impairment in associative learning in schizophrenia and bipolar disorder

Background

Schizophrenia (SCZ) and bipolar disorder (BD) share some cognitive commonalities. However, the role of associative learning, which is a cornerstone of human cognition mainly relying on hippocampus, has been under-investigated. We assessed behavioral performance during associative learning in a group of SCZ, BD and healthy controls (HC).

Methods

Nineteen patients with SCZ (36 ± 8.1 years; 13 males, 6 females; all Caucasians), 14 patients with BD (41 ± 9.6 years; 5 males, 9 females; all Caucasians) and 45 HC (27.7 ± 6.9 years; 18 males, 27 females; all Caucasians) were studied. Learning was assessed using an established object-location paired-associative learning paradigm. Subjects learned associations between nine equi-familiar common objects and locations in a nine-location grid. Performance data were analyzed in a repeated measures analysis of variance with time (repeated) and group as factors.

Results

Learning curves (performance = 1−e^−k?time) fitted to average performance data in the three groups revealed lower learning rates in SCZ and BD (k = 0.17 and k = 0.34) than HC (k = 0.78). Significant effects of group (F = 11.05, p < 0.001) and time (F = 122.06, p < 0.001) on learning performance were observed.

Conclusions

Our study showed that associative learning is impaired in both SCZ and BD, being potentially not affected by medication. Future studies should investigate the neural substrates of learning deficits in SCZ and BD, particularly focusing on hippocampus function and glutamatergic transmission.     

Reduced platelet response to aspirin in patients with coronary artery disease and type 2 diabetes mellitus

Introduction

Diabetes mellitus is complicated by accelerated atherosclerosis, resulting in an increased risk of coronary artery disease (CAD) and thrombosis. Despite the proven benefits of aspirin, previous studies indicate a reduced cardiovascular protection from aspirin in diabetic patients. We aimed to investigate whether diabetes mellitus influenced the platelet response to aspirin in patients with CAD.

Materials and Methods

Platelet aggregation and activation were evaluated during aspirin treatment in 85 diabetic and 92 non-diabetic patients with CAD. Adherence to aspirin was carefully controlled. All patients had CAD verified by coronary angiography and were taking 75 mg non-enteric coated aspirin daily.

Results

Diabetic patients showed significantly higher levels of platelet aggregation compared to non-diabetic patients evaluated by VerifyNow^® Aspirin (p = 0.03) and Multiplate^® aggregometry using arachidonic acid (AA) 0.5 mM (p = 0.005) and 1.0 mM (p = 0.009). In addition, platelet activation determined by soluble P-selectin was significantly higher in diabetics compared to non-diabetics (p = 0.005). The higher AA-induced aggregation was associated with higher levels of HbA_1c. Compliance was confirmed by low levels of serum thromboxane B₂ (below 7.2 ng/mL). Diabetics had significantly higher levels of serum thromboxane B₂ (p < 0.0001).

Conclusions

Diabetic patients with CAD had significantly higher levels of both platelet aggregation and activation compared to non-diabetic patients with CAD despite treatment with the same dosage of aspirin. These findings may partly explain the reduced cardiovascular protection from aspirin in diabetic patients.     

Has the incidence of deep vein thrombosis in patients undergoing total hip/knee arthroplasty changed over time? A systematic review of randomized controlled trials

Background

There is a perception in the orthopaedic and thromboembolism community that the incidence of deep vein thrombosis (DVT) has decreased in patients undergoing total knee arthroplasty (TKA) or total hip arthroplasty (THA).

Objectives

To assess the incidence of DVT with warfarin thromboprophylaxis over time in patients undergoing elective TKA or THA.

Methods

The MEDLINE, EMBASE, and Cochrane Library databases were searched to October 2006, supplemented by a manual search of reference lists. Two reviewers independently extracted data on study characteristics, quality and the frequency of total, symptomatic and proximal DVT.

Results

Fourteen studies (4,423 patients) were included. Total and proximal DVT after TKA declined over time (r = − 0.75, p = 0.031; r = − 0.86, p = 0.007 respectively). Total and proximal DVT after THA did not change. The risk of developing DVT after TKA was significantly higher than after THA (OR 1.85, 95% CI 1.6 - 2.14; p < 0.0001). The risk of developing symptomatic DVT after THA was significantly higher than after TKA (OR 2.18, 95% CI 1.11 - 4.27; p = 0.012).

Conclusions

The incidence of DVT in patients undergoing elective TKA appears to have declined in patients receiving warfarin thromboprophylaxis.     

High levels of platelet-monocyte aggregates after valve replacement for aortic stenosis: relation to soluble P-selectin and P-selectin glycoprotein ligand-1 genes

Background

Calcific aortic valve stenosis is linked to atherosclerosis. The latter is associated with increased levels of platelets adhering to monocytes (PMA).

Objective

The hemodynamic impairment in symptomatic aortic valve stenosis can be abated by valve replacement. We investigated the effect of valve replacement on PMA and receptor-ligand axis P-selectin - P-selectin glycoprotein ligand-1 (PSGL-1) in severe aortic valve stenosis.

Patients and Methods

PMA, plasma P-selectin (sP-selectin) and polymorphisms within the coding region for PSGL-1 (SELPLG) were determined in 42 patients with severe aortic valve stenosis before and 4 to 8 months after valve replacement. Ten patients suffered from significant coronary artery disease and received also a coronary artery bypass graft. Thirty-four patients received a bioprosthetic valve and 8 patients who were < 65 years old received a mechanical valve.

Results

Before the intervention, PMA levels were significantly higher in patients with aortic valve stenosis than in two control cohorts, namely healthy indviduals and 88 age- and sex-matched patients with severe atherosclerosis, but without aortic valve stenosis (p < 0.001). PMA decreased after surgery, but normalized in only 3 patients, while further increases were noted in 11 patients. sP-selectin was elevated in 3 and 4 patients before and after valve replacement, respectively. sP-selectin increased significantly after surgery, but remained within the normal range. There was no correlation between changes of PMA and sP-selectin or any of the polymorphisms within SELPLG.

Conclusions

Exceedingly high PMA in aortic stenosis are independent of SELPLG polymorphisms, and largely of the hemodynamic compromise caused by the stenotic valve.     

An experimental model to study isolated effects of thrombin in vivo

Background

In addition to a recognized role in the coagulation cascade and haemostasis, thrombin is known to have multiple functions. We hypothesized that protracted intravenous infusion of thrombin at steady state will allow to study isolated thrombin effects in vivo.

Methods

Thrombin (0.05-0.9 U/kg/min) was continuously infused in Sprague Dawley rats over five hours (n = 38). The study consisted of three parts: dose escalation (n = 21), dose verification (n = 5) and a parallel group study to investigate whether thrombin effects can be antagonised by concomitant infusion of lepirudin (n = 12).

Results

A thrombin dose of 0.9 U/kg/min decreased platelet counts by 70% compared to the control group (median 230 × 10^9/L vs. 752 × 10^9/L; p = 0.041). In accordance, infusion of 0.9 U/kg/min of thrombin decreased fibrinogen level by 75% compared to the control group (56 mg/dl vs. 220 mg/dl; p = 0.046). Cumulative thrombin doses of ≥ 0.1 U/kg/min caused bleedings but not thromboembolic events. Thrombin at doses ≥ 0.15 U/kg/min was lethal in four cases (30%). Platelet counts and fibrinogen levels after thrombin infusion correlated with bleeding events and mortality. Administration of thrombin at cumulative doses of 0.3-0.9 U/kg/min was associated with a 3 to 6.5 -fold increase in IL-6 levels (139-306 pg/ml vs. 47 pg/ml, p < 0.05). In contrast, thrombin infusion did not alter other markers of inflammation (IL-10, MCP-1 or TNF-alpha). In addition, lepirudin prevented thrombin- induced thrombocytopenia.

Conclusion

Protracted intravenous infusion of thrombin offers a new experimental model, where consumption of fibrinogen and platelets correlates with bleedings and mortality. Infusion of thrombin increased only IL-6 levels but not other cytokines.     

Subcutaneous Enoxaparin for Therapeutic Anticoagulation in Hemodialysis Patients

Background

Information regarding dosing of low-molecular-weight heparins (LMWH) for therapeutic anticoagulation in hemodialysis (HD) patients is limited. The aim of this study was to retrospectively compare the safety and efficacy of enoxaparin versus unfractionated heparin (UFH) for therapeutic anticoagulation in HD patients.

Materials and Methods

This retrospective chart review evaluated HD patients treated with subcutaneous enoxaparin that were matched based on the indication for anticoagulation with patients treated with intravenous UFH to achieve therapeutic anticoagulation. Primary outcome measures included 30-day incidence of thromboembolic events and major bleeding. Secondary outcomes included rehospitalization within 30 days, length of stay, and mortality.

Results

One hundred sixty-four patients were evaluated, 82 in each group. The average daily dose of enoxaparin used to target therapeutic levels was 0.7 ± 0.2 mg/kg/day (range = 0.4-1). Comparing enoxaparin to UFH, there was no significant difference in major bleeding (6.1% vs 11%, p = 0.4) or thromboembolism (0% vs 2.4%, p = 0.5). Hospital length of stay was shorter in the enoxaparin group (20 ± 53.8 vs 28.9 ± 44.5 days, p = 0.02); there was no significant difference between groups in mortality or readmission. Adjusting for risk factors for bleeding there was a slight but statistically non-significant difference between enoxaparin versus UFH (OR = 0.77, 95%CI: 0.2-3.5, p = 0.73).

Conclusions

These findings suggest that therapeutic dosing of enoxaparin, in doses that ranged from 0.4-1 mg/kg/day, was as safe as intravenous UFH in providing therapeutic anticoagulation in stable patients requiring chronic hemodialysis.     

G-455A polymorphism of β-fibrinogen gene and the risk of premature myocardial infarction in Greece

Introduction

There are limited and controversial data regarding the impact of G-455A polymorphism of β-fibrinogen gene in the pathogenesis of premature myocardial infarction (MI). We examined whether the G-455A polymorphism of β-fibrinogen gene is associated with the development of MI ≤ 35 years of age.

Methods

We recruited 181 consecutive patients who had survived their first acute MI ≤ 35 years of age (mean age = 32.2 ± 3.4 years). The control group consisted of 129 healthy individuals matched with cases for age and sex, without a family history of premature coronary heart disease. G-455A polymorphism of β-fibrinogen was tested with polymerase chain reaction and reverse hybridization.

Results

There was a higher prevalence of carriers of the A allele (GA+AA genotype) in controls than in patients (odds ratio [OR] 0.57, 95% confidence interval [CI] 0.36 to 0.91, p = 0.02). G-455A polymorphism of β-fibrinogen gene was associated with lower risk for acute MI (OR 0.46, 95% CI 0.25 to 0.83, p = 0.01) after adjusting for major cardiovascular risk factors. Fibrinogen levels were higher in patients compared to controls [332 (292-385) vs. 311 (262-373) mg/dL, p = 0.01], but the adjusted for classical risk factors fibrinogen levels did not differ (OR 1.003, 95% CI 0.99 to 1.01, p = 0.37). Patients possessing the A allele did not differ in their fibrinogen and lipid levels compared to patients with the -455GG genotype.

Conclusions

Our data indicate that the presence of the G-455A polymorphism of β-fibrinogen gene has a “protective effect” against the development of non-fatal acute MI ≤ 35 years of age in Greece.     

Continuous thrombin infusion leads to a bleeding phenotype in sheep

Background

In addition to a recognized role in the coagulation cascade and haemostasis, thrombin is known to have multiple functions. We aimed to establish an ovine model to study thrombin effects in vivo.

Methods

Thrombin (0.0004-0.42 IU/kg/min) was continuously infused in Austrian Mountain Sheep over five hours in the dose escalation study (n = 5 animals; 15 experiments). In the dose verification study animals received 0.42 IU/kg/min of thrombin vs. saline solution in a cross-over design (n = 3 animals; 7 experiments).

Results

Thrombin at an infusion rate of 0.42 IU/kg/min decreased fibrinogen levels by 75% (p < 0.001) and increased degradation products of the fibrinogen beta-chain as shown in a proteomic analysis. Thrombin decreased platelet counts by 36% (p = 0.006), prolonged thrombin time by 70% (p = 0.012) and activated partial thromboplastin time by 32%. Interestingly, thrombin infusion significantly increased the activity of coagulation factors V and X (p < 0.05) and decreased the activity of the coagulation factors VIII and XIII (p < 0.05). Accordingly, thrombin displayed predominantly anti-coagulant and anti-platelet effects: 1) thrombin prolonged clotting time/clot formation time 7-fold (p = 0.019) and induced a 65% decrease in maximal clot firmness (p < 0.001); 2) thrombin reduced collagen- induced platelet aggregation by 85% and prolonged collagen/adenosine diphosphate closure time 3-fold; and 3) thrombin caused lung haemorrhage but not thromboembolism.

Conclusion

Protracted intravenous infusion of thrombin over a period of five hours offers a new experimental model to study thrombin effects in a large animal species.