Activated protein C plasma levels in the fasting and postprandial states among patients with previous unprovoked venous thromboembolism

Introduction

The protein C anticoagulant system is of major importance in the regulation of thrombotic risk, but it is not known whether low plasma levels of activated protein C (APC) in vivo reflect a compromised anticoagulant situation with increased thrombotic risk. Previous studies have reported low, normal or increased plasma APC levels in unselected patients with venous thromboembolism (VTE).

Materials and methods

We performed a population-based, case-control study in patients with a previous history of unprovoked VTE and subjected the participants to a standard fat tolerance test (1 g fat/kg body weight) in order to promote physiological coagulation activation.

Results

VTE patients had higher BMI (28.3 ± 4.4 kg/m² versus 26.3 ± 3.9 kg/m², p = 0.045) and greater waist circumference (98.2 ± 12.5 cm versus 93.4 ± 13.4 cm, p = 0.041) than age and sex matched controls. APC levels were equal in fasting plasma (3.00 ± 0.74 ng/ml and 2.99 ± 0.60 ng/ml, p = 0.66) but higher in postprandial plasma (3.18 ± 0.57 ng/ml and 2.81 ± 0.38 ng/ml, p = 0.008) collected from VTE patients and controls, respectively. Endogenous thrombin generation in plasma following a standardized meal, assessed by thrombin-antithrombin complex (TAT), increased similarly in both groups, whereas APC increased only among the VTE patients during the postprandial state. Plasma levels of APC increased linearly with TAT in the postprandial state (p for linear trend = 0.012).

Conclusions

Our findings fail to support the hypothesis that low APC levels are linked to increased thrombotic risk in unprovoked VTE, and they suggest that plasma APC is a biomarker of thrombin generation.     

Variable plasma levels of Factor V Leiden correlate with circulating platelet microparticles in carriers of Factor V Leiden

Introduction

Inheritance of Factor V Leiden (FVL) is associated with an increased but variable level of risk for thrombosis. We have previously shown that FVL heterozygotes have elevated levels of circulating pro-coagulant microparticles (MP). Here we sought to determine if these subjects differed in their plasma levels of FVL and if this was related to MP concentrations and/or history of thrombosis.

Materials and Methods

The Hemoclot Quanti. V-L clotting assay was used to specifically measure FVL in plasma samples from 44 known carriers (12 M, 32 F; aged 46 ± 13 years). Circulating MP were quantified by flow cytometry using fluorochrome conjugated antibodies to platelet (CD41a), leukocyte (CD45), and endothelial (CD62e) surface markers, and MP prothrombinase activity was determined by ELISA.

Results

The cohort was found to have a mean FVL of 49.5 ± 5.6% and this was positively correlated to the total number of circulating CD41a + MP (R = 0.31, p = 0.03) but not to other MP subsets or to MP prothrombinase activity. The amount of FVL relative to normal factor V (FVL/FV clotting ratio) was calculated and found to be highly variable, ranging from 0.37 to 0.69, and significantly correlated with a history of thrombosis (n = 14; p = 0.04).

Conclusions

This is the first study to investigate the relationship between varying levels of FVL and plasma derived MP. These results are consistent with our previous findings of an increase in MP levels in carriers of FVL as compared to controls, and suggest a role for FVL/FV ratio in predicting risk of thrombosis in carriers of FVL.     

Lower tissue factor inhibition in patients with ST segment elevation than in patients with non ST elevation acute myocardial infarction

Introduction

Mechanisms to explain the different course of coronary thrombosis between ST elevation myocardial infarction (STEMI) and non-STEMI patients remain poorly defined. We hypothesize, however, that STEMI patients may present lower tissue factor plasma inhibition to partly account for their more persistent coronary thrombotic occlusion.

Materials and Methods

Total (t-TFPI ) and free tissue factor plasma inhibitor (f-TFPI), thrombin-antithrombin complex (TAT), plasminogen activator inhibitor 1 (PAI-1), von Willebrand factor (vWF), and fibrinogen were measured on admission and at 3 and 6 months in patients with a first STEMI (n:69) or non-STEMI (n:60). C reactive protein (CRP) was also measured on admission and at 3 months.

Results

STEMI patients showed lower admission levels of t-TFPI (p = 0.001), f-TFPI (p = 0.030) and fibrinogen (p = 0.022), and higher vWF levels (p = 0.005) than non-STEMI whereas TAT, PAI and CRP levels were comparable. At 3 and 6 months VWF, t-TFPI, f-TFPI, and TAT levels declined significantly in the 2 groups (p = 0.002) reaching similar values. CRP levels also declined at 3 months (p = 0.002). Moreover, the rate of cardiac mortality, non fatal MI or stroke during a 6 year follow-up were unrelated to admission coagulation parameters.

Conclusions

The lower inhibition of tissue factor and greater endothelial dysfunction in STEMI than in non-STEMI patients may enhance thrombosis at the culprit lesion and adjacent coronary plaques, and hence, account at least in part for their different pathophysiology. This condition, however, is limited to the acute phase.     

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.     

The impact of platelet membrane glycoprotein Ib alpha and Ia/IIa polymorphisms on the risk of thrombosis in the antiphospholipid syndrome

Background

Pathogenesis of thrombus formation in antiphospholipid syndrome (APS) is not clear. Platelet membrane glycoprotein (GP) receptors play important roles in development of thrombosis.

Objectives

We investigated the association between development of thrombosis in APS and polymorphisms of GPIb alpha variable number of tandem repeats (VNTR), Kozak, and GPIa C807T.Patients/MethodsSixty patients with APS (30 with proven thrombosis and 30 without thrombosis) and 63 controls were included. Presence of GPIa C807T polymorphism was determined with real-time PCR and GPIb alpha Kozak and VNTR polymorphisms by conventional PCR.

Results

Frequency of C807T TT genotype was significantly higher in APS with thrombosis than APS without thrombosis (p = 0.023) and also in APS with multiple thrombi compared to APS without thrombi (p = 0.023). Frequency of Kozak TC genotype was higher in APS with arterial thrombosis compared to APS with venous thrombosis, controls, and APS without thrombosis (p = 0.03, p = 0.0007, and p = 0.0024 respectively). D allele frequency and D allele carrier state for VNTR were significantly less in APS than controls (p = 0.0018 and p = 0.0046 respectively).

Conclusions

C807T TT genotype may confer a risk for thrombosis and Kozak TC genotype for arterial thrombosis. D allele of VNTR may protect from APS. No patients with C807T TT or Kozak TC genotypes carried the protective DD genotype of VNTR. These polymorphisms may increase risk for both arterial and venous thrombosis. The utility of prophylaxis with anti-platelet drugs in at least a subgroup of APS patients should be investigated with clinical trials.     

Risk of early recurrent fetal loss and levels of thrombin-activatable fibrinolysis inhibitor

Introduction

Though thrombin-activatable fibrinolysis inhibitor (TAFI) may contribute to hypercoagulability during pregnancy, limited data are available on the role of TAFI in women with recurrent fetal loss.

Material/Methods

We performed a case-control study aimed at evaluating any possible association between TAFI levels and early recurrent fetal loss (≥ 3, or 2 with at least one normal fetal karyotype, before the 10th week of gestation). 140 women with early recurrent fetal loss and 140 age-matched healthy controls with at least one normal pregnancy were included. The number of miscarriages was 2.59 and occurred at gestational age 6.89 weeks. TAFI levels were determined by a chromogenic assay measuring total potential activatable TAFI.

Results

TAFI levels were significantly lower in early recurrent fetal loss women (12.2 ± 2.3 μg/ml vs 13.2 ± 2.6 μg/ml in healthy controls, p = 0.001). ORs of early recurrent fetal loss (crude and adjusted for possible confounding variables) were calculated after stratification of TAFI levels into quartiles. 25/140 (17.8%) early recurrent fetal loss women had TAFI levels above 14.0 μg/ml (4th quartile) vs 44/140 (31.3%) in healthy women (p = 0.014). Crude and adjusted ORs of early recurrent fetal loss in women with TAFI levels in the 4th quartile vs those in the reference category (1st quartile = below 11.0 μg/ml) were 0.42 (95%CI: 0.22-0.82) and 0.39 (95%CI: 0.19-0.80), respectively.

Conclusions

Our study provides evidence that high TAFI levels are associated with reduced risk of early recurrent fetal loss. Further studies are needed to better understand the actual role of TAFI in recurrent fetal loss.     

Tissue factor-induced Thrombin Generation in the Fasting and Postprandial State among Elderly Survivors of Myocardial Infarction

Introduction

Tissue factor (TF)-induced thrombin generation (TG) ex vivo has been suggested to be an important method to assess thrombotic risk. No studies have investigated the impact of postprandial lipemia on TF-induced TG. Since myocardial infarction (MI) is associated with elevated postprandial levels of triglycerides, we hypothesized a differential impact of postprandial lipemia on coagulation activation in MI-patients and healthy controls.

Material and Methods

Elderly survivors of acute MI (n = 44) and healthy age-and sex matched controls (n = 43) underwent a fat tolerance test (1 gram per kg body weight) to assess coagulation activation during postprandial lipemia.

Results

The incremental area under the curve (AUCi) for serum triglycerides was higher in MI-patients than in healthy age-and sex matched controls (5.64 ± 0.52 mmol/L?h and 3.94 ± 0.39 mmol/L?h, p = 0.012) during the postprandial phase. Subsequent endogenous activation of coagulation, assessed by FVIIa and thrombin generation (F1 + 2), was similar among groups and not related to levels of triglycerides during the postprandial phase. Healthy individuals had a gradual decline in TF-induced thrombin generation ex vivo, assessed by endogenous thrombin potential (ETP) (AUCi = - 542.4 ± 71.4 nM?min?h, p < 0.001), whereas MI-patients retained their ETP (AUCi = 127.4 ± 89.0 nM?min?h, p = 0.47) in plasma during the postprandial phase (p for group difference = 0.005).

Conclusions

MI-patients had elevated postprandial lipemia and retained their ability for TF-induced TG in plasma ex vivo in the postprandial phase, whereas the capacity gradually decreased in healthy individuals. Further studies are warranted to reveal underlying mechanism(s) and clinical implications.     

Endothelial, platelet, and tissue factor-bearing microparticles in cancer patients with and without venous thromboembolism

Background

Cancer is a prothrombotic state, with an increased prevalence of venous thromboembolism (VTE). Microparticles (MPs) are sub-micron-sized vesicles derived from activated or apoptotic cells that may play a role in VTE, although evidence of this association is still limited.

Objectives

To evaluate the hypothesis that elevated numbers of endothelial (EMPs), platelets (PMPs), and Tissue Factor-bearing MPs (TF⁺MPs) in plasma may contribute to cancer-associated thrombosis.

Patients/Methods

EMPs, PMPs and TF⁺MPs plasma levels were measured in 90 consecutive patients (cases) referred to our Department (30 with a first episode of unprovoked VTE; 30 with active cancer; 30 with a diagnosis of acute VTE associated with active cancer), and in a group of 90 healthy subjects (controls). MPs analyses were performed by flow-cytometry (Cytomics FC500).

Results

Cases showed statistically significant higher (mean ± SD) circulating EMPs and PMPs plasma levels (920 ± 341 and 1221 ± 413 MP/μL, respectively) than controls (299 ± 102 and 495 ± 241 MP/μL; p < 0.005). Moreover cancer patients (with and without VTE) showed higher (mean ± SD) TF⁺MPs (927 ± 415 MPs/μL) than controls (204 ± 112 MPs/μL; p < 0.001). The subgroup of cancer patients plus VTE showed statistically significant higher TF⁺MPs plasma levels (1019 ± 656 MPs/μL) than cancer patients without VTE (755 ± 391 MPs/μL, p = 0.002). Multivariate analysis failed to show a significant association between elevated TF⁺MPs and VTE in cancer patients.

Conclusions

Our results suggest that MPs might be an important intermediate in the cascade of cellular injury and vascular dysfunctions underlying the process of thrombosis, particularly in cancer. Further clinical investigations are needed to confirm the precise role of MPs in predicting hypercoagulable state in patients with cancer.     

Plasma homocysteine level and left ventricular thrombus formation in acute anterior myocardial infarction patients following thrombolytic therapy with t-PA

Aims

The aim of this study was to evaluate the relationship between homocysteine levels and the development of left ventricular thrombus in acute anterior myocardial infarction patients directed to thrombolytic therapy.

Methods and Results

Seventy-nine patients presenting with ST elevated acute anterior myocardial infarction and treated with thrombolytic agent, t-PA, were included in the study. Two-dimensional echocardiography was used to divide patients into 2 groups according to the presence (n = 14) or absence (n = 65) of thrombus in the left ventricle following myocardial infarction. The levels of fasting plasma total homocysteine, total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol, vitamin B12 and folic acid were assessed. There were no significant differences between two groups in terms of age, gender, hyperlipidemia and smoking. History of diabetes mellitus (28.57% versus 6.15%, p = 0.04), peak creatine phosphokinase levels (4153.54 ± 1228.41 U/L versus 2456.92 ± 1421.36 U/L, p < 0.001), mean left ventricular wall motion score index (2.21 ± 0.18 versus 1.83 ± 0.23, p < 0.001) and total fasting homocysteine levels (18.24 ± 5.67 mmol/L versus 12.31 ± 3.52 mmol/L, p < 0.001) were significantly higher in patients with left ventricular thrombus. In multivariate analysis; only diabetes mellitus (p = 0.03), higher wall motion score index (p = 0.001) and higher homocysteine levels (p = 0.04) were independent predictors of left ventricular thrombus formation.

Conclusion

Our results suggest that; diabetes mellitus, higher wall motion score index and hyperhomocysteinemia independently increases the risk for the development of left ventricular thrombus formation in patients with acute anterior myocardial infarction following thrombolytic therapy.     

Endothelial haemostatic markers in members of families with familial combined hyperlipidemia

Introduction

The aim of this study was to evaluate the plasma levels of endothelial haemostatic markers - von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (t-PA) and soluble thrombomodulin (sTM) — in asymptomatic, nonsmoking members of families with familial combined hyperlipidemia (FCH). We investigated the association between these factors and the intima-media thickness (IMT) of the common carotid artery, selected risk factors of atherosclerosis and markers of insulin resistance.

Methods

82 members of 29 FCH families were divided into two groups: HL (probands and hyperlipidemic first-degree relatives, n = 47) and NL (normolipidemic first-degree relatives, n = 35). The control groups C-HL (n = 20) and C-NL (n = 20) consisted of sex- and age-matched healthy individuals. IMT was measured by ultrasound at a far wall of both common carotid arteries.

Results

Compared with healthy controls, hyperlipidemic subjects had significantly higher levels of vWF (146.4 ± 73.2% versus 112.2 ± 29.4%, p < 0.05), of PAI-1 (102.4[83.0-117.0] ng/ml versus 63.5[31.8-87.3] ng/ml, p < 0.01) and of t-PA (5.1[2.5-7.9] ng/ml versus 3.4[1.4-5.8] ng/ml, p < 0.05). They had increased IMT, which correlated with vWF (r = 0.29, p < 0.05). Their normolipidemic relatives had significantly higher levels of vWF (137.2 ± 42.8% versus 106.6 ± 24.0%, p < 0.01) and of PAI-1 (75.3[53.2-92.0] ng/ml versus 48.6[37.4-85.9] ng/ml, p < 0.05). Levels of vWF, PAI-l and t-PA were independently associated with several markers of insulin resistance.

Conclusions

Asymptomatic members of FCH families have increased endothelial haemostatic factors— vWF, PAI-1, t-PA, which are associated with insulin resistance. VWF correlates with morphological vascular changes, detected by the increase of IMT, presented in only hyperlipidemic subjects.     

Plasma activity of individual coagulation factors, hemodilution and blood loss after cardiac surgery: A prospective observational study

Background

Hemodilution and consumption of coagulation factors during cardiopulmonary bypass has been suggested to contribute to bleeding complications after cardiac surgery. The aim was to describe the activity of individual coagulation factors after CABG in relation to hemodilution and postoperative bleeding.

Materials and Methods

Plasma concentrations of fibrinogen and plasma activity of FII, FV, FVII, FVIII, FIX, FX, FXI and FXIII adjusted for hemodilution were analysed in 57 CABG patients before, and 2 h and 24 h after surgery. Postoperative bleeding was registered and correlations to coagulation factor activity were calculated.

Results

Adjusted plasma concentration of fibrinogen (-14 ± 6%), and plasma activity of FII (-9 ± 6%), FV (-13 ± 8%), FX (-13 ± 7%) and FXIII (-9 ± 14%) were reduced two hours after surgery compared to baseline (all p < 0.001). FVII (+ 3 ± 12%, p = 0.34) and FXI (+ 1 ± 19%, p = 0.50) were unchanged, while FVIII (+ 23 ± 44%, p = 0.006) and FIX (+ 23 ± 17%, p < 0.001) increased. Twenty-four hours after surgery fibrinogen (+ 45 ± 27%), FVIII (+ 93 ± 66%) and FIX (+ 33 ± 26%) were all increased (all p < 0.001), while FVII (-37 ± 14%, p < 0.001), FXI (-4 ± 18%, p = 0.02) and FXIII (-6 ± 15%, p = 0.004) were decreased.Median postoperative blood loss was 380 ml/12 h. There were significant inverse correlations between postoperative blood loss and fibrinogen concentration 2 h after surgery (r = -0.33, p = 0.019) and between postoperative blood loss and pre- and postoperative FXIII activity (r = -0.34, p = 0.009 and r = -0.41, p = 0.003, respectively), but not between blood loss and any of the other factors.

Conclusions

There is a marked dissociation in plasma activity of individual coagulation factors after CABG. Plasma concentration of fibrinogen and factor XIII activity correlates inversely to postoperative blood loss after CABG.     

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.     

Changes in plasma von Willebrand factor and ADAMTS13 levels associated with left atrial remodeling in atrial fibrillation

Introduction

Previous studies have shown raised plasma von Willebrand factor (VWF) levels in patients with atrial fibrillation (AF). However, little is known about changes of VWF associated with VWF-cleaving protease (ADAMTS13) in AF. The aim of this study was to examine the relationship between changes in plasma VWF and ADAMTS13 levels, and left atrial remodeling in AF patients.

Materials and Methods

We measured plasma VWF and ADAMTS13 antigen levels in 70 paroxysmal AF (PAF) patients, 56 chronic AF (CAF) patients, and 55 control subjects.

Results

Plasma VWF levels (mU/ml) were significantly higher in CAF and PAF patients compared with the controls (2103 ± 743, 1930 ± 676, 1532 ± 555, respectively, P < 0.0001 in CAF vs. controls, P = 0.001 in PAF vs. control), while ADAMTS13 levels (mU/ml) were significantly lower in CAF and PAF patients compared with the controls (795 ± 169, 860 ± 221, 932 ± 173, respectively, P = 0.0002 in CAF vs. controls, P = 0.04 in PAF vs. control). The VWF/ADAMTS13 ratio was significantly higher in patients with CAF than PAF or controls (2.81 ± 1.30, 2.34 ± 0.92, 1.73 ± 0.83, respectively; P = 0.01 in CAF vs. PAF, P < 0.0001 in CAF vs. controls). There was a significant correlation between the VWF/ADAMTS13 ratio and left atrial diameter (positive correlation; r = 0.275, P = 0.0002) and left atrial appendage flow velocity (negative correlation; r = - 0.345, P = 0.0018).

Conclusions

These findings suggest that the imbalance between plasma VWF and ADAMTS13 levels caused by left atrial remodeling might be closely associated with intra-atrial thrombus formation in AF patients.     

Short versus extended thromboprophylaxis after total knee arthroplasty: A randomized comparison

Introduction

The optimal duration of thromboprophylaxis after total knee arthroplasty remains uncertain.

Material and Methods

We performed a randomized, open trial to determine whether to stop thromboprophylactic therapy at Day 10 ± 2 (‘short thromboprophylaxis’) was non-inferior to continue thromboprophylactic therapy up to Day 35 ± 5 (‘extended thromboprophylaxis’) after total knee arthroplasty. At Day 7 ± 2, subjects were screened by ultrasonography for asymptomatic deep-vein thrombosis and randomized. The primary outcome was a composite of proximal deep-vein thrombosis, any symptomatic deep-vein thrombosis, non-fatal symptomatic pulmonary embolism, major bleeding, heparin-induced thrombocytopenia, or all-cause death up to Day 35 ± 5. The secondary outcome was ultrasonographic (extension or new onset) distal deep-vein thrombosis at Day 35 ± 5.

Results

Twenty-one patients (2.4%) were not randomized, because of asymptomatic proximal deep-vein thrombosis on systematic ultrasonography at Day 7 ± 2. Among the 857 randomized patients, mean (SD) duration of anticoagulant treatment was 11.2 (6.7) and 33.9 (3.7) days in the short and extended thromboprophylaxis groups, respectively. The respective rates of the primary outcome were 4.0% (17/420) and 2.4% (10/422), with an absolute difference of 1.7% (90% confidence interval, -0.3 to 3.7). In 285 patients with asymptomatic distal deep-vein thrombosis at Day 7 ± 2, the respective rates of the primary outcome were 7.8% and 2.8% (p = 0.067). The rates of the secondary outcome were 14.8% (62/420) and 4.5% (19/422), respectively (p < 0.001).

Conclusions

Short thromboprophylaxis was not non-inferior to extended thromboprophylaxis after total knee arthroplasty. In this setting, the thromboembolic risk persisted longer than seven days, notably in patients with asymptomatic distal deep-vein thrombosis at discharge.ClinicalTrials.gov number: NCT00362492     

Intra- and inter-rater reliability of motor unit number estimation and quantitative motor unit analysis in the upper trapezius

Objective

To collect normative data and assess the intra- and inter-rater reliability of decomposition-enhanced spike-triggered averaging (DE-STA) motor unit number estimation (MUNE) and quantitative MU analysis obtained using decomposition-based quantitative electromyography (DQEMG) in the upper trapezius (UT).

Methods

In 10 control subjects, the experimental protocol was performed twice by the same examiner, and once by a second examiner.

Results

Mean MUNE values were 339 ± 121 (rater 1a), 320 ± 131 (rater 1b), and 262 ± 115 (rater 2) MUs. Intra- and inter-rater reliability was good for maximum CMAP (ICC = 0.77 and 0.79, respectively) and moderate for MUNE (ICC = 0.69 and 0.73, respectively), with poor inter-rater reliability for mean S-MUP (ICC = 0.42). Significant differences between rater 1a and 2 were found for mean S-MUP (p = 0.014) and MUNE (p = 0.002), and moderate to good levels of reliability found for quantitative needle-detected MUP parameters.

Conclusions

Various components of the protocol may have contributed to mean S-MUP variability, and may require particular attention in a large, proximal muscle like the UT.

Significance

This study has established preliminary data using DQEMG in a novel muscle which may be relevant to study in patients with ALS.     

Aspirin resistance following pediatric cardiac surgery

Introduction

Aspirin is often used to prevent thrombosis in pediatric cardiac surgery. The primary study aim was to assess aspirin resistance in this context. Secondary aims were to evaluate (1) the relationship between elevated inflammatory markers and thrombosis and (2) aspirin's effect on these levels.

Materials and Methods

This was a prospective observational study of children undergoing cardiac surgery managed with and without aspirin. Aspirin response was assessed using the VerifyNow™ system and urinary 11-dehydrothromboxane B₂ (uTxB₂) measurements. Laboratory studies of inflammation were also obtained.

Results

101 subjects were studied; 50 received aspirin. Six subjects (5.9%), 5 aspirin-treated, experienced symptomatic thrombosis. When measured by VerifyNow™ resistance was 43% after aspirin suppositories and 14% after additional days of oral aspirin. There was no correlation with thrombosis. Upper quartile post-operative day (POD) #5 uTxB₂ was correlated with thrombosis in aspirin treated subjects (p < 0.01). High risk aspirin-treated subjects who experienced thrombosis had higher POD#5 uTxB_2. This finding did not reach statistical significance (p = 0.07). Elevated pre-operative C-reactive protein (CRP) was independently associated with thrombosis (p < 0.02) in all subjects and in high risk subjects (p = 0.01). Inflammatory markers were not affected by aspirin.

Conclusions

Aspirin inhibited ex-vivo platelet function with a low incidence of resistance. Elevated POD#5 uTxB₂ and pre-operative CRP were correlated with thrombosis in aspirin treated subjects. Further studies are needed to determine whether children with high levels of uTxB₂ despite aspirin therapy and/or those with elevated preoperative CRP are at increased risk for thrombosis.     

Depressive symptoms, perceived social support, and prothrombotic measures in patients with venous thromboembolism

Introduction

Psychosocial factors have been associated with both a prothrombotic state and an increased risk of venous thromboembolism (VTE). We examined the relation of depressive symptoms and social support with D-dimer, an integrative measure of enhanced coagulation activity, and several additional prothrombotic measures in patients with VTE.

Methods

We studied 173 patients with a previous deep venous thrombosis and/or pulmonary embolism (mean age ± SD 45 ± 14 years, 55% men). Clinical and lab assessments took place ≥ 3 months after VTE and ≥ 1 month after discontinuation of oral anticoagulants. The patients rated depressive symptoms and social support by validated questionnaires.

Results

After adjusting for sociodemographic and medical covariates, interactions emerged between depressive symptoms and social support for D-dimer (p = 0.012) and aPTT (p = 0.002). As opposed to patients with high levels of social support, those with low levels of social support showed a direct association of depressive symptoms with D-dimer (r = 0.19, p = 0.014) and an inverse relationship with aPTT (r = -0.14, p < 0.09). Depressive symptoms were associated with levels of thrombin-antithrombin complex (r = 0.19, p = 0.016). Greater social support was associated with prolonged aPTT (r = 0.16, p = 0.046). There were no significant associations of depressive symptoms and social support with D-dimer, fibrinogen, FII:C, FV:C, FVII:C, FVIII:C, FX:C, INR, and thrombin time.

Conclusions

Depressive symptoms are associated with enhanced coagulation activity in patients with VTE, particularly so in those who perceive low levels of social support. Conversely, high levels of social support may contribute directly and through buffering the effect of depressive symptoms to attenuated clotting activity in VTE patients.     

Low protein Z levels, but not the intron F G79A polymorphism, are associated with unexplained pregnancy loss

Introduction

The present case-control study was designed in order to investigate the association between plasma protein Z (PZ) levels, the intron F G79A polymorphism and unexplained pregnancy loss.

Materials and Methods

51 women with at least two consecutive or three non-consecutive fetal losses between the 8th and 12th week of gestation and 47 apparently healthy parous women of reproductive age with no history of pregnancy loss (controls) were enrolled. Allele frequencies of the PZ intron F G79A polymorphism and PZ levels were measured.

Results

PZ levels (mg/L) were significantly lower in cases (mean±S.D. 1.28 ± 0.56) than controls (1.97 ± 0.76, p < 0.001) and in carriers of the A allele (1.46 ± 0.62), compared to GG homozygous subjects (1.72 ± 0.81, p = 0.044). A higher proportion of cases (41.2%) were PZ-deficient (< 1 mg/L), compared to controls (10.6%, p = 0.001). No significant difference in the frequency of at least one A allele carriers was observed between cases (39.2%) and controls (40.4%).

Conclusion(s)

It is possible that low PZ levels are a novel risk factor for unexplained recurrent miscarriage or fetal death. The presence of the F 79A allele is associated with significantly lower PZ levels, but, in the present study, was unrelated to unexplained early pregnancy loss.     

Endogenous thrombin potential (ETP) in plasma from patients with AMI during antithrombotic treatment

Background

The beneficial impact of warfarin in preventing new events after AMI is well established. Decrease in thrombin generation seems to be the key element in anticoagulant treatment.

Objectives

The aims were to investigate the effect of warfarin and platelet inhibition on thrombin generation, assessed by the endogenous thrombin potential (ETP), and study the relation between coagulation parameters and ETP in patients with AMI.

Patients/Methods

In the present sub-study of the WARIS II trial, patients with AMI were randomly assigned to treatment with aspirin 160 mg/d (n = 57), aspirin 75 mg/d and warfarin (INR 2.0-2.5) (n = 68) or warfarin (INR 2.8-4.2) (n = 61). Fasting blood samples were collected from patients at discharge from hospital and after 6 weeks treatment.

Results

Correlation analyses showed that both ETP and peak thrombin levels were significantly correlated with Factor VII Ag (r = 0.38 and 0.36 respectively, p < 0.01 for both) and with F1+2 (r = 0.26 and 0.23 respectively, p = 0.01 for both) at baseline. Antithrombotic treatment for 6 weeks caused a highly significant inhibition of ETP in patients treated with warfarin (− 28% ± 5%, p < 0.001), and patients treated with aspirin/warfarin (− 24% ± 8%, p = 0.04). Similarly, peak thrombin levels were reduced in patients treated with warfarin (− 18% ± 7%, p = 0.049) and aspirin/warfarin (− 19% ± 5%, p = 0.029), whereas an increase (12% ± 4%, p = 0.029) occurred during aspirin treatment alone. F1+2 levels decreased by 64% and 58% in the warfarin and aspirin/warfarin groups, respectively (p = 0.001 for both).

Conclusions

In patients with AMI, warfarin significantly reduced the endogenous thrombin generation and the potential to generate thrombin in plasma ex vivo, whereas aspirin alone had no effect on thrombin generation in vivo or ex vivo, assessed by ETP.     

Prothrombotic changes with acute psychological stress: combined effect of hemoconcentration and genuine coagulation activation

Introduction

Acute psychosocial stress accelerates blood coagulation and elicits hemoconcentration which mechanisms are implicated in acute coronary thrombotic events. We investigated the extent to which the change in prothrombotic measures with acute stress reflects hemoconcentration and genuine activation of coagulation.

Material and methods

Twenty-one middle-aged healthy men underwent three sessions of a combined speech and mental arithmetic task with one-week intervals. Coagulation and plasma volume were assessed at baseline, immediately post-stress, and 45 min post-stress at sessions one and three. Measures of both visits were aggregated to enhance robustness of individual biological stress responses. Changes in eight coagulation measures with and without adjustment for simultaneous plasma volume shift were compared.

Results

From baseline to immediately post-stress, unadjusted levels of fibrinogen (p = 0.028), clotting factor VII activity (FVII:C) (p = 0.001), FVIII:C (p < 0.001), FXII:C (p < 0.001), and von Willebrand factor (VWF) (p = 0.008) all increased. Taking into account hemoconcentration, fibrinogen (p = 0.020) and FVII:C levels (p = 0.001) decreased, activated partial prothrombin time (APPT) shortened (p < 0.001) and prothrombin time (PT) was prolonged (p < 0.001). Between baseline and 45 min post-stress, unadjusted (p = 0.050) and adjusted (p = 0.001) FVIII:C levels increased, adjusted APTT was prolonged (p = 0.017), and adjusted PT was shortened (p = 0.033). D-dimer levels did not significantly change over time.

Conclusions

Adjustment for stress-hemoconcentration altered the course of unadjusted levels of several prothrombotic factors. After adjustment for hemoconcentration, APPT was shortened immediately post-stress, whereas 45 min post-stress, FVIII:C was increased and PT was shortened. Procoagulant changes to acute stress may reflect both hemoconcentration and genuine activation of coagulation molecules and pathways.