Admission markers predict lacunar and non-lacunar stroke in young patients

Stroke in young adults is an important cause of lifelong morbidity. The aim of this study was to explore some possible admission indicator of subsequent lacunar or non-lacunar strokes. We enrolled 626 patients with the first young cerebral strokes and divided them into lacunar and non-lacunar stroke based on clinical presentation and neuroradiological findings; and the analyses were adjusted for the effects of potential confounders. Hypertension, hyperlipidemia, atrial fibrillation, cerebral vascular moyamoya malformation were significantly more frequent in non-lacunar patients than lacunar patients (respectively P = 0.005, 0.048, 0.000, 0.015, 0.030). Serum BUN, Triglyceride, Cholesterol, HDL, UA, White cell count, Fibrinogen, INR and bilirubin (including Total bilirubin, Direct bilirubin, Indirect bilirubin) levels on admission were higher in non-lacunar strokes than in lacunar strokes. Serum white blood cell count (Odds Ratio 1.097; 95% Confidence Interval 1.006-1.195, P = 0.035), lower high-density lipoprotein levels (defined as HDL < 0.9 mmol/L)(Odds Ratio 1.884; 95% Confidence Interval 1.035-3.285, P = 0.038) and serum total bilirubin (Odds Ratio 1.054; 95% Confidence Interval 1.019-1.091, P = 0.003) were associated with increased risk for non-lacunar stroke, whereas lacunar stroke was related to age at onset (Odds Ratio 0.929; 95% Confidence Interval 0.888-0.972, P = 0.001) and SUA (Odds Ratio 0.997; 95% Confidence Interval 0.995-0.999, P = 0.015). The excess risks were blood WBC, lower HDL and total bilirubin levels for non-lacunar strokes, and serum UA and age at onset for lacunar strokes in young Chinese patients.     

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.     

Platelet activation in patients with peripheral vascular disease: reproducibility and comparability of platelet markers

Background

Many markers of platelet activation have been described but their reproducibility and comparability in patient populations are poorly defined.

Objectives

We sought to compare markers of platelet and monocyte activation with platelet-monocyte aggregates, a proposed gold standard of in vivo platelet activation, and assess their reproducibility in patients with peripheral arterial disease: a population with substantial platelet activation, inflammation and risk of thrombotic events.

Patients/Methods

Thirty patients with peripheral vascular disease attended on two occasions to permit within-day and between-day comparisons. In vivo platelet and monocyte activation were determined by flow-cytometric quantification of platelet-monocyte aggregation, platelet surface expression of P-selectin and CD40L, platelet-derived microparticles, and monocyte surface expression of CD40 and CD11b. Plasma concentrations of platelet-derived microparticles, soluble P-selectin and CD40L were measured by enzyme-linked immunosorbant assays.

Results

Platelet-monocyte aggregation (36.7 ± 7.86%), and platelet surface expression of P-selectin (5.8 ± 1.65%) and CD40L (3.3 ± 1.45%) demonstrated comparable within-day (mean difference ± co-efficient of reproducibility; 0.9 ± 15.4%, 0.21 ± 1.65% and 0.2 ± 2.8% respectively) and between-day reproducibility (2.0 ± 12.4%, 0.10 ± 2.25% and 0.9 ± 6.4% respectively). Platelet-monocyte aggregates correlated well with other platelet (r = 0.30-0.50, P < 0.02) and monocyte (r = 0.27-0.47, P < 0.03) activation markers. Flow cytometric and assay quantified platelet-derived microparticles showed poorer reproducibility (co-efficient of reproducibility > 40).

Conclusions

In patients with peripheral arterial disease, measurements of platelet-monocyte aggregates have good reproducibility and consistently reflect other markers of platelet and monocyte activation.     

Fibrin clot properties in acute ischemic stroke: relation to neurological deficit

Introduction

Hypercoagulable state occurs in patients with acute vascular events. We wondered whether clot structure/function is altered in acute ischemic stroke (AIS), like in acute myocardial infarction.

Patients and methods

In 45 consecutive patients with AIS (24M, 21F), aged 67.4 ± 10.9 years, and 45 healthy controls matched for age and sex, we investigated plasma fibrin clot structure/function by permeation, turbidity, and efficiency of fibrinolysis.

Results

Compared to controls, AIS patients produced clots that had 30.5% less porous network (p < 0.0001), were less susceptible to fibrinolysis (10.8% longer lysis time, p = 0.001), were 20.5% more compact (p < 0.0001), had 17.1% higher clot mass (p < 0.0001), and showed increased (by 10.2%) overall fiber thickness (p < 0.0001) with 8% shorter lag phase of fibrin formation (p = 0.0002). Maximum rate of D-dimer release from clots was similar. Multiple regression analyses for all subjects (n = 90) showed that being a stroke patient (p < 0.0001), fibrinogen (p < 0.0001) and lipoprotein(a) (p = 0.0075) were independent predictors of clot permeability (model R2 0.79). Only fibrinogen (p < 0.0001) and lipoprotein(a) (p = 0.0026) predicted lysis time. All other fibrin parameters were predicted only by being a stroke patient. Clot compaction was associated with neurological deficit on admission (r = -0.81; p < 0.0001) and at discharge (r = -0.69; p < 0.0001). Patients with 0 or 1 point in the modified Rankin scale (n = 19) had 13.3% higher clot permeability compared to the remainder (p = 0.02).

Conclusions

This study is the first to show that AIS is associated with unfavorably altered fibrin clot properties that might correlate with neurological deficit.     

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.     

The plasma levels of activated thrombin activatable fibrinolysis inhibitor and thrombomodulin in Behçet Disease and their association with thrombosis

Objective

To investigate the plasma levels of activated thrombin activatable fibrinolysis inhibitor (aTAFI) and thrombomodulin (TM) in Behçet disease (BD) and their relationship with thrombosis.

Methods

Plasma aTAFI and TM levels were measured by ELISA in 89 patients with BD (18 having venous thrombosis) and in 86 healthy controls.

Results

Compared with healthy controls, the BD group had significantly lower levels of aTAFI (13.49 ± 8.88 µg/ml vs. 26.76 ± 11.57 µg/ml, p < 0.0001) and significantly higher levels of TM (3.26 ± 1.85 ng/ml vs. 2.6 ± 0.69 ng/ml, p = 0.0003). Neither aTAFI, nor TM levels differed significantly between BD patients with and without thrombosis (p > 0.05). Despite a tendency to positive correlation (r = 0.37, p = 0.0004) between plasma levels of aTAFI and TM in healthy controls, there was a tendency for negative correlation (r = -0.51, p < 0.0001) between these two parameters in BD patients.

Conclusion

The plasma aTAFI and TM levels do not seem to be related with the presence of thrombosis observed in BD. Increased plasma TM levels in BD may simply reflect endothelial cell activation and dysfunction.     

Platelet glycoprotein VI (GPVI) for early identification of acute coronary syndrome in patients with chest pain

Background

Platelet glycoprotein VI (GPVI) is elevated in patients with acute coronary syndrome (ACS), stroke and associated with acute coronary events. GPVI may be helpful to distinguish an imminent ACS from non-coronary (NC) causes in patients with chest pain who were transferred to chest pain unit, before the myocardial necrosis is evident with classical biomarkers.

Methods

Based on the findings of our previous studies, we consecutively examined 1004 patients with chest pain in a prospective study design. ACS was found in 416 (41.4%), stable angina pectoris (SAP) in 233 (23.2%), and NC causes of chest pain (hypertension, musculoskeletal disease, pulmonary embolism, myocarditis, cardiophobia) in 355 patients (35.4%). Platelet surface expression of GPVI was measured by flow cytometry.

Results

Patients with ACS showed significantly enhanced GPVI expression levels compared to patients with SAP or NC causes of chest pain (ACSvs.SAP(mean fluorescence intensity (MFI) ± SD):18.9 ± 7.4vs.17.9 ± 9.5;P = 0.028;ACSvs.NC:15.4 ± 6.9;P = 0.002). Elevated GPVI expression was associated with ACS independent of markers of myocardial necrosis like troponin and creatine kinase-MB. Patients with an elevated GPVI expression (MFI ≥ 18.6) had a poorer clinical outcome than patients with baseline GPVI expression in regard to composite cumulative survival that included myocardial infarction, stroke, and cardiovascular death at three months (Log rank;P = 0.025).

Discussion

Platelet GPVI surface expression is enhanced in patients at risk for an ACS and is an early marker for imminent acute coronary events in patients with chest pain.     

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.     

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.     

Aging is associated with impaired thrombus resolution in a mouse model of stasis induced thrombosis

Introduction

To evaluate the effects of aging on venous thrombosis.

Material and Methods

Anesthetized male mice (C57BL/6, n = 125) underwent complete inferior vena cava occlusion to produce venous thrombosis. Experimental groups included 11-month-old mice (OLD), 2-month-old mice (YOUNG), and age-matched non-thrombosed controls. Mice were euthanized and the following parameters were evaluated two days post-thrombosis: thrombus mass (grams/cm), vein wall inflammatory cells (cells per 5 high powered fields), active plasma plasminogen activator inhibitor-1 (PAI-1, ng/mL), vein wall P-selectin protein determination by ELISA (pg/mL), circulating plasma microparticles (MPs, MPs/200 µL), MP tissue factor (TF) activity (pM), and in vivo MP re-injection experiments.

Results

Thrombosed OLD mice had greater thrombus mass than YOUNG mice (389 ± 18 vs. 336 ± 14 g × 10^− 4/cm, P < .05). OLD mice had decreased vein wall monocyte, lymphocyte, and total inflammatory cell populations versus YOUNG mice (P < .05). Vein wall P-selectin levels were greater in OLD thrombosed mice versus YOUNG (7306 ± 938 vs. 3805 ± 745 pg/mL, P < .05). Active plasma PAI-1 concentrations were increased in OLD mice versus YOUNG thrombosed animals (20 ± 4 vs. 8 ± 2 ng/mL, P < .05). OLD mice had significantly higher circulating leukocyte-derived MPs versus YOUNG mice (5817 ± 850 vs. 2563 ± 283 MPs/200 μL PPP, P < .01). OLD mice had plasma MPs with increased TF activity versus YOUNG animals post-thrombosis (34 ± 4 vs. 24 ± 2 pM, P < .05). Finally, YOUNG recipient animals, whether re-injected with OLD or YOUNG donor MPs, had a significant increase in thrombus mass versus OLD recipient animals (P < .01).

Conclusion

Aging influenced several circulating and vein wall factors that decreased thrombus resolution in older animals compared to younger ones in our mouse thrombosis model.     

Homocysteine and metalloprotease-3 and -9 in patients with ascending aorta aneurysms

Introduction

Matrix metalloprotease (MMP) activity is increased in ascending and abdominal aortic aneurysms. Elevated plasma homocysteine (Hc) levels have been reported in patients with abdominal aneurysms. However, there are no published reports correlating, Hc and MMP levels in patients with ascending aortic aneurysms (AAAs).

Materials and Methods

This study attempts to determine whether serum or tissue Hc in patients undergoing surgery for AAAs is associated with aneurysm diameter, circulating and tissue levels of MMP-3 and MMP-9 assessed by Enzyme-linked immunosorbent assay (ELISA) and their mRNA tissue expression assessed by real-time PCR. Twenty-seven patients were recruited in the study.

Results

Forty-three percent of the patients had abnormal Hc serum levels (> 35.9 μmol/L). Circulating MMP-3 (6.44 ± 4.20 ng/mL) and MMP-9 levels (134 ± 11.4 ng/mL) were elevated compared to healthy controls (p < 0.001). Positive correlations were observed between circulating MMP-9, tissue MMP-3 and MMP-9 concentrations with serum Hc (r = 0.773, p = 0.011; r = 0.461, p = 0.014; r = 0.526, p = 0.024, respectively). MMP-9 mRNA was expressed in 21% of the aneurysms. No MMP-3 mRNA expression was detected in the studied specimens. A negative correlation between tissue Hc and aneurysm diameter was detected. No associations of serum Hc, MMP-3 and MMP-9 levels in both serum and tissue with aneurysm diameter were noted.

Conclusion

Our results suggest that Hc, even in patients with mild hyperhomocysteinaemia, is involved in the pathophysiology of AAA, through the regulation of MMP-3 and MMP-9 activity.     

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.     

Activation of coagulation in amniotic fluid during normal human pregnancy

Introduction

Amniotic fluid (AF) is an important medium for fetal development which exhibits high procoagulant activities; however, the role of these procoagulants during pregnancy has not been elucidated and might be associated with pregnancy complications. The current study aimed to evaluate factor X (FX) activation and its association with tissue factor (TF), tissue factor pathway inhibitor (TFPI) and coagulation activation markers in AF during normal human pregnancy.

Methods

Activation of FX and concentration of TF, free TFPI, D-dimer and prothrombin fragments (F1 + 2) were evaluated in AF samples obtained for chromosome analysis from 91 women with normal pregnancy: 65 samples were taken from patients at 16-20 weeks of gestation, 9 samples were drawn at 21-30 weeks and 17 samples−after 30 weeks of gestation.

Results

Activation of FX in AF significantly increased during normal pregnancy (from 65 ± 41 to 205 ± 80 equivalent RVV ng/mg total protein, P < 0.0001). TF and TFPI levels in AF also rose with gestational age. In contrast, the AF concentration of D-dimer and F1 + 2, markers of coagulation activation significantly decreased when expressed per mg total protein. Levels of free TFPI correlated with TF (r = 0.5, P < 0.001), and were 8-fold higher than those of TF during pregnancy.

Conclusion

High levels of TFPI might be associated with the inhibition of procoagulant activity in amniotic fluid during normal pregnancy, which may account for the rarity of clinical amniotic fluid embolism.     

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.     

Relationship between aspirin and clopidogrel responses in acute coronary syndrome and clinical predictors of non response

Objectives

We have prospectively investigated the association between aspirin and clopidogrel responses and the clinical predictors of non response.

Methods

635 Non ST Elevation Acute Coronary Syndrome (NSTE ACS) patients were included and received loading doses of 250 mg aspirin and 600 mg clopidogrel. We analyzed post-treatment maximal intensity of arachidonic acid and ADP-induced platelet aggregation (AA-Ag and ADP-Ag) and Platelet Reactivity Index of VAsodilator-Stimulated Phosphoprotein (PRI VASP). Aspirin and clopidogrel non responses were defined respectively by AA-Ag > 30% and ADP-Ag > 70%.

Results

Aspirin non responders patients had significantly higher ADP-Ag and PRI VASP than aspirin responders: 63.7 ± 15.9% vs 55 ± 19% (p = 0.0001) and 73.6 ± 13.3% vs 53 ±23% (p = 0.0001) respectively and the rate of clopidogrel non responders was higher among aspirin non responders than aspirin responders: 36.7% vs 22.7% (p = 0.003). In addition, clopidogrel non responders had significantly higher AA-Ag and rate of aspirin non responders than clopidogrel responders: 21.6 ± 24% vs 10.3 ± 19% (p = 0.0001) and 22.8% vs 12.9% (p = 0.003) respectively. Age and Body Mass Index (BMI) were significantly associated with non response to Clopidogrel (p = 0.035 and 0.02 respectively) and diabetes mellitus by trend (p = 0.07).

Conclusion

We observed a relationship between aspirin and clopidogrel non responses and an association between age, BMI and diabetes mellitus and clopidogrel response.     

Characterisation and reproducibility of a human ex vivo model of thrombosis

Background

The Badimon chamber is a clinical ex vivo model of thrombosis that mimics flow conditions within the coronary circulation of man. The aims of this study were to characterise thrombus formation in the chamber and evaluate its reproducibility.

Methods

Using blood from 24 healthy human volunteers, thrombus formation was assessed at low and high shear rates with porcine aortic tunica media as the thrombogenic substrate. Thrombus area was measured histomorphometrically. Reproducibility was assessed by paired measurements made both within and between days. Platelet activation was assessed before and at selected points within the extracorporeal circuit using flow cytometry, and fibrin content and distribution within the thrombus were assessed by immunohistochemistry.

Results

Total thrombus area was highly reproducible within and between days in the low shear ([mean thrombus area, mean difference ± SEM] 8,018 μm², 58 ± 204 μm² and 8,177 μm², -154 ± 168 μm² respectively) and high shear chambers (11,802 μm², -52 ± 175 μm² and 11,877 μm², 220 ± 181 μm² respectively). Total thrombus area was greater in the high compared to the low shear chamber (11,970 ± 285 μm²versus 7,892 ± 298 μm²; P < 0.0001). Transit through the extracorporeal circuit did not result in platelet activation which was only detected after blood passed across the perfusion chambers (P = 0.02 for platelet-monocyte aggregate formation and P = 0.05 for P-selectin expression). Thrombus in the low shear chamber contained a greater proportion of fibrin (25.0 ± 6.0% versus 8.3 ± 1.6%, P < 0.001).

Conclusions

The Badimon chamber provides a highly reproducible technique for the assessment of ex vivo platelet-rich thrombus formation in man.     

The impact of selective and non-selective non-steroid anti-inflammatory drugs on secondary hemostasis in healthy volunteers

Background

Clinical and epidemiological studies have associated selective COX-2 inhibitors with an increased risk of cardiovascular events. There are no clinical studies on the possible effects of these drugs on secondary hemostasis. The hypothesis for this study is that the use of selective COX-2 inhibitors could affect the secondary hemostasis and by that increase the risk of cardiovascular events in a population at high risk.

Methods

An open-label randomized cross-over study was performed in 20 healthy male volunteers. The study consisted of two periods of each 21 days with medication, either celecoxib 100 mg b.i.d. or naproxen 250 mg b.i.d. Treatment periods were separated by a washout period of 28 days. Blood samples were obtained before the first medication period, and at the end of each medication period. Primary effect parameter was FXII level. Secondary effect parameters included a wide range of coagulation factors involved in secondary hemostasis.

Results

There was no statistically significant effect of celecoxib or naproxen on the primary effect parameter. Protein C activity was significantly decreased after treatment with naproxen (P < 0.01), compared to baseline. Platelet function, demonstrated as closure time (CT), was at baseline 118 ± 24 sec. (mean ± SD). Naproxen prolonged CT to 171 ± 50 sec. (P < 0.001). Celecoxib did not change CT significantly (119 ± 24 sec.).

Conclusions

Neither the selective COX-2 inhibitor celecoxib, nor the non-selective NSAID naproxen caused any change in the primary effect parameter from the secondary hemostasis.     

ABCB1 C3435T polymorphism and risk of adverse clinical events in clopidogrel treated patients: a meta-analysis

Introduction

The ABCB1 C3435T polymorphism limits oral bioavailability of clopidogrel and may influence prognosis of patients treated with clopidogrel. Several studies have examined the association between the C3435T polymorphism and risk of adverse clinical events in clopidogrel treated patients, but the results were inconsistent. To assess the role of the C3435T polymorphism in the impact on clinical outcomes, a meta-analysis was conducted.

Methods

6 studies with 10,153 subjects were included in this meta-analysis. Fixed- or random-effects model was chosen according to heterogeneity. Publication bias was evaluated by fail-safe numbers.

Results

The association of the C3435T polymorphism with risk of overall recurrent ischemic events in clopidogrel treated patients was not statistically significant for all genetic models (OR = 1.13, 95%CI: 0.78-1.64, P = 0.51; OR = 1.15, 95%CI: 0.99-1.33, P = 0.07; OR = 1.19, 95%CI: 0.81-1.76, P = 0.37). Significant association was identified between the C3435T polymorphism and risk of short-term recurrent ischemic events (OR = 1.55, 95% CI: 1.09-2.20, P = 0.01; OR = 1.41, 95% CI: 1.06-1.87, P = 0.02; OR = 1.77, 95% CI: 1.19-2.63, P = 0.005). No statistically significant association between the C3435T polymorphism and stent thrombosis (OR = 0.79, 95% CI: 0.47-1.32, P = 0.37) or bleeding (OR = 0.98, 95% CI: 0.79-1.21, P = 0.82) was identified. The results may be affected by publication bias.

Conclusions

This meta-analysis failed to show an association between the ABCB1 C3435T polymorphism and risk of overall recurrent ischemic events, stent thrombosis or bleeding in clopidogrel treated patients. However, the association between TT homozygotes of the C3435T polymorphism and risk of short-term recurrent ischemic events may exist, but needs more studies to confirm.     

Serum D-dimer changes and prognostic implication in 2009 novel influenza A(H1N1)

Background

The patients with Influenza A (H1N1) have a higher mortality compared with suffering from seasonal influenza. However, many clinical characteristics are still not clear. In the course of clinical treatment on H1N1, we found there were some apparent abnormal clinical indexes being detected at the preliminary diagnosis for severely ill patients, especially the obvious increasing of D-dimer. D-dimer may be associated with the prognosis of Influenza A (H1N1).

Methods

Patients' clinical data (age, gender, body mass index, primary diseases, etc.) and the preliminary diagnostic clinical indexes including blood creatine kinase (CK), creatine kinase isoenzyme (CK-MB), lactic dehydrogenase (LDH), T cell subsets, blood gas analysis, D-dimer, activated partial thromboplastin time (APTT), prothrombin time (PT) and plasma fibrinogen (FG) were retrospectively analyzed.

Results

Compared with the non-respiratory failure group, the cases in respiratory failure group, especially in death sub-group have lower lymphocytes, higher LDH and D-dimer, as well as decreasing oxygenation index during the preliminary diagnosis(P < 0.05). The disease severity (Apche II scores) was independently associated with preliminary oxygenation index and LDH (R² = 0.511, p < 0.01). The correlation analysis shows that there is a negative correlation between the D-dimer and oxygenation index (r = − 0.510, P < 0.01) in the preliminary diagnosis. Meanwhile, there is also a negative correlation between preliminary diagnostic D-dimer and the lowest oxygenation index after admission (r = − 0.573, P < 0.01).

Conclusions

The peripheral blood lymphocytes (including CD3, CD4 and CD8), LDH, oxygenation index and D-dimer detected in the preliminary diagnosis are important indexes that may affect the disease progress and prognosis of H1N1 patients. The significantly increased D-dimer and corresponding hyoxemia indicate the probability of formation of pulmonary microthrombus. Thus, it may be necessary to consider the anticoagulant therapy.     

Analysis of unfractionated heparin dose requirements to target therapeutic anti-Xa intensity during pregnancy

Introduction

Unfractionated heparin (UFH) does not cross the placenta and has demonstrated utility in the prevention and treatment of thrombosis during pregnancy. Limited information is available to guide initiation and monitoring of therapeutic UFH targeting an anti-Xa concentration of 0.3-0.7 u/ml during pregnancy. The objective of this study was to describe UFH doses and monitoring strategies required to achieve and maintain therapeutic anti-Xa intensity in a cohort of women treated with UFH during pregnancy.

Materials/Methods

Patients prescribed anti-Xa adjusted UFH during pregnancies occurring between January 1998 and March 2005 were included.

Results

A total of 39 pregnancies for 37 women were identified. Unfractionated heparin doses were titrated to achieve a mid-interval anti-Xa level of 0.3-0.7 u/ml. Patients required a median 6.5 days and a mean UFH dose of 403.5 u/kg/day to achieve therapeutic anti-Xa levels. Most anti-Xa levels were within the target range (59%). The final UFH dose/kg required at the end of pregnancy was similar to that at the first therapeutic level (P > 0.05); however some patients did require dose modification. Patients required a mean 14.1 anti-Xa determinations and 4.6 dose modifications during a mean 23.9 weeks of antenatal UFH therapy. Patient weight and UFH dose at the first therapeutic anti-Xa level were correlated (r = 0.383, P = 0.018).

Conclusions

Pregnant women required a mean UFH dose of 403.5 u/kg/day to achieve midinterval anti-Xa levels of 0.3-0.7 u/ml. The required dose was correlated with patient weight and most anti-Xa measurements were within the target range.