Activated inflammatory cells participate in thrombus size through tissue factor and plasminogen activator inhibitor-1 in acute coronary syndrome: Immunohistochemical analysis

Introduction

Recent studies have suggested that circulating inflammatory cells augment the growth of thrombus in acute coronary syndrome (ACS). We therefore immunohistochemically analyzed thrombi in aspirates obtained from patients immediately after the onset of ACS.

Materials and Methods

Two hundred twenty samples were studied. Total thrombus area, white thrombus area, and red thrombus area were measured. As antibodies in immunohistochemical staining, myeloperoxidase (MPO), CD66b, CD68, p-selectin, tissue factor (TF) and PAI-1were employed respectively.

Results

The ratios of areas of red and white thrombi correlated with whole sample areas of enlarged thrombi (r = 0.48, p < 0.001). The immunohistochemical findings revealed granulocytes and macrophages aggregated around p-selectin-positive platelets that shared the boundary between white and red thrombi, a region where MPO and CD66b expression was abundant in neutrophils. The ratios (%) of MPO- and CD66b-positive cells significantly correlated with whole sample areas (r = 0.50; p < 0.001 and r = 0.49; p < 0.001, respectively). Neutrophils and macrophages within thrombi were positive for TF and PAI-1. Along the boundary between red and white thrombi, TF and PAI-1 positivity coincided with MPO-, CD66b- and CD68-positive cells. The ratios of cells positive for both TF and PAI-1 in this area significantly correlated with the whole sample area (r = 0.43, p < 0.001 and r = 0.60, p < 0.001, respectively).

Conclusions

These results suggested that enhanced activation of peripheral neutrophils together with increased TF and PAI-1 expression might comprise a considerable portion of thrombus enlargement.     

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.     

Circulating monocytes mirror the imbalance in TF and TFPI expression in carotid atherosclerotic plaques with lipid-rich and calcified morphology

Background

Thrombogenicity of atherosclerotic plaque largely depends on plaque morphology and their content of tissue factor (TF) and tissue factor pathway inhibitor (TFPI). The relationship between morphological composition of plaque (lipid-rich or calcified) and expression of TF and TFPI in circulating blood monocytes and within the plaques is not characterized.

Objective

To investigate whether lipid-rich (echolucent) or calcified (echogenic) morphology of carotid atherosclerotic plaques is associated with differences in TF and TFPI expression in circulating blood monocytes and within carotid atherosclerotic plaques.

Methods

We studied levels of monocyte TF and TFPI mRNA and protein expression and association with traditional risk factors for atherosclerosis in asymptomatic subjects with echolucent (n = 20) or echogenic (n = 20) carotid plaques, or controls without carotid atherosclerosis (n = 20) determined by ultrasonography. Sections of calcified or lipid-rich carotid plaques obtained from symptomatic patients were assessed for TF and TFPI antigen expression.

Results

TF and TFPI surface presentation, surface TF/TFPI ratio, and TF activity were higher in monocytes obtained from subjects with echolucent than with echogenic plaques or controls without carotid atherosclerosis. Multiple regression analyses revealed inverse association between serum apoA1 and monocyte surface TF antigen expression (p = 0.007), and positive association between serum apoB and monocyte surface TFPI expression (p = 0.028). Sections from lipid-rich carotid plaques contained 2.5-fold more TF and 1.5-fold more TFPI antigens relative to calcified lesions, also yielding a higher TF/TFPI ratio.

Conclusions

Our findings indicate that circulating monocytes of asymptomatic individuals with echolucent lipid-rich carotid atherosclerosis express an imbalance between TF and TFPI expression cohering with changes found within advanced carotid atherosclerotic plaques obtained from symptomatic patients.     

Venous thromboembolism risk assessment and thromboprophylaxis among hospitalized acute medical patients in China - the RAMP study

Background

In developed countries, hospitalized patients with acute medical conditions are at significant risk for venous thromboembolism (VTE). Little is known about VTE risk and prophylaxis practices in China.

Objective

To determine the VTE risk and the frequency of recommended VTE prophylaxis in hospitalized Chinese patients with acute medical conditions.

Methods

Multi-center, cross-sectional, observational study. Eligibility criteria: ≥ 30 years, admitted to an intensive care unit (ICU)/coronary care unit (CCU) for acute medical illness, had ≥ 1 VTE risk factor/1 disease that predisposes to VTE, and provided informed consent. We used 2004 American College of Chest Physicians (ACCP) evidence-based consensus guidelines to assess VTE risk and the frequency of recommended VTE prophylaxis.

Results

1247 patients from 19 hospitals in 11 cities across 11 provinces of China were enrolled from July 2007 to June 2008. 57.3% patients had > 2 VTE risk factors. Only 20.2% received ACCP-recommended VTE prophylaxis (CCU patients: 22.7%, ICU patients: 16.9%, p = 0.0117).

Limitations

Excluding some patients with VTE risk factors did not allow assessment of the prevalence of VTE risk in the acute hospital-care setting. We could not determine whether the duration of prophylaxis complied with the ACCP recommendations. Our results may not be representative of hospitals in small cities/rural areas in China.

Conclusions

The prevalence of VTE risk factors in Chinese patients was similar to that in developed countries; however, only a small proportion of eligible patients received the recommended VTE prophylaxis. Our findings highlight the need for dissemination and implementation of appropriate VTE prophylaxis guidelines in China.     

Age, sex and first treatment of schizophrenia in a population cohort

Objective

Schizophrenia affects men more than women, but this may not be true at all ages. This study examines the incidence of first hospitalization for treatment of schizophrenia in each sex over different ages.

Methods

We compared the incidence of first admission for treatment in a cohort of 46,388 males and 43,680 females followed from birth until ages 29-41, using life tables and proportional hazards methods.

Results

Life table estimates of cumulative incidence by age 40 were 1.44% in males and 0.86% in females. For over all ages the relative risk (RR) in males was 1.6 (95% confidence limits = 1.4-1.8) compared with females. Before age 17 there was no significant difference between the sexes (RR = 0.86, 0.56-1.3). Excess risk in males was observed only from age 17 (RR = 1.7, 1.4-1.9). There was no evidence of the incidence in females catching up with that in males, during the 30s.

Conclusion

In this population, there was a significant change, over age, in the relative incidence of first hospitalization for schizophrenia between the sexes; the excess incidence in males first developed at age 17.     

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.     

Antiplatelet effects of antidepressant treatment: A randomized comparison between escitalopram and nortriptyline

Introduction

Depressive disorders have been identified as independent risk factors for coronary heart disease. The present study (i) compared platelet function of depressed patients with that of healthy controls, (ii) analysed possible aggregability changes during 3 months of treatment with antidepressants, and (iii) sought to assess different effects of escitalopram and nortriptyline on platelet aggregation.

Methods

Blood samples of 91 major depressed patients and 91 healthy controls were analysed with whole blood aggregometry in a case-control setting. Depressed patients were randomized to two groups treated either with escitalopram (n = 47) or nortriptyline (n = 44). Platelet aggregation was studied on days 0, 1, 3, 7, 14, 21, 84 of continuing medication and was determined in response to adenosine diphosphate (ADP) and collagen.

Results

Platelet aggregation induced by ADP was increased among depressive patients compared with that of healthy controls (26%, p = 0.006). With antidepressant treatment, changes in platelet aggregation remained comparable in both groups at early time points (d1 to 21). In contrast, at day 84, patients with antidepressive response revealed significant differences in both medication groups: Patients receiving escitalopram showed a 23% decrease of ADP induced aggregation (p = 0.03) and a 15% decrease of collagen induced aggregation (p = 0.03). With nortriptyline the increase in impedance was reduced by 29% after ADP induction (p = 0.046).

Conclusion

Depressed patients have higher ex vivo platelet aggregation that may contribute to increased cardiovascular morbidity. After three months of antidepressant treatment with either escitalopram or nortriptyline, platelet aggregation was significantly reduced in antidepressant responders, irrespective of the antidepressant medication type.     

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.     

Extracorporeal cardiopulmonary support may be an efficient rescue of patients after massive pulmonary embolism. An experimental porcine study

Introduction

Treatment of massive pulmonary embolism leading to cardiac arrest is controversial but restitution of circulation within a shorter time is crucial. Cardiopulmonary support and therapeutic hypothermia is an option for cardiac arrest and could be used to treat massive PE. However, hypothermia may influence the effect of the ongoing intrinsic fibrinolysis.

Objectives

To establish a porcine model of massive pulmonary embolism, to show that cardiopulmonary support can rescue pigs with massive pulmonary embolism and to examine the effect of hypothermia on fibrinolysis.

Methods

Pigs ~ 80 kg were anesthetised and prepared for cardiopulmonary support. Repetitive injections of preformed blood thrombi into the right atrium were done until cardiac arrest. Cardiopulmonary support was established and eighteen pigs were randomised into 3 groups: Normothermia (38-39 °C); hypothermia (33-34 °C); or medication with recombinant tissue plasminogen activator. After three hours the pigs were weaned from cardiopulmonary support, and after 15 minutes with spontaneous circulation assassinated and autopsied. Remaining thrombi in the lungs were weighed.

Results

The development of fatal pulmonary embolism was highly reproducible. All 18 pigs could be weaned from cardiopulmonary support and survived more than 15 minutes. The amount of remaining thromboemboli was substantial in all groups and not significantly different between groups. Normothermic group 20.0 ± 2.2 g, Hypothermic group 17.0 ± 3.7 g, and rt-PA group 14.3 ± 3.2 g.

Conclusions

Cardiopulmonary support could rescue pigs with massive pulmonary embolism. Hypothermia did not reduce the emboli but may for other reasons be beneficial. The optimal additional treatment is still unknown but treatment modalities can be tested in this model.     

Eosinophil count predicts mortality following percutaneous coronary intervention

Introduction

Several inflammatory markers have been shown to be independent predictors for both the development of clinically significant atherosclerosis and for adverse outcome in patients with symptomatic coronary artery disease (CAD). We investigated the prognostic role of eosinophil count in low to intermediate risk patients with CAD.

Methods

We studied 909 patients admitted for elective or urgent percutaneous coronary intervention (PCI) from April 2002 to December 2004, and measured pre-procedural total and differential white blood cell (WBC) counts. Inter-tertile WBC differences in short (6 months) and long term (up to 74 months) mortality were analysed after adjusting for differences in baseline characteristics.

Results

Over a median period of 54 months (inter-quartile range 47-65), a total of 138 deaths (15.2%) occurred, of which 24 were in the first 6 months of follow-up. Cox regression analysis showed that high pre-procedural eosinophil count (top tertile) was associated with improved outcome within the first 6 months (OR = 0.23 [0.06-0.84]; p = 0.03) but after this period there was an increased risk of mortality (OR = 2.21, [1.26-3.88]; p = 0.006).

Conclusions

Eosinophil count is a novel biomarker for risk stratification of CAD patients, which was associated initially with reduced mortality, but after 6 months with increased mortality.     

Formation of the venous thrombus after venous occlusion in the experimental mouse model of metabolic syndrome

Introduction

The metabolic syndrome is considered to be a risk factor for the venous thromboembolism (VTE) as well as arterial thrombosis. Although obesity, hyperglycemia and dyslipidemia are considered to be important triggering factors, it is difficult to evaluate the relationship between VTE and the metabolic syndrome in a clinical study. Furthermore the mechanism of venous thrombosis initiation still remains elusive.

Materials and Methods

20 min clamp of superior mesenteric vein was applied to 7 w, 16 w-old KK-A^y mouse and 16 w-old B6J mouse (n = 6 in each group), after de-clamp, the view of the mesenteric vein and intestinal submucosal venule were observed by the intravital microscopy.

Results

Massive thrombi formed in the mesenteric vein in 16 w-old KK-A^y mice, moderate thrombi formation was observed in 7 w-old KK-A^y mice, while very few thrombi were observed in B6J mice. The first event in submucosal venule after de-clamp was the adhesion of leukocytes to the endothelium. Subsequently, leukocytes assembled and platelets covered the leukocyte cluster. These leukocyte-platelet aggregates move from the venule to the vein and finally formed a venous thrombus.

Conclusion

Metabolic syndrome is a risk factor for venous thrombosis. Intravital microscopic examination revealed leukocyte and platelet recruitment to the venule in the early stages of venous thrombosis formation.     

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.     

Incidence and predictive factors of symptomatic thrombosis related to peripherally inserted central catheters in chemotherapy patients

Introduction

The incidence of symptomatic catheter-related deep vein thrombosis (DVT) in cancer patients remains unclear and there is a lack of reliable data on the risk factors of PICC-related DVT.

Materials and Methods

We performed a retrospective cohort study of consecutive cancer patients who received an ultrasound guided PICC line for the administration of chemotherapy. Univariable and multivariable logistic regression analyses were performed to identify risk factors for symptomatic PICC-related DVT.

Results

In total, 340 cancer patients obtained PICC lines for the administration of chemotherapy. Of these patients, 19 (5.6%; 95% CI: 3.6-8.6) developed symptomatic PICC-related DVT. Factors previously associated with catheter-related DVT, including side of catheter placement, lumen size, tip location, need for repositioning, and number of insertion attempts, were not significant determinants in our analysis. Patients with diabetes were three times more likely to develop PICC-related DVT (OR 3.0, p = 0.039), while the presence of COPD and metastatic cancer also increased the odds (OR 3.3, p = 0.078 and OR 2.3, p = 0.083 respectively). Diabetes remained a significant risk factor after adjustment for effect of metastases and COPD (OR 3.175, p = 0.039). Further, the presence of metastases was a significant predictor (OR 3.34, p = 0.024) in our multivariable model.

Conclusions

Symptomatic PICC-related DVT are frequent in cancer patients receiving chemotherapy. Previously described factors associated with catheter-related thrombosis were not predictive of PICC-related DVT in our study. Diabetes, advanced disease and COPD appear to increase the risk of developing PICC-related DVT in chemotherapy patients.     

Sustained enhancement of residual platelet reactivity after coronary stenting in patients with myocardial infarction compared to elective patients

Introduction

Elevated platelet reactivity despite antiplatelet therapy is associated with an increased cardiovascular risk after percutaneous coronary interventions. Current guidelines recommend uniform antiplatelet maintenance regimen after percutaneous coronary interventions for patients with myocardial infarction and elective patients. We sought to demonstrate that there is a persistent enhancement of residual platelet reactivity after myocardial infarction, requiring an intensified antiplatelet maintenance therapy.

Materials and Methods

A total of 66 patients after coronary stenting for myocardial infarction (n = 36) or elective coronary stenting (n = 30) were included in this prospective, controlled study. Platelet reactivity to adenosine-5-diphosphate and arachidonic acid under treatment with clopidogrel (75 mg) and acetyl salicylic acid (100 mg) were assessed 48 hours and 30 days after coronary stenting using light transmission aggregometry and multiple electrode platelet aggregometry (Multiplate analyzer) simultaneously.

Results

Fourty-eight hours after coronary stenting all measures of residual platelet reactivity were significantly elevated in the infarction group. After a mean follow up of 37 days, residual platelet reactivity to adenosine-5-diphosphate was still consistently elevated, albeit statistically not significant. Contrarily, residual platelet reactivity to arachidonic acid significantly decreased and returned to normal by the time of follow up. Regression analyses revealed myocardial infarction, C-reactive protein and fibrinogen as predictors of enhanced platelet reactivity 48 hours after coronary stenting.

Conclusions

Patients undergoing coronary stenting for acute myocardial infarction exhibit an enhancement of residual platelet reactivity sustaining for at least 48 hours following coronary stenting. This finding provides a rationale for a continued intensified antiplatelet therapy after myocardial infarction.     

Cost of acute ischemic and hemorrhagic stroke in Turkey

Objective

The aim of this study is to examine the direct medical costs and outcomes of patients with stroke.

Material and methods

The records of the patients admitted with ischemic and hemorrhagic stroke to the University of Trakya, School of Medicine, Department of Neurology were reviewed retrospectively in year 2007. Direct medical costs (total costs, radiological, laboratory, medicine, and other) were calculated, additionally cost per life saved and per life-year saved were calculated for stroke patients.

Results

The study group consisted of 328 patients (169 male/159 female) and mean age was 66.5 ± 12.4 years. Length of hospital stay was 10.7 ± 7.5 days. Mortality rate was 20.4% and the mRS score of the patients was 3.2 ± 2.1. The average cost of stroke was US$ 1677 ± 2964 (29.9% medicine, 19.9% laboratory, 12.8% neuroimaging, and 38% beds and staff). Cost per life saved and per life-year saved were US$ 2108 and US$ 1070, respectively.

Conclusion

This is the first study in order to determine direct medical cost of stroke in Turkey, therefore, it may be guideline for disease-cost management of stroke.     

Effects of G-CSF on systemic inflammation, coagulation and platelet activation in patients with acute myocardial infarction

Introduction

In the prospective, randomised, double-blind, placebo-controlled Regenerate Vital Myocardium by Vigorous Activation of Bone Marrow Stem Cells (REVIVAL)-2 trial patients with acute myocardial infarction (AMI) and successful mechanical reperfusion received granulocyte-colony stimulating factor (G-CSF, 10 μg/kg KG s.c.) or placebo for 5 days. Aim of this substudy was to assess the impact of G-CSF on systemic inflammatory and procoagulant responses and platelet activation.

Methods and Results

Before and five days after G-CSF (n = 56) or placebo (n = 58) circulating cytokine concentrations of interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12 and Tumor-Necrosis Factor-α (TNF-α? were measured. Prothrombin fragment F1 + 2 and Tissue Factor activity served as a measure for activated coagulation. Platelet activation was characterized by cell surface expression of the activated fibrinogen receptor (PAC-1), P-selectin and CD40L by flow cytometry. Administration of G-CSF was associated with elevated TNF-α and CRP?concentrations compared to the placebo group after 5 days. Other cytokines (IL-1ß, IL-6, IL-8, IL-10, IL-12) were comparable after treatment with G-SCF or placebo. Similarly, circulating prothrombin fragments F1 + 2, TF activity and platelet activation did not differ in both groups.

Conclusion

Treatment with G-CSF in patients with AMI was associated with enhanced proinflammatory TNF-α and CRP levels but no activation of coagulation.     

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.     

Activated factor XI and tissue factor in chronic obstructive pulmonary disease: links with inflammation and thrombin generation

Introduction

Increased cardiovascular mortality and risk of venous thromboembolism are serious extra-pulmonary complications of chronic obstructive pulmonary disease (COPD). Previously, circulating active tissue factor (TF) and factor XIa (FXIa) have been reported to be associated with acute coronary syndromes.

Objective

To measure plasma FXIa and active TF, prothrombin fragment 1.2 (F1.2), and markers of systemic inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], tumor necrosis factor α [TNFα] and matrix metalloproteinase 9 [MMP-9]) in 60 patients with documented stable COPD free of previous thromboembolic events.

Methods

In-house clotting assays using inhibitory monoclonal antibodies against FXIa and TF.

Results

FXIa was detected in 9 (15%) and TF activity in 7 (11.7%) COPD patients. Subjects positive for FXIa and/or TF (n = 10; 16.7%) had higher F1.2 (median [interquartile range], 398 [216] vs 192 [42] pM, p < 0.000001), fibrinogen (5.58 [2.01] vs 3.97 [2.47] g/L, p = 0.0007), CRP (14.75 [1.20] vs 1.88 [2.95] mg/L, p < 0.000001), IL-6 (8.14 [4.74] vs 2.45 [2.24] pg/mL, p = 0.00002), and right ventricular systolic pressure (47 [15] vs 38 [12] mmHg, p = 0.023), and lower vital capacity (66 [15] vs 80 [17] % predicted, p = 0.04) than COPD patients without detectable FXIa and TF. COPD severity was not associated with the presence of circulating FXIa and active TF.

Conclusions

This is the first study to show that active FXIa and TF are present in stable COPD patients, who exhibit enhanced systemic inflammation and thrombin generation. Our findings suggest a new prothrombotic mechanism which might contribute to elevated risk of thromboembolic complications in COPD.     

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.