Activation Of Extrinsic Coagulation Pathway Research Articles

Assessment of systemic immune-inflammation index as an independent surrogate biomarker of no-reflow phenomenon in acute coronary syndrome patients with coronary artery bypass grafting undergoing percutaneous coronary intervention of saphenous vein graft.

Numerous mechanisms have been proposed for the no-reflow phenomenon (NRP) in the literature including leukocyte intravascular plugging, microembolisms, and extrinsic coagulation pathway activation. Some of the more recent studies suggested a relationship between NRP and systemic immune-inflammation index (SII) in different contexts. To this end, the objective of this study was to investigate the relationship between NRP and SII in acute coronary syndrome (ACS) patients with coronary artery bypass grafting (CABG) who underwent percutaneous transluminal coronary angioplasty (PTCA) or percutaneous coronary intervention (PCI) of saphenous vein graft (SVG). The sample of this retrospective study consisted of 124 ACS patients with CABG who underwent PTCA/PCI of SVG. The incidence of NRP in the study group was 30.6% (n=38). The results of the multivariate logistic regression analysis indicated that ST-elevation myocardial infarction (STEMI) and SII were independent predictors for NRP (p<0.05). The receiver operating characteristic (ROC) curve analysis revealed that the optimal cut-off value of SII in predicting the development of NRP in patients undergoing PTCA/PCI of SVG and the sensitivity and specificity values thereof are 975, 74%, and 80%, respectively [Area under the curve (AUC): 0.84, 95% confidence interval (CI): 0.76-0.91, p-value <0.001]. The study findings indicated that SII, which can be easily calculated from a single complete blood count test, is an independent predictor of the development of NRP in ACS patients undergoing PTCA/PCI of the SVG.

Bariatric surgery in morbidly obese individuals affects plasma levels of protein C and thrombomodulin

Obesity is associated with a prothrombotic milieu and an increased risk for thrombotic events. Bariatric surgery is the most effective treatment for obesity resulting in dramatic weight loss and reduced inflammation and extrinsic coagulation pathway activation. Blood samples were drawn from 60 patients undergoing Roux-en-Y gastric bypass surgery before and 1 year after the intervention. Protein C (PC), activated PC (APC), soluble thrombomodulin (TM), soluble E-selectin (E-Sel), prothrombin time (PT) and activated partial thromboplastin time (aPTT) were evaluated. Both PC (187.4 ± 64.5% before surgery to 118.1 ± 48% 1 year after surgery, p < 0.001) and APC (138.7 ± 64.4% before surgery to 69.1 ± 65.7% after surgery, p < 0.001) were reduced following surgical intervention. TM showed a similar behavior with a reduction of soluble TM after the procedure from 5.7 ± 2.6 to 3.2 ± 1.4 ng/ml (p < 0.001). Similarly, soluble E-Sel was reduced after surgery from 26.6 ± 12.7 to 5.5 ± 4.1 ng/ml (p < 0.001). In contrast, aPTT was not shortened but slightly increased from 29.1 ± 4.8 s. before surgery to 31 ± 4.4 s. (p = 0.001) after surgery and levels of PT were reduced after surgery to 89.6 ± 15.5% from an initial 97.5 ± 13.5% (p < 0.001). In conclusion, we demonstrate a reduction of PC and APC 1 year after bariatric surgery accompanied by a reduction in soluble TM and soluble E-Sel. The reduction of PC and APC is not paralleled by a reduction but in contrast by a prolongation of aPTT suggesting a compensatory upregulation of PC during obesity. The reduction of TM and E-Sel might hint towards an improved endothelial function in this cohort of patients.

Role of Vascular Endothelial Cells in Disseminated Intravascular Coagulation Induced by Seawater Immersion in a Rat Trauma Model

Trauma complicated by seawater immersion is a complex pathophysiological process with higher mortality than trauma occurring on land. This study investigated the role of vascular endothelial cells (VECs) in trauma development in a seawater environment. An open abdominal injury rat model was used. The rat core temperatures in the seawater (SW, 22°C) group and normal sodium (NS, 22°C) group declined equivalently. No rats died within 12 hours in the control and NS groups. However, the median lethal time of the rats in the SW group was only 260 minutes. Among the 84 genes involved in rat VEC biology, the genes exhibiting the high expression changes (84.62%, 11/13) on a qPCR array were associated with thrombin activity. The plasma activated partial thromboplastin time and fibrinogen and vWF levels decreased, whereas the prothrombin time and TFPI levels increased, indicating intrinsic and extrinsic coagulation pathway activation and inhibition, respectively. The plasma plasminogen, FDP, and D-dimer levels were elevated after 2 hours, and those of uPA, tPA, and PAI-1 exhibited marked changes, indicating disseminated intravascular coagulation (DIC). Additionally, multiorgan haemorrhagia was observed. It indicated that seawater immersion during trauma may increase DIC, elevating mortality. VECs injury might play an essential role in this process.

Activation of Extrinsic Coagulation Pathway in Myeloproliferative Neoplasms – Preliminary Report

The aim of the study was to assess the activation of extrinsic blood coagulation pathway, based on the TF and TFPI measurements in patients with MPNs. The study group consisted of 17 patients with MPNs (mean age 59 years). The control group was made of 30 healthy volunteers (mean age 52 years). In blood samples tissue factor TF, tissue factor pathway inhibitor (TFPI), thrombin-antithrombin complexes (TAT) concentration and antithrombin (AT) activity were determined. The present study showed a significantly higher level of tissue factor and decreased TFPI concentration in patients with polycythemia vera, essential thrombocythemia and primary myelofibrosis. Conclusions: 1. The results showed that in all groups of patients with MPNs an extrinsic activation of coagulation, resulting in a high concentration of TF in the blood of these patients, occurs. 2. It seems that in patients with ET, PMF and PV, an extrinsic activation of coagulation is inhibited by TFPI inhibitor as evidenced by its reduced concentration observed in the blood of these patients (the result of extrinsic consumption in the track).

Activation of Extrinsic Coagulation Pathway in Myeloproliferative Neoplasms – Preliminary Report

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Alterations of sympathetic nervous system, coagulation and platelet function in gestational diabetes

Gestational diabetes is associated with increased risk for venous thromboembolism. Activation of sympathetic nervous system affects blood coagulation, fibrinolysis and platelet activation by several mechanisms. We aimed to study the relationship of sympathetic nervous system, coagulation and platelet function in gestational diabetes. Forty-one white women with gestational diabetes, 22 healthy pregnant and 14 nonpregnant controls were studied. We assayed serial nocturnal (at 12 p.m., 4 a.m. and 7 a.m.) changes of the adrenergic transmitter noradrenaline, coagulation variables and platelet activation with PFA-100. Plasma noradrenaline increased from 4 to 7 a.m. in both pregnant groups. During the same time period, prothrombin time (PT) shortened in gestational diabetes compared with healthy pregnant and nonpregnant controls. In gestational diabetes, nocturnal FVIII:C levels were lower compared with normal pregnancy and also variables associated with von Willebrand factor tended to be lower. Platelet activity increased at midnight in pregnant women compared with nonpregnant women without differences between gestational diabetes and normal pregnancy. Gestational diabetes is associated with concomitant early morning sympathetic stimulation and activation of extrinsic coagulation pathway (shortened PT). Decreased FVIII:C may refer to compensatory anticoagulatory mechanism. These alterations could reflect increased risk of pregnancy-related thromboembolism in gestational diabetes.

Role of coagulation factor VII in pathogenesis of ischemic heart disease

To study the variation and significance of plasma coagulation factor VII (FVII) in different kinds of ischemia heart disease (IHD) and examine its relation with plasma lipid and gene polymorphism. FVIIa was determined with one stage clotting assay by using a recombinant soluble tissue factor (rsTF). FVIIc was measured with one stage clotting assay. FVIIag was quantified with an enzyme-linked immunosorbent assay (ELISA). Polymorphism was analyzed with PCR-urea-polyacrylamide gel electrophoresis. Our results showed that FVIIa in stable angina (SA), unstable angina (UA), obsolete and acute myocardial infraction (OMI, AMI) patients was higher than those of normal group with the differences being significant within any two groups. FVIIag in UA, OMI and AMI was higher than those in SA and normal groups. There were positive correlations between FVIIa and serum triglycerides, FVIIa and FVIIc, FVIIc and FVIIag. FVII-323 0/10 bp polymorphism analysis was performed in 60 patients and 0/10 bp polymorphism was found in 5 cases. FVIIc and FVIIag were much lower in cases of 0/10 bp groups than those in cases of 0/0 bp groups. It is concluded that there was activation of extrinsic coagulation pathway in every kind of IHD to different extent. FVIIa was the risk factor in the development of IHD, and more sensitive in reflecting the severity of cardiovascular disease than FVIIc or FVIIag. FVIIa was higher in OMI, which may be one of the risk factors of re-infraction. Serum triglyceride may indirectly lead to the development of IHD by increasing the level of FVIIa. FVII-323 0/10 bp polymorphism was present in Chinese patients with IHD and it was correlated with the level of FVIIc, FVIIag in plasma. 10 bp allelomorphic gene was a protective factor against thrombogenesis.

Oxidative Stress – a Link between Endothelial Injury, Coagulation Activation, and Atherosclerosis in Haemodialysis Patients

Background/Aim: Recently emerging evidence suggests that oxidative stress (SOX) may participate in atherogenesis. The aim of the present study was to establish whether enhanced SOX, involving endothelial injury, activation of coagulation, and inflammatory reaction, could be implicated in atherosclerotic diseases in haemodialysis (HD) patients. Methods: Markers of SOX, endothelial injury, coagulation, and cytokines, were measured in the plasma of HD patients with and without cardiovascular disease (CVD), and of healthy controls by ELISA methods. Remodeling of the carotid arteries was assessed by measuring the intima-media thickness (IMT) as a surrogate of atherosclerotic disease in all groups. Results: Markers of SOX, endothelial injury, and extrinsic coagulation pathway activation and IMT values were significantly elevated in HD patients, especially in those with CVD when compared with the control group. The von Willebrand factor antigen (vWF:Ag) levels were more increased in the patients with CVD than in those without. Furthermore, the plasma levels of tumour necrosis factor alpha, monocyte chemo-attractant protein 1, and macrophage inflammatory protein 1 beta were significantly higher only in the HD group with CVD when compared with the controls. The IMT was strongly and directly correlated with Cu/Zn superoxide dismutase. Both IMT and Cu/Zn superoxide dismutase were positively correlated with age, thrombomodulin, vWF:Ag, tissue factor, tissue factor pathway inhibitor, prothrombin fragment F1 + 2, monocte chemo-attractant protein 1, macrophage inflammatory protein 1 beta, and tumour necrosis factor alpha levels. Multivariate analysis identified vWF:Ag as the only independent variable significantly associated with an increased IMT. Conclusions: The present study suggests that enhanced SOX, involved pro-atherogenic cytokine and chemokines levels, endothelial injury, and coagulation activation may constitute a pathway for accelerated atherosclerosis in HD patients. The significant, independent association between IMT and vWF:Ag should be assessed in future studies to determine whether vWF:Ag elevation is causative or a by-product of the increased IMT.

Extrinsic coagulation pathway activation and metalloproteinase-2/TIMPs system are related to oxidative stress and atherosclerosis in hemodialysis patients.

Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), together with extrinsic coagulation pathway activation and increased oxidative stress (SOX) have all been implicated as important factors in atherosclerosis and vascular remodelling. The aim of the present study was to investigate whether the MMPs/TIMPs system is associated with activation of the extrinsic coagulation pathway in conditions of increased SOX in hemodialysis (HD) patients. In HD patients, with and without cardiovascular disease (CVD), and in controls, we compared pre-dialysis levels of MMP-2, MMP-9,TIMP-1,TIMP-2; the markers of extrinsic coagulation pathway-tissue factor (TF) and its inhibitor (TFPI), prothrombin fragment F1+2 (F1+2); a marker of SOX-Cu/Zn superoxide dismutase (Cu/Zn SOD) and a surrogate of atherosclerotic disease-intima media thickness (IMT). Hemodialysis patients, particularly those with CVD, showed a significant increase in values of MMP-2/TIMPs, markers of the extrinsic coagulation pathway, Cu/Zn SOD and IMT as compared to controls. The markers of coagulation activation positively correlated with the MMP-2/TIMPs system, whereas they did not correlate with MMP-9. In addition, both MMP-2/TIMPs as well as extrinsic coagulation parameters were related to the prevalence of increased SOX, IMT and CVD. Multiple stepwise regression analysis showed that low TIMP-2 followed by increased Cu/Zn SOD and MMP-2 levels independently and significantly predicted elevated IMT on maintenance HD patients. In conclusion, our data suggest that the MMP-2/TIMPs system and an activated extrinsic coagulation pathway could cooperate in conditions of elevated SOX and could influence arterial remodeling resulting in the presence of CVD in haemodialysis patients.

Tissue factor pathway inhibitor expression in human crescentic glomerulonephritis

Tissue factor (TF) pathway inhibitor (TFPI), the major endogenous inhibitor of extrinsic coagulation pathway activation, protects renal function in experimental crescentic glomerulonephritis (GN). Its glomerular expression and relationship to TF expression and fibrin deposition in human crescentic GN have not been reported. Glomerular TFPI, TF, and fibrin-related antigen (FRA) expression were correlated in renal biopsies from 11 patients with crescentic GN. Biopsies from 11 patients with thin basement membrane disease and two normal kidneys were used as controls. TFPI was undetectable in control glomeruli but was detectable in interstitial microvessels. In crescentic biopsies, TFPI was detected in cellular crescents and was more prominent in fibrous/fibrocellular crescents, indicating a correlation with the chronicity of crescentic lesions. TFPI appeared to be associated with macrophages but not endothelial or epithelial cells. TFPI was generally undetectable in regions of the glomerular tuft with minimal damage. In contrast, TF and FRA were strongly expressed in regions of minimal injury, as well as in more advanced proliferative and necrotizing lesions. Despite prominent TF expression, FRA was less prominent in fibrous/fibrocellular crescents in which TFPI expression was maximal. These data suggest that TFPI is strongly expressed in the later stages of crescent formation and is inversely correlated with the presence of FRA in human crescentic GN. This late induction of TFPI may inhibit TF activity and favor reduced fibrin deposition in the chronic stages of crescent formation.

Endothelial Cell Markers and Fibrinopeptide A to D-Dimer Ratio as a Measure of Coagulation and Fibrinolysis Balance in Normal Pregnancy

Objective: Changes in hemostatic system were evaluated in healthy pregnant women. Methods: Blood was sampled in the 1st, 2nd and 3rd trimesters of gestation, during delivery and 3 days postpartum and plasma factors were measured using commercial tests. Results: Thrombin-antithrombin III complexes, fibrinopeptide A and D-dimer were higher during pregnancy. The endothelial cell markers, fibronectin and tissue factor, remained within the normal reference values in the healthy nonpregnant population. This result suggests no endothelial injury and shows no activation of extrinsic coagulation pathway during pregnancy. The balance coagulation/fibrinolysy is maintained during pregnancy and delivery, as shown by the ratio fibrinopeptide A/D-dimer, however, a tendency towards coagulation process is developed in the early puerperium.

In vitro study of the hemocompatibility of superparamagnetic contrast agent for magnetic resonance imaging

Five different nanoparticles, potentially useful in magnetic resonance imaging (MRI) after venous administration, were studied for their hemo-compatibility. The in vitro methodology evaluated these materials by several parameters: cytotoxicity towards cells cultured in vitro, aggregation ability of platelets, hemolysis inducibility, intrinsic and extrinsic coagulation pathway activation, and complement activation. With the proposed clinical dose, regardless of the cell type used (murine cell line or human endothelial cells) no toxicity was observed. The presence of the particles in blood did not produce any considerable damage: either hemolysis or platelet aggregation or blood coagulation were recorded. However, a slight decrease in aggregation ability of platelets was noticed as well as an increase in partial thromboplastin time. Because of the quick removal of the particles from the bloodstream, these phenomena must be short-lived, thus avoiding significant adverse clinical effects.