Blood Hypercoagulability Research Articles

Adiponectin alleviates blood hypercoagulability via inhibiting endothelial cell apoptosis induced by oxidative stress in septic rats.

Objective(s): The purpose of this study was to detect the protective effects of adiponectin on coagulation dysfunction and its mechanism in sepsis of rats.Materials and Methods:The experimental samples were composed of sham group, model group that was underwent cecal ligation and puncture (CLP) and three adiponectin treatment groups that treated by adiponectin with different dose (72 μg/kg, 96 μg/kg and 120 μg/kg) after CLP. The prothrombin time (PT), activated partial thromboplastin time (APTT) was measured, respectively, the level of malondialdehyde (MDA), tissue factor (TF), activated coagulation factor VIIa and Xa, p-selectin were detected, the histology structure of vascular was observed, the expressions of Caspase 9, Caspase 3, Bax, Bcl-2 and vWF in vascular were measured.Results:The results demonstrated that adiponectin treatment lengthened PT and APTT, reduced the expression of MDA, TF, activated coagulation factor VIIa, Xa and p-selectin in plasma of septic rats. Additionally, adiponectin treatment alleviated endothelial cell apoptosis and oxidative stress, down-regulated the levels of Caspase 3, Caspase 9, Bax, Bcl-2 and vWF in vascular.Conclusion:These findings suggest that adiponectin treatment might be a promising therapeutic strategy for relieving septic endothelial cell injury and coagulation dysfunction via inhibiting endothelial cell apoptosis in septic rats.

Assessment of Thrombelastography and Platelet Life Span in Ovines.

Ovines are a common animal model for the study of cardiovascular devices, where consideration of blood biocompatibility is an essential design criterion. In the ovine model, tools to assess blood biocompatibility are limited and continued investigation to identify and apply additional assays is merited. Toward this end, the thrombelastograph, clinically utilized to assess hemostasis, was used to characterize normal ovine parameters. In addition, platelet labeling with biotin was evaluated for its potential applicability to quantify ovine platelet life span. Mean ovine thrombelastograph values were reaction-time: 4.9 min, K-time: 2 min, angle: 64.1°, maximum amplitude: 68.6mm, actual clot strength: 11.9 kd/s, and coagulation index: 1.5. Reaction time was significantly shorter and maximum amplitude, actual clot strength, and coagulation index were all significantly higher when compared to normal human thrombelastograph values suggesting some hypercoagulability of sheep blood. Biotinylation and reinfusion of ovine platelets allowed temporal tracking of the labeled platelet cohort with flow cytometry. These data indicated a mean ovine platelet life span of 188h with a half-life of 84h. The collection of these parameters for normal ovines demonstrates the applicability of these techniques for subsequent studies where cardiovascular devices may be evaluated and provides an indication of normal ovine values for comparison purposes.

Prospective Assessment of Clinical Risk Factors and Biomarkers of Hypercoagulability for the Identification of Patients with Lung Adenocarcinoma at Risk for Cancer-Associated Thrombosis: The Observational ROADMAP-CAT Study.

The aim of this prospective study was to identify the most clinically relevant hypercoagulability biomarkers in lung adenocarcinoma patients for elaboration of an improved risk assessment model (RAM) for venous thromboembolism (VTE). One hundred fifty ambulatory patients with lung adenocarcinoma were prospectively enrolled. Thrombin generation, procoagulant phospholipid-dependent clotting time (Procoag-PPL), tissue factor activity (TFa), factor VIIa (FVIIa), factor V (FV), antithrombin, D-Dimers, P-selectin, and heparanase levels were assessed in platelet-poor plasma at inclusion (baseline) and at the end of the third chemotherapy cycle (third chemotherapy). Cox regression analysis was used to identify independent VTE predictors. At baseline, patients had significantly attenuated thrombin generation, shorter Procoag-PPL, higher levels of TFa, D-Dimers, and heparanase, and lower levels of FVIIa and P-selectin, compared with controls. A significant increase in Procoag-PPL, FV, and FVIIa and a decrease of P-selectin levels were observed between baseline and third chemotherapy. Hospitalization within the last 3 months prior to assessment, time since cancer diagnosis less than 6 months, mean rate index (MRI) of thrombin generation, and Procoag-PPL were independently associated with symptomatic VTE. Accordingly, a prediction model including Procoag-PPL and MRI showed significant discriminating capacity (area under the curve: 0.84). Ambulatory patients with lung adenocarcinoma may display pronounced blood hypercoagulability due to decreased Procoag-PPL, increased endothelial cell activation, and increased degradation of fibrin. Incorporation of Procoag-PPL and MRI of thrombin generation may improve the accuracy of a VTE-RAM in the above setting. The prospective ROADMAP-CAT study identified two biomarkers of hypercoagulability, the procoagulant phospholipid-dependent clotting time (Procoag-PPL) and the mean rate index (MRI) of the propagation phase of thrombin generation assessed with the Calibrated Automated Thrombinoscope, as being clinically relevant for the classification of ambulatory patients with lung adenocarcinoma receiving a maximum of one cycle of chemotherapy into high and intermediate/low risk for venous thromboembolism. Measurement of Procoag-PPL and MRI within 1 month after the administration of the first chemotherapy cycle provides significant accuracy of the assessment. Association of the Procoag-PPL and MRI with the clinical risk assessment model for cancer-associated thrombosis in ambulatory patients with solid tumors (COMPASS-CAT RAM) further improved its accuracy.

Attenuation of type-1 diabetes-induced cardiovascular dysfunctions by direct thrombin inhibitor in rats: a mechanistic study.

Chronic diabetes is associated with ventricular dysfunctions in the absence of hypertension and coronary artery diseases. This condition is termed as diabetic cardiomyopathy (DCM). There is no favourable treatment available for the management of diabetic cardiomyopathy. Recent studies have reported increase in circulating thrombin level among diabetic patients which is responsible for hypercoagulability of blood. Thrombin induces inflammation and fibrosis, and enhances cardiac cell growth and contractility in vitro. In this study, we have investigated the effects of argatroban; a direct thrombin inhibitor against DCM in streptozotocin-induced type-1 diabetes. Diabetes was induced by single dose of streptozotocin (STZ; 50mg/kg, i.p.) in male Sprague-Dawley rats. After 4 weeks of diabetes induction, the animals were treated with argatroban (0.3 and 1mg/kg, i.p. daily) for the next 4 weeks. The effect of argatroban was evaluated against diabetes-associated cardiac dysfunction, structural alteration and protein expression. STZ-induced diabetic rats exhibited significant decline in left ventricular functions. Four weeks of treatments with argatroban significantly improved ventricular functions without affecting heart rate. Further, it also protected heart against structural changes induced by diabetes as shown by reduction in fibrosis, hypertrophy and apoptosis. The improvement in cardiac functions and structural changes was associated with significant reduction in left ventricular expression of thrombin receptor also termed as protease-activated receptor-1 or PAR1, p-AKT (ser-473), p-50 NFκB and caspase-3 proteins. This study demonstrates beneficial effects of argatroban via improvement in cardiac functions and structural changes in STZ-induced DCM. These effects may be attributed through reduction in cardiac inflammation, fibrosis and apoptosis.

Association between use of aspirin or non-aspirin non-steroidal anti-inflammatory drugs and erectile dysfunction

Objective:There are various etiologies of erectile dysfunction (ED), including endothelial dysfunction, atherosclerosis, and chronic inflammation. Aspirin has a protective role against endothelial dysfunction and atherosclerosis, whease all non-steroidal anti-inflammatory drugs (NSAIDs) are known for their anti-inflammatory properties. However, association between the use of aspirin or non-aspirin NSAIDs and ED is controversial. Therefore, we reviewed this relationship.Methods:We systematically reviewed the pathophysiology of ED, physiological effect of prostaglandins, pharmacological action of NSAIDs, and clinical and basic research studies that evaluated the effect of aspirin or non-aspirin NSAIDs on ED.Results:The research studies that assessed association between aspirin or non-aspirin NSAIDs are limited, and only 12 articles have been published. One clinical and three basic studies have claimed that aspirin or non-aspirin NSAIDs are beneficial for ED by preserving nitric oxide synthase impairment or penile blood hypercoagulability. One basic and two clinical studies considered them as risk factors because they interfered with prostaglandin production. By contrast, four clinical studies showed irrelevant results after controlling various medical indications. In addition, the mechanical effect of aspirin or non-aspirin NSAIDs on the nitric oxide pathway is still controversial.Conclusions:The available research studies revealed that association between aspirin or non-aspirin NSAIDs and ED is controversial. Considering the high frequency of drug use, further clinical and basic investigations should be conducted to clarify their exact relationship.

Experimental hypercoagulable state induced by tissue factor expression in monocyte-derived dendritic cells and its modulation by C1 inhibitor.

The crosstalk between immune and coagulation systems plays pivotal roles in host defense, which may involve monocyte-derived dendritic cells (moDCs). Our objectives were to elucidate the role of moDCs in coagulation under inflammatory conditions and the involvement of the complement system. We assessed the effects of lipopolysaccharide (LPS)-stimulated moDCs on coagulation using whole blood thromboelastometry in the presence of complement inhibitors. The sum of clotting time and clot formation time (CT plus CFT) in whole blood thromboelastometry was significantly more reduced in the presence of moDCs than in the absence of monocytes or moDCs and in the presence of monocytes, indicating a more potent coagulability of moDCs. The mRNA expression of coagulation-related proteins in moDCs was analyzed by quantitative PCR, which showed an increase only in the mRNA levels of tissue factor (TF). TF protein expression was assessed by western blot analysis and an activity assay, revealing higher TF expression in moDCs than that in monocytes. The in vitro moDC-associated hypercoagulable state was suppressed by a TF-neutralizing antibody, whereas LPS enhanced the in vitro hypercoagulation further. C1 inhibitor suppressed the in vitro LPS-enhanced whole blood hypercoagulability in the presence of moDCs and the increased TF expression in moDCs. These results suggest a significant role of moDCs and the complement system through TF expression in a hypercoagulable state under inflammatory conditions and demonstrate the suppressive effects of C1 inhibitor on moDC-associated hypercoagulation.

RERATA VOLUME TROMBOSIT DAN AGGREGASI TROMBOSIT DI DIABETES MELITUS TIPE 2 (Mean Platelet Volume and Platelet Aggregation in Diabetes Mellitus Type 2)

Diabetes mellitus patients often have hypercoagulable blood, as evidenced by the increased coagulation, impaired fibrinolysis,endothelial dysfunction and platelet hyperactivity. Hyperactive platelet is the major determinant of pro thrombotic state in DM. Byassessing the MPV and platelet aggregation, which is a marker of platelet activity, in patients with type 2 DM, it is expected to help theprediction of acute events. This research is aimed to know the differences of MPV and the aggregation of platelet between poor glycemiccontrol as well as good the control group in type 2 DM patients. This study was conducted in cross sectional method using 22 people withgood glycemic control and 28 people with poor one (glycemic control) from June to August 2013. Fasting blood samples were analyzedfor CBC, HbA1c, TG and platelet aggregation. MPV and platelet aggregation value were compared between groups using independentt-test. Based on this study, there is no significant difference in MPV and platelet aggregation between groups (p=0.598, p=0.464 (1 μM),p=0.868 (2 μM), p=0.984 (5 μM), p=0.401 (10 μM)). Mean Platelet Volume (MPV) correlate significantly with platelet aggregationat 1 μM and 5μM ADP concentration in good glycemic control group (r=0.591; p=0.004 at 1 μM ADP and r=0.521; p=0.013 at 5 μMADP). Mean platelet volume correlate significantly with the platelet aggregation at 2 μM ADP and the concentration in poor glycemiccontrol group (r=0.405; p=0.033). There are no significant differences in MPV and platelet aggregation between groups, but there is asignificant correlation between them (MPV and platelet aggregation) in the good glycemic control of the type 2 DM group.

Coarse-grained molecular dynamics simulations of fibrin polymerization: effects of thrombin concentration on fibrin clot structure.

Studies suggest that patients with deep vein thrombosis and diabetes often have hypercoagulable blood plasma, leading to a higher risk of thromboembolism formation through the rupture of blood clots, which may lead to stroke and death. Despite many advances in the field of blood clot formation and thrombosis, the influence of mechanical properties of fibrin in the formation of thromboembolisms in platelet-poor plasma is poorly understood. In this paper, we combine the concepts of reactive molecular dynamics and coarse-grained molecular modeling to predict the complex network formation of fibrin clots and the branching of fibrin monomers. The 340-kDa fibrinogen molecule was converted into a coarse-grained molecule with nine beads, and using our customized reactive potentials, we simulated the formation and polymerization process of a fibrin clot. The results show that higher concentrations of thrombin result in higher branch-point formation in the fibrin clot structure. Our results also highlight many interesting properties, such as the formation of thicker or thinner fibers depending on the thrombin concentration. To the best of our knowledge, this is the first successful molecular polymerization study of fibrin clots to focus on thrombin concentration.

A non-hydrocephalic goat experimental model to evaluate a ventriculosinus shunt.

The ventriculosinus shunt is a promising treatment for hydrocephalus. Currently, different shunt techniques exist, and it is not clear whether one is preferable. This pilot study reports on a non-hydrocephalic goat model (Saanen breed) that provides opportunities to evaluate and optimize several aspects of the ventriculosinus shunt technique. Analysis of the coagulation properties of 14 goats by a viscoelastic coagulation monitor showed that goats have a hypercoagulable state compared to humans. This property can be partially counteracted by antiplatelet drugs. During implantation of a ventriculosinus shunt, a pulsatile reflux of blood was observed. After implantation, the animals recovered to their preoperative state, and none of them developed a superior sagittal sinus thrombosis. Evaluation of the shunts after 16 days showed an obstructing luminal clot. Several model-related factors may have promoted this obstruction: the absence of hydrocephalus, the hypercoagulability of caprine blood and the smaller dimensions of the caprine superior sagittal sinus. However, the pulsatile reflux of blood, which is caused by the compliance of the shunt system distal to the valve, may have been an important factor as well. In conclusion, the non-hydrocephalic goat model limits animal suffering and simplifies the study protocol. This model allows researchers to evaluate their implantation technique and shunt hardware but not the efficacy of the treatment or shunt survival.

Pathophysiology of Trousseau’s syndrome

SummaryClinically relevant clotting abnormalities in cancer patients are referred to as Trousseau’s syndrome. While thrombotic complications such as venous thromboembolism are most frequent in every day’s practice, cancer patients may also experience severe bleeding symptoms due to complex systemic coagulopathies, including disseminated intravascular coagulation, haemolytic thrombotic microangiopathy, and hyperfibrinolysis. The pathophysiology of Trousseau’s syndrome involves all aspects of Virchow’s triad, but previous basic research has mainly focused on the cellular and molecular mechanisms underlying blood hypercoagulability in solid cancers and haematological malignancies. In this regard, over-expression of tissue factor (TF), the principal initiator of the extrinsic coagulation pathway, by primary tumour cells and increased shedding of TF-bearing plasma microparticles are critical to both thrombus formation and cancer progression. However, novel findings on intrinsic contact activation in vivo, such as the release of polyphosphates or DNA by activated platelets and neutrophils, respectively, have pointed to additional pathways in the complex pathophysiology of Trousseau’s syndrome.

Risk of Thromboembolic Complications in Morbidly Obese Patients Treated with Laparoscopic Bariatric Surgery

Purpose: The obesity is a metabolic disturbance which is associated with blood hypercoagulability. The purpose of the study was to evaluate if the bariatric procedure increases the risk of thromboembolic complications in morbidly obese patients. Methods: The study involved 38 patients with BMI over 35 who underwent laparoscopic gastric banding. The reference group consisted of 30 surgical patients. The following parameters were examined: Tissue Factor (TF) antigen (TF: Ag) and activity (TF: Ac), its inhibitor - Tissue Factor Pathway Inhibitor (TFPI) antigen (TFPI: Ag) and activity (TFPI: Ac), concentration of thrombin/antithrombin complexes (TAT) and activity of antithrombin (AT). Results: Bariatrics patients had significantly higher levels of TF: Ag (151,9)(p<0.04) and TF: Ac (1,42)(p<0.05) in comparison with reference group (91,3 and 0.1 respectively). Similar was with TFPI, where its TFPI: Ag (85,3) TFPI: Ac (1.16) were higher compared to reference group (67.3 and 1.1 respectively) however the differences did not reach statistically significant level. The level of TAT complexes was also significantly higher in morbidly obese patients (16,7 vs 8.3) (p<0.031) but the activity of AT III was similar in both groups. Based on above in morbidly obese patients a hypercoagulable state can be recognized which was caused by TF. After procedure TF:Ag was almost in the same level as before with the same tendency to reference group (p<0.05) however IF:Ac was insignificant lower (p<0.48). Similar tendency was observed with other parameters which was an evidence for persistent hypercoagulable state despite of a postoperative decrease of TF activity (p<0.27). This means that the bariatric procedure did not influence on blood coagulation of morbidly obese patients. In multivariate regression analysis was shown that only BMI, history of deep vein thrombosis or history of pulmonary complications are an independent factor of postoperative complications connecting with haemostasis. Conclusions: Laparoscopic bariatric procedures are not at increased risk of thromboembolic complications in morbidly obese patients.

Blood homocysteine levels are increased in hepatocellular carcinoma patients with portal vein thrombosis. A single centre retrospective cohort study

BackgroundPortal vein thrombosis (PVT) is reported in 10–40% of hepatocellular carcinoma (HCC) patients. The development of PVT is a multifactorial process, resulting from a reduction in portal blood flow and hypercoagulability. MethodsWe evaluated 44 HCC patients with PVT, 50 HCC patients without PVT and 50 healthy subjects. Homocysteine (Hcy), Vitamin B6, Vitamin B12 and folate were measured. ResultsHcy in HCC patients with PVT is significant higher than the patients without PVT and controls subjects. ConclusionTotal Hcy is a sensitive marker of PVT in patients with HCC.

Low Self-rated Health Is Related to Blood Hypercoagulability in Patients Admitted with Acute Myocardial Infarction.

Self-rated health (SRH) is independently associated with all-cause mortality and adverse cardiovascular outcomes in individuals with and without cardiovascular disease. We examined whether SRH relates to haemostatic factors of a hypercoagulable state with prognostic impact in patients admitted with acute myocardial infarction (MI). We assessed 190 patients (median age: 59 years; all Caucasian; 83% men) within 48 hours of an acute coronary intervention in terms of demographic factors, medical and psychiatric comorbidity, health behaviours, cardiac-related variables and psychosocial characteristics. Patients rated their health state before MI retrospectively with the EuroQol Visual Analogue Scale ranging from 0 ('worst imaginable health state') to 100 ('best imaginable health state'). Circulating levels of fibrinogen, fibrin D-dimer and von Willebrand factor (VWF) antigen were measured the morning after hospital referral. The median score of SRH was 75 (range: 20-100). SRH was inversely associated with fibrinogen (r = - 0.25, p = 0.001) and D-dimer (r = - 0.17, p = 0.021) levels in the bivariate analysis. Stronger relationships emerged for fibrinogen (r = - 0.33, p < 0.001), D-dimer (r = - 0.25, p = 0.001) and also VWF (r = - 0.19, p = 0.015) levels in fully adjusted linear regression models. As for SRH, the Global Registry of Acute Coronary Events (GRACE) risk score was the only covariate showing an independent association with all haemostatic factors (fibrinogen: r = 0.31, D-dimer: r = 0.29, VWF: r = 0.30; all p-values < 0.001). Lower SRH was associated with greater coagulability in patients with acute MI, independent of covariates and comparable with the GRACE risk score. The findings provide a novel psychobiological mechanism that may potentially link SRH with cardiovascular outcome in patients with an acute coronary syndrome.

Left Atrial 4D Blood Flow Dynamics and Hemostasis following Electrical Cardioversion of Atrial Fibrillation.

Background: Electrical cardioversion in patients with atrial fibrillation is followed by a transiently impaired atrial mechanical function, termed atrial stunning. During atrial stunning, a retained risk of left atrial thrombus formation exists, which may be attributed to abnormal left atrial blood flow patterns. 4D Flow cardiovascular magnetic resonance (CMR) enables blood flow assessment from the entire three-dimensional atrial volume throughout the cardiac cycle. We sought to investigate left atrial 4D blood flow patterns and hemostasis during left atrial stunning and after left atrial mechanical function was restored.Methods: 4D Flow and morphological CMR data as well as blood samples were collected in fourteen patients at two time-points: 2–3 h (Time-1) and 4 weeks (Time-2) following cardioversion. The volume of blood stasis and duration of blood stasis were calculated. In addition, hemostasis markers were analyzed.Results: From Time-1 to Time-2: Heart rate decreased (61 ± 7 vs. 56 ± 8 bpm, p = 0.01); Maximum change in left atrial volume increased (8 ± 4 vs. 22 ± 15%, p = 0.009); The duration of stasis (68 ± 11 vs. 57 ± 8%, p = 0.002) and the volume of stasis (14 ± 9 vs. 9 ± 7%, p = 0.04) decreased; Thrombin-antithrombin complex (TAT) decreased (5.2 ± 3.3 vs. 3.3 ± 2.2 μg/L, p = 0.008). A significant correlation was found between TAT and the volume of stasis (r2 = 0.69, p < 0.001) at Time-1 and between TAT and the duration of stasis (r2 = 0.34, p = 0.04) at Time-2.Conclusion: In this longitudinal study, left atrial multidimensional blood flow was altered and blood stasis was elevated during left atrial stunning compared to the restored left atrial mechanical function. The coagulability of blood was also elevated during atrial stunning. The association between blood stasis and hypercoagulability proposes that assessment of left atrial 4D flow can add to the pathophysiological understanding of thrombus formation during atrial fibrillation related atrial stunning.

Panax notoginseng saponins reduce high-risk factors for thrombosis through peroxisome proliferator-activated receptor -γ pathway

The classic Virchow theory suggests that blood stasis, hypercoagulability and endothelial dysfunction are three major factors that cause venous thrombosis (VT). It is a complicated biological process involved multi-factors. Platelet plays a central role and participates in multiple links of this process. Panax notoginseng saponins (PNS), the principal constituents derived from panax notoginseng, has been widely described for its anti-platelet activity. However, its potential mechanism against platelet aggregation has not been clarified. In this present study, we evaluated the anti-platelet effects of PNS on thrombin-induced platelet activation and its possible molecular mechanism of action, and further explored the therapeutic action of PNS on thrombin induced hypercoagulability in rat. Our results showed that PNS treatment inhibited platelet aggregation induced by thrombin, which was accompanied with over-expression of Peroxisome proliferator-activated receptor γ (PPAR-γ) protein, mRNA and upregulation of phosphatidylinositol 3 kinase (PI3K)/ protein kinase B (Akt)/ endothelial nitric oxide synthase (eNOS) pathway in platelet, and this effect could be reversed by PPAR-γ inhibitor T0070907. In vivo, PNS significantly reversed thrombin-induced hypercoagulable state in rat which was accompanied by PPAR-γ protein and mRNA upregulation in rat lung. In conclusion, these data suggested that PNS could suppress thrombin-induced platelet aggregation in vitro and effectively improve hypercoagulable state in vivo and PNS-induced activation of PPAR-γ and its downstream PI3K/Akt/eNOS pathway played the central role.

From vulnerable plaque to blood healthy therapy.

Cardiovascular atherosclerotic disease is the leading cause of death in China and in Western nations. People with plaque or stenosis in the coronary artery or the carotid artery are the most susceptible population to suffer from acute events. Current investigations showed that plaque with the characteristics of intra-plaque hemorrhage or a thin cap with a large lipid core was causally associated with vulnerable plaque and plaque rupture. Of the many plaque ruptures occurring in patients with atherosclerotic disease, very few will trigger symptomatic events, rendering it exceedingly difficult to predict adverse outcomes. The assumption that identifying lesions prone to rupture will prevent acute coronary events was unrealistic. Factors in blood, especially those risk factors associated with thrombosis, play an important role as a bridge between plaque rupture and subsequent clinical events. Since there is little management to efficiently decrease the frequency of plaque rupture or erosion, blood healthy therapy, as a therapeutic apheresis to decrease the blood hypercoagulability to modulate the blood to be thrombosis resisting, should be considered as a potential therapeutic approach to reducing the incidence of acute coronary syndrome and stroke.

Tongqiaozuoxue Decoction, a Traditional Korean Medicine, Improves Hypercoagulation Through Stimulating Adiponectin Expression

The efficacy and safety of traditional medicine could be proved through human trial for a long time, and now it has been required for the scientific evidence of its efficacy and identification of specific functional target. Tongqiaozuoxue Decoction (THD) is a water extract of 8 species of medicinal herb including Cnidium officinale Makino and Prunus persica Batsch, and has been used for the treatment of blood stasis and hypercoagulation in traditional Korean medicine. This study investigated the efficacy of THD and its functional target using animal model. Early vascular model was established through feeding high‐fat diet (HFD, 60% fat) for 12 weeks to C57BL/6 mice; these mice showed the phenotype of obesity, insulin resistance, chronic metabolic inflammation, hyperlipidemia, and prothrombotic state. THD was orally administered for last 4 weeks in a dose of 100mg/kg/day. THD significantly decreased plasminogen activator inhibitor‐1 (PAI‐1) level in serum and adipose tissue (AT) by 30% and 60%, respectively. Also, the plasma activity of tissue‐type plasminogen activator (tPA), the downstream target of PAI‐1, was increased by 2‐fold. Fibrin deposition was notably reduced in AT, demonstrated by immunohistochemistry. Meanwhile, adiponectin level was significantly increased both in serum and adipose tissue by 30% and 60%, respectively, although adipose tissue weight or total body weight were not changed by THD. Taken together, these results demonstrated that THD improve hypercoagulation through stimulating adiponectin expression.Support or Funding InformationThis study was supported by the grant of Korea Institute of Oriental Medicine

Clinical and biochemical characterization of the prothrombin Belgrade mutation in a large Serbian pedigree: new insights into the antithrombin resistance mechanism

Background The recently reported c.1787G>A mutation in the prothrombin gene leads to Arg596Gln replacement in the protein molecule (prothrombin Belgrade). This substitution impairs binding of antithrombin to thrombin and results in inherited thrombophilia, known as antithrombin resistance. Objectives We aimed to elucidate the clinical and biochemical characteristics of thrombophilia associated with antithrombin resistance in a large Serbian family with the prothrombin Belgrade mutation. Patients and methods Nineteen family members were investigated, among whom 10 were carriers of the c.1787G>A mutation. In all subjects the clinical phenotype was determined and laboratory investigations of hemostatic parameters were performed. Results Six out of the 10 mutation carriers developed thromboembolic events, mainly deep venous and mesenteric vein thrombosis. The median age of the first thrombotic event was 26.5 (12-41) years, whereas the incidence rate of first thrombosis was 2.2% per year. In all mutation carriers prothrombin activity was significantly decreased in comparison with non-carriers, clearly distinguishing each group. However, the presence of the mutation did not affect the prothrombin antigen level in plasma. The endogenous thrombin potential was significantly increased in all carriers in comparison with non-carriers, indicating the presence of blood hypercoagulability. Interestingly, levels of D-dimer and the F1+2 fragment were similar in both groups. Conclusions Although rare, the prothrombin Belgrade mutation represents strong thrombophilia with early onset of thrombosis in the investigated family. According to our results, decreased prothrombin activity may be a simple screening test for detection of this mutation in thrombotic patients.

Effect of circulating tissue factor on hypercoagulability in type 2 diabetes mellitusstudied by rheometry and dielectricblood coagulometry.

Background:Hypercoagulability in type 2 diabetes mellitus (T2DM) patients increases their risk of cardiovascular diseases.Objective:The aim of this work was to investigate the hypercoagulation mechanism in T2DM patients in terms of circulating tissue factor (TF).Methods:Whole blood coagulation tests by damped oscillation rheometry and dielectric blood coagulometry (DBCM) were performed.Results:The average coagulation time was significantly shorter for T2DM patients than for healthy controls. In vitro addition of either anti-TF or anti-activated factor VII (FVIIa) antibody to hypercoagulable blood samples prolonged coagulation times for one group of patients, while coagulation times remained short for another group. The levels of circulating TF were estimated in the former group by measuring the coagulation times for blood samples from healthy subjects with addition of various concentrations of TF and comparing them with the coagulation times for the group. The results indicated that the levels of circulating TF were on the order of subpicomolar at most.Conclusions:Circulating TF is at least partially responsible for a hypercoagulable group of T2DM patients, while an abnormality in the intrinsic coagulation pathway probably occurs in the other group.

Impact of blood hypercoagulability on in vitro fertilization outcomes: a prospective longitudinal observational study

BackgroundBlood coagulation plays a crucial role in the blastocyst implantation process and its alteration may be related to in vitro fertilization (IVF) failure. We conducted a prospective observational longitudinal study in women eligible for IVF to explore the association between alterations of coagulation with the IVF outcome and to identify the biomarkers of hypercoagulability which are related with this outcome.MethodsThirty-eight women eligible for IVF (IVF-group) and 30 healthy, age-matched women (control group) were included. In the IVF-group, blood was collected at baseline, 5–8 days after administration of gonadotropin-releasing hormone agonist (GnRH), before and two weeks after administration of human follicular stimulating hormone (FSH). Pregnancy was monitored by measurement of βHCG performed 15 days after embryo transfer. Thrombin generation (TG), minimal tissue factor-triggered whole blood thromboelastometry (ROTEM®), procoagulant phospholipid clotting time (Procoag-PPL®), thrombomodulin (TMa), tissue factor activity (TFa), factor VIII (FVIII), factor von Willebrand (FvW), D-Dimers and fibrinogen were assessed at each time point.ResultsPositive IVF occurred in 15 women (40%). At baseline, the IVF-group showed significantly increased TG, TFa and TMa and significantly shorter Procoag-PPL versus the control group. After initiation of hormone treatment TG was significantly higher in the IVF-positive as compared to the IVF-negative group. At all studied points, the Procoag-PPL was significantly shorter and the levels of TFa were significantly higher in the IVF-negative group compared to the IVF-positive one. The D-Dimers were higher in the IVF negative as compared to IVF positive group. Multivariate analysis retained the Procoag-PPL and TG as predictors for the IVF outcome.ConclusionsDiagnosis of women with hypercoagulability and their stratification to risk of IVF failure using a model based on the Procoag-PPL and TG is a feasible strategy for the optimization of IVF efficiency that needs to be validated in prospective trials.