Hemostatic Markers Research Articles

Evaluation of Total Adiponectin, Adipocyte Fatty Acid Binding Protein and Fibroblast Growth Factor 21 Levels in Individuals With Metabolic Syndrome

Although many studies have investigated the relationships of several adipokines to metabolic syndrome (MetS), the interrelationships of adiponectin (ADP), adipocyte fatty acid binding protein (A-FABP) and fibroblast growth factor 21 (FGF 21) have not been described in detail. We examined 209 asymptomatic dyslipidemic patients divided into MetS+ (n=73) and MetS- (n=136) groups. The aim of study was to evaluate the relationships between observed adipokines, to compare the levels of total ADP, A-FABP and FGF 21 in individuals with and without MetS, and to elucidate the relationships of individual adipokines to lipid parameters, markers of insulin resistance and endothelial hemostatic markers in these groups. In MetS+ group, we found the independent positive association ADP with A-FABP (beta=0.4888, p=0.0382), A-FABP with FGF 21 (beta=0.3811, p=0.0002) and von Willebrand factor (beta=0.4502, p=0.0013), and FGF 21 with A-FABP (beta=0.4422, p=0.0002). Our study has confirmed the well-established risk profile of subjects with MetS, although clinically asymptomatic. MetS+ patients had also lower levels of ADP and higher levels of A-FABP and FGF 21. Our study evaluated the interrelationships of ADP, A-FABP and FGF 21 in asymptomatic dyslipidemic subjects with diagnosis of MetS. Especially strong association between A-FABP and FGF 21 needs to be clarified in further studies.

Vulnerable blood in high risk vascular patients: Study design and methods

BackgroundBasic research suggests that rapid increases in circulating inflammatory and hemostatic blood markers may trigger or indicate impending plaque rupture and coronary thrombosis, resulting in acute ischemic heart disease (IHD) events. However, these associations are not established in humans. Methods and resultsThe Biomarker Risk Assessment in Vulnerable Outpatients (BRAVO) Study will determine whether levels of inflammatory and hemostatic biomarkers rapidly increase during the weeks prior to an acute IHD event in people with lower extremity peripheral artery disease (PAD). The BRAVO Study will determine whether biomarker levels measured immediately prior to an IHD event are higher than levels not preceding an IHD event; whether participants who experience an IHD event (cases) have higher biomarker levels immediately prior to the event and higher biomarker levels at each time point leading up to the IHD event than participants without an IHD event (controls); and whether case participants have greater increases in biomarkers during the months leading up to the event than controls. BRAVO enrolled 595 patients with PAD, a population at high risk for acute IHD events. After a baseline visit, participants returned every two months for blood collection, underwent an electrocardiogram to identify new silent myocardial infarctions, and were queried about new hospitalizations since their prior study visit. Mortality data were also collected. Participants were followed prospectively for up to three years. ConclusionsBRAVO results will provide important information about the pathophysiology of IHD events and may lead to improved therapies for preventing IHD events in high-risk patients.

D-dimer relates positively with increased blood pressure in black South Africans: The SABPA study

IntroductionHypertension is highly prevalent in black South Africans in which morbidity and mortality from stroke are on the increase. Elevated blood pressure and haemostatic markers can induce changes in blood rheology and endothelial function which could result in a procoagulant state that increases the risk for cerebrovascular disease. Information about the coagulation and fibrinolytic systems of people from African descent are limited. We therefore, investigated the haemostatic profile and its relationships with blood pressure in black South Africans. Materials and methodsWe measured ambulatory blood pressure and haemostatic markers of 201 black and 208 white school teachers. The haemostatic markers included measurements representing coagulation and fibrinolysis (von Willebrand factor, fibrinogen, plasminogen activator inhibitor-1, fibrin D-dimer and clot lysis time). ResultsBlack participants displayed significantly higher blood pressure, von Willebrand factor, fibrinogen, plasminogen activator inhibitor-1 and D-dimer levels and longer clot lysis times (p≤0.001). Single, partial and multiple regression analyses showed that systolic (p≤0.011) and diastolic blood pressure (p=0.010) correlated positively with D-dimer in black participants, while systolic (p≤0.001) and daytime diastolic blood pressure (p=0.011) correlated negatively with clot lysis time in white participants. ConclusionThe black population had a more prothrombotic profile, with higher levels of coagulation markers and inhibited fibrinolysis, than the white study participants. The positive association between blood pressure and elevated D-dimer in the blacks may contribute to the high prevalence of hypertension and related increased cardiovascular and cerebrovascular risk in this group.

Modulation of Inflammatory and Hemostatic Markers in Obstructive Sleep Apnea Patients Treated with Mandibular Advancement Splints: A Parallel, Controlled Trial

Obstructive sleep apnea (OSA) is associated with systemic inflammation and a hypercoagulable state. The current study aim was to investigate whether mandibular advancement splint (MAS) therapy affects inflammatory and hemostatic parameters in patients with mild-to-moderate OSA. Twenty-two patients with mild-to-moderate OSA and 16 control subjects were studied. OSA subjects were treated with a titratable MAS for 6 months. Baseline plasma C-reactive protein, interleukin-1β, interleukin-10, interleukin-6, P-selectin, fibrinogen, D-dimer, plasminogen activator inhibitor-1 (PAI-1), thrombin-antithrombin complex, activated thrombin-activatable fibrinolysis inhibitor (TAFIa), 6-keto-PGF1α, glucose, and fibrin clot lysis time (CLT) were measured in all subjects. After 3 months of MAS therapy, measurements were repeated for the 22 patients, and after 6 months all measurements were repeated for all study subjects. MAS treatment reduced significantly AHI at 3 months (24 vs 13.1/h) and further improved it at 6 months (13.1 vs 7.05/h). Compared with controls, OSA subjects had a significant higher baseline mean levels of fibrinogen, TAFIa, 6-keto-PGF1α, and glucose. MAS treatment significantly improved levels of IL-1β, D-dimer, TAFIa, and CLT. Despite residual apneas, MAS treatment group presented similar measured homeostatic and inflammatory levels to controls except for glucose. Treatment with MAS in mild-to-moderate OSA subjects improves the inflammatory profile and homeostatic markers. Niżankowska-Jędrzejczyk A; Almeida FR; Lowe AA; Kania A; Nastałek P; Mejza F; Foley JH; Niżankowska-Mogilnicka E; Undas A. Modulation of inflammatory and hemostatic markers in obstructive sleep apnea patients treated with mandibular advancement splints: a parallel, controlled trial.

Associations of overall sitting time and TV viewing time with fibrinogen and C reactive protein: the AusDiab study

Background/aimSedentary behaviour is associated with increased risk for all-cause and cardiovascular mortality. Plasma fibrinogen and C reactive protein (CRP)—key inflammatory and/or haemostatic markers—may contribute to this association; however, few studies...

Long-Term Coagulation Changes after Resection of Thoracoabdominal Malignancies

The purpose of this study was to evaluate the long-term coagulation status of patients undergoing malignancy resection. A prospective observational trial was conducted with informed consent in 52 patients (age 66 ± 10 years and 60% male) with thoracoabdominal tumors (pancreas [n = 18, 35%], esophagus [n = 13, 25%], liver [n = 7, 14%], stomach [n = 6, 12%], bile duct [n = 3, 6%], retroperitoneal [n = 3, 6%], and duodenum [n = 2, 4%]) with 6- to 12-month follow-up. Coagulation was evaluated with rotational thromboelastography (ROTEM) on whole blood and with a panel of hemostatic markers on stored plasma. Maximum clot firmness (MCF) in the intrinsic, extrinsic, and fibrinogen pathways increased immediately postoperatively and then decreased by 9.2 ± 4.1 months (p < 0.05). Markers of thrombin generation (prothrombin fragment 1 + 2, fibrinolysis [D-dimer], and endothelial activation [coagulation factor VIII]) were elevated at all time points. The ROTEM pattern depended on histologic type and cancer location. All esophageal tumors were adenocarcinoma and demonstrated similar patterns to the overall population, with MCF differences over time in all 3 pathways (all p < 0.05). Regarding tumors of the pancreas or liver, there were no statistically significant differences when comparing all 3 time periods, but there were time-related differences when evaluating only primary adenocarcinomas of the liver (all p < 0.05). Three patients (6%) developed venous thromboembolism (VTE) and had decreased clot formation time, increased angle, and increased MCF (all p < 0.05). Cancer patients at risk for VTE can be identified with a point-of-care ROTEM test and may benefit from additional anticoagulation. Biomarkers reflecting different functional hemostasis activity groups (fibrinolysis, thrombin generation, and endothelial activation) confirm the ongoing prothrombotic state. The ROTEM demonstrated increased hypercoagulability postoperatively, which returned to baseline in long-term follow-up. Reversal of cancer-induced hypercoagulability occurred in some patients and varied with tumor histology and location.

Increased Levels of Metalloproteinase 10 and Hemostatic Markers in Patients With Noncomplicated Primary Varicose Veins

The purpose of the study was to analyze a systemic activation of hemostasis and concentration of matrix metalloproteinase 10 (MMP-10) in patients with primary varicose veins (PVVs). A study group consisted of 41 patients with noncomplicated PVVs. A control group consisted of 30 age- and sex-matched healthy individuals without varicose veins. The concentration of d-dimers (DD), prothrombin fragments 1 and 2 (F1+2), antigen of von Willebrand factor (vWF), and activity of plasminogen activator inhibitor (PAI-1) in plasma and concentration of MMP-10 in serum were analyzed. In patients with PVVs, higher concentrations of DD (P < .001), F1+2 (P < .001), vWF (P = .027), MMP-10 (P = .006), and higher activity of PAI-1 (P < .001) were observed. However, no correlation between the concentrations of MMP-10 and prothrombotic markers was found. Noncomplicated PVVs are associated with systemic, prothrombotic activation of hemostasis and increased concentration of MMP-10, suggesting a prothrombotic and proinflammatory state.

Blood Coagulation at Major Orthopaedic Surgery

Thromboelastography (TEG) provides a means of monitoring coagulation postoperatively, the triggers involved are not clear. We studied the TEG parameters after total hip arthroplasty (THA), exploring the relationship with markers of hemostasis. In samples collected from 61 patients (33-72 years old), TEG parameters, global coagulation indices and specific hemostatic markers (TAT, D-dimer, and β-thromboglobulin) were assessed. Blood samples were taken before THA, 30 min after completion of surgery, and post-THA (Days 1, 3, 7, and 14). TAT levels peaked upon completion of THA, declining on Day 1 and normalizing by Day 3; β-thromboglobulin levels increased sharply to peak upon completion of THA, returning to baseline levels after Day 7; and the TEG coagulation index (CI) of whole blood increased immediately after THA, peaked within 7 days, and remained elevated for up to 14 days. After surgery (30 min), CI correlated significantly with platelet count (r=0.31, p<0.05) and β-thromboglobulin level (r=0.60, p<0.05). On postoperative Day 1, CI correlated with fibrinogen level (r=0.42, p<0.05) and platelet count (r=0.36, p<0.05). By Day 3, a correlation between CI and activity of the external coagulation pathway was noted. CI and PT also correlated significantly on Day 7 (r=-0.45, p<0.05) and Day 14 (r=-0.47, p<0.05). D-dimer concentration increased sharply at completion of surgery, declined at Day 3, rose again by Day 7, and remained elevated until Day14. On the other hand, the whole blood lysis index (Ly30) was unchanged at completion of surgery and during postoperative Day 1, increased significantly on Day 3, and then returned to baseline levels by Day 7. In conclusion, thrombin formation after major orthopedic surgery declines; but the total coagulation potential of blood (under standard anticoagulant treatment) peaks within one week and remains elevated at least until postoperative Day 14, correlating with activity of the external coagulation pathway during this time.

Improvement of fibrin clot structure after factor VIII injection in haemophilia A patients treated on demand

Patients with haemophilia A have seriously impaired thrombin generation due to an inherited deficiency of factor (F)VIII, making them form unstable fibrin clots that are unable to maintain haemostasis. Data on fibrin structure in haemophilia patients remain limited. Fibrin permeability, assessed by a flow measurement technique, was investigated in plasma from 20 patients with severe haemophilia A treated on demand, before and 30 minutes after FVIII injection. The results were correlated with concentrations of fibrinogen, FVIII and thrombin-activatable fibrinolysis inhibitor (TAFI), and global haemostatic markers: endogenous thrombin potential (ETP) and overall haemostatic potential (OHP). Fibrin structure was visualised using scanning electron microscopy (SEM). The permeability coefficient Ks decreased significantly after FVIII treatment. Ks correlated significantly with FVIII levels and dosage, and with ETP, OHP and levels of TAFI. SEM images revealed irregular, porous fibrin clots composed of thick and short fibers before FVIII treatment. The clots had recovered after FVIII replacement almost to levels in control samples, revealing compact fibrin with smaller intrinsic pores. To the best of our knowledge, this is the first description of fibrin porosity and structure before and after FVIII treatment of selected haemophilia patients. It seems that thrombin generation is the main determinant of fibrin structure in haemophilic plasma.

Association Between Inflammatory Markers, Hemostatic Markers, and Traditional Risk Factors on Coronary Artery Spasm in Patients with Normal Coronary Angiography

Coronary artery spasm is an important pathophysiological mechanism in some forms of myocardial ischemic disease. The relationship between inflammatory markers, mean platelet volume (MPV), and coronary artery spasm is unclear. During coronary angiography, methylergometrin was injected intravenously to 345 patients with chest pain but without significant coronary disease on angiogram to provoke coronary artery spasm. Based on provocation test results, patients were divided into 2 groups: spasm group (60 patients) and nonspasm group (285 patients). Inflammatory markers (C-reactive protein, CRP; white blood cells; polymorphonuclear neutrophils, PMN; monocytes, MO; lymphocytes, LY), hemostasis markers (MPV; platelet count; fibrinogen [FIB]; D-dimers), and traditional risk factors (body mass index; hyperlipidemia; triglycerides [TGs]; total, low-density, and high-density lipoprotein cholesterol [TC, LDL-C, and HDL-C]) were measured and compared between groups. More male patients experienced spasm (23.56% vs. 11.11%, P = 0.002). CRP, PMN, and MO were significantly higher in the spasm group (P < 0.05). There was no significant difference in serum levels of LDL-C, HDL-C, TG, TC, LY, MPV, and FIB between groups. Smoking and hyperlipidemia were more common among patients with spasm; males more frequently were smokers (58.04% vs. 46.78%, P = 0.041). By multivariate analysis, smoking, PMN, and MO were significantly associated with coronary artery spasm with odds ratios of 3.52 (95% CI 1.79-6.90, P = 0.0001), 1.21 (95% CI 1.07-1.46, P = 0.04), and 5.35 (95% CI 1.37-21.07, P = 0.01), respectively. Inflammation may partake in the pathogenesis of coronary artery spasm. Smoking, PMN count, and MO count appear to be clinical risk factors for coronary artery spasm. Conversely, coronary artery spasm does not seem to be associated with abnormalities in thrombogenesis.

Regional and Systemic Prothrombotic Biomarkers in Varicose Vein Patients and Healthy Controls.

The relationship between thrombosis and varicose veins is poorly understood. Varicose veins are seen in approximately 50% of patients with post-thrombotic syndrome and may be a risk factor for thrombosis. Furthermore, hemostatic markers are assessed usually from arm blood. Recirculating leg blood may be different in varicose veins. The aim of this study was to determine whether prothrombotic biomarkers varied between patients with varicose veins and healthy controls and whether standard venous samples from the arm differed from leg samples.

Hemostatic markers in shift working female nurses

Studies indicate an increased risk of cardiovascular disease (CVD) among shift workers, yet the mechanisms underlying this relationship are not well understood. The hemostatic system significantly impacts CVD, and several hemostatic markers demonstrate circadian rhythmicity. Thus, circadian misalignment of hemostatic markers due to shift work may be involved in the increased risk of CVD. This study aimed to compare hemostatic markers among healthy shift working vs. daytime working female nurses. It was hypothesized that hemostatic markers are elevated in shift compared to day workers, beyond the effects of sleep disturbance and other factors known to detrimentally affect health in shift workers. Thirty shift and 30 day working female nurses ages 30–45 were recruited by quota sampling at Rambam Health-Care Campus. Nurses were included if they were healthy, did not smoke, had a BMI¡‘Ü26, had no family history of CVD at a young age, were not using medication regularly (except oral contraceptives), did not have a fever in the past month and were not pregnant. Shift workers had at least two non day shifts and one night shift per week. For all participants, blood was drawn at 07:00 in the morning (not following a night shift) for the measurement of seven markers of coagulation, including Plasminogen activator inhibitor-1 (PAI-1), heparanase procoagulant activity, tissue factor (TF) + heparanase complex, protein C, D- dimer, Von Willebrand factor (vWF) and fibrinogen. Sleep quality was assessed by self report (Pittsburgh Sleep Quality Index). All coagulation markers were in the normative range. PAI-1 levels were significantly higher among shift compared to day workers (36.6 ng/ml vs 24.3 ng/ml, p < 0.05). In shift workers, Heparanase procoagulant activity was 2- fold and TF + heparanase complex was 1.5-fold compared to day work nurses (both p < 0.05). Sleep quality was significantly lower for shift compared to day workers ( p < 0.001). No group differences were found for Protein C, D-dimer, vWF and fibrinogen. Logistic regression analyses showed that shift work and poor sleep quality were significant predictors of high levels of PAI-1 ( R 2 = 0.17), heparanase procoagulant activity ( R 2 = 0.13) and TF + heparanase ( R 2 = 0.10). Elevated levels of PAI-1 and heparanase markers in healthy shift working nurses suggest subclinical disturbances in the hemostatic system, which together with reduced sleep quality may contribute to future cardiovascular morbidity. The authors acknowledge the support and assistance of the coagulation laboratory at Rambam Health Care Campus .

Estrogens and cardiovascular disease risk revisited: the Women's Health Initiative.

In 2002 and 2004, the Women's Health Initiative found no evidence that hormone therapy with estrogen or estrogen with progestin (E + P) protected against cardiovascular disease (CVD). Since then, further analyses have been performed. This review summarizes current analyses on the effects of hormone therapy on CVD and CVD risk factors. The negative effects of hormone therapy vary by the type of CVD event. Estrogen alone and E + P show consistent effects on CVD, but E + P has more impact on coronary heart disease (CHD) and venous thromboembolism. Women of all ethnicities, including those who are obese, have diabetes, or are taking daily aspirin or statins remain at risk for adverse effects from hormone therapy. Although younger women or more recently menopausal women taking hormone therapy may be at relatively lower risk for CHD and myocardial infarction, they remain at risk for stroke, venous thromboembolism and peripheral artery disease. Adverse effects are enhanced in older women with menopausal symptoms. Although hormone therapy lowers LDL cholesterol and lipoprotein (a) and raises high-density lipoprotein cholesterol, it has adverse effects on triglyceride, lipoprotein composition, and inflammatory and hemostatic markers. Baseline metabolic syndrome and high LDL cholesterol increase the CHD risk with hormone therapy. Analyses of discontinuation data in the estrogen-alone and E + P trials suggest that the adverse effects of hormone therapy on CVD are reversible. Recent analyses do not justify postmenopausal hormone therapy for CVD prevention. Further research on the role of hormone therapy-induced changes in CVD risk factors along with genetic studies may increase understanding and aid in developing safer therapies for menopausal symptoms.

Dysregulation of Inflammatory and Hemostatic Markers in Sepsis and Suspected Disseminated Intravascular Coagulation

Inflammatory mediators and hemostatic markers were evaluated in patients enrolled in a phase-2b study evaluating the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with sepsis and suspected disseminated intravascular coagulation (DIC). In contrast to controls, patients with sepsis and suspected DIC showed an increase in the circulating levels of inflammatory and fibrinolytic markers. The levels of procalcitonin (PCT), interleukin 6 (IL-6), interleukin 10 (IL-10), anaphylatoxin C5a, plasminogen activator inhibitor 1 (PAI-1), and myeloperoxidase were higher in the patients with sepsis and suspected DIC, whereas protein C (PrC) exhibited a significant decrease. When the patients with overt and nonovert DIC were compared, the PrC level was lower, and PCT, PAI-1, IL-6, and IL-10 levels were higher in the patients with overt DIC. These results indicate that inflammation is elevated in sepsis and suspected DIC, and inflammation, impairment of fibrinolysis, and overconsumption of PrC may play a key role in the pathogenesis of DIC.

A Comparison Of Hemostatic and Inflammatory Markers In Overt and Non-Overt DIC

▪Disseminated intravascular coagulation (DIC) is a complex pathophysiologic syndrome with marked alterations in the hemostatic system, which may lead to microvascular thrombosis and multi-organ failure. The International Society of Thrombosis and Hemostasis (ISTH) classifies DIC into two distinct categories; overt and non-overt DIC (NO). Overt DIC is characterized by a decompensated hemostatic system whereas non-overt is characterized as a stressed, compensated system. DIC is a frequently observed in sepsis patients. An association between the hemostatic aberrations and inflammation has been previously reported. Therefore we studied the level of hemostatic activation and inflammation in patients with sepsis and suspected DIC enrolled in the ART-123, Phase 2b study. The level of inflammatory mediators such as anaphylatoxin C5a (C5a), procalcitonin (PCT), interleukin 6 (IL-6), interleukin 10 (IL-10), myeloperoxidase (MPO), and circulating levels of hemostatic markers including protein C inhibitor (PCI), plasminogen activator inhibitor 1 (PAI-1), and protein C (Pr C) were evaluated in 617 subjects enrolled in a randomized, double-blind, placebo-controlled, Phase-2b study evaluating the safety and efficacy of recombinant thrombomodulin (ART-123) in subjects with sepsis and suspected DIC. When the subjects with overt DIC and with NO DIC were compared, the PrC level was lower and PCT, PAI-1, IL-6 and IL-10 levels were higher, in the overt DIC subjects (Table). The upregulation of the inflammatory cytokines observed in this study may contribute to the decreased levels of Pr C. Inflammatory cytokines may dysregulate the endothelial thrombomodulin resulting impaired hemostatic regulation. Pr C levels are also low due to consumption and impaired synthesis, especially in the overt DIC patients. These results suggest that profiling these mediators may be useful in the diagnostic and prognostic management of sepsis and differentiation between overt and non-overt DIC. Disclosures:Hoppensteadt:Asahi Kasei Pharma: Research Funding. Tsuruta:Asahi Kasei Pharma: Employment. Hirman:Asahi Kasei Pharma: Consultancy. Kaul:Asahi Kasei Pharma: Employment. Osawa:Asahi Kasei Pharma: Employment. Fareed:Asahi Kasei Pharma: Research Funding.BiomarkerGroupNMeanSEMMedianP ValuePr C (%)Normal4094.52.491.80.0043Overt9824.71.828.30.0043NO15746.52.637.00.0043PCTNormal240.260.020.270.0001(ng/ml)Overt9836.87.011.220.0001NO51918.031.45.330.0001PAI-1Normal3120.62.118.7<0.0001(ng/ml)Overt98232.925.0137.5<0.0001NO519147.18.676.0<0.0001Il-6Normal306.80.536.10.0003(pg/ml)Overt981017.6121.7374.40.0003NO519576.739.6174.70.0003IL-10Normal3210.42.43.50.0049(pg/ml)Overt98187.339.146.00.0049NO518108.114.831.00.0049

Protective Effect of Time Spent Walking on Risk of Stroke in Older Men

Older adults have the highest risks of stroke and the lowest physical activity levels. It is important to quantify how walking (the predominant form of physical activity in older age) is associated with stroke. A total of 4252 men from a UK population-based cohort reported usual physical activity (regular walking, cycling, recreational activity, and sport) in 1998 to 2000. Nurses took fasting blood samples and made anthropometric measurements. Among 3435 ambulatory men free from cardiovascular disease and heart failure in 1998 to 2000, 195 first strokes occurred during 11-year follow-up. Men walked a median of 7 (interquartile range, 3-12) hours/wk; walking more hours was associated with lower heart rate, D-dimer, and higher forced expiratory volume in 1 second. Compared with men walking 0 to 3 hours/wk, men walking 4 to 7, 8 to 14, 15 to 21, and >22 hours had age- and region-adjusted hazard ratios (95% confidence intervals) for stroke of 0.89 (0.60-1.31), 0.63 (0.40-1.00), 0.68 (0.35-1.32), and 0.36 (0.14-0.91), respectively, P (trend)=0.006. Hazard ratios were somewhat attenuated by adjustment for established and novel risk markers (inflammatory and hemostatic markers and cardiac function [N-terminal pro-brain natriuretic peptide]) and walking pace, but linear trends remained. There was little evidence for a dose-response relationship between walking pace and stroke; comparing average pace or faster to a baseline of slow pace, the hazard ratio for stroke was 0.65 (95% confidence interval, 0.44-0.97), which was fully mediated by time spent walking. Time spent walking was associated with reduced risk of onset of stroke in dose-response fashion, independent of walking pace. Walking could form an important part of stroke-prevention strategies in older people.

Prospective associations between inflammatory and hemostatic markers and physical functioning limitations in mid-life women: Longitudinal results of the Study of Women's Health Across the Nation (SWAN)

BackgroundDue to the public health burden of age-related declines in physical functioning, it is important to identify targets for intervention for the prevention of functional decline. We prospectively examined whether higher levels of inflammatory and hemostatic markers (high-sensitivity C-reactive protein (hs-CRP), plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator antigen (tPA-ag), fibrinogen, and Factor VIIc (FVIIc)) were prospectively associated with reporting greater limitations in perceived physical functioning, and explored potential racial differences in the associations, in a multi-ethnic sample of mid-life women. MethodsWomen (45–56years) in the Study of Women's Health Across the Nation who completed the physical functioning scale of the Medical Outcome Short Form (SF-36) at follow-up visits 4, 6, or 8 and had inflammatory/hemostatic measures in the preceding year were included (n=2296). The continuous SF-36 physical function score was categorized as: no limitation (86–100 points), some limitation (51–85 points), and substantial limitation (0–50 points). Physical function category at time t was modeled a function of each biomarker, separately, at time t−1 using ordinal generalized estimating equations. ResultsAfter adjusting for age, race/ethnicity, body size, sociodemographic, medical and lifestyle factors, higher levels of tPA-ag and hs-CRP were associated with subsequently reporting greater limitations in physical functioning, although the latter was only marginally significant (p=0.13). For each standard deviation (SD) increase in logtPA-ag, the odds of some or substantial limitations was 1.18 (95%CI 1.09,1.27); for each SD increase in loghs-CRP, the odds of some or substantial limitation was (1.08, 95%CI 0.98,1.19). In African American women only, higher fibrinogen levels were associated with subsequently reporting greater limitations (OR=1.30, 95%CI 1.13,1.50, for each one SD increase in fibrinogen). ConclusionsHigher levels of inflammatory and hemostatic markers were prospectively associated with greater limitations in perceived physical functioning in mid-life women.

Menopause, complement, and hemostatic markers in women at midlife: The Study of Women's Health Across the Nation

ObjectiveTo evaluate whether higher circulating levels of complement proteins C3 and C4 are associated with menopausal status and with hemostatic/thrombus formation markers (circulating factor VII (factor VIIc), fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator antigen (tPA-ag)) in a sample of midlife women. Methods and resultsA total of 100 women (50 late peri-/postmenopausal and 50 pre-/early peri- menopausal women) from the Study of Women's Health Across the Nation (SWAN) Pittsburgh site were included in the present analysis. Factor VIIc and PAI-1 were log transformed. Linear regression was used for analysis. The mean age of the study participants was 50.5 ± 2.6 years with 73% were Caucasian and 27% were African American. C3 but not C4 was significantly higher in postmenopausal women compared to premenopausal women (P value = 0.03), adjusting for age, race and BMI. In final model (adjusting for age, race, BMI and menopausal status), C3 was associated with higher levels of log PAI-1 (P value = 0.0009) and tPA-ag (P value = 0.0003), while C4 was associated with higher levels of log factor VIIc (P value = 0.04) and fibrinogen (P value = 0.005). ConclusionsThese data suggest that C3 and C4 may be related to blood clots via their associations with hemostatic markers and that C3 is related to menopausal status. Complement proteins C3 and C4 could be possible pathways by which postmenopausal women are at higher risk of atherosclerosis and cardiovascular related events. It is important to replicate these findings in a larger sample size.

The relationships among hemostatic markers, the withdrawal of fondaparinux due to a reduction in hemoglobin and deep vein thrombosis in Japanese patients undergoing major orthopedic surgery

BackgroundThe relationships among the hemostatic markers, the development of deep vein thrombosis (DVT) and the withdrawal of fondaparinux due to a reduction in the hemoglobin levels were examined. MethodsTwo-hundred twenty-one Japanese patients who underwent major orthopedic surgery and were treated with 1.5mg of fondaparinux instead of 2.5mg of fondaparinux were studied. Forty-seven of 221 patients discontinued fondaparinux treatment (withdrawal group) and 37 patients developed DVT. ResultsThe age, frequency of total knee arthroplasty (TKA), withdrawal of fondaparinux, reduction of hemoglobin and the plasma levels of soluble fibrin (SF), D-dimer and fibrinogen and fibrin degradation product (FDP) on day 1 after the operation were significantly higher in the patients with DVT. Elevated SF, D-dimer or FDP levels were associated with the risk for DVT. The age, frequency of TKA or DVT, anti-Xa activity and the creatinine, FDP and D-dimer levels were significantly higher in the withdrawal group. An anti-Xa level >0.33mg/l and an elevated D-dimer or FDP level were associated with the risk of withdrawal. ConclusionThe age and SF levels, TKA and withdrawal of fondaparinux were related to the risk of DVT, and the anti-Xa activity, creatinine level and DVT were related to the risk of withdrawal of fondaparinux due to a reduction in hemoglobin.

Investigating the association of vitamin D seasonality on inflammatory and hemostatic markers

Seasonal variations in health outcomes are commonly used to hypothesize a link with nutritional vitamin D (25-hydroxyvitamin D, 25(OH)D) status. The majority of vitamin D intake is from skin exposure to sunlight and varies seasonally in countries at a distance away from the Equator. However, despite the strong seasonality of vitamin D intake, no statistical method using cyclical patterns has been proposed to deduce an association between 25(OH)D and health indicators. Our motivation was to overcome the influence of related confounders, such as obesity, between 25(OH)D and health indicators: obesity would be expected to have little or no effect on the seasonal variations in 25(OH)D and in five inflammatory/hemostatic health outcomes (fibrinogen, tissue plasminogen activator [tPA], von Willebrand factor [vWF], C-reactive protein [CRP], and D-dimer). The data analyzed was from the 1958 British birth cohort biomedical survey (n = 6195) and the biomarkers were ascertained from blood drawn over an 18-mo period. We used mediation analysis to determine whether the seasonal variations of the outcomes were mediated by 25(OH)D to infer an association. The assumptions of mediation analysis fit naturally into the study’s cross-sectional setting, where day of year of blood collection is the independent variable transformed by the harmonic function, and 25(OH)D is the mediator of the seasonal variation of the outcomes. The harmonic terms were tested to establish the presence of seasonal variation in the outcomes and 25(OH)D in order to determine whether the statistical mediation test could be applied. The data were collected over an 18-mo period and assayed in multiple batches to measure the serum biomarkers. When the assay batches were modeled as fixed effects, significant correlation was found with date of when blood was drawn. Thus, variation in assay batches was accounted for as random effects terms on the intercept in linear mixed-effects models. Inferences were based on tests from mediation analysis defined by the product of regression coefficients; we extended this test to allow for harmonic functions with multiple frequencies in order to statistically test the mediated effect through 25(OH)D. This was done using parametric bootstrap when the models were run in the Frequentist setting. We also replicated the analyses in the Bayesian setting to ascertain the change in amplitude of the seasonal variation that was due to 25(OH)D. Out of the five health outcomes, three (tPA, D-dimer, and fibrinogen) had significant seasonal associations that were partially mediated through 25(OH)D, one (vWF) had a seasonal pattern not mediated through 25(OH)D, and finally another (CRP) had no significant seasonal pattern. The association of 25(OH)D was strongest for tPA, and less so for D-dimer and fibrinogen. Our results and adaption of the mediation test show that there is broad potential in using seasonal variations of health indicators to deduce an association that may have not been affected by nonseasonal confounding.