Lower D-dimer Research Articles

Inverse association between habitual alcohol drinking and d-dimer in patients with type 2 diabetes mellitus.

Alcohol is known to inhibit blood coagulation. Patients with diabetes mellitus are prone to show hypercoagulability. However, it remains to be clarified whether and how habitual alcohol drinking affects coagulability in patients with diabetes. The purpose of this study was to determine the relationship between alcohol intake and d-dimer, a sensitive marker of blood coagulation, in patients with diabetes. We investigated the relationship between alcohol intake and d-dimer in plasma of 269 patients with type 2 diabetes by using analysis of covariance and logistic regression analysis after adjustment for age, gender, body mass index, hemoglobin A1c, and histories of smoking and anti-coagulation therapy. Log-transformed d-dimer and HDL cholesterol were significantly lower and higher, respectively, in regular drinkers than in nondrinkers, while there were no significant differences in log-transformed d-dimer and HDL cholesterol in occasional drinkers and nondrinkers. Odds ratios of regular drinkers vs. nondrinkers for high d-dimer (0.46 [0.21-0.98]) and low HDL cholesterol (0.20 [0.08-0.50]) were significantly lower than the reference level, while the odds ratios of occasional drinkers for high d-dimer (1.24 [0.41-3.73]) and low HDL cholesterol (0.43 [0.15-1.25]) were not significantly different from the reference level. HDL cholesterol showed a significant inverse correlation with log-transformed d-dimer both in overall subjects and in nondrinkers. Regular drinking, but not occasional drinking, was associated with lower d-dimer levels, suggesting that habitual alcohol drinking suppresses hypercoagulability in patients with diabetes. There is an alcohol intake-independent inverse association between HDL cholesterol and d-dimer.

Impact of initial coagulation and fibrinolytic markers on mortality in patients with severe blunt trauma: a multicentre retrospective observational study

BackgroundAcute coagulopathy is a well-known predictor of poor outcomes in patients with severe trauma. However, using coagulation and fibrinolytic markers, how one can best predict mortality to find out potential candidates for treatment of coagulopathy remains unclear. This study aimed to determine preferential markers and their optimal cut-off values for mortality prediction.MethodsWe conducted a retrospective observational study of patients with severe blunt trauma (injury severity score ≥ 16) transferred directly from the scene to emergency departments at two trauma centres in Japan from January 2013 to December 2015. We investigated the impact and optimal cut-off values of initial coagulation (platelet counts, fibrinogen and prothrombin time-international normalised ratio) and a fibrinolytic marker (D-dimer) on 28-day mortality via classification and regression tree (CART) analysis. Multivariate logistic regression analysis confirmed the importance of these markers. Receiver operating characteristic curve analyses were used to examine the prediction accuracy for mortality.ResultsTotally 666 patients with severe blunt trauma were analysed. CART analysis revealed that the initial discriminator was fibrinogen (cut-off, 130 mg/dL) and the second discriminator was D-dimer (cut-off, 110 μg/mL in the lower fibrinogen subgroup; 118 μg/mL in the higher fibrinogen subgroup). The 28-day mortality was 90.0% (lower fibrinogen, higher D-dimer), 27.8% (lower fibrinogen, lower D-dimer), 27.7% (higher fibrinogen, higher D-dimer) and 3.4% (higher fibrinogen, lower D-dimer). Multivariate logistic regression demonstrated that fibrinogen levels < 130 mg/dL (adjusted odds ratio [aOR], 9.55; 95% confidence interval [CI], 4.50–22.60) and D-dimer ≥110 μg/mL (aOR, 5.89; 95% CI, 2.78–12.70) were independently associated with 28-day mortality after adjusting for probability of survival by the trauma and injury severity score (TRISS Ps). Compared with the TRISS Ps alone (0.900; 95% CI, 0.870–0.931), TRISS Ps with fibrinogen and D-dimer yielded a significantly higher area under the curve (0.942; 95% CI, 0.920–0.964; p < 0.001).ConclusionsFibrinogen and D-dimer were the principal markers for stratification of mortality in patients with severe blunt trauma. These markers could function as therapeutic targets because they were significant predictors of mortality, independent from severity of injury.

Inhibition of renin-angiotensin axis reduces the risk of thrombus formation in the left atrial appendage in patients with hypertension complicated by atrial fibrillation.

Aims:We examined whether the use of a renin-angiotensin-aldosterone system (RAS) inhibitor plays a role in protecting against left atrial appendage thrombus (LAAT) in patients with hypertension complicated by atrial fibrillation (AF).Methods:Two observational studies were conducted on patients with diagnoses of hypertension and AF, who were categorized into RAS inhibitor user or nonuser groups. Demographic characteristics, clinical characteristics, echocardiographic parameters and hemostatic markers were examined and the occurrence of LAAT during follow-up were recorded.Results:In the first study (n = 131), LA peak systolic strain and LAA emptying flow velocity (LAA eV) were significantly increased in patients on RAS inhibitors compared with the nonuser group (p < 0.05). Lower D-dimer and fibrinogen levels were observed in patients on RAS inhibitors (p < 0.05). In the second study (n = 99), 25.9% (n = 11) of patients on RAS inhibitors developed LAAT, compared with 46.7% (n = 21) in the nonuser group (p < 0.05). After controlling for risk factors related to LAAT, use of RAS inhibitors remained associated with a significantly lower risk of developing LAAT (HR, 0.406; 95% CI, 0.191–0.862; p = 0.019).Conclusions:RAS inhibitors use was associated with a significant reduction in the risk of LAAT in patients with hypertension and AF.

Prognostic value of pretreatment plasma D-dimer levels in patients with diffuse large B cell lymphoma (DLBCL)

BackgroundWe assessed the prognostic significance of D-dimer in patients of diffuse large B cell lymphoma (DLBCL). MethodsWe performed a retrospective study including 254 patients who were newly diagnosed DLBCL. X-tile was used to generate a cutoff value for D-dimer. Both univariate screen by Cox proportional hazard model and multivariable analysis by Cox regression model were used to assess the impact of pretreatment D-dimer levels on the overall survival (OS). ResultAccording to X-tile, the optimal cut-off value of D-dimer for prediction of survival was set as 1.6 μg/mL, and a D-dimer level ≥ 1.6 μg/mL was significantly associated with poor overall survival (OS) (OS: 31.7 vs. 79.1%, P < 0.001). In multivariable analysis, it was found that a higher D-dimer level was an independent predictor for worse OS (Hazard ratio (HR): 3.594 95% Confidence interval (CI): 2.296–5.267, P < 0.001). In subgroup analysis of International Prognostic Index (IPI), survival of low-risk and intermediate-risk group with a D-dimer level ≥ 1.6 μg/mL were both similar to that of the high-risk group (OS: 31.6 vs. 36.5%, P = 0.957; OS: 38.0 vs. 36.5%, P = 0.758). In addition, among patients treated with surgery, those with higher D-dimer had substantially worse survival than that with lower D-dimer (OS: 27.0 vs. 84.5%, P < 0.001). ConclusionPretreatment D-dimer is a simple but effective predictor of survival among patients with DLBCL.

Physical Activity, Sedentary Behavior, and Inflammatory and Hemostatic Markers in Men.

This study aimed to determine whether higher levels of physical activity (PA) and less sedentary behavior (SB) are associated with less inflammation, indicated by inflammatory and hemostatic biomarkers, in older men. A cross-sectional study of 1139 men, from the British Regional Heart Study (mean ± SD age = 78 ± 5 yr), and longitudinal analyses of 490 men with two PA measures 1 yr apart were used in this study. Single fasting venous blood samples were analyzed for several biomarkers. PA and SB were measured using ActiGraph GT3X accelerometers. Total time and time spent in bouts of moderate to vigorous PA (MVPA), light PA, and SB were derived. Linear regression analyses were used to investigate associations. Cross-sectionally, higher total PA, daily steps, and MVPA were all associated with lower levels of interleukin 6 (IL-6), C-reactive protein (CRP), tissue plasminogen activator (tPA), von Willebrand factor (vWF), and D-dimer, whereas higher levels of SB were associated with higher levels of IL-6, CRP, and tPA. Each additional 10 min of MVPA was associated with a 3.2% lower IL-6 (95% confidence interval [CI] = -4.5% to -1.8%), 5.6% lower CRP (95% CI = -7.8 to -3.3), 2.2% lower tPA (95% CI = -3.0 to -1.4), 1.2% lower vWF (95% CI = -2.1 to -0.3), and 1.8% lower D-dimer (95% CI = -2.9 to -0.7), and for CRP, vWF, and D-dimer independently of SB. Associations between SB and IL-6 or tPA were independent of MVPA. Longer bouts of PA or SB were not more strongly associated with outcomes than shorter bouts. Longitudinal analyses were inconsistent with these findings, possibly because of power limitations. Although PA (particularly MVPA) was generally associated with inflammatory and hemostatic biomarkers, we found no evidence that longer bouts were more important than shorter bouts.

Abstract 13007: Prognostic Significance of Persistent D-dimer Elevation in Patients With Acute Decompensated Heart Failure

Backgrounds: Heart failure is associated with a prothrombotic state. D-dimer (DD) is a marker of fibrin turn over, and increased DD levels predict poor outcomes in patients with chronic heart failure. However, data regarding the DD level in patients with acute heart failure (AHF) are limited. Methods: Of 651 consecutive AHF patients who admitted to our institution between January 2013 and March 2015 from prospective registry, patients with acute coronary syndrome, oral anticoagulant therapy, and venous thromboembolism were excluded. Finally, 296 patients were divided into two groups according to the higher DD (above 2.7 μg/ml, the median), or lower DD (below 2.7 μg/ml) on admission. DD level was measured within 24 hours from admission and at discharge. Results: Although patients with higher DD were older (77±11 vs. 73±14 years; P&lt;0.01), other baseline characteristics in terms of sex, NYHA classification, prevalence of co-morbidities including atrial fibrillation, and echocardiographic parameters including left ventricular ejection fraction were comparable between the two groups. During the median follow-up of 281 days, 4 patients died during hospitalization and 19 patients died after discharge. Kaplan-Meier curves for all-cause mortality are shown in the figure. Higher DD level on admission was associated with higher mortality (HR: 2.78, 95% CI: 1.19-7.25, P=0.02), even after adjustment by age. At discharge, DD level was persistently elevated (above 2.7 μg/ml) in 62% of patients with higher DD on admission. Among patients with higher DD on admission, persistent elevation of DD level during hospitalization was associated with higher mortality after discharge (HR: 7.00, 95% CI: 1.33-128.52, P=0.02). Conclusions: In patients with AHF, higher DD level on admission, especially persistently higher DD level during hospitalization, was associated with higher all-cause mortality, suggesting an importance of DD level as a prognostic surrogate marker of AHF.

Abstract 17095: Clinical Characteristics and Short-term Outcomes of Aortic Disease Patients With Cardiovascular Shock: Results From the Shock Registry of the Japanese Circulation Society

Background: The mortality rate of aortic disease patients with cardiovascular shock (CVS) is still high. We examined the factors related to short-term outcomes of aortic disease patients with CVS. Methods: The Japanese Circulation Society Shock Registry was a prospective, observational, multi-center (83 institutions), cohort study that enrolled 980 patients presenting with CVS when transported to the emergency room between May 2012 and June 2014. Of those, 82 aortic dissection (AD) and 63 aortic aneurysm (AA) patients were enrolled in this study. Because each institution used a different D-dimer kit, adjusted D-dimer levels were calculated by dividing the measured D-dimer value by the upper limit of the normal range of the kit. Results: The mean age was 76 years and 52% were male. The 30-day mortality rate was 46% (AD, 39%; AA, 56%). In AD, Stanford type A accounted for 95% and surgical intervention was performed in 68%. In AA, 24% were thoracic; 6%, thoracoabdominal; 69%, abdominal AA, and surgical intervention was performed in 57%. In AD, adjusted D-dimer levels on admission of non-survivors were significantly higher than those of survivors [median (interquartile range): 75.6 (19.5-229.4) vs. 25.8 (8.0-61.3) arbitrary units, respectively; P=0.01]. In AD, surgical intervention, a transferred case, absence of aortic rupture, and low D-dimer levels (adjusted D-dimer &lt; 33.2 arbitrary units, which was the median value) were associated with the 30-day survival. In AA, surgical intervention, a transferred case, higher consciousness level, higher systolic blood pressure, and abdominal AA were associated with 30-day survival. Cox proportional hazards analysis indicated that surgical intervention (hazard ratio 0.14; 95%CI, 0.049-0.40; P&lt;0.001) and low D-dimer level (hazard ratio 0.21; 95%CI, 0.067-0.57; P&lt;0.001) were independent predictors of 30-day survival in AD, and surgical intervention (hazard ratio 0.087; 95%CI, 0.023-0.28; P&lt;0.001) was an independent predictor of 30-days survival in AA. Conclusions: Surgical intervention was the only method to improve short-term outcomes of aortic disease patients with CVS. In AD, lower D-dimer level was associated with more favorable short-term outcomes regardless of surgical intervention.

Obesity and clotting: Body mass index independently contributes to hypercoagulability after injury.

Although obese patients have high thrombosis rates following injury, the role of obesity in coagulation after trauma remains unknown. We hypothesized that body mass index (BMI) is independently associated with increased measures of hypercoagulability longitudinally after injury. Data were prospectively collected for 377 consecutive highest-level trauma activation patients with a BMI of 18.5 kg/m² or greater. Standard coagulation measures, citrated kaolin and functional fibrinogen thromboelastography, as well as clotting factors were measured at 0 hour to 120 hours. BMI categories were defined as normal weight (18.5-24.99 kg/m²), overweight (25-29.99 kg/m²), and obese (≥30 kg/m²). The 377 patients were mostly male (81%) and had blunt injury (61%), with a median BMI of 25.8 kg/m². Of the patients, 42% were normal weight (median BMI, 22.5 kg/m²). There were no differences in age, sex, Injury Severity Score (ISS), or base deficit between groups. There were no differences in admission international normalized ratio/partial thromboplastin time or factors II, V, VII, VIII, and X; antithrombin III; or protein C. However, obese patients had higher admission platelet counts (303 × 10⁹/L vs. 269 × 10⁹/L, p = 0.004), lower D-dimer (1.88 μg/mL vs. 4.00 μg/mL, p = 0.004), and a trend toward higher factor IX (134% vs. 119% activity, p = 0.042) compared with normal weight patients. Measured by thromboelastography, clot strength (maximum amplitude) and functional fibrinogen level (FLEV) were also higher on admission for obese patients (maximum amplitude, 65.7 mm vs. 63.4 mm, p = 0.016; FLEV, 407 mg/dL vs. 351 mg/dL, p = 0.008). In multiple linear regression, the relationship of BMI to clot strength, FLEV, and factor IX persisted through 24 hours. Similarly, the relationship of BMI and platelet count persisted through 120 hours (all p < 0.05). In multiple logistic regression, for every 5-kg/m² increase in BMI, there was an 85% increase in odds of thromboembolic complication (odds ratio, 1.85; 95% confidence interval, 1.13-3.08; p = 0.017). Obese trauma patients are hypercoagulable compared with their similarly injured normal-weight counterparts, which persists longitudinally after injury. The significance of this hypercoagulability requires elucidation for guidance of anticoagulation in this at-risk group. Prognostic study, level III.

A Randomized, Double-Blind, Placebo-Controlled, Phase-2B Study to Evaluate the Safety and Efficacy of Recombinant Human Soluble Thrombomodulin, ART-123, in Patients with Sepsis and Suspected Disseminated Intravascular Coagulation

Abstract 24 IntroductionSevere sepsis remains the most common cause of death in critically ill patients (1) and new therapeutic approaches are urgently needed. DIC is also a frequent complication of severe sepsis (3), and when present is associated with increased mortality in these patients (4, 5). Current management of DIC is primarily focused on treating any associated underlying medical condition, although use of supplemental clotting factors or platelets, or anticoagulant therapy may occasionally be required (6). ART-123 (Artisan Pharma, Waltham, MA, USA) is a soluble recombinant human thrombomodulin that acts by reducing thrombin-mediated clotting and enhancing protein C activation at the site of clotting. We sought to determine the safety and efficacy of ART-123 when combined with standard care in patients with sepsis-associated DIC. Study DesignThis study was a Phase 2b, multicenter, international double-blind, randomized, placebo-controlled, parallel group trial, conducted in compliance with the ethical principles of the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. Two hundred and thirty intensive care units (ICUs) in seventeen countries enrolled 750 adult patients with sepsis and suspected DIC as assessed using a modified international society of hemostasis and thrombosis score. Patients were randomized to receive intravenous ART-123 (0.06 mg/kg/day) for 6 days or placebo, in addition to standard of care. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt DIC and reduction in disease severity. Patients were randomized to receive intravenous ART-123 (0.06 mg/kg/day) for 6 days or placebo, in addition to standard of care. Blood samples were also obtained at different time points to measure various coagulation and inflammatory biomarkers. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt DIC and reduction in disease severity. ResultsA total of 750 patients were randomized, 9 of whom did not receive the allocated treatment so that 371 patients received ART-123 and 370 received placebo. There were no meaningful differences between groups in any of the baseline variables. Twenty-eight-day mortality was 17.8% in the ART-123 group and 21.6% in the placebo group (Cochran-Mantel-Haenszel two-sided p-value of 0.273 in favor of ART-123, which met the predefined statistical test for evidence suggestive of efficacy). There were no statistically significant differences in event free and alive days between groups. D-dimer, F1.2 and TATc concentrations were lower in the ART-123 group than in the placebo group. There were no differences between groups in bleeding or thrombotic events or in the development of new infections. In post hoc analyses, greatest benefit from ART-123 was seen in patients with at least one organ system dysfunction and an international normalized ratio >1.4 at baseline. ConclusionsAdministration of ART-123 at a dose of 0.06 mg/kg/day for a 6-day treatment period was associated with clear pharmacologic effects (lower D-dimer, F1.2 and TATc levels) and plausible probability of efficacy. ART-123 was found to be a safe intervention in critically ill patients with coagulopathy due to sepsis, even in settings where patients are administered prophylactic doses of heparin, with no difference in bleeding complications between ART-123 and placebo-treated patients. These findings provide support for undertaking a phase III study, based on the population identified from the post hoc analyses, to extend these observations. Future trials using ART-123 should also be designed to better characterize the complex interactions present within the coagulation cascade in septic patients and to enable a description of the interactions between ART-123 and other anticoagulant modalities in these patients. Disclosures:Kaul:Asahi Kasei Pharma America Corporation: Employment. Tsuruta:Asahi Kasei Pharma America Corporation: Employment. Gorelick:Asahi Kasei Pharma America Corporation: Employment. Osawa:Asahi Kasei Pharma America Corporation: Employment. Vincent:Asahi Kasei Pharma America Corporation: Employment.

Clinical Significance of Thrombosis-Related Markers in Ischemic Heart Disease

The D-dimer, plasmin-α2 plasmin inhibitor complex (PIC), plasminogen activator inhibitor-1 antigen (PAI-1 Ag) and thrombin-antithrombin III complex (TAT) in plasma were studied by enzyme immunoassay in 96 patients with ischemic heart disease (IHD), 114 young normal volunteers (mean age 30) and 72 aged normal controls (mean age 70).All patients underwent coronary artery angiography for evaluation of coronary arterial disease.D-dimer, PIC and TAT concentrations were higher in the aged controls than in young normal volunteers. PAI-1 Ag in the two groups was the same. D-dimer (161.64±116.40ng/ml), PAI-1 Ag (77.93±45.82ng/l) and TAT (4.19±4.53ng/l) concentrations were higher in patients with IHD (p<0.05, 0.005 and 0.01 respectively) than in the aged controls. PIC in the patients and aged normal controls was the same.D-dimer concentrations were remarkably higher in 61 patients (174.76±122.85ng/ml) with angiographically positive findings (luminal diameter reduction greater than 75%) than in 18 patients (109.35±62.24ng/ml) with negative findings (p<0.01). A marketly higher proportion of patients (28/29) with higher D-dimer concentration than patients (33/50) with lower D-dimer concentration had positive coronary angiography (X2=7.115, p<0.01).No remarkable differences in TAT, PIC and PAI-1 Ag could be found in patients with angiographically positive and negative findings.Increase in D-dimer, TAT and PAI-1 Ag concentrations would thus appear to be associated with increased risk of coronary thrombosis, and particularly increase in the D-dimer with the severity of coronary atherosclerosis.