Log D-dimer Research Articles

Clonal Hematopoiesis, Inflammation, Hemostasis, and Cardiometabolic Biomarkers: The Reasons for Geographic and Racial Differences in Stroke Study

CONCLUSIONS Clonal hematopoiesis (CH) is implicated in the pathogenesis of multiple age-associated disorders including malignancy, cardiovascular disease (CVD), chronic kidney disease, and mortality. Some of these adverse outcomes may be mediated by CH-driven inflammatory dysregulation, but the association of CH with biomarkers in other pathways related to these outcomes has not been studied. We studied the association between CH and biomarkers of inflammation, hemostasis and cardiometabolic risk in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. REGARDS is a prospective study that enrolled 30,239 Black and White individuals ≥45 years across United States between 2003 and 2007, and collected extensive health data by telephone and in-person exams. Biomarkers listed in Table 2, and CH were measured in baseline blood samples in an age-, sex-, and race-stratified cohort random sample (CRS). We excluded participants with prior history of CVD. Sequencing was performed at >500x depth to identify somatic mutations in 24 of the most common CH genes, capturing >95% of CH observed in the general population. CH was categorized based on variant allele frequency (VAF) of the dominant mutation as 0%, >0-<2%, 2-10% and >10%. Linear regression was used to calculate the age-, sex-, and race-adjusted difference in mean biomarker level for those with versus those without CH. The study included 781 participants (mean age at enrollment: 66 years [SD 12.1], 46% male, 50% Black individuals). The prevalence of CH at varying VAF was: VAF 0% - 43.3%; VAF >0 to <2% - 32.5%; 2 to 10% - 18.4%; >10% - 5.8%. Mutations were most prevalent in DNMT3A (60.3%), then TET2 (13.8%) and ASXL1 (10.1%). The mean age was higher in participants with CH (73 years, SD 10) than in those without CH (61 years, SD 11). Distributions of the most common CH mutations at VAF ≥2% by age, sex and race are shown in Table 1. Mutations in DNMT3A were overrepresented in Black participants and women, whereas mutations in TET2 and ASXL1 were more common in White participants. Associations of CH with inflammation, hemostasis and cardiometabolic biomarkers were presented in Table 2. Mean Log IL-8 was 0.23 (95% CI 0.05-0.41) units higher in those with high VAF CH (>10%) versus those without CH, with no association among other inflammation biomarkers.Among hemostasis biomarkers, mean log D-dimer was 0.26 (95% CI 0.01-0.52) units higher in those with high VAF CH versus those without CH. There was a non-significant trend towards an association between CH and lower Factor VIII and higher fibrinogen (Table 2). Among cardiometabolic biomarkers, mean log Adiponectin was 0.32 (95% CI 0.04-0.61) units higher in those with high VAF CH versus no CH. We did not identify a statistically significant association between CH and other cardiometabolic markers. CH is prevalent in the general population, especially at low VAF. In addition to inflammatory dysregulation, findings here suggest possible other pathways for deleterious effects of CH on health via hemostasis and cardiometabolic pathways. Since our study was cross-sectional, we could not ascertain if CH leads to abnormal biomarker levels or if pathways represented by the above biomarkers predispose to CH. Studying associations of CH with serial biomarkers in a larger population, by specific mutations, and by sex and race will provide mechanistic insights on CH associated adverse outcomes.

Arterial partial pressure of oxygen and procalcitonin levels correlate with pulmonary artery systolic pressure in patients with active pulmonary tuberculosis

ObjectWe aimed to study whether arterial blood gas parameters, inflammatory markers, and coagulation indicators correlate with pulmonary artery systolic pressure (PASP) values in patients with active pulmonary tuberculosis (PTB). MethodsA total of 121 patients with PTB who had a measurement of PASP by Doppler echocardiography in the active phase of tuberculosis were included in this study. We carried out univariate and multivariate linear regression analyses to determine factors correlated with PASP values. We excluded patients with other diseases or conditions that might lead to increased PASP. ResultsUnivariate linear regression analysis revealed positive correlations of age, white blood cell count, neutrophils ratio, Log procalcitonin, erythrocyte sedimentation rate, Log C-reactive protein, fibrinogen, Log D-dimer with PASP and showed an inverse correlation of arterial partial pressure of oxygen (PaO2) and arterial oxygen saturation (SaO2) with PASP. Multiple linear regression analysis demonstrated that PaO2 and Log procalcitonin remained correlated with PASP values. ConclusionPaO2 and procalcitonin were strongly correlated with PASP values in patients with active PTB. The degree of hypoxia and severity of secondary respiratory bacterial infection may influence PASP value in active PTB.

Associations of longitudinal D-Dimer and Factor II on early trauma survival risk

BackgroundTrauma-induced coagulopathy (TIC) is a disorder that occurs in one-third of severely injured trauma patients, manifesting as increased bleeding and a 4X risk of mortality. Understanding the mechanisms driving TIC, clinical risk factors are essential to mitigating this coagulopathic bleeding and is therefore essential for saving lives. In this retrospective, single hospital study of 891 trauma patients, we investigate and quantify how two prominently described phenotypes of TIC, consumptive coagulopathy and hyperfibrinolysis, affect survival odds in the first 25 h, when deaths from TIC are most prevalent.MethodsWe employ a joint survival model to estimate the longitudinal trajectories of the protein Factor II (% activity) and the log of the protein fragment D-Dimer (upmug/ml), representative biomarkers of consumptive coagulopathy and hyperfibrinolysis respectively, and tie them together with patient outcomes. Joint models have recently gained popularity in medical studies due to the necessity to simultaneously track continuously measured biomarkers as a disease evolves, as well as to associate them with patient outcomes. In this work, we estimate and analyze our joint model using Bayesian methods to obtain uncertainties and distributions over associations and trajectories.ResultsWe find that a unit increase in log D-Dimer increases the risk of mortality by 2.22 [1.57, 3.28] fold while a unit increase in Factor II only marginally decreases the risk of mortality by 0.94 [0.91,0.96] fold. This suggests that, while managing consumptive coagulopathy and hyperfibrinolysis both seem to affect survival odds, the effect of hyperfibrinolysis is much greater and more sensitive. Furthermore, we find that the longitudinal trajectories, controlling for many fixed covariates, trend differently for different patients. Thus, a more personalized approach is necessary when considering treatment and risk prediction under these phenotypes.ConclusionThis study reinforces the finding that hyperfibrinolysis is linked with poor patient outcomes regardless of factor consumption levels. Furthermore, it quantifies the degree to which measured D-Dimer levels correlate with increased risk. The single hospital, retrospective nature can be understood to specify the results to this particular hospital’s patients and protocol in treating trauma patients. Expanding to a multi-hospital setting would result in better estimates about the underlying nature of consumptive coagulopathy and hyperfibrinolysis with survival, regardless of protocol. Individual trajectories obtained with these estimates can be used to provide personalized dynamic risk prediction when making decisions regarding management of blood factors.

Changes in D-dimer after initiation of antiretroviral therapy in adults living with HIV in Kenya

BackgroundIncreased coagulation biomarkers are associated with poor outcomes among people living with HIV (PLHIV). There are few data available from African cohorts demonstrating the effect of antiretroviral therapy (ART) on coagulation biomarkers.MethodsFrom March 2014 to October 2014, ART-naïve PLHIV initiating non-nucleoside reverse transcriptase inhibitor-based ART were recruited from seven clinics in western Kenya and followed for up to 12 months. Demographics, clinical history and blood specimens were collected. Logistic regression models adjusted for intrasite clustering examined associations between HIV viral load and D-Dimer at baseline. Mixed linear effects models were used to estimate mean change from baseline to 6 months overall, and by baseline viral load, sex and TB status at enrollment. Mean change in D-dimer at 6 months is reported on the log10 scale and as percentage change from baseline.ResultsAmong 611 PLHIV enrolled, 66% were female, median age was 34 years (interquartile range (IQR) 29–43 years), 31 (5%) participants had tuberculosis and median viral load was 113,500 copies/mL (IQR: 23,600-399,000). At baseline, 311 (50.9%) PLHIV had elevated D-dimer (> 500 ng/mL) and median D-dimer was 516.4 ng/mL (IQR: 302.7–926.6) (log baseline D-dimer: 2.7, IQR: 2.5–3.0). Higher baseline D-dimer was significantly associated with higher viral load (p < 0.0001), female sex (p = 0.02) and tuberculosis (p = 0.02). After 6 months on ART, 518 (84.8%) PLHIV had achieved viral load < 1000 copies/mL and median D-dimer was 390.0 (IQR: 236.6–656.9) (log D-dimer: 2.6, IQR: 2.4–2.8). Mean change in log D-dimer from baseline to 6 months was − 0.12 (95%CI −0.15, − 0.09) (p < 0.0001) indicating at 31.3% decline (95%CI −40.0, − 23.0) in D-dimer levels over the first 6 months on ART. D-dimer decline after ART initiation was significantly greater among PLHIV with tuberculosis at treatment initiation (− 172.1, 95%CI −259.0, − 106.3; p < 0.0001) and those with log viral load > 6.0 copies/mL (− 91.1, 95%CI −136.7, − 54.2; p < 0.01).ConclusionsIn this large Kenyan cohort of PLHIV, women, those with tuberculosis and higher viral load had elevated baseline D-dimer. ART initiation and viral load suppression among ART-naïve PLHIV in Kenya were associated with significant decrease in D-dimer at 6 months in this large African cohort.

Variable predictors of acute pulmonary embolism recurrence with duration of follow-up.

BackgroundAcute pulmonary embolism (PE) is a critical disease and often leads to a high mortality and morbidity. Several studies have identified predictors of PE recurrence, but whether these predictors have prognostic value and how they vary during varied follow-up periods remain unclear.MethodsWe retrospectively assessed the occurrence of recurrent PE and the survival time of patients with a diagnosis of acute PE at Shanghai Pulmonary Hospital from May 2007 to May 2018. Potential predictors of recurrent PE were evaluated at different points (1, 3, 6, 12, 24, 60 and 120-month) during a long-term follow-up for each patient. Patients were stratified into two groups by gender to analyze the impact of sex in period-guided prognostic prediction. Receiver operating characteristic curve analysis, survival analysis and multivariate Cox proportional hazards analysis were implemented as statistical analysis methods.ResultsIn total, 597 acute PE patients were included, of whom 62 reported a PE recurrence. Male patients tend to have a lower risk of PE recurrence than female patients during 3- to 60-month follow-up period but have a higher risk of PE recurrence than female patients during 120-month follow-up period. The independent predictors of recurrence-free survival varied among different follow-up periods: In all patients, diabetes was an independent predictor only within 30 days follow-up period and female was considered as an independent predictor during 3- to 120-month follow-up period. Among male patients, hyperlipidemia and Log D-dimer (cut-off value =3.436) was observed as a predictor of recurrent PE within 6-month and over 12-month follow-up respectively. However, there is no unified independent prognostic indicator for female patients identified.ConclusionsIn the early stage of follow-up, male PE patients have better prognosis, but with the extension of follow-up, female PE patients have better prognosis. The independent predictors of recurrence-free survival vary in different follow-up periods in PE patients when stratified based on gender and associated medical conditions.

Identification of Frailty and Its Risk Factors in Elderly Hospitalized Patients from Different Wards: A Cross-Sectional Study in China.

ObjectivesTo survey the difference of frailty prevalence in elderly inpatients amongdifferent wards; to compare the diagnostic performance of five frailty measurements (Clinical Frailty Scale [CFS], FRAIL, Fried, Edmonton, Frailty Index [FI]) in identifying frailty; and to explore the risk factors of frailty in elderly inpatients.Participants and methodsThis was a cross-sectional study including 1000 inpatients (mean age 75.2±6.7 years, 51.5% male; 542, 229, and 229 patients from cardiology, non-surgical, and surgical wards, respectively) in a tertiary hospital from September 2018 to February 2019. We applied the combined index to integrate the five frailty measurements mentioned above as the gold standard of frailty diagnosis. Multivariate logistic regression models were used to determine the independent risk factors of frailty.ResultsFrailty prevalence was 32.3% (Fried), 36.2% (CFS), 19.2% (FRAIL), 25.2% (Edmonton), 35.1% (FI) in all patients. The frailty was more common in non-surgical wards, regardless of the frailty assessment tools used (non-surgical wards: 27.5% to 51.5%; cardiology ward: 14.9% to 29.3%; surgical wards: 18.8% to 41.9%). CFS≥5 showed a sensitivity of 94.1% and a specificity of 85.2% for all patients. FI≥0.25 showed a sensitivity of 94.8% and a specificity of 87.0% for all patients. Age [odds ratio (OR) = 1.089, P<0.001], education level (OR = 0.782, P=0.001), heart rate (OR = 1.025, P<0.001), albumin (OR = 0.911, P=0.002), log D-dimer (OR = 2.940, P<0.001), ≥5 comorbidities (OR = 2.164, P=0.002), and ≥5 medications (OR = 2.819, P<0.001) were independently associated with frailty in all participants.ConclusionFrailty is common among elderly inpatients, especially in non-surgical wards. CFS is a preferred screening tool and FI may be an optimal assessment tool. Old age, low educational level, fast heart rate, low albumin, high D-dimer, ≥5 comorbidities, and polypharmacy are independent risk factors of frailty in elderly hospitalized patients.

Longitudinal evaluation of markers of inflammation in HIV‐positive and HIV‐negative Rwandan women

African women are disproportionately affected by HIV infection and may experience non-AIDS-related complications associated with inflammation. High-sensitivity C-reactive protein (hsCRP), d-dimer and transthyretin have been examined as inflammatory markers elsewhere, but it is unclear how they change over time in HIV-negative or HIV-positive African women with or without antiretroviral therapy (ART) initiation. We examined hsCRP, d-dimer and transthyretin levels at baseline and at follow-up of ≥2years in 185 HIV-negative and 510 HIV-positive Rwandan women who were ART naïve at study entry. Generalized estimating equations for each marker were used to investigate the association with HIV infection/CD4 count, ART and follow-up time. Compared with HIV-negative women, HIV-positive women had higher hsCRP and d-dimer and lower transthyretin concentrations, with greater differences at lower CD4 counts. After adjusting for CD4 count and other factors, ART was not significantly associated with log hsCRP (P=0.36) at follow-up, but was independently associated with lower log d-dimer (P=0.03) and higher transthyretin (P=0.0008) concentrations. At ≥2years of follow-up, hsCRP had not significantly changed in any group but log d-dimer had decreased significantly in all groups. Transthyretin declined significantly over time in HIV-negative women and HIV-positive non-ART initiators, but increased significantly in HIV-positive ART initiators. HIV infection and advanced immune suppression were associated with higher hsCRP and d-dimer and lower transthyretin concentrations. ART (independently of CD4 changes) was significantly associated with decreases in d-dimer and increases in transthyretin, but, in contrast to other studies, was not associated with decreases in hsCRP. We found no change in hsCRP over time in any group.

Elevated level of D-dimer increases the risk of stroke

The aim of this study was to systematically evaluate the association between D-dimer level and the risk of stroke through performing a meta-analysis. PubMed, Web of Science, EMBASE and Cochrane Library were searched for potentially eligible literature. Prospective observational studies or case-control studies were included. The study characteristics and relevant data were extracted. Hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were pooled to estimate the association between D-dimer level and the risk of stroke. Seven prospective studies with 22,207 patients and three case-control studies with 2,248 patients were included. For the prospective studies, the pooled HRs of higher D-dimer level for all types of stroke, ischemic stroke and hemorrhagic stroke were 1.55 (95% CI, 1.28- 1.87), 1.62 (95% CI, 1.18-2.22) and 1.30 (95% CI, 0.63-2.68), respectively. The pooled HRs per SD increase in log D-dimer for all types of stroke, ischemic stroke and hemorrhagic stroke were 1.16 (95% CI, 1.06-1.26), 1.11 (95% CI, 1.03-1.21) and 1.11 (95% CI, 0.95-1.30), respectively. For the case-control studies, the pooled OR of higher D-dimer level for acute ischemic stroke was 2.06 (95% CI, 1.08-3.96). No significant publication bias was found in the meta-analysis. In conclusion, our results suggested that higher D-dimer level was associated with higher risk of stroke, especially ischemic stroke.

Abstract 19620: Impact of D-dimer for Prediction of Occult Cancer in Patients With Unprovoked Venous Thromboembolism

Introduction: Unprovoked venous thromboembolism (VTE) is related higher incidence of occult cancer. However, routine screening for cancer in this population is still controversial. D-dimer is a biomarker reflecting the activation of hemostasis and fibrinolysis. D-dimer is clinically used to exclude VTE, also related in patients with malignancy. Hypothesis: We aimed to explore the predictive value of d-dimer level for detecting occult cancer in patients with unprovoked VTE. Methods: We retrospectively analyzed 840 patients who diagnosed deep vein thrombosis or pulmonary thromboembolism. Among them, 175 (20.8%) patients who diagnosed with unprovoked VTE selected to participate in this study. Odds ratios (OR) with 95% confidence intervals (95% CI) were calculated for incidence of occult cancer as well as d-dimer level reference to patient without occult cancer. Results: During follow-up for 5.0±1.9 years, 30 of 840 patients diagnosed cancer in this population. The primary origin of tumor was 6 (20%) of stomach, 6 (20%) of lung, 4 (13%) of colon and others. Number of patients with metastatic cancer was 17 (57%). Log d-dimer was significantly higher in occult cancer group than unprovoked VTE without cancer (3.5 ± 0.5 vs. 3.2 ± 0.5, p=0.009). When the patients with unprovoked VTE were divided by d-dimer according to Youden index, high d-dimer (≥2432) was associated with higher prevalence of occult cancer (26.9% vs. 9.2%, p=0.002). In logistic regression analysis, d-dimer is independently associated with occult cancer (OR: 3.93, 95% CI: 1.46-10.54, p=0.007) after adjusted gender, age, type of VTE (i.e., deep vein thrombosis or pulmonary thromboembolism) and tumor markers. In addition, d-dimer is more significantly associated with patients who diagnosed cancer with distant metastasis (OR: 4.31, 95% CI: 1.16-15.99, p=0.029) Conclusions: High level of d-dimer concentrations are indicator of an increased risk of occult cancer in patients with unprovoked VTE.

Associations Between Fibrin D‐Dimer, Markers of Inflammation, Incident Self‐Reported Mobility Limitation, and All‐Cause Mortality in Older Men

ObjectivesTo examine the independent relationships between fibrin D-dimer, interleukin 6 (IL-6), C-reactive protein (CRP), and fibrinogen and incident mobility limitation and mortality.DesignProspective.SettingGeneral practice in 24 British towns.ParticipantsMen aged 60 to 79 without prevalent heart failure followed up for an average of 11.5 years (N = 3,925).MeasurementsAll-cause mortality (n = 1,286) and self-reported mobility disability obtained at examination in 1998 to 2000 and in a postal questionnaire 3 to 5 years later in 2003.ResultsHigh D-dimer (top vs lowest tertile: adjusted odds ratio (aOR) = 1.46, 95% confidence interval = 1.02–2.05) and IL-6 (aOR = 1.43, 95% CI = 1.01–2.02) levels (but not CRP or fibrinogen) were associated with greater incident mobility limitation after adjustment for confounders and prevalent disease status. IL-6, CRP, fibrinogen, and D-dimer were significantly associated with total mortality after adjustment for confounders. Only D-dimer and IL-6 predicted total mortality independent of each other and the other biomarkers. The adjusted hazard ratio (aHR) was 1.16 (95% CI = 1.10–1.22) for a standard deviation increase in log D-dimer and 1.10 (95% CI = 1.04–1.18) for a standard deviation increase in log IL-6. D-dimer was independently related to vascular and nonvascular mortality, and IL-6 was independently related to vascular mortality. Risks of mobility limitation and mortality were greatest in those with a combination of high D-dimer and IL-6 levels.ConclusionD-dimer and IL-6 are associated with risk of mobility limitation and mortality in older men without heart failure. The findings suggest that coagulation leads to functional decline and mortality s that inflammation does not explain.

Biomarkers From Late Pregnancy to 6 Weeks Postpartum in HIV-Infected Women Who Continue Versus Discontinue Antiretroviral Therapy After Delivery

Women who use antiretroviral therapy (ART) solely for the prevention of mother-to-child transmission of HIV discontinue postpartum. We hypothesized that women discontinuing ART by 6 weeks postpartum ("discontinuers") would have elevated postpartum inflammatory biomarker levels relative to women remaining on ART postpartum ("continuers"). Data from HIV-infected pregnant women enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group P1025 with CD4 counts >350 cells per cubic millimeter before initiating ART or first pregnancy CD4 counts >400 cells per cubic millimeter after starting ART and with available stored plasma samples at >20 weeks of gestation, delivery, and 6 weeks postpartum were analyzed. Plasma samples were tested for highly sensitive C-reactive protein, D-dimer, and interleukin-6. We used longitudinal linear spline regression to model biomarkers over time. Data from 128 women (65 continuers and 63 discontinuers) were analyzed. All biomarkers increased from late pregnancy to delivery, then decreased postpartum (slopes different from 0, P < 0.001). Continuers had a steeper decrease in log D-dimer between delivery and 6 weeks postpartum than discontinuers (P = 0.002). In contrast to results from treatment interruption studies in adults, both ART continuers and ART discontinuers had significant decreases in the levels of D-dimer, highly sensitive C-reactive protein, or interleukin-6 postpartum. Continuation was associated with a more rapid decline in D-dimer levels compared with discontinuation.

Relation between D-dimer level, venous valvular reflux and the development of post-thrombotic syndrome after deep vein thrombosis.

The pathophysiology of post-thrombotic syndrome (PTS) is postulated to involve persistent venous obstruction and venous valvular reflux. To study the association between D-dimer level, valvular reflux and the PTS in a well-defined cohort of deep vein thrombosis (DVT) patients. Consecutive patients with acute symptomatic DVT were recruited at eight centers and were followed for 24months. D-dimer was measured at 4months. A standardized ultrasound assessment for popliteal valvular reflux was performed at 12months. Using the Villalta scale, patients were assessed for PTS during follow-up by evaluators who were unaware of D-dimer or reflux results. Three hundred and eighty-seven patients were recruited; of these, 305 provided blood samples for D-dimer and 233 had a 12-month reflux assessment. PTS developed in 45.1% of subjects. Mean D-dimer was significantly higher in patients with vs. without PTS (712.0 vs. 444.0μgL(-1) ; P=0.02). In logistic regression analyses adjusted for warfarin use at the time of D-dimer determination and risk factors for PTS, D-dimer level significantly predicted PTS (P=0.03); when stratifying for warfarin use at the time of blood draw, adjusted odds ratio (OR) for developing PTS per unit difference in log D-dimer was 2.33 (95% CI 0.89, 6.10) in those not on warfarin vs. 1.25 (95% CI 0.87, 1.79) in those on warfarin. Ipsilateral reflux was more frequent in patients with moderate-to-severe PTS than in patients with mild PTS (65% vs. 40%, respectively; P=0.01) and was independently associated with moderate-to-severe PTS in logistic regression analyses (P=0.01). D-dimer levels, measured 4months after DVT in patients not on warfarin, are associated with subsequent development of PTS. Venous valvular reflux is associated with moderate-to-severe PTS.

D-dimer level is associated with the extent of pulmonary embolism

ObjectivesOur aim was to study the association between the level of D-dimer and the severity of pulmonary embolism (PE) as determined by various biochemical and radiological prognostic markers in order to investigate the potential value of D-dimer as a prognostic marker for the severity of PE. Patients and methodsPE was diagnosed in 100 consecutive out-patients by multi-detector computerized tomography. One patient was excluded and the final cohort consisted of 99 patients. Pulmonary Artery Obstruction Index (PAOI) and Right Ventricular/Left Ventricular (RV/LV) ratio were assessed. ResultsThe median value for D-dimer was 5.0 mg/L (inter-quartile range: 1.8, 12.2). There was a significant association between log D-dimer, and between log RV/LV (r=0.45), log PAOI (r=0.5), and PaO2 (r=0.40). The multivariate analysis showed an increased association between log D-dimer and between log RV/LV ratio (r=0.54) and log PAOI (r=0.52) after adjusting for age, gender and for the duration of symptoms. Significant association was found between the level of D-dimer and the most proximal level of PE (p<0.0005). There was a significant dose–response relationship between the level D-dimer and between Troponin-T and the frequency of thrombolysis (p<0.0005). In the subgroup of patients with D-Dimer over the upper quartile (>12.2), 12 (67%) patients had elevated Troponin-T and 8 (32%) patients received thrombolysis, compared to 1 (5%) patient with elevated Troponin-T and none treated with thrombolysis in the subgroup of patients with D-dimer<lower quartile. ConclusionsWe have shown that the level of D-dimer is related to the severity of PE assessed by various radiological, biochemical and clinical markers and might have a potential value as prognostic marker for the severity of PE.

Maintenance Therapy with Thalidomide/Prednisone Post Autologous Stem-Cell Transplant for Patients with Multiple Myeloma Elevates D-Dimer and Possibly Factor VIII Levels.

Background: Thalidomide is commonly used for the treatment of multiple myeloma (MM). Several studies have observed that venous thromboembolism (VTE) is a complication for up to 10% of patients receiving thalidomide therapy, especially when used as combination chemotherapy as part of primary treatment. Elevated Factor VIII and D-dimer levels are well described markers of thrombin generation and for an increased risk of VTE. The purpose of this study was to assess whether MM patients allocated to receive maintenance therapy with thalidomide and prednisone (thal/pred) post stem cell transplant for MM have increased levels of Factor VIII and D-dimer as laboratory confirmation for the reported increased clinical occurrence of VTE with thalidomide therapy.Methods: This is a correlative sub-study of NCIC CTG MY.10 which is an open-label randomized multicentre trial assessing the efficacy (time to progression) of maintenance therapy with the combination of thalidomide 200mg/day and prednisone 50mg every other day compared to no maintenance therapy post stem cell transplant. No clinical outcomes are available at this time as the study is ongoing. This laboratory companion study was incorporated in MY.10 a priori. Eligible patients were registered and randomized 60–100 days post transplantation. All consenting patients had plasma samples collected and frozen at baseline and two months post study enrollment. An unmatched comparison by MY.10 treatment arm was performed to assess the change in D-dimer and Factor VIII from baseline to two months for the first 79 patients entered into the trial.Results: There were 37 patients allocated to thal/pred (28 males, 76%) and 42 on observation (29 males, 69%). The mean ages were 56.6 and 55.8 years respectively. Based on continuous log D-dimer and log Factor VIII using two-way ANOVA, the results are shown in Table 1. Since D-dimer is also reported as positive or negative (<200 or =/>200μg/l) this was also assessed and the results as shown in Table 2. D-dimer results were significantly different (Bonferroni, p = 0.05) at two months compared with baseline for patients allocated to thal/pred rather than observation alone. At two months there were also significantly more patients allocated to thal/pred who had elevated D-dimers, 13 (72%) versus 5 (28%), (Bonferroni p < 0.05). There was a trend towards higher Factor VIII levels in patients allocated to thal/pred than on observation.Conclusion: These results provide clinical laboratory evidence of thrombin activation with the use of thal/pred post autologous transplant in patients with MM, and offer a potential mechanism, as well as, potential predictive markers for the clinical observations to date that patients receiving treatment with thalidomide for MM have an increased risk of VTE.Table 1MeanUnadjustedBaseline2 monthsp-valuethal/predObservationthal/predObservaton(D-dimer μg/l)11910113775.60.03FVIII (units/ml)1.251.301.601.260.09Table 2D-dimer# ≥200(μg/l)Unadjusted p-valueNthal/predObservationPearsonExactChi-squareFisherBaseline2310 (43%)13 (57%)0.700.81At 2 months1813 (72%)5 (28%)0.010.02

Inflammatory markers, D-dimer, pro-thrombotic factors, and physical activity levels in patients with peripheral arterial disease

Men and women with lower extremity peripheral arterial disease (PAD) have reduced physical activity levels compared with persons without PAD. We describe associations between physical activity levels with D-dimer, pro-coagulant factors, and inflammatory markers in patients with PAD. Participants were 188 patients with PAD identified from non-invasive vascular laboratories. Physical activity was measured over 7 days with a vertical accelerometer. We measured the ankle-brachial index (ABI) and levels of D-dimer, C-reactive protein (CRP), fibrinogen, serum amyloid A (SAA), prothrombin 1.2, t-PA antigen, PAI-1, and the t-PA antigen/PAI-1 ratio. Adjusting for age, sex, race, body mass index, ABI, comorbidities, smoking, total cholesterol/HDL ratio and statin use (for CRP only), we found significant inverse linear associations between physical activity levels and log D-dimer (p = 0.002), log CRP (p < 0.001), fibrinogen (p = 0.014), and log SAA (p = 0.012). There were no significant associations between physical activity levels and other blood factors. In an analysis adjusting for all blood factors simultaneously along with known and potential confounders, log D-dimer was the only blood factor associated significantly with physical activity levels (p = 0.036). Based on these findings, future studies should assess whether interventions to increase physical activity in patients with PAD reduce levels of D-dimer and inflammatory markers.

Hemostatic function and progressing ischemic stroke: D-dimer predicts early clinical progression.

Early clinical progression of ischemic stroke is common and is associated with increased risk of death and dependency. We hypothesized that activation of the coagulation system is an important contributor in some cases of deterioration. We aimed to characterize alterations in circulating hemostatic markers in patients with progressing stroke. Consecutive acute ischemic stroke admissions were recruited. Progressing stroke was defined by deterioration in components of the Scandinavian Stroke Scale. Hemostatic markers (coagulation factors VIIc, VIIIc, and IXc, prothrombin fragments 1+2 [F1+2], thrombin-antithrombin complexes [TAT], D-dimer, fibrinogen, von Willebrand factor [vWF] and tissue plasminogen activator) were measured within 24 hours of symptom recognition. Fifty-four (25%) of the 219 patients met criteria for progressing stroke. F1+2 (median 1.28 versus 1.06 nmol/L, P=0.01), TAT (5.28 versus 4.07 microg/L, P<0.01), D-dimer (443 versus 194 ng/mL, P<0.001) and vWF (216 versus 198 IU/dL, P<0.05) levels were higher in these patients than in stable/improving patients. In logistic regression analysis, with all important clinical and laboratory variables included, only natural log D-dimer (odds ratio [OR]: 1.87; 95% confidence interval [CI]: 1.38 to 2.54; P=0.0001) and mean arterial blood pressure (OR: 1.26 per 10 mm Hg change; 95% CI: 1.05 to 1.51; P=0.01) remained independent predictors of progressing stroke. There is evidence of excess thrombin generation and fibrin turnover in patients with progressing ischemic stroke. Measurement of D-dimer levels can identify patients at high risk for stroke progression. Further research is required to determine whether such patients benefit from acute interventions aimed at modifying hemostatic function.

Relation of levels of hemostatic factors and inflammatory markers to ankle-brachial index: McDermott M, Green D, Greenland P, et al. Am J Cardiol 2003; 92:194-9

Conclusiond-Dimer levels may be the most sensitive inflammatory or hemostatic marker in providing a serologic indication of the extent of lower extremity atherosclerosis. SummarySome components of the hemostatic system, including tissue plasminogen activator, plasminogen activator inhibitor, and prothrombin 1.2, as well as d-dimer, are increased in patients with lower extremity peripheral arterial disease (PAD) compared with patients without PAD. Inflammatory markers such as C-reactive protein, fibrinogen, and serum amyloid A have been less consistently associated with PAD.The authors correlated levels of these hemostatic and inflammatory markers with ankle-brachial index (ABI) in 370 subjects with an ABI less than 0.9 and 231 subjects with an ABI of 0.9 to 1.50. In patients without a history of cardiac or cerebrovascular disease the ABI, in an unadjusted analysis, was inversely associated with log d-dimer (P < .001), log C-reactive protein (P < .001), log prothrombin 1.2 (P = .001), and log fibrinogen (P = .005). At multivariable regression analysis, CRP was associated independently with ABI only in patients with a history of cardiac or cerebrovascular disease and not in patients without a history of cardiac or cerebrovascular disease. d-Dimer, however, was associated independently with ABI in patients with a history of cardiac or cerebrovascular disease and also in patients without a history of cardiac or cerebrovascular disease. CommentThe results demonstrate that d-dimer levels are associated with the extent of lower extremity PAD as measured by ABI. The data suggest that patients with more severe PAD, as reflected by ABI, have ongoing fibrinolysis and thrombosis that is reflected in higher d-dimer levels.

Relation of levels of hemostatic factors and inflammatory markers to the ankle brachial index

Associations between hemostatic and inflammatory markers relative to the ankle brachial index (ABI), an indicator of the presence and severity of peripheral arterial disease (PAD), are not fully understood. We studied relations among selected hemostatic factors, inflammatory markers, and the ankle brachial index (ABI) in patients with and without peripheral arterial disease (PAD). Participants were 370 men and women with ABI <0.90 and 231 patients with ABI 0.90 to 1.50 identified from noninvasive vascular laboratories and general medicine practice. Blood factors were d-dimer, prothrombin 1.2, tissue plasminogen activator (t-PA) antigen, plasminogen activator inhibitor-1 (PAI-1), and inflammatory markers (high-sensitivity C-reactive protein [CRP], fibrinogen, and serum amyloid A [SAA]). Among patients without a history of cardiac or cerebrovascular disease, the ABI was significantly inversely associated with log d-dimer (p <0.001), log prothrombin 1.2 (p = 0.001), log CRP (p <0.001), and log fibrinogen (p = 0.005) in unadjusted analyses. In multivariable regression analyses adjusting for all blood factors as well as potential confounders, d-dimer was associated independently with ABI in participants with a history of cardiac or cerebrovascular disease (p = 0.003) and in participants without a history of cardiac or cerebrovascular disease (p = 0.017). In these analyses, CRP was associated independently with ABI among participants with a history of cardiac or cerebrovascular disease (p = 0.026). CRP was not associated independently with ABI in participants without a history of cardiac or cerebrovascular disease. We conclude that d-dimer levels may be more sensitive than other blood markers for measuring the extent of atherosclerosis in lower extremity arteries.

D-dimer determination as a screening tool to exclude atrial thrombi in atrial fibrillation

Conversion of atrial fi brillation (AF) to sinus rhythm carries a defi nite risk of systemic embolism. This risk can be reduced to an acceptable level by prior anticoagulation for 3 weeks or, alternatively, by exclusion of atrial thrombi with transesophageal echocardiography (TEE) before cardioversion. 1 Although earlier cardioversion according to TEE-guided strategy has potential advantages, 2,3 TEE requires special equipment and advanced skills, which may limit its availability. D-dimer, an indirect marker of fi brin formation, has been demonstrated to be a sensitive marker of activation of coagulation in various clinical conditions. 4 –7 In AF, elevated D-dimer levels have been reported to be associated with the duration of AF, 8 left atrial appendage dysfunction, 9 and the presence of atrial thrombus. 10,11 The potential role of D-dimer in refi ning embolic risk prediction in AF remains to be determined. The aims of our study were to analyze the relation of serum D-dimer to embolic risk determined on clinical grounds in patients with AF and to assess the test’s diagnostic utility to predict the presence or absence of atrial thrombi.  In a prospective design, we measured the plasma D-dimer concentration of consecutive patients admitted to our echocardiography laboratory for TEE before cardioversion. The local ethics committee approved the protocol. The examinations were performed after obtaining written informed consent. Patients with AF of 48 hours duration or atrial fl utter with documented history of AF were eligible. The exclusion criteria included any thromboembolic events within the previous 2 months and anticoagulant therapy for 7 days. Subjects underwent transthoracic and TEE. Echocardiographic studies were performed with an ATL instrument (HDI 3500 CV, Philips Ultrasound, Bothell, Washington) using a 1.67- to 3.2-MHz, phased-array head (P4 to P2) for transthoracic examination, and a 4- to 7-MHz omniplane probe (MPT7 to MPT4) for TEE. An intravenous line was placed and blood samples were obtained without tourniquet immediately before TEE. D-dimer measurements were obtained with the use of a quantitative sandwich immunochromatographic technique (Cardiac D-dimer; Roche Diagnostics, Mannheim, Germany). The investigators and attending physicians were blinded to the D-dimer test results. The fi nal interpretations of the TEEs were the result of the consensus of the same 2 experienced investigators based on real-time observation or off-line analysis of the studies. For D-dimer results below the measurement range, 0.1 g/ml was entered. Values are presented as mean SEM. To obtain normal distribution, D-dimer values were logarithmically transformed, and unpaired 2-tailed t tests were used to compare means. The independent predictive role of embolic predictors for log D-dimer was evaluated by multiple regression analysis. Sensitivity,

Correlation between cholesterol, soluble P-selectin, and D-dimer in obese children and adolescents.

Thirty-eight obese children and adolescents were investigated for a possible relation between cholesterol and markers of platelet activation, endothelial cell dysfunction, and activation of the coagulation system. Soluble P-selectin, von Willebrand factor antigen (vWf-Ag), D-dimer, and prothrombin fragment 1 + 2 (F1 + 2) were determined by enzyme-linked immunosorbent assays, and factor VIII coagulant activity (VIIIc) was measured by means of one-stage clotting assay. Cholesterol correlated significantly with log P-selectin (r = 0.43, P = 0.003) and log D-dimer (r = 0.33, P = 0.02). Cholesterol did not correlate with vWf-Ag, factor VIIIc, and F1 + 2. Log P-selectin correlated significantly with log D-dimer (r = 0.42, P = 0.003), which remained significant after adjustment for cholesterol (P = 0.02). Log D-dimer correlated significantly with F1 + 2 (r = 0.38, P = 0.01). Our study demonstrates that, in obese children and adolescents, cholesterol is significantly associated with P-selectin and D-dimer, and suggests an unfavorable intercorrelation between metabolic and hemostatic risk factors for coronary heart disease in childhood obesity.