Elevated baseline D-dimer plasma levels are associated with a prompt response to omalizumab in patients with severe CSU

Introduction: Plasma concentrations of prothrombotic factors such as fibrinogen have previously been associated with ischemic stroke risk. To extend this observation, we examined the association of polygenic risk scores (PRS) for increased plasma levels of thrombosis-related factors with ischemic stroke. Our hypotheses were that these PRS would be more associated with early than late onset stroke and with non-lacunar than lacunar stroke. Methods: We identified 9053 late onset (≥ 60 years) stroke cases from the NINDS International Stroke Genetics Consortium (SiGN) with 24804 controls and 6594 early onset (< 60 years) stroke cases from the Genetics of Early Onset Ischemic Stroke Consortium with 30561 controls. We identified previously known loci associated with plasma levels of four thrombosis-related factors: fibrinogen, fibrin D-dimer, tPA and PAI-1 from prior GWAS studies and developed genome-wide PRS for plasma concentrations of these factors. We then used logistic regression to test the association of these scores with risk of stroke and stroke subtype. Results: PRS for fibrin D dimer levels were associated with increased risk for all stroke and specifically for older (p = 0.019), but not younger (p = 0.22) onset stroke. PRS for tPA levels were also marginally associated with older (p = 0.06), but not younger (p = 0.24) onset stroke. Genetic risk scores for both D dimer and tPA were associated with non-lacunar stroke (Table 1). Further analyses stratified by age revealed PRS for D dimer to be significantly associated with non-lacunar stroke (but not lacunar stroke) in both late and early onset cohorts. PRS for fibrinogen and PAI-1 were not associated with stroke. Conclusion: Genomic risk scores for thrombosis-related factors including D dimer and tPA levels were associated with risk for ischemic stroke, and specifically, non-lacunar stroke.

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PLASMA LEVELS OF FRAGMENT D-DIMER OF CROSSLINKED FIBRIN DURING THROMBOLYTIC THERAPY WITH RECOMBINANT TISSUE-TYPE PLASMINOGEN ACTIVATOR

10.1055/s-0038-1643652 ◽

1987 ◽

Author(s):

P Declerck ◽

P Mombaerts ◽

P Holvoet ◽

D Collen

Keyword(s):

Thrombolytic Therapy ◽

Plasma Levels ◽

Degradation Products ◽

Fibrin Clot ◽

Tissue Type ◽

Fibrin Degradation Products ◽

Type Plasminogen Activator ◽

Rate Of Increase ◽

Significant Difference ◽

D Dimer

Plasma levels of crosslinked fibrin degradation products (XLDP) were measured before and at the end of the administration of rt-PA (40 to 100 mg over 1.5 to 8 hours) in healthy volunteers (n=5) and patients with deep venous thrombosis (DVT) (n=8), pulmonary embolism (PE) (n=16)and myocardial infarction(MI)(n=10). Determinations were performed using our newly developed ELISA, specific for crosslinked fibrin derivatives, based on two monoclonal antibodies (15C5 and 8D3H2) raised against purified human fragment D-dimer. All plasma samples were collected on citrate and trasylol. Results are expressed as mean and range of D-dimer equivalents (μg/ml).Baseline levels in patients with MI are only slightly elevated. The increased levels inDVT and PE are in agreement with previous studies. After infusion of rt-PA a small increase of XLDP is seen even innormal subjects. A very marked increasof XLDP is detected in patients with PE and DVT but not in patients with MI. This may reflect differences in the amounts of fibrin clot dissolved in these patient groups.No significant correlation was found between the increase of XLDP and success of therapy, although a significant difference in D-dimer levels was formed between the two groups with PE: successful (n=ll): 116 (range 61-192) vs. unsuccessful (n=5): 68 (36-155).Thus, XLDP are already elevated under baseline conditions in patients with DVT and PE and increase very markedly during thrombolytic therapy. The absolute levels after thrombolytic therapy do not strictly correlate with success of therapy. It could be useful to measure D-dimer levels during early stages of therapy, because the rate of increase of XLDP levels might correlate with the efficacy of thrombolytic treatment.

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Effects of dark chocolate consumption on the prothrombotic response to acute psychosocial stress in healthy men

Thrombosis and Haemostasis ◽

10.1160/th14-05-0450 ◽

2014 ◽

Vol 112 (12) ◽

pp. 1151-1158 ◽

Cited By ~ 9

Author(s):

Roland von Känel ◽

Rebecca Meister ◽

Monika Stutz ◽

Petra Kummer ◽

Angela Arpagaus ◽

...

Keyword(s):

Plasma Levels ◽

Psychosocial Stress ◽

Cardiovascular Health ◽

Stress Reactivity ◽

Mental Arithmetic ◽

Dark Chocolate ◽

Clotting Factor ◽

Significant Group ◽

Healthy Men ◽

D Dimer

SummaryFlavanoid-rich dark chocolate consumption benefits cardiovascular health, but underlying mechanisms are elusive. We investigated the acute effect of dark chocolate on the reactivity of prothrombotic measures to psychosocial stress. Healthy men aged 20–50 years (mean ± SD: 35.7 ± 8.8) were assigned to a single serving of either 50 g of flavonoid-rich dark chocolate (n=31) or 50 g of optically identical flavonoid-free placebo chocolate (n=34). Two hours after chocolate consumption, both groups underwent an acute standardised psychosocial stress task combining public speaking and mental arithmetic. We determined plasma levels of four stress-responsive prothrombotic measures (i. e., fibrinogen, clotting factor VIII activity, von Willebrand Factor antigen, fibrin D-dimer) prior to chocolate consumption, immediately before and after stress, and at 10 minutes and 20 minutes after stress cessation. We also measured the flavonoid epicatechin, and the catecholamines epinephrine and norepinephrine in plasma. The dark chocolate group showed a significantly attenuated stress reactivity of the hypercoagulability marker D-dimer (F=3.87, p=0.017) relative to the placebo chocolate group. Moreover, the blunted D-dimer stress reactivity related to higher plasma levels of the flavonoid epicatechin assessed before stress (F=3.32, p = 0.031) but not to stress-induced changes in catecholamines (p’s=0.35). There were no significant group differences in the other coagulation measures (p’s≥0.87). Adjustments for covariates did not alter these findings. In conclusion, our findings indicate that a single consumption of flavonoid- rich dark chocolate blunted the acute prothrombotic response to psychosocial stress, thereby perhaps mitigating the risk of acute coronary syndromes triggered by emotional stress.

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Active Cancer and Elevated D-Dimer Are Risk Factors for In-Hospital Ischemic Stroke

Cerebrovascular Diseases Extra ◽

10.1159/000504163 ◽

2019 ◽

Vol 9 (3) ◽

pp. 129-138 ◽

Cited By ~ 1

Author(s):

Izumi Yamaguchi ◽

Yasuhisa Kanematsu ◽

Kenji Shimada ◽

Masaaki Korai ◽

Takeshi Miyamoto ◽

...

Keyword(s):

Ischemic Stroke ◽

Plasma Levels ◽

Functional Dependence ◽

Multivariate Logistic Regression Analysis ◽

Stroke Onset ◽

Stroke Severity ◽

Significant Difference ◽

Poor Outcomes ◽

D Dimer ◽

Active Cancer

Background and Purpose: Little attention has been paid to the pathogenesis of in-hospital stroke, despite poor outcomes and a longer time from stroke onset to treatment. We studied the pathophysiology and biomarkers for detecting patients who progress to in-hospital ischemic stroke (IHS). Methods: Seventy-nine patients with IHS were sequentially recruited in the period 2011–2017. Their characteristics, care, and outcomes were compared with 933 patients who had an out-of-hospital ischemic stroke (OHS) using a prospectively collected database of the Tokushima University Stroke Registry. Results: Active cancer and coronary artery disease were more prevalent in patients with IHS than in those with OHS (53.2 and 27.8% vs. 2.0 and 10.9%, respectively; p < 0.001), the median onset-to-evaluation time was longer (300 vs. 240 min; p = 0.015), and the undetermined etiology was significantly higher (36.7 vs. 2.4%; p < 0.001). Although there was no significant difference in stroke severity at onset between the groups, patients with IHS had higher modified Rankin Scale (mRS) scores (3–6) at discharge (67.1 vs. 50.3%; p = 0.004) and rates of death during hospitalization (16.5 vs. 2.9%; p < 0.001). D-dimer (5.8 vs. 0.8 µg/mL; p < 0.001) and fibrinogen (532 vs. 430 mg/dL; p = 0.014) plasma levels at the time of onset were significantly higher in patients with IHS after propensity score matching. Multivariate logistic regression analysis revealed that active cancer (odds ratio [OR] 2.30; 95% confidence interval [CI] 1.26–4.20), prestroke mRS scores 3–5 (OR 6.78; 95% CI 3.96–11.61), female sex (OR 1.57; 95% CI 1.19–2.08), and age ≥75 years (OR 2.36; 95% CI 1.80–3.08) were associated with poor outcomes. Conclusions: Patients with IHS had poorer outcomes than those with OHS because of a higher prevalence of active cancer and functional dependence before stroke onset. Elevated plasma levels of D-dimer and fibrinogen, especially with active cancer, can help identify patients who are at a higher risk of progression to IHS.

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Activity Pattern Analysis Indicates Increased but Balanced Systemic Coagulation Activity in Response to Surgical Trauma

TH Open ◽

10.1055/s-0038-1673390 ◽

2018 ◽

Vol 02 (04) ◽

pp. e350-e356

Author(s):

Max Friedrich ◽

Jan Schmolders ◽

Yorck Rommelspacher ◽

Andreas Strauss ◽

Heiko Rühl ◽

...

Keyword(s):

Activity Pattern ◽

Plasma Levels ◽

Thrombin Generation ◽

Pattern Analysis ◽

Activity Level ◽

Surgical Trauma ◽

Coagulation Activity ◽

Increased Risk ◽

D Dimer

AbstractIn the nonbleeding patient, constant low-level activation of coagulation enables a quick procoagulant response upon an injury. Conversely, local activation of coagulation might influence the systemic activity level of coagulation. To characterize this interaction in more detail, activity pattern analysis was performed in patients undergoing elective surgeries. Blood samples were taken before, during, and 24 hours after surgery from 35 patients undergoing elective minor (n = 18) and major (n = 17) orthopaedic surgeries. Plasma levels of thrombin and activated protein C (APC) were measured using oligonucleotide-based enzyme capture assays, while those of prothrombin fragment 1.2, thrombin–antithrombin-complexes, and D-dimer were measured using commercially available enzyme-linked immunosorbent assays. In vitro thrombin generation kinetics were recorded using calibrated automated thrombography. Results showed that median plasma levels of up to 20 pM thrombin and of up to 12 pM APC were reached during surgery. D-dimer levels started to increase at the end of surgery and remained increased 24 hours after surgery, while all other parameters returned to baseline. Peak levels showed no significant differences between minor and major surgeries and were not influenced by the activity state at baseline. In vitro thrombin generation kinetics remained unchanged during surgery. In summary, simultaneous monitoring of the procoagulant and anticoagulant pathways of coagulation demonstrates that surgical trauma is associated with increased systemic activities of both pathways. Activity pattern analysis might be helpful to identify patients at an increased risk for thrombosis due to an imbalance between surgery-related thrombin formation and the subsequent anticoagulant response.

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Serial D-dimer plasma levels in a patient with chronic spontaneous urticaria developing resistance to omalizumab

Clinical and Experimental Dermatology ◽

10.1111/ced.13181 ◽

2017 ◽

Vol 42 (6) ◽

pp. 667-669 ◽

Cited By ~ 4

Author(s):

R. Asero

Keyword(s):

Plasma Levels ◽

Chronic Spontaneous Urticaria ◽

D Dimer

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Plasma Tissue Factor (TF) Antigen, Cellular Microparticles and Markers of Coagulation and Platelet Activation in Localized Prostate Cancer.

Blood ◽

10.1182/blood.v106.11.1943.1943 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1943-1943

Author(s):

Florian Langer ◽

Karl-Heinz F. Chun ◽

Ali Amirkhosravi ◽

Barbara Eifrig ◽

Carsten Bokemeyer ◽

...

Keyword(s):

Prostate Cancer ◽

Platelet Activation ◽

Plasma Levels ◽

Early Stage ◽

Treatment Strategies ◽

Localized Prostate Cancer ◽

Resection Margins ◽

Patient Groups ◽

D Dimer

Abstract Coagulation and platelet activation are involved in tumor growth and dissemination, and recent trials have demonstrated promising efficacy of low-molecular-weight heparin (LMWH) in cancer treatment. It is unclear, however, which subgroup of patients benefits most from anticoagulant therapy, although LMWH may be most effective in limited-stage malignancy. About 15–20% of patients with localized prostate cancer (PC) experience recurrent local and/or metastatic disease after radical prostatectomy. We conducted a prospective study to identify laboratory markers of hypercoagulability in early-stage PC, providing a potential rational for adjuvant anticoagulant treatment strategies in this tumor entity. In 98 consecutive patients with clinically localized PC (62±6 years), we found significantly higher preoperative plasma levels of TF (median, 95 vs. 0 pg/ml), prothrombin fragment F1+2 (1.6 vs. 1.1 nmol/l), plasmin-antiplasmin complex (339 vs. 238 ng/ml), and D-dimer (0.27 vs. 0.17 mg/l) than in 42 sex- and age-matched controls (P<0.001). Patients with organ-confined (pT2) and histologically more differentiated tumors (Gleason sum, <7) had lower D-dimer levels than patients with pT3 (P=0.06) and less differentiated tumors (P=0.02). No association was found between hemostatic parameters and preoperative PSA values, lymph node involvement, or positivity of resection margins. Since TF has been implicated in tumor angiogenesis and metastasis, additional studies were performed to elucidate the cellular origin of measured TF antigen levels. To this end, platelet- (PMP) and leukocyte-derived microparticles (LMP) were enumerated by flow cytometry in 18 controls and 36 patients using FITC-conjugated antibodies against CD41 for PMP detection and CD11b or CD14 for LMP detection. Background fluorescence was determined by IgG-FITC control antibody. Calibration microspheres were used to gate all FITC+ events according to their size (forward scatter) and to correct for variations in sample flow. Only FITC+ events <1 μm were included in the analysis. The intra- and inter-assay CVs for this methodology were <10%. Controls had TF levels <50 pg/ml, and patients had TF levels of either <50 pg/ml (low-TF, n=18) or >200 pg/ml (high-TF, n=18). Compared to controls, median PMP numbers were increased 2-fold in low-TF (P<0.05) and 5-fold in high-TF patients (P<0.001). PMP numbers but not whole blood platelet counts were significantly different between patient groups (P<0.05). Compared to low-TF patients, high-TF patients also had elevated plasma levels of sP-selectin (37±15 ng/ml vs. 23±7, P<0.01) and sCD40L (361±817 vs. 47±95 pg/ml, P=0.26), two markers of in vivo platelet activation. LMP were barely detectable in controls, and their numbers were only slightly increased in patients, representing not more than 5–10% of PMP counts. Using immunohistochemistry on paraffin-embedded specimens, TF was localized predominantly to tissue macrophages and adventitial fibroblasts but not to tumor cells, showing a similar staining pattern in both patient groups. In summary, laboratory evidence of coagulation and platelet activation is already present in early-stage PC. Although TF has been associated with a poor clinical outcome in various types of malignancy, its plasma antigen levels may not reflect tumor cell TF expression in localized PC.

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Correlation between Angiogenic and Coagulation-Fibrinolysis Factors and Stage of Disease in Non Hodgkin’s Lymphoma Patients.

Blood ◽

10.1182/blood.v106.11.4678.4678 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4678-4678

Author(s):

Grzegorz Mazur ◽

Malgorzata Poreba ◽

Tomasz Wrobel ◽

Rafal Poreba ◽

Angelika Pyszel ◽

...

Keyword(s):

Plasma Levels ◽

Hodgkin’S Lymphoma ◽

Stage Ii ◽

Hodgkin's Lymphoma ◽

Coagulation System ◽

Stage Of Disease ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

D Dimer ◽

Angiogenic Cytokines

Abstract BACKGROUND: Angiogenesis and activation of coagulation system in cancer patients are common and are thought to be unfavorable clinical parameters. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (bFGF) are well-known angiogenic cytokines. The elevations of plasma fibrinogen and D-dimer level indicate coagulation and fibrinolysis activation. There may be links between angiogenic cytokines and coagulation - fibrinolysis factors in cancer. Possible specific interactions include releasing angiogenic factors, such as VEGF by activated platelets and binding of VEGF and bFGF to fibrin and fibrinogen resulting in an increase in endothelial cell proliferation. AIM: The purpose of our study was: (a) to analyze relations of VEGF, bFGF serum levels and fibrinogen, D-dimer plasma levels with stage of disease according to Ann Arbor Staging System (AASS); (b) to evaluate correlation between serum levels of angiogenic cytokines and plasma levels of coagulation-fibrinolysis factors in non Hodgkin’s lymphoma patients. MATERIAL AND METHODS: 52 non Hodgkin’s lymphoma patients (31 men, 21 women; median age 52,1 ± 14,7 years) in II, III or IV stage of disease according to AASS were assessed. In stage II were 15, in stage III- 10 and in stage IV- 27 persons. Serum VEGF, bFGF and plasma D-dimer levels were measured by enzyme-linked immunosorbent assay (ELISA). Plasma levels of fibrinogen were determined using Behring Coagulation System (BCS) equipment. RESULTS: Plasma level of D-dimer was elevated in majority of patients, mean plasma D-dimer levels [ng/ml] were in stage II: 1654,3 ± 1301,5, in stage III: 1816,6 ± 1370,7, in stage IV: 2747,1 ± 1410,8. There was significantly higher D-dimer level in IV stage of disease in comparison to stage II and III. p<0,01. The mean serum VEGF levels [pg/mL] in following stages of disease were: in II: 387,4 ± 219,8, in III: 399,2 ± 235,0, in IV: 406,9 ± 308,8; mean serum bFGF levels [pg/mL] were: in II: 4,3 ± 2,9, in III: 4,6 ± 2,5, in IV: 4,4 ± 3,4; mean plasma fibrinogen levels [mg%] were: in II: 514,3 ± 198,7, in III: 518,0 ± 209,2, in IV: 495,4 ± 155,3). Differences in levels of VEGF, bFGF and fibrinogen between II, III and IV stage of disease were not statistically significant We observed positive linear correlation between VEGF and fibrinogen (r = 0,45; p<0,01) and between bFGF and fibrinogen (r = 0,52; p<0,05) and negative linear correlation between VEGF and D-dimer (r = −0,69; p<0,001) and between bFGF and D-dimer (r = −0,72; p<0,001). CONCLUSIONS: Our study indicates that D-dimer level correlates with Ann Arbor Staging System in non Hodgkin’s lymphoma patients. Significant correlations between levels of VEGF/bFGF and fibrinogen/D-dimer suggest specific interactions between angiogenic and coagulation-fibrinolysis system.

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