Hemostatic Markers Research Articles

Effect of metformin on selected parameters of hemostasis in fenofibrate-treated patients with impaired glucose tolerance

BackgroundNo previous study has assessed whether the addition of metformin potentiates fibrate action on hemostasis in prediabetic subjects. MethodsOur study included 41 fenofibrate-treated patients with impaired glucose tolerance allocated to either metformin (3g daily) or placebo. ResultsTwelve-week treatment with fenofibrate and metformin reduced plasma levels of fibrinogen and PAI-1 and tended to change the other hemostatic markers measured, as well as improved insulin sensitivity. ConclusionsOur results show that high-dose metformin exhibits beneficial effects on coagulation and fibrinolysis in isolated IGT patients treated with a fibrate.

P-054 Hemostatic markers and sleep quality among shift work and day work female nurses

P-054 Hemostatic markers and sleep quality among shift work and day work female nurses

Hypercoagulable state in Cushing's syndrome is reversible following remission

Hypercoagulability is a commonly described complication in patients with Cushing's syndrome (CS). The aim of this study was to assess the long-term effects of surgical remission from CS on serum levels of coagulation and fibrinolytic markers. Eighteen patients with active CS (16 women, 2 men; age: 38.6 ± 13.7 years) were enrolled in the study. We measured serum levels of coagulation and fibrinolytic markers during active CS and 6 months after remission. The control group comprised 18 age- and sex-matched healthy individuals. Six months after remission from CS, patients had lower levels of factors II (P < 0.001), V (P = 0.02), XI (P = 0.04) and XII (P < 0.001), protein C (P < 0.001), protein S (P = 0.002), antithrombin (P = 0.03), antithrombin Ag (P = 0.008), plasminogen (P = 0.03) and C1 inhibitor (P = 0.001), and aPTT was longer than at enrollment (P = 0.001). Levels of PAI-1 and factors VII, VIII and IX tended to normalize, but there were no significant differences in these parameters before and after surgery, nor were differences found in haemostatic and fibrinolytic markers between the patients in remission and control individuals, except for factor XII (P = 0.02) and protein C (P = 0.004), which were lower among patients in remission. Six months after remission from CS, patients' risk of thromboembolism is comparable to that of healthy individuals.

The Effect of Vitamin D Supplementation on Inflammatory and Hemostatic Markers and Disease Activity in Patients with Systemic Lupus Erythematosus: A Randomized Placebo-controlled Trial

Systemic lupus erythematosus (SLE) is a chronic multisystem inflammatory autoimmune disease. Vitamin D has potent immunomodulatory properties that support its use in the treatment of autoimmune conditions, including SLE. We assessed vitamin D status in patients with SLE and determined alterations in inflammatory and hemostatic markers and disease activity before and after vitamin D supplementation. Patients with SLE (n = 267) were randomized 2:1 to receive either oral cholecalciferol 2000 IU/day or placebo for 12 months. Outcome measures included assessment of alterations in levels of proinflammatory cytokines and hemostatic markers, and improvement in disease activity before and after 12 months of supplementation. Disease activity was measured by the SLE Disease Activity Index. Vitamin D levels were measured by Liaison immunoassay (normal 30-100 ng/ml). Serum levels between 10 and 30 ng/ml were classified as vitamin D insufficiency and levels < 10 ng/ml as vitamin D deficiency. The mean 25(OH)D level at baseline was 19.8 ng/ml in patients compared to 28.7 ng/ml in controls. The overall prevalence of suboptimal and deficient 25(OH)D serum levels among patients with SLE at baseline was 69% and 39%, respectively. Lower 25(OH)D levels correlated significantly with higher SLE disease activity. At 12 months of therapy, there was a significant improvement in levels of inflammatory and hemostatic markers as well as disease activity in the treatment group compared to the placebo group. Vitamin D supplementation in patients with SLE is recommended because increased vitamin D levels seem to ameliorate inflammatory and hemostatic markers and show a tendency toward subsequent clinical improvement. Clinical Trial Registry NCT01425775.

Diagnostic criteria and laboratory tests for disseminated intravascular coagulation

Three diagnostic criteria for disseminated intravascular coagulation (DIC) have been established by the Japanese Ministry of Health, Labor and Welfare, the International Society on Thrombosis and Hemostasis (ISTH) and the Japanese Association for Acute Medicine. The diagnostic criteria involving global coagulation tests, such as the Japanese Ministry of Health, Labor and Welfare criteria and the ISTH overt diagnostic criteria, are first-generation DIC diagnostic criteria, those involving global coagulation tests and changes in these tests such as the Japanese Association for Acute Medicine criteria, are second-generation DIC diagnostic criteria, and those including non-overt DIC diagnostic criteria involving global coagulation tests, changes in these tests and hemostatic molecular markers will be the future (third-generation) DIC diagnostic criteria. There are no significant differences in the three diagnostic criteria with respect to predicting poor outcomes. Therefore, the third generation of diagnostic criteria including hemostatic molecular markers is expected to be established. Standardization and the determination of adequate cutoff values should be required for each laboratory test.

Maternal familial hypercholesterolaemia (FH) confers altered haemostatic profile in offspring with and without FH

IntroductionPatients with familial hypercholesterolaemia (FH) are characterized by high total and LDL cholesterol. Pregnant women with FH have higher absolute levels of total and LDL cholesterol, and a more pro-coagulant pattern compared with healthy pregnant women. Maternal hypercholesterolaemia has been shown to affect early atherosclerosis formation in the offspring. The aim of the present study was to investigate whether maternal FH leads to differences in plasma or serum levels of haemostatic and fibrinolytic markers in children with and without FH born of mothers with FH compared to control children born of non-FH mothers. Methods and resultsChildren with (n=9) and without (n=7) FH born of mothers with FH, as well as control children (n=16) born of non-FH mothers were included in the study. The concentrations of tissue plasminogen activator, plasminogen activator inhibitor (PAI-1), tissue factor (TF), TF pathway inhibitor (TFPI), thrombomodulin, fibrinogen, prothrombin fragment 1+2 and von Willebrand Factor were measured. Our findings show i) higher levels of PAI-1 and TFPI in children with and without FH born of mothers with FH compared with control children, ii) lower levels of thrombomodulin in children with FH compared with control children, and iii) significant correlations between maternal PAI-1 levels during pregnancy and PAI-1 levels in the offspring. ConclusionsWe found that maternal FH may confer an unfavourable phenotype by affecting haemostatic and fibrinolytic markers in offspring independent of the children's FH status. However, the association between maternal hypercholesterolaemia and haemostatic risk markers in the offspring needs to be further elucidated.

Dysregulation of Inflammatory and Hemostatic Markers in Sepsis Associated Disseminated Intravascular Coagulation.

Abstract 2223Disseminated intravascular coagulation (DIC) represents a complex pathophysiologic syndrome where marked alterations in the hemostatic system are manifested. As a result several inflammatory mediators are up regulated through multiple mechanisms. The up regulation of inflammatory mediators such as anaphylatoxin C5a (C5a), procalcitonin (PCT), interleukin 6 (IL-6), interleukin 10 (IL-10), myeloperoxidase (MPO), C reactive protein (CRP), 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 758 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. Thirty healthy male and female volunteers served as the control group. Commercially available ELISA methods were used to measure the various mediators. Marked deviations in the circulating levels of these markers, as compared to controls, were noted as shown in the following table. Compared with controls, subjects in DIC showed an increase in the circulating levels of most inflammatory markers. The levels of PCT, IL-6 and CRP, where considerably higher in the DIC subjects whereas PCI, Pr C and AT exhibited slight decreases. Wide individual variations were present. The PAI-1 levels were also increased in the DIC subjects. These results are tabulated below. These results clearly indicate that inflammation and impairment of fibrinolysis play a key role in the pathogenesis of DICParameterNomal (NHP Mean+SEM)DIC (Baseline Mean+SEM)% ChangeProtein C (% Ag)82.5 ± 13.647.6 ± 23.7−42.2%Functional Protein C (%)83.4 ± 13.246.2 ± 29.8−44.6%PCI (% Inhibition)130.0 ± 24.679.4 ± 105.5−38.9%PAI-1 (ng/ml)35.4 ± 10.8140.6 ± 165.6297.1%CRP (ug/ml)2.6 ± 0.448.0 ± 14.21736.9%C5a (ng/ml)9.2 ± 3.217.2 ± 13.385.1%IL-6 (pg/ml)9.3 ± 3.7620.3 ± 1883.46583.9%IL-10 (pg/ml)13.9 ± 13.1130.2 ± 118.6836.1%MPO (ng/ml)16.0 ± 4.2108.1 ± 68.6574.6%PCT (ng/ml)0.2 ± 0.1321.9 ± 43.314514.5% Disclosures:Osawa:Asahi Kasei Pharma America Corporation: Employment. Kaul:Asahi Kasei Pharma America Corporation: Employment.

Evaluation of hemostatic and fibrinolytic markers in dogs with ascites attributable to right-sided congestive heart failure

To determine whether dogs with ascites secondary to right-sided congestive heart failure (CHF) have bleeding disorders associated with hypofibrinogenemia and discordant plasma fibrin-fibrinogen degradation products (FDPs) and D-dimer assay results (ie, a circulating concentration of FDPs higher than the reference range and a circulating concentration of D-dimer within the reference range). Retrospective case-control study. 80 client-owned dogs. Dogs with ascites secondary to right-sided CHF (group 1; n = 20), unhealthy dogs without cardiac disease (group 2; 40), and dogs with left-sided CHF (group 3; 20) were included in the study. Urine bile acids-to-creatinine concentration ratios were calculated as a marker of liver function. Differences among groups regarding coagulation profile analysis results and prevalence of discordant FDPs and D-dimer assay results were determined. No significant differences were detected among the 3 groups regarding urine bile acids-to-creatinine concentration ratios. Plasma fibrinogen concentration was significantly lower for group 1 versus groups 2 or 3. Prevalence of discordant FDPs and D-dimer assay results was significantly higher for group 1 versus groups 2 or 3. Eighteen group 1 dogs had discordant FDPs and D-dimer assay results. Ten of these dogs had concurrent hypofibrinogenemia, 2 of which had clinical signs of bleeding. Only 10 dogs in groups 2 or 3 had discordant FDPs and D-dimer assay results; none of these dogs had hypofibrinogenemia or clinical signs of bleeding. Dogs with right-sided CHF and ascites may be at increased risk for primary hyperfibrinogenolysis (ie, hypofibrinogenemia and discordant FDPs and D-dimer assay results).

Haemostatic activation in acute coronary syndrome patients in relation to physical exercise

Backgound: Thrombosis is regarded to be a key factor in the development of acute coronary syndromes in patients with coronary artery disease (CAD), Platelets are known to play a fundamental role in acute coronary syndromes(ACS). After atherosclerotic plaque rupture, platelets can form pathogenic, occlusive thrombi leading to acute ischemic events. The precise mechanisms of platelet activation in acute coronary syndromes are still under investigation. Physical activity could regulate the development of ACS via effects on platelet function. Several studies have shown that acute physical exercise increases platelet reactivity, typically assessed by aggregation assays, in both healthy individuals and in patients with cardiovascular disease. The aim of this study was to investigated the effect of moderate and strenuous exercise on arterial thrombus formation. Subjects and Methods: Assay of some hemostatic marker as Platelet activation , thrombin generation (TF(pg/ml),TAT_ µ g/l and dimerand tPA concentration ) von Willebrand factor,platelet aggregation tests,Coronary Angiography. haemostatic parameters in patients with ACS correlated with other clinical parameters under physical exercise . Results: Patients with ACS showed higher values for fibrinogen , tPA , TAT_ , as indicators for a thrombin synthesis, and a marker for prothrombotic conditions, was elevated in patients with ACS,. Von Willebrand factor and D-dimer showed no statistical significant differences during rest., Exercise increased hemostatic parameters in an strenuous physical exercise in ACS Patients( < 0.05). Exercise also increased plasma levels of fibrinogen and von Willebrand factor ,but there was an increase in the generation of T-AT complexes,. (P < 0.05). Exercise did not affect platelet aggregation regardless of its intensity when triggered by the agonists ADP or collagen. Conclusion: Strenuous but not moderate exercise increases the thrombotic tendency in healthy sedentary male volunteers .

Haemostatic activation in acute coronary syndrome patients in relation to physical exercise

Backgound: Thrombosis is regarded to be a key factor in the development of acute coronary syndromes in patients with coronary artery disease (CAD), Platelets are known to play a fundamental role in acute coronary syndromes(ACS). After atherosclerotic plaque rupture, platelets can form pathogenic, occlusive thrombi leading to acute ischemic events. The precise mechanisms of platelet activation in acute coronary syndromes are still under investigation. Physical activity could regulate the development of ACS via effects on platelet function. Several studies have shown that acute physical exercise increases platelet reactivity, typically assessed by aggregation assays, in both healthy individuals and in patients with cardiovascular disease. The aim of this study was to investigated the effect of moderate and strenuous exercise on arterial thrombus formation. Subjects and Methods: Assay of some hemostatic marker as Platelet activation , thrombin generation (TF(pg/ml),TAT_ µ g/l and dimerand tPA concentration ) von Willebrand factor,platelet aggregation tests,Coronary Angiography. haemostatic parameters in patients with ACS correlated with other clinical parameters under physical exercise . Results: Patients with ACS showed higher values for fibrinogen , tPA , TAT_ , as indicators for a thrombin synthesis, and a marker for prothrombotic conditions, was elevated in patients with ACS,. Von Willebrand factor and D-dimer showed no statistical significant differences during rest., Exercise increased hemostatic parameters in an strenuous physical exercise in ACS Patients( < 0.05). Exercise also increased plasma levels of fibrinogen and von Willebrand factor ,but there was an increase in the generation of T-AT complexes,. (P < 0.05). Exercise did not affect platelet aggregation regardless of its intensity when triggered by the agonists ADP or collagen. Conclusion: Strenuous but not moderate exercise increases the thrombotic tendency in healthy sedentary male volunteers .

D-dimer, factor VIII and von Willebrand factor predict a non-dipping pattern of blood pressure in hypertensive patients

The aim of this study is to assess whether the haemostatic markers D-dimer, factor VIII (FVIII) and von Willebrand factor (VWF) are predictive of non-dipping status in treated hypertensive patients; so, as easy available laboratory data can predict non-dipping pattern and help with the selection of the patients whom circadian blood pressure should be re-examined. Forty treated hypertensive patients with essential hypertension were included in the study. Twenty-four-hour ambulatory blood pressure monitoring was performed in all patients. Daytime and nocturnal average systolic, diastolic and mean blood pressures were calculated. Patients were characterised as "non-dippers" on the basis of a less than 10 % decline in nocturnal blood pressure (BP); either systolic or diastolic or mean (MAP). D-dimer as marker of fibrinolytic function, FVIII activity and VWF antigen as marker of endothelial dysfunction were measured on plasma. The predictive efficiency was analysed by receiver operating characteristic (ROC) curves. Youden index was used for the estimation of the cut-off points and the associated values for sensitivity and 1-specificity. Plasma levels of D-dimer, FVIII and VWF were significantly higher in non-dippers as compared with dippers, irrespective of the classification used (BP index); all P < 0.05. The ROC curves indicated a good diagnostic efficiency for D-dimer (AUC(ROC) = 0.697, 0.715 and 0.774), FVIII (AUC(ROC) = 0.714, 0.692 and 0.755) and VWF (AUC(ROC) = 0.706, 0.740 and 0.708) in distinguishing non-dipping pattern (systolic, diastolic or mean) in the study population; all P < 0.05. Among the three haemostatic markers, D-dimer presents the most satisfactory sensitivity/1-specificity for the differentiation of non-dippers, with a cut-off point >168 ng/ml (sensitivity/1-specificity for systolic BP non-dippers of 0.789/0.381, for diastolic BP non-dippers 0.923/0.444 and for MAP non-dippers 0.875/0.375). In conclusion, D-dimer has a good predictive value for non-dipping pattern and the decision for the 24-h ambulatory blood pressure re-monitoring among dippers could rely on its values.

Plasma transfusion for bedside, radiologically guided, and operating room invasive procedures

Frozen plasma (FP) is commonly used in an attempt to correct coagulation defects before performing bedside, radiologically guided, or operating room procedures. Use of FP prophylactically is closely linked to results for standard coagulation tests in the laboratory, including prothrombin time, but there is a general lack of evidence supporting the predictive value of abnormalities of these tests for bleeding. Use of FP has little effect on correcting abnormal coagulation tests when mild and moderate results are recorded. There is no support for evidence of effectiveness for the prophylactic use of FP when reviewing the wider randomized controlled trial literature. When the lack of clinical effectiveness is combined with the risks of FP transfusion, such as transfusion-related acute lung injury and transfusion-associated circulatory overload, the need to challenge continued preprocedure prophylactic use of FP becomes pressing. In clinical practice, abnormalities of standard coagulation tests should not be interpreted in isolation, but alongside review of clinical bleeding history and other hemostatic markers such as platelet count. A more appropriate transfusion strategy may be one that emphasizes the therapeutic use of FP.

Prospective study of seasonal patterns in hemostatic factors in older men and their relation to excess winter coronary heart disease deaths

In England and Wales, approximately 20% extra deaths from coronary heart disease (CHD) occur between December and March, among older people. Circulating concentrations of tissue plasminogen activator (t-PA), von Willebrand factor (VWF) and fibrin D-dimer are associated with arterial disease, and tend to peak in winter. The potential contributions of these hemostatic activation measures to excess winter mortality are unknown. To estimate contributions of hemostatic factors to excess winter mortality. Seasonal patterns in t-PA, VWF and D-dimer were investigated in 4088 men aged 60-79 years from 24 British towns. Data on established coronary risk factors were collected by questionnaire, physical examination and blood sampling. The adjusted mean increase in hemostatic markers during winter months, after adjustment for a range of coronary risk factors, was combined with associations of each marker with CHD mortality obtained from 9 years' follow-up of participants, to predict degree of excess CHD winter mortality. Associations of hemostatic markers with CHD incidence from large meta-analyses were also used. All three markers showed peaks in winter; the adjusted mean increases during winter months were 0.21, 0.15 and 0.12 standard deviations for t-PA, VWF and log(D-dimer), respectively. Predicted excess hazard ratios for winter CHD mortality were 3.0%, 2.4% and 3.1%, respectively, in combination, representing an 8.6% excess. This increased to 14% when applying meta-analysis estimates. Seasonal patterns in three hemostatic markers predict at least 8.6% excess CHD mortality in winter in Great Britain, potentially accounting for over half the excess observed in recent years.

Association of perioperative factor XIII activity levels and other haemostatic markers with the risk of postoperative intracranial haematoma in a selected cohort of neurosurgical patients

Coagulation factor XIII and other haemostatic markers are known strengthen fibrin clot formation and, hence, may facilitate safer surgery. Currently however, factor XIII activity levels are not routinely screen. Therefore, the purpose of this study was to determine the association of perioperative factor XIII activity levels and other haemostatic markers with postoperative intracranial haematoma formation in neurosurgical patients. Between January 2008 to Jun 2009, all neurosurgical patients who underwent intracranial surgery were screened for the study. Patients had blood samples taken preoperatively and within 24 h post-surgery for factor XIII and other haemostatic markers. The intracranial surgeries for the patients involved were performed according to their respective indications using standard neurosurgical techniques. Postoperatively, patients had a computed tomography (CT) brain scan, with the imaging results grouped into three classes: significant haematoma (group I), insignificant haematoma (group II) and no haematoma (group III). Of the total 84 enrolled patients, 5 (6%), 28 (33.3%) and 51 (60.7%) patients were assigned to group I, II and III respectively. Significant postoperative haematoma that required re-surgery was related to low postoperative platelet count (p < 0.01), and higher odds ratio of developing postoperative intracranial haematoma were shown with two combination factors: low postoperative factor XIII and platelet levels; and low postoperative factor XIII and antithrombin levels. Low platelet count can cause significant volume postoperative intracranial haematoma and in presence of multiple defects in haemostatic markers appears to be clinically useful to predict the formation of postoperative intracranial haematoma in neurosurgical patients.

Increased fibrinolysis increases bleeding in orthopedic patients receiving prophylactic fondaparinux

We evaluated hemostatic markers in patients who underwent major orthopedic surgery, including total hip and total knee arthroplasty, and were treated for the prophylaxis of deep vein thrombosis (DVT) with or without fondaparinux (anti-Xa group, n = 98 and without anti-Xa group, n = 20). The frequency of DVT was significantly higher in the without anti-Xa group than in the anti-Xa group, but the reduction of hemoglobin and fibrinolytic marker levels was significantly lower in the without anti-Xa group than in the anti-Xa group. Eighteen patients in the anti-Xa group showed a reduction in hemoglobin of more than 2 g/dl, and those individuals were considered to be the increased bleeding (IB) group. The concentration of fibrinolytic markers in the anti-Xa group was significantly higher in the IB group than in the non-IB group. There were also no significant differences in the levels of anti-Xa activity, plasminogen activator inhibitor-I, soluble fibrin and antithrombin between the IB and non-IB groups. In conclusion, elevated fibrinolysis induced by increased bleeding may lead to further increases in bleeding in patients receiving thromboprophylaxis with fondaparinux following major orthopedic surgery.

Evaluation of coagulation and fibrinolytic parameters in adult onset GH deficiency and the effects of GH replacement therapy: A placebo controlled study

ObjectiveIncreased cardiovascular mortality/morbidity observed in patients with hypopituitarism is ascribed to growth hormone deficiency (GHD) because of its unfavorable cardiovascular risk profile. Abnormalities in the coagulation system may also contribute to increased cardiovascular morbidity/mortality. To get a better insight into the role of hemostasis in GHD we assessed several hemostatic markers at baseline and after 6months of GH replacement therapy (GHRT). Design-patientsNineteen patients with adult onset GHD were enrolled (twelve patients into the treatment and seven patients into the placebo group) into the study. Platelet count, collagen/epinephrine closure time, collagen/ADP closure time, fibrinogen, prothrombin time (PT), activated partial thromboplastin time (aPTT), antithrombin III (AT III), protein C activity, protein S activity, lupus anticoagulant, antiphospholipid antibody immunoglobulin M, and antiphospholipid antibody immunoglobulin G were measured at baseline and 6months after treatment. ResultsThe investigated parameters in the groups were similar at baseline except for low protein S (PS) activity. Protein S deficiency was observed in three of the patients in the GH treatment group at baseline, however the PS activity values normalized following GHRT. AT III and protein C activities decreased when compared to baseline values in the treatment group but not in the placebo group. ConclusionsWe observed protein S deficiency more frequent than seen in the general population and normalization of protein S activity and decreases, in other natural anticoagulants following GHRT. Further studies are required to understand the impact of these changes in cardiovascular morbidity and mortality in this patient population.

Hemostatic markers are associated with the risk and prognosis of atrial fibrillation: The ARIC study

Hemostatic markers are associated with the risk and prognosis of atrial fibrillation: The ARIC study

Asymmetric Dimethylarginine Levels are Highly Associated With Atrial Fibrillation in an Elderly Population.

BackgroundThe importance of endothelial dysfunction in atrial fibrillation (AF) is not clarified. The aim of this study was to evaluate endothelial dysfunction assessed by selected inflammatory and haemostatic endothelial markers and nitric oxide (NO) associated variables as related to the presence of AF in an elderly population. NO is known to express anti-thrombotic as well as vasoactive properties.MethodsThis is a cross sectional study of 75-year old subjects with AF (n = 62) and control subjects in sinus rhythm (n = 124), matched for gender. Fasting blood samples were collected for analyses of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO-synthase, L-arginine, E-selectin, vascular cell adhesion molecule-1 (VCAM-1) and von Willebrand factor (vWF).ResultsLevels of vWF and ADMA were significantly higher in AF patients vs controls (P = 0.023 and P < 0.001, respectively) and the L-arginine/ADMA ratios were lower (P = 0.015), the latters still significant after adjustment for relevant covariates (P = 0.007 and P = 0.037, respectively). No significant differences in the levels of VCAM-1 and E-selectin were observed between the groups. When dividing the ADMA levels into quartiles there was a significant trend for having AF with increasing levels of ADMA (P < 0.001) with a cut-off at the 25th percentile (< 0.54 µmol/L), giving an adjusted OR for having AF of 12.46 (95% CI 3.11 - 49.86) (P < 0.001) with higher levels. A similar inverse trend was seen for the L-arginine/ADMA ratio.ConclusionOur population of 75-year-old AF patients had significantly impaired endothelial function assessed by increased levels of vWF, and more pronounced by high levels of ADMA. The results indicate AF in the elderly to be closely associated with the regulatory pathway of NO.

Prospective Evaluation of Hemostatic Abnormalities in Overt DIC Due to Various Underlying Diseases

Abstract 4652 [Introduction]Disseminated intravascular coagulation (DIC) is often found in patients with infections, leukemia, solid tumors, trauma, aneurysms or obstetricdiseases. The causes of DIC associated with leukemia are considered to be an elevated expression of tissue factor, tissue type plasminogen activator or anexin II in leukemic cells. The factors thought to be responsible for DIC associated with sepsis are an elevated inflammatory response, including an increased production of inflammatory cytokines. [Materials and Methods]In this study, 692 patients with suspected DIC were prospectively evaluated for various types of underlying diseases using the DIC diagnostic criteria established by International Society of Thrombosis and Haemostasis (ISTH) and Japanese Ministry Health Labor and Welfare (JMHLW), and the usefulness of hemostatic markers were examined for each patient with DIC due to various underlying diseases. [Results]The main underlying disease of DIC was infectious diseases, hematologic malignancies, and solid tumors, and a high resolution rate from DIC was observed in obstetric diseases and hematologic malignancies. The diagnosis of DIC was related to a poor outcome in trauma/burn victims and those with infectious disease. In the main underlying disease, it is suggested that DIC would be excluded in patients with hematologic malignancies or solid tumors with a platelet count of more than 1×108/ml and in the patients with fibrinogen and fibrin degradation products (FDP) of less than 10 mg/L, and fibrinogen of less than 100 mg/dl, suggesting the presence of DIC. The prothrombin time was a sensitive marker, but fibrinogen levels were not sensitive for DIC due to infectious diseases. The plasmin plasmin inhibitor complex in hematologic malignancy, and soluble fibrin monomer complex, antithrombin and thrombomodulin in patients with infectious disease, were sensitive markers for the diagnosis of DIC. [Discussion and conclusion]Although hemostatic markers were useful for the diagnosis of DIC, the usefulness varied depending on the different underlying diseases. The global coagulation tests are therefore considered to be useful for the diagnosis of DIC, and hemostatic molecular markers are useful for examining the pathophysiology of patients with DIC. Disclosures:No relevant conflicts of interest to declare.

A Recombinant Thrombomodulin Improves Haemostatic Disturbance and Inflammation in Setpic Patients with DIC

Abstract 2293 Background:Recently, a recombinant human soluble thrombomodulin (rTM) has become commercially available for patients with disseminated intravascular coagulation (DIC) in Japan, which is composed of the active, extracellular domain of thrombomodulin. However, its anti-thromobotic and anti-inflammatory effect during the clinical course in patients with DIC has not been reported. Aim: To investigate the effect of rTM on mortality, haemostatic disturbance, and inflammation in septic patients with DIC. Methods: The patients with sepsis who met the Japanese diagnostic criteria for acute DIC and showed a level of antithrombin (AT) lower than 70% were recruited and divided into two groups, one group (Control group) treated with AT products and Gabexate mesilate (GM), and the other group (TM group) treated with rTM (0.06 mg kg(-1) for 30 min, once daily) in addition to AT and GM. The effect of rTM during the clinical course were investigated from the differences between TM and Control groups in mortality, DIC scoring, haemostatic and inflammatory markers on days 0, 3, 5, 7 (day 0 is just before initiation of therapy). Results & Discussion: Eighteen patients were included in the TM group, and 16 patients in the Control group. There were no differences in APACHEII score at day 0, DIC score at day 0, or mortality at day 28 between the groups. The effects of the rTM were as follows; 1) Patients in the TM group showed earlier DIC resolution at day 5 than Control at day 7. 2) Hypercoagulable state expressed by the increased levels of soluble fibrin monomer (SF) or thrombin-antithrombin complex (TAT) was improved more quickly in TM group compared with Control group, suggesting that rTM decreased thrombin generation. 3) AT was increased much more at day 3 after AT product administration in TM group than in Control group, which also can be explained by suppression of thrombin generation by rTM. 4) Increased levels of the complex of α2PI/plasmin, D-dimer, and fibrin/fibrinogen degradation product were also improved earlier in TM group than Control group. 5) Plasmin-alfa2 plasmin inhibitor complex (PIC) was significantly lower at day 7 in TM group than Control group, suggesting anti-fibrinolytic effect of rTM. 6) Decreased level of ADAMTS13 increased more quickly in TM group. 5) TNF-α, IL-6, HMGB1 were decreased significantly at day 3 compared with day 1 only in TM group. These anti-inflammatory effect can be evoked through direct sequestration of HMGB1 by rTM or decreased thrombin generation by rTM, because thrombin is a strong pro-inflammatory molecule through PAR1. Conclusion: rTM may be beneficial in improving septic DIC via its anti-thrombotic and anti-inflammatory properties. Disclosures:No relevant conflicts of interest to declare.