International Society Of Thrombosis And Haemostasis Research Articles

Prediction of survival in patients suspected of disseminated intravascular coagulation.

Although antithrombin (AT), protein C (PC), and antiplasmin (AP) are consumed during disseminated intravascular coagulation (DIC), their association with mortality in patients initially suspected of acute DIC is unknown. We examined how these proteins associate with mortality in consecutive patients initially suspected of DIC, fulfilling or not fulfilling overt DIC criteria. All consecutive patients clinically suspected of acute DIC during 5years at a tertiary referral hospital were scored according to overt International Society of Thrombosis and Haemostasis (ISTH) DIC criteria. The influence of ISTH DIC score and measurements of AT, PC, and AP measured in all on mortality was assessed. During 1825 occurrences in 1814 patients, 91 fulfilled ISTH criteria for overt DIC (score ≥5). Both 28-day and 1-year mortality increased progressively as AT and in particular PC decreased. AT and PC correlated inversely with ISTH score (AT: R(2) =0.14, P<0.001, PC: R(2) =0.21, P<0.001). AP decreased when ISTH score of >3 was reached. The 28-day mortality was 3%, 11%, 16%, 23%, 35%, and 52% and 1-year mortality 5%, 18%, 24%, 36%, 54%, and 63%, respectively for patients with an ISTH score of 0, 1, 2, 3, 4, and ≥5 (P<0.001 for all). Lowered AT and in particular PC activity was predictive of mortality risk upfront in critically ill patients suspected of acute DIC. Mortality in patients suspected of acute DIC increased progressively across the spectrum of the overt ISTH score and not only in those fulfilling overt DIC criteria.

Enhanced expression of cell-specific surface antigens on endothelial microparticles in sepsis-induced disseminated intravascular coagulation.

ABSTRACTSepsis-induced disseminated intravascular coagulation (DIC) is a major cause of death in patients admitted to intensive care units. Endothelial injury with microparticle production is reported in the pathogenesis of sepsis. Endothelial microparticles (EMPs) present several cell-specific surface antigens with different bioactivities, for example, tissue factor (TF), thrombomodulin (TM), and endothelial protein C receptor (EPCR). We investigated associations between these three different surface antigen–positive EMPs and sepsis-induced DIC. This cross-sectional study composed of 24 patients with sepsis and 23 healthy controls was conducted from November 2012 to September 2013. Blood samples were collected from patients within 24 h of diagnosis of severe sepsis and from healthy controls. Numbers of TF-positive EMPs (TF+ EMPs), TM-positive EMPs (TM+ EMPs), and EPCR-positive EMPs (EPCR+ EMPs) were measured by flow cytometry immediately thereafter. Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were assessed in the severe sepsis patients at enrollment. We assessed DIC with the International Society of Thrombosis and Haemostasis (ISTH) overt DIC diagnostic criteria algorithm. Numbers of antigen-positive EMPs were increased significantly in both severe sepsis patients and controls and with the increase in ISTH DIC score. Numbers of TF+ EMPs and EPCR+ EMPs correlated significantly with Sequential Organ Failure Assessment score, and numbers of EPCR+ EMPs correlated significantly with Acute Physiology and Chronic Health Evaluation II score. Numbers of the three antigen-positive EMPs were increased significantly in severe sepsis patients versus those in healthy controls and with the increase of ISTH DIC score, suggesting that the specific bioactivity of each antigen-positive EMP may play a role in the progression of sepsis-induced DIC.

Risk of Arterial and Venous Thrombosis in Patients with “Indeterminate” Lupus Anticoagulant Testing

Background: Laboratory criteria for antiphospholipid antibody syndrome (APS) include lupus anticoagulant (LAC), anti cardiolipin antibodies, and anti-β2 glycoprotein antibodies. International Society of Thrombosis and Hemostasis (ISTH) criteria for the diagnosis of LAC include a positive screening test, positive mixing study, phospholipid dependence and absence of a co-existing factor inhibitor or anti-coagulant drug effect. Patients with test results that fulfill some but not all of the above criteria are considered to have indeterminate LAC. While a positive LAC is an established risk factor for thrombosis, there are limited data about the significance of indeterminate LAC test results.Objective: Our study aimed at determining the prevalence of venous and arterial thrombotic events in patients with indeterminate LAC.Results: We reviewed the clinical course of 500 patients that underwent LAC testing at Cleveland Clinic from 1/11/2008 to 12/28/2010; 346 had indeterminate results. Patients with indeterminate results while on warfarin (n=52) and enoxaparin (n=4) were excluded. Patients treated with heparin at the time of testing (n=50) were included, as heparin in the plasma was neutralized prior to testing. Multivariate logistic regression modeling was performed using XLSTAT software to study the value of various thrombotic risk factors as predictive factors for venous and arterial thrombosis. Associations between categorical variables were tested using the χ2 test or Fisher’s exact test. Differences were considered statistically significant at an alpha level of 0.05.In our final cohort of 281 patients with indeterminate results, there were 110 males (39.1%) and 171 females (60.8%), with a median age of 52.5 yrs. Thrombotic manifestations of patients with indeterminate LAC are summarized in Table 1. There were a total of 170 venous thrombotic events in 119 patients (42.5%). Seventy-nine patients had one or more (≥1) instances of deep vein thrombosis (DVT); 45 patients had pulmonary embolism. There were 17 patients with porto-mesenteric thrombosis and 6 patients with other venous thrombotic events. Forty-five patients had concurrent malignancy (16 %) and 22 (8%) had other prothrombotic risk factors including factor V Leiden (n=14), prothrombin G20210A mutation (n=6), elevated homocysteine (n=1), and protein S deficiency (n=1). On multivariate analysis, a relationship was confirmed between the presence of associated prothrombotic disorders and venous thrombosis (OR = 3.36, 95% CI: 1.31- 8.61, P=0.012) (Table 2).Arterial thrombosis was noted in 63 patients, with stroke, myocardial infarction and acute limb ischemia being most common (Table 1). On multivariate analysis, taking into account atherosclerotic risk factors, co-existing hypertension, hyperlipidemia and smoking history were associated with arterial thrombosis (Table 2).Conclusion: Indeterminate results are common among patients referred for LAC testing. In this retrospective cohort, patients with indeterminate LAC had significant rates of venous and arterial thrombosis. Close observation, analysis of other prothrombotic risk factors, and repeat testing of these individuals at a later date should be considered. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Diagnosis and treatment of disseminated intravascular coagulation (DIC) according to four DIC guidelines.

Disseminated intravascular coagulation (DIC) is categorized into bleeding, organ failure, massive bleeding, and non-symptomatic types according to the sum of vectors for hypercoagulation and hyperfibrinolysis. The British Committee for Standards in Haematology, Japanese Society of Thrombosis and Hemostasis, and the Italian Society for Thrombosis and Haemostasis published separate guidelines for DIC; however, there are several differences between these three sets of guidelines. Therefore, the International Society of Thrombosis and Haemostasis (ISTH) recently harmonized these differences and published the guidance of diagnosis and treatment for DIC. There are three different diagnostic criteria according to the Japanese Ministry Health, Labour and Welfare, ISTH, and Japanese Association of Acute Medicine. The first and second criteria can be used to diagnose the bleeding or massive bleeding types of DIC, while the third criteria cover organ failure and the massive bleeding type of DIC. Treatment of underlying conditions is recommended in three types of DIC, with the exception of massive bleeding. Blood transfusions are recommended in patients with the bleeding and massive bleeding types of DIC. Meanwhile, treatment with heparin is recommended in those with the non-symptomatic type of DIC. The administration of synthetic protease inhibitors and antifibrinolytic therapy is recommended in patients with the bleeding and massive bleeding types of DIC. Furthermore, the administration of natural protease inhibitors is recommended in patients with the organ failure type of DIC, while antifibrinolytic treatment is not. The diagnosis and treatment of DIC should be carried out in accordance with the type of DIC.

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

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

Mild to moderate bleeding: diagnostic and therapeutic paths

We consider mild to moderate bleedings all bleeding events that do not meet the criteria proposed by the International Society of Thrombosis and Haemostasis (ISTH) for the definition of major bleeding. As regards the approach to the bleeding patient, the first step is undoubtedly an accurate collection of clinical history and overall physical examination. Then, the etiological diagnosis of a bleeding disorder uses a series of laboratory investigations, divided into first level tests, which are intended to identify the altered phase of the hemostatic process, and second level ones, i.e. more specific tests used if screening tests are negative or to better characterize the alteration identified by them. For the treatment of a bleeding disorder there are several approaches, all strictly dependent on the etiologic diagnosis of this disorder.

Malignancies and Disseminated Intravascular Coagulation

The article entitled “Predictive Value of Baseline Plasma D-dimers for Chemotherapy- induced Thrombocytopenia in Patients with Stage III Colon Cancer: A Pilot Study” written by Tanriverdi (2013) and published in one of the recent issues of your journal was quite interesting. Here, we would like to emphasize some points. Disseminated intravascular coagulation (DIC) is a well known hemostatic complication of solid tumors. In a retrospective study of 1,117 patients with solid tumors, a clinical and laboratory diagnosis of DIC could be made in 76 (6.8%) (Sallah et al., 2001) Classiclaboratoryfindingsassociated with chronicDIC and solid tumors include thrombocytopenia and circulating fibrindegradation products. Hypofibrinogenemiaalso occurs. Fragmented red blood cells, although reported in patients with DIC, rarely constitute greater than 10% of the red cells. However, in some cases of chronic DIC with elevated D-Dimers but normal coagulation screening assay results, the presence of fragmented red cells may provide supportive evidence. Several scoring system combining clinical and laboratory date have been devised to assist in the diagnosis and determination of prognosis of patients with DIC (overt or non-overt). The International Society of Thrombosis and Haemostasis (ISTH) scoring system uses a combination of risk assessment and simple, widely available coagulation assays [including platelet count, fibrinrelated marker, prolongation of prothrombin time (PT), fibrinogen level] (Taylor et al., 2001). In conclusion, to me, low platelet count and high D-dimer value in the first group compared with the other group may be associated with non- overt DIC. The diagnosis can be supported with fibrinogen,fragmented red blood cells and PT levels.

Pre-analytical issues in the measurement of circulating microparticles: current recommendations and pending questions

Pre-analytical issues in the measurement of circulating microparticles: current recommendations and pending questions

The CDC Hemophilia A Mutation Project (CHAMP) Mutation List: A New Online Resource

Genotyping efforts in hemophilia A (HA) populations in many countries have identified large numbers of unique mutations in the Factor VIII gene (F8). To assist HA researchers conducting genotyping analyses, we have developed a listing of F8 mutations including those listed in existing locus-specific databases as well as those identified in patient populations and reported in the literature. Each mutation was reviewed and uniquely identified using Human Genome Variation Society (HGVS) nomenclature standards for coding DNA and predicted protein changes as well as traditional nomenclature based on the mature, processed protein. Listings also include the associated hemophilia severity classified by International Society of Thrombosis and Haemostasis (ISTH) criteria, associations of the mutations with inhibitors, and reference information. The mutation list currently contains 2,537 unique mutations known to cause HA. HA severity caused by the mutation is available for 2,022 mutations (80%) and information on inhibitors is available for 1,816 mutations (72%). The CDC Hemophilia A Mutation Project (CHAMP) Mutation List is available at http://www.cdc.gov/hemophiliamutations for download and search and will be updated quarterly based on periodic literature reviews and submitted reports.

Identifying Major Hemorrhage with Automated Data: Results of the Veterans Affairs Study to Improve Anticoagulation (VARIA)

IntroductionIdentifying major bleeding is fundamental to assessing the outcomes of anticoagulation therapy. This drives the need for a credible implementation in automated data for the International Society of Thrombosis and Haemostasis (ISTH) definition of major bleeding. Materials and MethodsWe studied 102,395 patients who received 158,511 person-years of warfarin treatment from the Veterans Health Administration (VA) between 10/1/06-9/30/08. We constructed a list of ICD-9-CM codes of “candidate” bleeding events. Each candidate event was identified as a major hemorrhage if it fulfilled one of four criteria: 1) associated with death within 30days; 2) bleeding in a critical anatomic site; 3) associated with a transfusion; or 4) was coded as the event that precipitated or was responsible for the majority of an inpatient hospitalization. ResultsThis definition classified 11,240 (15.8%) of 71, 338 candidate events as major hemorrhage. Typically, events more likely to be severe were retained at higher rates than those less likely to be severe. For example, Diverticula of Colon with Hemorrhage (562.12) and Hematuria (599.7) were retained 46% and 4% of the time, respectively. Major, intracranial, and fatal hemorrhage were identified at rates comparable to those found in randomized clinical trials however, higher than those reported in observational studies: 4.73, 1.29, and 0.41 per 100 patient years, respectively. ConclusionsWe describe here a workable definition for identifying major hemorrhagic events from large automated datasets. This method of identifying major bleeding may have applications for quality measurement, quality improvement, and comparative effectiveness research.

Editorial introductions

Editorial introductions

Evaluation of the Innovance d-Dimer Assay for the Diagnosis of Disseminated Intravascular Coagulopathy in Different Clinical Settings

Disseminated intravascular coagulopathy (DIC) is a serious disease with fatal consequences. We prospectively analyzed Innovance d-dimer immunoturbidimetric assay in 68 patients diagnosed with DIC on the background of malignancy (22), severe infection (20), or multitrauma (26) at a single institution between January 2010 and January 2011. Median age was 61 years (range 20-89). All patients were assessed according to the International Society of Thrombosis and Haemostasis (ISTH) DIC score. Applying a threshold of Innovance d-dimer of 10 mg/L fibrinogen equivalent unit (normal <0.5) was correlated with the highest sensitivity in malignancy (86%) and trauma/surgery (80%) compared to 54% in infection. The specificity remained high at 97% in infection, 81% in trauma and 77% in malignancy with a negative predictive value of 97% in trauma and malignancy, and 88% in infection. Our data suggest that Innovance d-dimer is a useful and simple tool that enhances the ISTH DIC diagnostic criteria. Further studies to confirm these findings are warranted.

Standardization of antiphospholipid antibody assays. Where do we stand?

The laboratory criteria (lupus anticoagulants (LA), and/or anti-cardiolipin (aCL) antibodies and/or anti-β2-glycoprotein I antibodies (aβ2GPI)) that define patients with antiphospholipid syndrome (APS) were set in the Sapporo and Sydney criteria published in 1999 and 2006, respectively, and led to a substantial improvement in the recognition of APS. In addition, guidelines for LA detection were published by the Scientific Standardisation Subcommittee (SSC) of the International Society of Thrombosis and Haemostasis (ISTH) in 2009. However, a number of questions on this respect remain unresolved. Recommendations for the aCL and aβ2GPI assays intended to ameliorate the performance of these solid-phase assays. Despite efforts over the years, standardization has not been reached. This review will focus on methodological issues of the three antiphospholipid antibody (aPL) subtypes that are the subject of debate. The use of an international standard for aPL detection might help solve many of the problems caused by a lack of standardization of these assays.

International guidelines for antithrombotics in cancer patients.

e13062 Background: Venous thromboembolism (VTE), defined as deep-vein thrombosis (DVT) or pulmonary embolism (PE), including those related to indwelling central venous catheter (CVCT), is reported in 15 to 20% of patients with cancer. To date, VTE impact on oncology patients remains elusive and the increased incidence of cancers and of CVC for chemotherapy leads to an increased number of VTE. Methods: Heterogeneity in clinical practices worldwide, and lack of international recommendations led us to establish international guidelines for the management of VTE in cancer patients according to the GRADE methodology. These international guidelines were elaborated under the auspices of the International Society of Thrombosis and Haemostasis (ISTH) following an initiative from the “Groupe Francophone Thrombose et Cancer” (GFTC,www.thrombose-cancer.com) with the collaboration of the Academic Medical Centre (AMC), Amsterdam, The Netherlands, and the methodological support and quality control of the French national cancer institute (INCa). A literature review of the studies published on this topic between 1996 and 2011 was performed. A first version of the guidelines was established based on the corresponding levels of evidence derived from analysis of the selected studies. The recommendations were classified as Strong or Weak according to GRADE and Best Clinical Practices based on international expert’ agreement in the absence of literature data. In the absence of data we provided guidance based on experts opinion. The document was then peer-reviewed by a group of 200 international independent experts. Results: The main topics of the guidelines are the treatment and the prophylaxis of VTE with heparins and vitamin K antagonists in medical and surgical cancer patients, including CVC related thrombosis. Recommendations on the use of vena cava filters, thrombolysis and VTE treatment in patients with intracranial malignancies as well as for prophylaxis in the ambulatory setting are also proposed. Conclusions: These first international guidelines, the methodological steps, the data analysis and critical appraisal, the conclusions with their levels of evidence and the argued judgement of the experts will be available on the GTC, INCa and ISTH web sites

"Indeterminate lupus anticoagulant" as the third category

TO THE EDITOR: Laboratory testing for the detection of lupus anticoagulant (LAC) is important for the diagnosis of antiphospholipid syndromes and hypercoagulable states. LACs are heterogeneous circulating autoantibodies directed against epitopes found on negatively charged phospholipids and proteins associated with the cell membrane and inhibit phospholipid-dependent coagulation tests in vitro. However, is actually prothrombotic agents and cause thrombosis in vivo; therefore, accurate diagnosis is critical for risk assessment and long-term patient management with anticoagulants. To improve the diagnostic sensitivity of testing, the International Society of Thrombosis and Haemostasis (ISTH) published testing guidelines in 1995 [1], and in 2009, it updated guidelines for detection, patient selection, choice of tests, calculation of cut-off value, and interpretation of results [2]. Although mixing studies are simple in principle, interpretation of their results poses a considerable challenge. The 2009 ISTH guidelines recommended using the 99th percentile of the normal values as a cut-off for determining clotting time correction. When the concentrations of are low, the clotting time after mixing can erroneously return to the normal range, and the results may be interpreted as negative. This shows that low concentrations of cannot be detected when the 99th percentile of the normal values is used as a cut-off. Therefore, it is necessary to adopt a more stratified diagnostic strategy for LAC, especially for the clotting-time based test, to reduce the possibility of a false-negative result when the concentration of is low. In this context, separate, third strategy should be introduced for individuals with LAC. The results can be classified as LAC when the outcomes of both screening and the confirmatory test are positive but that of the mixing test is weakly positive. By introducing LAC as a separate category, we can focus on patients who are thought to have a low concentration of LAC. Alkayed and Kottke-Marchant reported that indeterminate results were common, and that the clinical characteristics of these individuals differed from those with negative results [3]. In our laboratory, we classify test results into 3 different categories: positive, negative, and indeterminate. Our data also show that patients with LAC have heterogeneous clinical characteristics, from absence of clinical symptoms to evident deep-vein thrombosis, pulmonary thromboembolism, or recurrent fetal loss. If indeterminate results are ignored, these thrombotic diseases may remain undiagnosed. We think that adding this third category will prove to be a good strategy both practically and clinically. We completely agree with the opinion of Alkayed and Kottke-Marchant.

Prospective comparison of new Japanese Association for Acute Medicine (JAAM) DIC and International Society of Thrombosis and Hemostasis (ISTH) DIC score in critically ill septic patients

IntroductionWe prospectively compared the new Japanese Association for Acute Medicine (JAAM) score with the International Society of Thrombosis and Hemostasis (ISTH) score for diagnosis of disseminated intravascular coagulation (DIC) in septic patients admitted in a general critical care intensive care unit. Material and methodSeptic patients with platelet count of <150×109/L were included. Both DIC scores were estimated from day 1 to day 4 along with APACHE II and SOFA scores. ResultsOut of the 148 blood samples drawn from 42 patients (28 male & 14 female) the JAAM and ISTH DIC scores had an overall significant agreement (k=0.246, p<0.001) in 83 samples. JAAM score had higher diagnostic rates on all four days. Significant (p≤0.001) day wise variation existed in JAAM and ISTH DIC scores. Correlation between JAAM DIC and ISTH DIC scores on day 1 (r=0.631) & day 4 (r=0.609) was significant (p<0.001). Pneumonia was the predominant cause of sepsis. Twenty seven (64.3%) patients died during their stay in ICU. Amongst DIC patients both severity scores (SOFA/APACHE II) and DIC scores (JAAM/ISTH) did not discriminate between survivors and non-survivors. Health care associated infection (p=0.040), high lactate levels (p=0.020) on day 1 and high procalcitonin levels (p=0.036) were found to have significant discriminating ability between survivors and non-survivors. Significantly shorter length of stay was observed amongst non-survivors (p=0.002). ConclusionsIn sepsis the JAAM DIC score identified most of the patients diagnosed by the overt ISTH criteria, but failed to discriminate between survivors and non-survivors amongst DIC patients.

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.

Disseminated intravascular coagulation or acute coagulopathy of trauma shock early after trauma? An observational study

IntroductionIt is debated whether early trauma-induced coagulopathy (TIC) in severely injured patients reflects disseminated intravascular coagulation (DIC) with a fibrinolytic phenotype, acute coagulopathy of trauma shock (ACoTS) or yet other entities. This study investigated the prevalence of overt DIC and ACoTS in trauma patients and characterized these conditions based on their biomarker profiles.MethodsAn observational study was carried out at a single Level I Trauma Center. Eighty adult trauma patients (≥18 years) who met criteria for full trauma team activation and had an arterial cannula inserted were included. Blood was sampled a median of 68 minutes (IQR 48 to 88) post-injury. Data on demography, biochemistry, injury severity score (ISS) and mortality were recorded. Plasma/serum was analyzed for biomarkers reflecting tissue/endothelial cell/glycocalyx damage (histone-complexed DNA fragments, Annexin V, thrombomodulin, syndecan-1), coagulation activation/inhibition (prothrombinfragment 1+2, thrombin/antithrombin-complexes, antithrombin, protein C, activated protein C, endothelial protein C receptor, protein S, tissue factor pathway inhibitor, vWF), factor consumption (fibrinogen, FXIII), fibrinolysis (D-dimer, tissue-type plasminogen activator, plasminogen activator inhibitor-1) and inflammation (interleukin (IL)-6, terminal complement complex (sC5b-9)). Comparison of patients stratified according to the presence or absence of overt DIC (International Society of Thrombosis and Hemostasis (ISTH) criteria) or ACoTS (activated partial thromboplastin time (APTT) and/or international normalized ratio (INR) above normal reference).ResultsNo patients had overt DIC whereas 15% had ACoTS. ACoTS patients had higher ISS, transfusion requirements and mortality (all P < 0.01) and a biomarker profile suggestive of enhanced tissue, endothelial cell and glycocalyx damage and consumption coagulopathy with low protein C, antithrombin, fibrinogen and FXIII levels, hyperfibrinolysis and inflammation (all P < 0.05). Importantly, in non-ACoTS patients, apart from APTT/INR, higher ISS correlated with biomarkers of enhanced tissue, endothelial cell and glycocalyx damage, protein C activation, coagulation factor consumption, hyperfibrinolysis and inflammation, that is, resembling that observed in patients with ACoTS.ConclusionsACoTS and non-ACoTS may represent a continuum of coagulopathy reflecting a progressive early evolutionarily adapted hemostatic response to the trauma hit and both are parts of TIC whereas DIC does not appear to be part of this early response.

Enhanced thrombin formation and fibrinolysis during acute Puumala hantavirus infection

IntroductionNephropathia epidemica (NE) is a viral hemorrhagic fever with renal syndrome associated with thrombocytopenia and mild bleeding. We assessed activation of coagulation and fibrinolysis during the acute phase of NE. Materials and methods19 hospital-treated patients were involved. Plasma levels of D-dimer, prothrombin fragments 1+2 (F1+2), activated partial thromboplastin time (APTT), prothrombin time (PT%), thrombin time (TT), fibrinogen, antithrombin (AT), protein S free antigen (PS), protein C (PC) and complete blood count (CBC) were measured three times during the acute phase and once at 32-54days after the onset of fever (recovery phase). Laboratory abnormalities were evaluated by the disseminated intravascular coagulation (DIC) scoring advocated by the International Society of Thrombosis and Haemostasis (ISTH). ResultsAPTT was prolonged and D-dimer and F1+2 increased during the acute phase of NE. AT, PC and PS decreased, and TT was shortened, all implying increased thrombin generation. Acutely F1+2 was 3.4-fold and D-dimer even 24-fold higher compared with the recovery phase (median 726 vs 213pmol/l, and median 4.8 vs 0.2mg/l, respectively, p<0.001 for both). Platelet count correlated with AT, PC, and PS (r=0.73, r=0.81, and r=0.71, respectively, p<0.001 for all) as well as with fibrinogen (r=0.72, p<0.001). Only five patients fulfilled the ISTH diagnosis of DIC. ConclusionsDuring acute NE thrombocytopenia was associated with decreased natural anticoagulants, shortened thrombin time and enhanced fibrinolysis. Augmented thrombin formation and fibrinolysis characterize this hantavirus infection.

Evaluation of Non Overt DIC Diagnostic Criteria.

Abstract 1297Poster Board I-319 IntroductionSeveral diagnostic criteria for disseminated intravascular coagulation (DIC) have been proposed by Colman RW et al, Japanese Ministry Health and Welfare (JMHW) and International Society of Thrombosis and Haemostasis (ISTH) etc. The efficacy of treatment in relation to the DIC score when the treatment was begun showed that greater efficacy was achieved in pre-DIC than in DIC patients, suggesting that early diagnosis and early treatment are important. Then, the diagnostic criteria for non-overt DIC was proposed by ISTH/SSC subcommittee in order to diagnose of early phase DIC but it was still not established. In this study, modified non-overt DIC diagnostic criteria using molecular hemostatic markers and antithrombin (AT) has been prospectively evaluated.Total 613 patients suspected to be associated with DIC in nine institutes were registered in this prospective study for DIC diagnostic criteria from January 1, 2005 to December 31, 2008. There were 219 patients with infectious disease, 142 with solid cancer, 115 with hematopoietic tumor, 29 with aneurysm, 10 with obstetrics disease, 23 with trauma, 5 with liver disease, 70 with other disease. Materials and MethodsOvert-DIC or non-overt DIC was diagnosed by modified overt-DIC diagnostic criteria or modified non-overt DIC diagnostic criteria using abnormalities or changes of platelet count, prothrombin time (PT), fibrinogen, fibrin and fibrinogen degradation products (FDP), AT, soluble fibrin monomer complex (SFMC), D-dimer and thrombin-AT complex (TAT). Pre-DIC was considered the state within a week before onset of DIC. Measurement of PT, fibrinogen, platelet count, FDP were carried out in each institutes based on numerous previous reports. TAT, SFMC, D-dimer and AT activity were measured in SRL Inc. TAT was measured by enzyme immunoassay (EIA) using. SFMC and D-dimer were measured by latex immune agglutination test using T-test, respectively. AT activity was measured by heparin cofactor activity. ResultsFrequency of overt-DIC was 29.5 % in 613 patients suspected to be associated with DIC, and the highest frequency of overt-DIC was observed in the patients with obstetrics disease or liver disease. Pre-DIC state was detected in 44 of 613 patients (7.2 %) and the highest frequency of pre-DIC was observed in the patients with hematopoetic tumor (12.2 %). Frequency of non-overt DIC in the patients with overt-DIC, with pre-DIC or without overt-DIC was 97.8 %, 97.7 % or 17.0%, respectively. The mortality of 28 days was the highest in the patients with overt DIC (37.6%), and it was also high in those with non-overt DIC (32.9%) and with pre-DIC (27.3%) in comparison to the patients without overt DIC (15.2%) and those without non-overt DIC (13.8%). DiscussionModified non-overt DIC diagnostic criteria is more sensitive for DIC than overt DIC diagnostic criteria and is related to the outcome. Non overt DIC diagnostic criteria might be able not only to diagnose DIC but also to predict early phase of DIC. DisclosuresNo relevant conflicts of interest to declare.