Non-overt Disseminated Intravascular Coagulation Research Articles

Diagnostic Criteria and Laboratory Tests for Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is associated with organ failure and it is often fatal condition. The main underlying diseases are infection, hematological malignancy and solid cancer. DIC is subclassified into overt DIC and non-overt DIC. The International Society on Thrombosis and Haemostasis (ISTH) and the Japanese Association for Acute Medicine (JAAM) published the diagnostic criteria for DIC after several recent clinical trials. These diagnostic criteria are modified versions of the Japanese Ministry of Health, Labor and Welfare (JMHLW) criteria. The JAAM diagnostic criteria demonstrated excellent sensitivity for mortality but low specificity. The mechanisms of onset of DIC vary based on the underlying diseases, and depend on tissue factor, cytokines, etc. Early diagnosis and early treatment for DIC are important, and the use of hemostatic molecular markers is necessary to successfully make an early and rapid diagnosis. The mortality of DIC might be improved by the administration of recombinant activated protein C or recombinant thrombomodulin. Further investigation to improve the mortality of DIC is required, including new methods for diagnosing and treating the disease.

Thrombomodulin phenotype of a distinct monocyte subtype is an independent prognostic marker for disseminated intravascular coagulation

IntroductionThrombomodulin, which is expressed solely on monocytes, along with tissue factor (TF), takes part in coagulation and inflammation. Circulating blood monocytes can be divided into 3 major subtypes on the basis of their receptor phenotype: classical (CD14brightCD16negative, CMs), inflammatory (CD14brightCD16positive; IMs), and dendritic cell-like (CD14dimCD16positive DMs). Monocyte subtype is strongly regulated, and the balance may influence the clinical outcomes of disseminated intravascular coagulation (DIC). Therefore, we investigated the phenotypic difference in thrombomodulin and TF expression between different monocyte subtypes in coagulopathy severity and prognosis in patients suspected of having DIC.MethodsIn total, 98 patients suspected of having DIC were enrolled. The subtypes of circulating monocytes were identified using CD14 and CD16 and the thrombomodulin and TF expression in each subtype, expressed as mean fluorescence intensity, was measured by flow cytometry. Plasma level of tissue factor was measured by ELISA. In cultures of microbead-selected, CD14-positive peripheral monocytes, lipopolysaccharide (LPS)- or interleukin-10-induced expression profiles were analyzed, using flow cytometry.ResultsThe proportion of monocyte subtypes did not significantly differ between the overt and non-overt DIC groups. The IM thrombomodulin expression level was prominent in the overt DIC group and was well correlated with other coagulation markers. Of note, IM thrombomodulin expression was found to be an independent prognostic marker in multivariate Cox regression analysis. In addition, in vitro culture of peripheral monocytes showed that LPS stimulation upregulated thrombomodulin expression and TF expression in distinct populations of monocytes.ConclusionsThese findings suggest that the IM thrombomodulin phenotype is a potential independent prognostic marker for DIC, and that thrombomodulin-induced upregulation of monocytes is a vestige of the physiological defense mechanism against hypercoagulopathy.

Modified non‐overt DIC diagnostic criteria predict the early phase of overt‐DIC

Diagnostic criteria for non-overt disseminated intravascular coagulation (DIC) have been proposed by the International Society of Thrombosis and Hemostasis, but are not useful for the diagnosis of early phase of overt-DIC (pre-DIC). Therefore, in the current study the non-overt DIC diagnostic criteria were modified using the global coagulation tests, the change rate in the global coagulation tests and molecular hemostatic markers to detect the pre-DIC state and were prospectively evaluated in 613 patients with underlying DIC disease. The frequencies of patients with DIC (DIC positive), late onset DIC, and without DIC (DIC absent) were 29.5%, 7.2%, and 63.3%, respectively. The modified non-overt-DIC criteria can correctly predict 43/44 patients (97.7%) who were DIC absent at admission and became DIC positive, within a week (late onset DIC state). The mortality rate was higher in DIC positive compared with pre-DIC (37.6% vs. 22.7%, P < 0.05) or DIC negative (37.6 vs. 13.7%, P < 0.01). It was also significantly higher in pre-DIC compared with DIC negative (P < 0.05). Thus, these modified non-overt DIC diagnostic criteria might therefore be useful for the diagnosis of early-phase DIC.

Purified thromboplastin causes haemostatic abnormalities but not overt DIC in an experimental rabbit model

Validation of animal models of disseminated intravascular coagulation (DIC) to human DIC is crucial in order to translate findings in research models to treatment modalities for DIC in humans. ISTH classifications of overt and non-overt human DIC have proven to have a high diagnostic accuracy, and we have previously established a rabbit model of non-overt DIC based on the ISTH classification of non-overt DIC. In this rabbit model, we used purified rabbit brain thromboplastin to induce DIC and test applicability of ISTH classifications of overt human DIC. Cardiovascular and haematological parameters from rabbits, either saline-injected or administered a 2.5 mg thromboplastin/kg bolus and a 15 minutes 1.25 mg thromboplastin/kg infusion, were determined at four time points over a 90 minute period. All groups of rabbits were scored at each time point according to the ISTH classifications of overt DIC. Despite the fact that injection of purified thromboplastin resulted in decreased platelet count, increased prothrombin time, activated partial thromboplastin time, level of thrombin-antithrombin complexes and fibrin degradation products, and pulmonary micro-thrombosis, none of the rabbits were diagnosed as having overt DIC according to ISTH classification. We conclude that purified thromboplastin causes haemostatic abnormalities in the rabbit but this experimental model was not diagnosed as overt DIC.

A Novel Thromboelastographic Score to Identify Overt Disseminated Intravascular Coagulation Resulting in a Hypocoagulable State

Thromboelastography (TEM) yields a multitude of data that are complicated to analyze. We evaluated its value in identification of global coagulopathy in overt disseminated intravascular coagulation (DIC). We studied 21 patients, each with International Society for Haemostasis and Thrombosis scores of 5 or more (compatible with overt DIC) and less than 5 (suggestive of nonovert DIC), who underwent whole blood nonadditive TEM. A TEM score based on the reaction and kappa times, alpha angle, and maximum amplitude was defined as the total number of TEM parameters deranged in the direction of hypocoagulability. The TEM score at a cutoff of 2 or more achieved sensitivity of 95.2%, specificity of 81.0%, and the highest receiver operating characteristic area under the curve of all parameters of 0.957 for identifying overt DIC. Individual TEM parameters correlated variably with conventional tests. Their combination into a cohesive TEM score possibly better captured the multiple hemostatic derangements occurring in DIC. The TEM score may bring objectivity to the analysis of TEM data.

Limited Utility of a Rapid Quantitative Enzyme-Linked Fluorescent Assay for the D-Dimer in the Diagnosis of Overt Disseminated Intravascular Coagulation

The role of quantitative D-dimer assay in screening for and diagnosing overt disseminated intravascular coagulation (DIC), conventionally diagnosed by the International Society of Thrombosis and Haemostasis' (ISTH) score, was evaluated. Of patients with clinical conditions associated with overt DIC, 142 with ISTH scores ≥5 (compatible with overt DIC) and 61 with ISTH scores <5 (suggestive of nonovert DIC) underwent the quantitative D-dimer assay. Accuracy indices, receiver operating characteristic (ROC) curve-derived cutoffs, and areas under curve were compared. Mean D-dimer level in overt DIC was 4147.2 ± 2707 ng/mL. In nonovert DIC, it was 1678.9 ± 1888.3 ng/mL. Both were higher than healthy controls (229.6 ± 129.9 ng/mL). An optimized cutoff (2040 ng/mL) had relatively low sensitivity (75.4%) and specificity (73.8%). Extensive overlap between groups at this cutoff reduced diagnostic utility. Lowered cutoffs increased sensitivity (eg, 91.5% at 1000 ng/mL) but diminished specificity (59%), limiting use of screening. In conclusion, the quantitative D-dimer as a stand-alone assay has a limited role in diagnosis of overt DIC.

Evaluation of modified non-overt DIC criteria on the prediction of poor outcome in patients with sepsis

Background The diagnostic performance of modified criteria for non-overt disseminated intravascular coagulation (DIC) with the addition of antithrombin (AT) levels, protein C (PC) levels, and organ system failure scoring (OSF) to the International Society on Thrombosis and Hemostasis (ISTH) criteria for non-overt DIC was studied to determine the effect on predicting poor outcome in patients with sepsis. Methods In total, 135 consecutive patients were studied. Hemostatic markers (platelet count, prothrombin time, D-dimer, AT, PC) were examined on days 0, 1, 2, 3, 4, and 7. ISTH overt and non-overt DIC scoring, OSF, and 28-day mortality were analyzed. Results The numbers of patients with overt DIC, non-overt DIC and non-DIC were 42, 17 and 76 respectively. The 28-day mortality rates for ISTH overt DIC, ISTH non-overt DIC, and non-DIC were 47.6, 47.1, and 9.2%, respectively. By adding AT and PC to the ISTH non-overt DIC criteria, the 28-day mortality rate of overt DIC, non-overt DIC, and non-DIC changed to 47.6, 25.0, and 6.7%, respectively. By adding OSF to the ISTH non-overt DIC criteria to predict 28-day mortality in septic patients, receiver operating characteristic (ROC) curve analysis demonstrated that the area under the curve (AUC) of ISTH non-overt DIC (0.777) was significantly increased to 0.878 ( P = 0.018). However, neither AT nor PC increased the AUC. Conclusions Addition of OSF to the ISTH criteria for non-overt DIC gives a better prediction of poor outcome in patients with sepsis.

Diagnosis of non-overt disseminated intravascular coagulation made according to the International Society on Thrombosis and Hemostasis criteria with some modifications

BackgroundAn early diagnosis of disseminated intravascular coagulation (DIC) before its progression to an overt stage is necessary for early treatment and positive outcomes. In 2001, the Scientific and Standardization Committee (SCC) of the International Society on Thrombosis and Hemostasis (ISTH) proposed new criteria for the preclinical diagnosis of overt and non-overt DICs. We investigated the clinical usefulness of the modified ISTH criteria for non-overt DIC diagnosis.MethodsWe enrolled 296 DIC patients (170 males and 126 females) admitted and evaluated at the Gangnam Severance Hospital, Seoul, Korea, between March 2006 and April 2007. Hemostatic tests, including platelet counts, prothrombin time (PT), D-dimer levels with antithrombin, and protein-C levels, were evaluated by excluding negative scores with clinical signs, in which more than 5 points of interest denoted non-overt DIC. Mortality rates were also evaluated.ResultsThere were 289 patients with increased D-dimer levels and significant parametric changes suggesting DIC progression. Protein C and antithrombin levels were lower (99.2% each) and appeared earlier in patients with non-overt DIC than in patients with overt DIC. In all, 125 (43.3%) patients had non-overt DIC and, of which 27 died (mortality rate, 21.6%). The sensitivity and specificity for mortality were 73.0% and 55.9%, respectively, which were same as those for the original ISTH criteria.ConclusionThe modified ISTH criteria can be used for the early detection of non-overt DIC, and may be useful for the improvement of outcomes of non-overt DIC patients.

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.

Tissue Factor Pathway Inhibitor and P-Selectin as Markers of Sepsis-Induced Non-overt Disseminated Intravascular Coagulopathy

Inflammation and coagulation occur concomitantly in sepsis. Thrombin activates platelet that leads to P-selectin translocation, which upregulate tissue factor (TF) generation. Tissue factor pathway inhibitor (TFPI) is an anticoagulant that modulates coagulation induced by TF. The term non-overt disseminated intravascular coagulation (DIC) refers to a state of affairs prevalent before the occurrence of overt DIC. It was suggested that an initiation of treatment in non-overt DIC has better outcome than overt DIC. This study investigated the role of TFPI level, P-selectin, and thrombin activation markers in non-overt and overt DIC induced by sepsis and its relationship to outcome and organ dysfunction as measured by the Sequential Organ Failure Assessment (SOFA) score. It included 176 patients with sepsis. They were admitted to the pediatric intensive care unit (ICU).They included 144 cases of non-overt DIC and 32 cases of overt DIC. There was a significant difference in hemostatic markers, platelet count, partial thromboplastin time (PTT), P-selectin, thrombin activation markers, TFPI, and DIC score between overt and non-overt DIC in both groups. It was noticed that P-selectin was positively correlated with DIC score, fibrinogen consumption, fibrinolysis (D-dimer), thrombin activation markers, and TFPI. Tissue factor pathway inhibitor was significantly correlated with fibrinolysis, DIC score, and prothrombin fragment 1+2. Sequential Organ Failure Assessment score was correlated with DIC score and other hemostatic markers in patients with overt DIC. To improve the outcome of patients with DIC, there is a need to establish more diagnostic criteria for non-overt-DIC. Plasma levels of TFPI and P-selectin may be helpful in this respect.

Implementation of the ISTH classification of non-overt DIC in a thromboplastin induced rabbit model

Validation of animal models of disseminated intravascular coagulation (DIC) to human DIC is crucial in order to translate findings in research models to treatment modalities for DIC in humans. ISTH classifications of overt and non-overt human DIC have proven to have a high diagnostic accuracy, but the scoring systems have rarely been applied to animal models of DIC. In this study, we use rabbit brain thromboplastin (thromboplastin) to induce DIC in a rabbit model and test the applicability of the ISTH criteria for standardized diagnosis of DIC. Cardiovascular and haematological parameters from rabbits, either saline-injected or administered 0.625, 1.25, 2.5 or 5 mg thromboplastin/kg as a single bolus, were collected at four timepoints over a 90 minute period. All groups of rabbits were scored at each time point according to the ISTH diagnostic criteria for non-overt DIC. Injection of 5 mg thromboplastin/kg was lethal. For the remaining groups, a dose dependent decrease in blood pressure, platelet count and fibrinogen level together with a dose dependent increase in prothrombin time, activated partial thromboplastin time, level of thrombin-antithrombin complexes, fibrin degradation products and number of thrombi in lung vasculature was seen. The administration of a bolus of 1.25 - 2.5 mg thromboplastin/kg to rabbits induced a reproducible dose dependent model of non-overt DIC according to the ISTH diagnostic criteria. We conclude that the non-overt ISTH score can be applied to evaluate severity and progression of DIC in a standardized manner in this thromboplastin induced rabbit model.

Non-overt disseminated intravascular coagulation scoring for critically ill patients: The impact of antithrombin levels

Validation of a scoring algorithm for non-overt disseminated intravascular coagulation (DIC) proposed by the International Society on Thrombosis and Haemostasis (ISTH) is still incomplete. It was the objective of this study to assess the impact of including AT to non-overt DIC scoring on the predictability for intensive care unit (ICU) death and the later development of overt-DIC defined by the Japanese Ministry of Health and Welfare (JMHW) or the ISTH. We performed a retrospective observational study conducted in 364 patients in critical care. Coagulation parameters obtained daily for DIC screening were utilised for scoring. There were 194 and 196 patients scored as positive non-overt DIC with and without AT, respectively; diagnostic agreement between the two was 78%. As compared with patients without non-overt DIC, these non-overt DIC patients had significantly higher mortality. In 37 ICU non-survivors, positive non-overt DIC scoring with AT preceded ICU death by a median of 6.8 days, which was significantly earlier as compared with a median of 5.4 days for non-overt DIC without AT (p = 0.022). In patients who developed overt-DIC after admission, the time period from positive non-overt DIC to positive overt-DIC was significantly longer when AT was utilised (overt-DIC ISTH; 1.3 days vs. 0.1 days, p = 0.004, overt-DIC JMHW; 2.5 days vs. 2.0 days, p = 0.04, with AT vs. without AT, respectively). Non-overt DIC scoring predicted a high risk of death in critically ill patients. When information on AT levels was included, non-overt DIC scoring was found to predict development of overt-DIC significantly earlier than non-overt DIC scoring without AT.

Clinical Usefulness of Plasma Interleukin-6 and Interleukin-10 in Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is a syndrome characterized by a systemic activation of coagulation leading to the intravascular deposition of fibrin and the simultaneous consumption of coagulation factors and platelets. Inflammatory cytokines can activate the coagulation system. This study investigated the diagnostic and prognostic usefulness of the plasma level of interleukin-6 (IL-6) and interleukin-10 (IL-10) for predicting DIC. The study populations were 15 healthy controls and 81 patients who were clinically suspected of having DIC and were requested to perform DIC battery tests. The presence of overt DIC was defined by the International Society on Thrombosis and Haemostasis Subcommittee cumulative score of 5 or above. The 28 day mortality was used to assess the prognostic outcome. The plasma levels of the cytokines were measured by ELISA. The plasma levels of IL-6 and IL-10 in patients (N=81) were higher than those of control (N=15). IL-6 and IL-10 levels of overt DIC group (N=31) were 3 times and 1.5 times higher than those, respectively, of non-overt DIC group (N=50). In infection group (N=48), IL-6 and IL-10 levels of overt DIC group (N=18) were 5 times and 3 times higher than those, respectively, of non-overt DIC group (N=30). The diagnostic efficiency of IL-6 (optimal cut off >40.4 pg/mL) and IL-10 (>9.7 pg/mL) for the diagnosis of overt DIC were 67% and 69%, respectively, which were similar to that of D-dimer. Plasma levels of IL-6 and IL-10 were also higher in non-survivors than in survivors. The patients with higher levels of IL-6 and IL-10 showed a poorer prognosis. The proinflammatory cytokine, IL-6 and anti-inflammatory cytokine, IL-10 were useful for the diagnosis of overt DIC and the prediction of its prognosis. These results also showed the evidence of a close interaction between coagulation and inflammation.

A Prospective Comparative Study of Three Sets of Criteria for Disseminated Intravascular Coagulation: ISTH Criteria vs Japanese Criteria

Clinical and laboratory criteria and a scoring system for disseminated intravascular coagulation (DIC) were recently published by the International Society on Thrombosis and Haemostasis (ISTH). In Japan, the DIC Diagnostic Standards published in 1988 have been widely used for more than 10 years. In a general intensive care unit, we prospectively compared the diagnostic properties of the overt DIC, nonovert DIC, and Japanese DIC criteria sets, and investigated the influences of each set on patient morbidity and mortality. Seventy-four patients with platelet counts below 150 x 10(9)/L were included in this study. Blood samples were collected daily from day 0 to day 4 after inclusion in the study. The Japanese DIC included the overt DIC and both of these were included in the nonovert DIC. The Japanese DIC criteria diagnosed DIC earlier than the nonovert DIC criteria did (P = .020). The DIC patients diagnosed by the Japanese criteria and those diagnosed by the overt DIC criteria showed a higher incidence of multiple organ failure than those without DIC (P = .013 and P = .022, respectively). The Japanese and the nonovert DIC criteria tended to predict patient prognoses effectively. In conclusion, the Japanese and the nonovert DIC criteria are of value in predicting outcome. However, the nonovert DIC criteria take more time to diagnose DIC than the Japanese criteria do. A more precise clinical study is needed to determined appropriate specific criteria and cutoff points in the nonovert DIC criteria set.

Plasma Factor XIII Activity in Patients with Disseminated Intravascular Coagulation

The objective of this study was to investigate the correlation between factor XIII (FXIII) activity and disseminated intravascular coagulation (DIC) parameters and also to evaluate the clinical usefulness of DIC diagnosis. Citrated plasma from eighty patients with potential DIC was analyzed for FXIII activity. The primary patient conditions (48 male and 32 female, mean age, 51 years) were malignancy (n = 29), infection (n = 25), inflammation (n = 6), heart disease (n = 3), thrombosis (n = 2), injury (n = 2), and other miscellaneous conditions (n = 13). FXIII testing was performed using the CoaLinkTM FXIII Incorporation Assay Kit (PeopleBio Inc.). Among 80 patients who were suspected to have DIC based on clinical analysis, 46 (57.5%) fulfilled the overt DIC criteria (DIC score > = 5) according to the International Society of Thrombosis and Haemostasis. FXIII levels in the plasma were significantly decreased in overt DIC compared to non-overt DIC patients (mean 75.1% and 199.7% respectively, p < 0.0001). Interestingly, we found a significant inverse correlation between DIC scores and FXIII activity. In addition, FXIII activity significantly correlated with other hemostatic markers that included platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen, and D-dimer. FXIII levels were significantly lower in patients with liver or renal dysfunction. In conclusion, FXIII cross-linking activity measurements may have differential diagnostic value as well as predictive value in patients who are suspected to have DIC.

Performance and prognostic importance of a new clinical and laboratory scoring system for identifying non-overt disseminated intravascular coagulation

A template for diagnosing the non-overt phase of disseminated intravascular coagulation (DIC) has recently been proposed. However, validation of its performance and the proposal of a defining score are required. The aim was to assess feasibility of the non-overt DIC scoring template and its potential prognostic significance. Consecutive patients admitted to a university hospital intensive care unit were initially assessed over 2 months. Following this, a 12-month study examined the prognostic performance of the derived scores prospectively. Outcome parameters were overt DIC and 28-day mortality. The 2-month study, involving 66 patients and 919 time points, demonstrated practical feasibility and prognostic associations for mortality with scores of 5 and greater. The 12-month study involving 450 patients showed that the mortality rate was 29% (105 of 360) and 78% (70 of 90) for scores below 5 and scores of 5 or above, respectively. The mortality rate for overt DIC was also 78% (38 of 49). The non-overt DIC scoring template is workable and has prognostic relevance. A score of 5 and greater is recommended as diagnostic of non-overt DIC.

Increased soluble fibrin in plasma of patients with disseminated intravascular coagulation.

Plasma levels of soluble fibrin (SF) were measured in 1184 patients with disseminated intravascular coagulation (DIC) according to Japanese Ministry of Health and Welfare (JMHW) criteria. The usefulness of SF for the diagnosis of DIC was compared with other hemostatic molecular markers. Most hemostatic markers were significantly increased in patients with DIC than in those without DIC. Plasma levels of fibrin and fibrinogen degradation products, thrombin-antihtrombin complex, plasmin-plasmin inhibitor complex, D-dimer, thrombomodulin, and SF levels were also significantly higher in those with pre-DIC than in those without DIC. In classification of overt DIC by International Society of Thrombosis and Haemostasis (ISTH) criteria, most hemostatic markers were significantly increased in patients with overt DIC than in those without overt DIC. Plasma levels of SF 'in patients with DIC were significantly higher than those in patients with pre-DIC, which were significantly higher than in those without DIC. Plasma levels of SF were also significantly higher in patients with overt DIC than in those with non-overt DIC. The correlation between plasma SF levels and DIC score according to JMHW criteria or ISTH criteria was good. Receiver operating characteristic analysis shows that SF was the best marker for the diagnosis of DIC or overt DIC. These findings suggest that plasma SF might be useful marker for the diagnosis of DIC or overt DIC.

Non-overt disseminated intravascular coagulation in patients during treatment with antithymocyte globulin for unrelated allogeneic hematopoietic stem cell transplantation.

We assessed the effect of rabbit antithymocyte globulin manufactured by Fresenius (ATG-F) on the hemostatic system in patients (n=12) with various hematological malignancies undergoing hematopoietic stem cell transplantation (HSCT) from HLA-matched unrelated donors. For this purpose, we monitored different parameters of coagulation before, during and after the administration of ATG-F. As a control group, we recruited patients (n=10) undergoing HSCT from their HLA-identical siblings who did not receive ATG-F as part of their preparative regimens. At 24 and 48 h after ATG-F treatment had been initiated, we found a temporary rise in D-Dimer, tissue factor, soluble thrombomodulin and thrombin-antithrombin III complex levels and a significant decrease of platelet counts in patients treated with ATG-F as compared to the control group. No differences between the two groups could be detected with regard to global coagulation tests as well as the incidence of bleeding manifestations, thromboembolic complications or the development of vascular-occlusive-disease of the liver. This temporary state of a stressed but compensated coagulation system under ATG-F therapy can be addressed as nonovert disseminated intravascular coagulation (DIC). The effect was independent from the different conditioning regimens and eased off after cessation of ATG-F. We conclude that ATG-F can induce nonovert DIC in patients receiving antithymocyte globulin as part of their conditioning regimen for HSCT.

Consumption of plasma factor VII in a rabbit model of non-overt disseminated intravascular coagulation

Introduction: We have recently described an experimental animal model of non-overt disseminated intravascular coagulation (DIC) in the rabbit in which the induction of tissue factor (TF) mRNA and TF antigen expression in peripheral blood leukocytes (PBL) was demonstrated to occur within 2 h of administration of low-dose endotoxin [Hematol. J. 2 (2001) 188]. In the present study, we demonstrate that the leukocyte TF expressed has procoagulant activity leading to a rapid decline in the concentration of factor VII (FVII) in rabbit plasma. Methods: Total plasma FVII antigen and FVIIa were quantitated by rabbit FVII-specific immunoassay and FVIIa-specific clotting assays, respectively. Plasma samples from either saline-injected rabbits or rabbits administered a single bolus of 10 μg/kg Salmonella lipopolysaccharide were compared over a 24-h period. Results: Total plasma FVII antigen decreased progressively post-endotoxin injection, reaching 71% of the baseline concentration at 8 h ( p<0.001, n=18), and remained low (78%) at 24 h post-injection ( p<0.01, n=16), returning to normal by 48 h. Plasma FVIIa levels increased to 120% within 2 h of endotoxin injection, fell to 73% of the baseline concentration at 8 h ( p<0.05, n=18) and returned to normal by 24 h post-endotoxin administration. Procoagulant activity of rabbit peripheral blood leukocytes was enhanced at 2 h ( p<0.01, n=6) and 4 h ( p<0.05, n=6) post-endotoxin injection. The prothrombin time (PT) was increased by <3 s, and thrombin–antithrombin (TAT) complex formation was not significantly increased in the plasma of endotoxin-treated rabbits. No significant changes in total plasma FVII antigen, FVIIa or leukocyte procoagulant activity were observed in rabbits treated with saline. Conclusions: We conclude that the activation of FVII to FVIIa and rapid consumption of total FVII/FVIIa occur very early and likely are integral events linked to the initiation and propagation of non-overt DIC induced by endotoxin.

Comparison of the Responses of Global Tests of Coagulation with Molecular Markers of Neutrophil, Endothelial, and Hemostatic System Perturbation in the Baboon Model of E. coli Sepsis

This study correlates changes in neutrophilic activity and endothelial injury with markers of hemostatic activity following the infusion of increasing concentrations of E. coli organisms. It focuses on the hemostatic response as a marker of microvascular injury and uses the response to increasing concentrations of E. coli to refine our definition of disseminated intravascular coagulation (DIC) and distinguish between a compensated (non-overt DIC) and uncompensated (overt DIC) response. We observed that the global coagulation tests reflected activation of the hemostatic system in a dose dependent manner (overt DIC) in the early phases (T+2 to 6 h) of the response to increasing concentrations of E. coli, but that they failed to do so in the late phases (T+ 24 to 48 h). We observed that molecular markers, soluble thrombomodulin and elastase, unlike thrombin/antithrombin and plasmin/antiplasmin complexes, remained elevated out to T+24 to 48 h indicating endothelial injury that persists beyond the initial inflammatory insult in compensated as well as uncompensated DIC.