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The contact system activation can play a role in microthrombus formation of disseminated intravascular coagulation (DIC). This study investigated whether the activity of prekallikrein and high-molecular-weight kininogen (HMWK) correlated DIC progression. Contact system factors (prekallikrein, HMWK, activated factor XII), coagulation factors (IX, XI, XII) and tissue factor were measured in 140 patients who clinically suspected of having DIC. Prekallikrein and HMWK activity levels showed significant linear relationships with DIC score and antithrombin level, whereas prekallikrein and HMWK antigen levels did not. The activated factor XII, factor XII, factor XI and tissue factor were significant risk factors of overt-DIC. This finding suggests that consumption of prekallikrein and HMWK contributes to microvascular thrombosis in DIC. Measurements of prekallikrein and HMWK activity could be used as potential diagnostic markers for overt-DIC., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: ADAMTS13 deficiency increases the circulating level of von Willebrand factor (vWF). Low ADAMTS13 and high vWF can provide a milieu for microthrombosis, including disseminated intravascular coagulation (DIC). This study investigated the prognostic values of ADAMTS13-vWF axis markers and their correlation with DIC severity., Methods: ADAMTS13-vWF axis markers (vWF antigen (vWF:Ag), vWF ristocetin cofactor (vWF:Rco), ADAMTS13 activity, and anti-ADAMTS13 antibody) were measured in patients (n = 152) suspected of having DIC along with the well-known DIC markers including antithrombin and protein C., Result: The vWF:Ag level was significantly increased, and ADAMTS13 activity was significantly decreased in overt DIC. The vWF:Ag level (hazard ratio 7.365, p = .009), ADAMTS13 activity/vWF:Ag ratio (hazard ratio 3.777, p = .037), ADAMTS13 activity/vWF:Rco ratio (hazard ratio 3.027, p = .028), and platelet count/vWF:Ag ratio (hazard ratio 8.538, p < .001) were significant prognostic markers in Cox regression analysis and correlated well with DIC score and antithrombin and protein C levels., Conclusion: The platelet count/vWF:Ag was the strongest prognostic marker among ADAMTS13-vWF axis markers. The measurement of vWF:Ag may improve prognostic insights of DIC in clinical practice., (© 2021 John Wiley & Sons Ltd.)

Objective: The factor VIIa-Antithrombin (VIIa-AT) complex is a relatively new biomarker associated with the activation of the extrinsic coagulation pathway. Since disseminated intravascular coagulation (DIC) is primarily driven by issue factor (TF)-induced extrinsic coagulation activation, the plasma level of factor VIIa-AT, via its role as an activation marker of the extrinsic pathway, could be a potential marker for DIC. The clinical significance of extrinsic coagulation markers, including factor VIIa-AT, in DIC was investigated., Methods: The extrinsic coagulation markers, including factor VIIa-AT, TF, factor VII, and antithrombin (AT), were measured in 148 patients clinically suspicious for DIC. Multiple linear regression and Cox proportional-hazard analysis were conducted to evaluate both contributing factors and the prognostic power of the markers., Results: The factor VIIa-AT complex, factor VII, and AT levels were significantly lower in the overt-DIC group and gradually decreased according to the severity of DIC based on the DIC scores. On the contrary, TF was significantly higher in the overt-DIC group. The factor VII level was revealed as a significant independent contributor to the factor VIIa-AT level. Upon multivariable Cox proportional-hazard analysis, the factor VIIa-AT complex showed the highest hazard ratio (3.41; 95% confidence interval 1.11-10.44)., Conclusion: The factor VIIa-AT complex reflects the severity of DIC and is an independent prognostic factor of DIC. Our findings hint at the potential of the factor VIIa-AT complex to be used as a complementary marker to well-established biomarkers such as AT., (© 2021 by the Association of Clinical Scientists, Inc.)

Background: The contact system that initiates the intrinsic coagulation pathway plays a role in thrombus formation. Since neutrophil extracellular traps (NET), which are mainly composed of histone and DNA, are actively formed in disseminated intravascular coagulation (DIC) and the NET can activate factor XII, it is plausible that a NET component strongly activates the contact system in patients with DIC., Methods: In 146 patients suspected of having DIC, the plasma levels of contact system factors including factor XII, activated factor XII (XIIa), prekallikrein, high-molecular-weight kininogen (HMWK), bradykinin, extrinsic factor VII and histone–DNA complex were measured. In an in vitro plasma clotting assay, factor XII–deficient plasma was stimulated with silica or histone., Results: The levels of not only extrinsic coagulation factor VII but also intrinsic coagulation factors including factors XI and XII were significantly decreased in patients with overt DIC in comparison with those with no overt DIC. Factor XIIa and histone-DNA complex were also significantly increased in patients with overt DIC. However,HMWK, prekallikrein and bradykin inw ere not significantly different between patients with and without overt DIC. Interestingly, factors XII and XIIa were revealed as significantly independent potential prognostic markers for DIC. The histone-DNA complex level significantly contributed to the factor XIIa level (20.6%). In an in vitro clotting assay, histone, a major component of NET, activated coagulation that was dependent, in part, on the presence of factor XII., Conclusion: These findings suggest that active NET formation can induce factor XII-mediated coagulation activation in patients with DIC with poor prognosis. The resulting factor XIIa release can be used as an independent potential prognostic marker for DIC. Activation of factor XII-mediated coagulation may be a potential therapeutic target in DIC,

Disseminated intravascular coagulation (DIC) is characterized by consumption of coagulation factors and anticoagulants. Thrombin generation assay (TGA) gives useful information about global hemostatic status. We developed a new TGA system that anticoagulant addition can deplete thrombin generation in plasma, which may reflect defective anticoagulant system in DIC. TGAs were measured on the calibrated automated thrombogram with and without thrombomodulin or protein Z in 152 patients who were suspected of having DIC, yielding four parameters including lag time, endogenous thrombin potential, peak thrombin and time-to-peak in each experiment. Nonsurvivors showed significantly prolonged lag time and time-to-peak in TGA-protein Z system, which was performed with added protein Z. In multivariate Cox regression analysis, lag time and time-to-peak in TGA system were significant independent prognostic factors. In TGA-protein Z system, lag time and time-to-peak were revealed as independent prognostic factors of DIC. Protein Z addition could potentiate its anticoagulant effect in DIC with poor prognosis, suggesting the presence of defective protein Z system. The prolonged lag time and time-to-peak in both TGA and TGA-protein Z systems are expected to be used as independent prognostic factors of DIC.

Introduction: Neutrophils can be induced to release DNA combined with histones. The resulting neutrophil extracellular trap (NET) provides a scaffold for growing hemostatic plug. Therefore, the NET formation may be inevitable in clinical conditions that are characterized by formation of vascular thrombi. Thus far, there have been no reports on the clinical significance of NET in disseminated intravascular coagulation (DIC). Therefore, we investigated circulating levels of NET in DIC and analyzed their potential values to assess coagulation severity and predict clinical outcome., Methods: The plasma levels of DNA-histone complexes and double-stranded DNA (dsDNA), considered to be in vivo markers of NET, were measured in 199 patients suspected of having DIC and 20 healthy controls., Result: The circulating levels of DNA-histone complexes and dsDNA were significantly elevated in overt-DIC. The increased levels of these two markers correlated with the severity of coagulopathy including DIC score and D-dimer. Multivariable Cox regression analysis, adjusted for the conventional DIC markers, revealed that elevated DNA-histone complexes and dsDNA are poor independent prognostic markers., Conclusion: The circulating levels of NET release reflect the coagulation activation and adverse clinical outcomes in patients with DIC, thereby providing potential clinical relevance for mortality prediction in DIC., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The underlying inflammatory or infectious condition in disseminated intravascular coagulation (DIC) may stimulate the formation of antiheparin/platelet factor 4 (PF4) antibody, and the resulting antibody may affect the clinical course of DIC. We investigated the prognosis of antiheparin/PF4 antibodies in patients with suspected DIC. We measured heparin/PF4 immunoglobulin G (IgG) and total antibody levels using an automated chemiluminescence system in 118 patients with DIC. Of the 118 patients, 13 (11.0%) patients were positive for total antiheparin/PF4, and 6 (5.1%) patients were positive for antiheparin/PF4 IgG. These 13 patients were negative for platelet-activating antibody and had low-heparin-induced thrombocytopenia probability scores. Patients with antiheparin/PF4 IgG were older and had lower antithrombin levels than patients without antiheparin/PF4 IgG. Patients with antiheparin/PF4 IgG had a higher risk of mortality than those without antiheparin/PF4 IgG. The presence of antiheparin/PF4 IgG in old age or low antithrombin level patients with DIC with old age or low antithrombin level suggests a poor prognosis., (© The Author(s) 2013.)

Background: The protein C receptor (PROCR), toll-like receptor (TLR) and L-selectin leukocyte receptor play roles in systemic inflammatory response including disseminated intravascular coagulation (DIC). Expression of these receptors, which mediate systemic immune or coagulation responses, is tightly regulated by physiologic or pathologic signals. We investigated whether the expressions of 3 leukocyte receptors (PROCR, TLR4, L-selectin) was related to clinical outcomes in patients suggestive of having DIC., Methods: RNA was extracted from the peripheral blood buffy coats of patients suggestive of having DIC. After reverse transcription, mRNA expression levels of PROCR, TLR4, and L-selectin were measured using Taqman Gene Expression Assays. The 28-day hospital mortality rate was used as a clinical outcome., Results: The expression level of PROCR mRNA in leukocytes was lower in those with overt-DIC as compared to those without overt-DIC, however, this difference was not statistically significant. As for TLR4 and L-selectin mRNA expression, there were no significant differences observed between those with and without overt-DIC. A Kaplan-Meier survival analysis revealed that patients with low PROCR mRNA expression levels showed significantly lower survival rates than those with high expression levels. On multivariate cox regression analysis, low levels of PROCR mRNA expression were an independent prognostic marker. However, expression levels of TLR4 and L-selectin mRNA were not associated with any prognostic value., Conclusion: Considering that the PROCR is an important anticoagulant receptor, low PROCR mRNA expression levels associated with a poor prognosis in patients with DIC represents an exhaustion of the natural anticoagulant system, and reflects the final decompensate stage of DIC. The leukocyte PROCR may contribute to a dampening of florid activation of coagulation reactions in vivo., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Overall assessment of the hemostatic system including procoagulant and anticoagulant changes may help assess the clinical status and prognosis of disseminated intravascular coagulation (DIC). The thrombin generation assay provides useful information about the global hemostatic status. Therefore, we measured several parameters of global hemostatic potential by the thrombin generation assay in patients suspected of having DIC. A total of 114 patients with suspected DIC were included. The thrombin generation assay was performed on the calibrated automated thrombogram using tissue factor with or without the addition of thrombomodulin, showing three parameters: lag time, endogenous thrombin potential (ETP), and peak thrombin. Both 1 and 5 pmol/l tissue factor-stimulated ETP and peak thrombin were well correlated with DIC severity. Interestingly, antithrombin level greatly affected ETP, whereas protein C influenced lag time. Prognostic analysis revealed that the area under the curve of peak thrombin stimulated by 1 pmol/l tissue factor was superior to that of D-dimer. Moreover, multivariate Cox analysis showed that the lag time and time to peak with both 1 and 5 pmol/l tissue factor were independent prognostic markers. ETP and peak thrombin well reflect DIC severity. Hypocoagulability manifesting as prolonged lag time and time to peak is expected to be an independent prognostic marker in DIC.

Background: Neutrophil gelatinase-associated lipocalin (NGAL) exists as monomers, homodimers, and NGAL/matrix metalloproteinase-9 (MMP-9) complexes. Circulating neutrophils are activated in ongoing disseminated intravascular coagulation (DIC); therefore, plasma NGAL levels are likely to be increased in DIC. We investigated the diagnostic performance of the plasma NGAL level in predicting acute kidney injury (AKI) in patients with DIC and determined the prognostic value of NGAL., Methods: A total of 126 patients with suspected DIC were enrolled. The plasma free NGAL was analyzed with a point-of-care immunoassay. Plasma total NGAL and NGAL/MMP-9 complex levels were measured using commercial kits., Results: Median free and total NGAL levels were markedly higher in patients with AKI than those without AKI. However, no significant difference in the NGAL/MMP-9 complex level was found between the groups. In patients without AKI, the plasma free and total NGAL levels were significantly higher in those with overt-DIC than in those without overt-DIC. Of note, the free NGAL level showed a significant prognostic value in DIC., Conclusion: Plasma free and total NGAL proved to be powerful markers for AKI in DIC patients and plasma free NGAL also has a prognostic relevance in DIC patients without AKI., (Copyright © 2014. Published by Elsevier B.V.)

Background: Dysfunctional natural anticoagulant systems enhance intravascular fibrin formation in disseminated intravascular coagulation (DIC), and plasma levels of natural anti coagulants can be used in the diagnosis and prognosis of DIC. Herein, the diagnostic value of 4 natural anticoagulants was assessed, and the prognostic value of antithrombin and protein C were validated in a large population., Methods: Part 1 study included 126 patients with clinically suspected DIC and estimated plasma levels of 4 candidate anticoagulant proteins: antithrombin, protein C, protein S, and protein Z. Part 2 comprised 1,846 patients, in whom plasma antithrombin and protein C levels were compared with other well-known DIC markers according to the underlying dis eases. The 28-day mortality rate was used to assess prognostic outcome., Results: Antithrombin and protein C showed higher areas under the ROC curve than protein S and protein Z. In part 2 of the study, antithrombin and protein C levels significantly correlated with DIC score, suggesting that these factors are good indicators of DIC severity. Antithrombin and protein C showed significant prognostic power in Kaplan-Meier analyses. In patients with sepsis/severe infection, antithrombin and protein C showed higher hazard ratios than D-dimer. Platelet count showed the highest hazard ratio in patients with hemato logic malignancy. In patients with liver disease, the hazard ratio for antithrombin levels was significantly high., Conclusions: Decreased plasma anticoagulant levels reflect florid consumption of the physiologic defense system against DIC-induced hypercoagulation. Plasma antithrombin and protein C levels are powerful prognostic markers of DIC, especially in patients with sepsis/severe infection.

Background: Monocytes express substantial amounts of thrombomodulin, which is consumed throughout ongoing thrombin generation. The modulation of thrombomodulin may aggravate intravascular fibrin deposition and the clinical course of disseminated intravascular coagulation (DIC). Although thrombomodulin restoration has received considerable attention, no reports have been published on the in vivo expression status of thrombomodulin. CD14 expression on monocytes is important for regulation of the inflammatory response. We used an ex vivo stimulation study to evaluate the association of the levels of monocyte-expressed thrombomodulin and CD14 messenger RNA (mRNA) with the severity and prognosis of disseminated intravascular coagulation., Methods: A total of 78 patients with suspected DIC were enrolled. Thrombomodulin and CD14 mRNA levels were measured in peripheral blood by real-time quantitative reverse-transcription polymerase chain reaction. Thrombomodulin and CD14 mRNA were also assessed in ex vivo cultures of peripheral whole blood that were stimulated by lipopolysaccharide or thrombin., Results: The levels of monocyte-expressed thrombomodulin mRNA were significantly lower in the non-survivors than in the survivors. A low level of monocyte-expressed thrombomodulin mRNA was a significant prognostic marker, but CD14 did not possess prognostic power. Monocyte-expressed CD14 mRNA correlated significantly with the severity of DIC in survivors. In addition, stimulation of ex vivo cultures of whole blood demonstrated that thrombin upregulates both thrombomodulin and CD14 mRNA, and lipopolysaccharide downregulates thrombomodulin mRNA., Conclusions: The downregulation of thrombomodulin on monocytes reflects the decompensated status of physiological defenses against hypercoagulopathy and represents the poor prognosis in DIC. The expression levels of thrombomodulin on monocytes may be a useful marker to screen for candidates eligible for recombinant thrombomodulin therapy in future., (© 2013.)

Introduction: Disseminated intravascular coagulation (DIC) is diagnosed based on the combination of predisposing underlying conditions and laboratory tests for plasma coagulation markers. Because the collection of blood plasma samples is a fastidious procedure, the serum sample method may be preferred for measurement of coagulation markers when feasible., Materials and Methods: The novel serum marker des-R prothrombin activation peptide fragment 2 (des-R F2) was measured using a sandwich enzyme-linked immunosorbent assay in 181 patients suspected of having DIC. Thrombin generation potential was estimated with a calibrated automated thrombogram., Results: Serum des-R F2 was generated with an in vitro clotting process within a serum separation tube after blood collection. Carboxypeptidase inhibitor inhibited the formation of des-R F2 during in vitro clotting. Low levels of prothrombin and thrombin generation potential resulted in low serum des-R F2 levels. Serum des-R F2 was significantly decreased in overt DIC. Levels of des-R F2 correlated with DIC severity and other coagulation markers. Of note, the decrease in serum des-R F2 levels was a significant marker for predicting mortality., Conclusions: The serum marker, des-R F2, can be used for the investigation of DIC severity and prognosis. It should be considered a useful marker, especially when only serum samples are available., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Fibrin-related markers may help differentiate disseminated intravascular coagulation (DIC) from liver cirrhosis-associated dysfunctional coagulation. We investigated the significance of three fibrin-related markers [D-dimer, fibrin degradation product (FDP), and soluble fibrin complexes (sFC)] for the assessment of DIC status and prognosis. We classified 235 patients with suspected DIC into two groups according to their condition: the liver cirrhosis group (n = 47) and the no liver cirrhosis group (n = 188). Prothrombin time (PT), and fibrinogen, sFC, D-dimer, antithrombin, and protein C concentrations were measured and DIC scores were calculated using four parameters: platelet count, D-dimer, fibrinogen, and PT. In the liver cirrhosis group, the sFC concentration increased significantly in accordance with DIC score compared with the no liver cirrhosis group, and this increase was more prominent than D-dimer and FDP concentration increases. For the diagnosis of overt DIC in patients with liver cirrhosis, the area under the concentration curve (AUC) was larger for sFC (0.746) than for D-dimer (0.733) and FDP (0.687). Cox analysis also indicated that an elevated sFC concentration is a more significant prognostic factor of DIC than D-dimer or FDP (hazard ratio: 10.78; P = 0.036) in liver cirrhosis group; however, it was not a prognostic factor in the no liver cirrhosis group. sFC is a powerful diagnostic and prognostic marker of DIC in patient with liver cirrhosis. The use of sFC is expected to enhance the diagnosis and prognosis of DIC, particularly in patients with liver cirrhosis.

Monocyte and neutrophil activation occur during microvascular disturbance of disseminated intravascular coagulation (DIC). This study investigated the diagnostic and prognostic value of circulating neutrophil elastase (NE) and neutrophil volume distribution width (NDW) as neutrophil activation markers and circulating soluble CD163 (sCD163) and monocyte volume distribution width (MDW) as monocyte activation markers in 168 patients suspected of having DIC. The sCD163 provided significant diagnostic value. The prognostic value of sCD163 was comparable to that of D-dimer, but was dependent on other coagulation markers. In vitro, thrombin significantly induced sCD163 from monocytes upregulated with IL-10 or dexamethasone. NDW was an independent and powerful prognostic marker. MDW and NE did not provide diagnostic and prognostic power. Excessive thrombin during ongoing DIC induces florid secretion of CD163; sCD163 might therefore be a potential diagnostic and prognostic marker for DIC. NDW, a convenient parameter measured by an automated hematology analyzer, may be an independent prognostic parameter for DIC., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Introduction: Thrombomodulin, 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., Methods: In 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., Results: The 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., Conclusions: These 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.

Platelet counting in patients with acute leukemia or disseminated intravascular coagulation (DIC) may have a risk for erroneous counts owing to the presence of nonplatelet particles or platelet activation. We evaluated automated platelet counting methods using the Abbott Cell-Dyn Sapphire (Abbott Diagnostics, Santa Clara, CA), Sysmex XE-2100 (Sysmex, Kobe, Japan), ADVIA 2120 (Siemens Diagnostics, Tarrytown, NY), and Beckman Coulter LH 750 (Beckman Coulter, Miami, FL) compared with the international reference method (IRM). Automated platelet counting methods were inaccurate compared with the IRM, without evidence of interfering nonplatelet particles. It is interesting that platelet activation markers were associated with DIC severity and erroneous platelet counting, suggesting that platelet activation is a potential source of inaccuracy. Furthermore, the artifactual in vitro platelet activation induced a high degree of intermethod variation in platelet counts. The inaccuracy of automated platelet counts increased the risk for misdiagnosis of DIC. More attention needs to be given to the accuracy of platelet counts, especially in clinical conditions with florid platelet activation.

Background: Hepatocyte growth factor (HGF), a pleiotropic factor regulating development and wound healing, is secreted as inactive pro-HGF and is converted into active HGF by coagulation serine proteases. HGF receptor overexpression can cause massive venous thrombi, and factor Xa is reported to release soluble HGF from granulocytes. We hypothesized that a hypercoagulable condition, such as disseminated intravascular coagulation (DIC), may increase circulating HGF through active cleavage by coagulation serine proteases., Methods: In 172 DIC-suspected patients, plasma levels of total and active HGF, thrombin-antithrombin complex (TAT), plasmin-antiplasmin complex (PAP), and interleukin (IL)-6 were measured by ELISA. Active HGF release in granulocytes was examined in patients with and without overt-DIC. HGF-induced tissue factor expression in peripheral monocytes was measured by flow cytometry., Results: Circulating levels of total and active HGF correlated well with coagulopathy severity, including DIC score, D-dimer, TAT and PAP levels. HGF positively correlated with IL-6 and absolute neutrophil count. In contrast to the cancer group, HGF levels were significantly increased in accordance with increased DIC scores in non-cancer group. Elevated circulating HGF was an independent prognostic marker in the non-cancer group, while HGF level failed to predict mortality in the cancer group. Amounts of HGF released from stimulated granulocytes were not significantly different between overt-DIC and no overt-DIC patients. HGF potentiated endotoxin-induced tissue factor expression of monocytes in vitro., Conclusion: These findings suggest that circulating HGF is a potential laboratory marker reflecting coagulation activity and DIC prognosis in non-cancer patients and that HGF may play a role in a vicious cycle of hypercoagulability., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Although platelet count is a good parameter for the diagnosis of disseminated intravascular coagulation (DIC), a single measurement of platelet is not enough to reflect the ongoing platelet consumption because of compensatory synthesis of circulating platelet number. Increased thrombopoiesis owing to peripheral destruction is expected in patients with DIC. Reticulated platelet, measured as immature platelet fraction (IPF), and plasma thrombopoietin (TPO) are markers of platelet production. We investigated the potential usefulness of circulating IPF and TPO in 222 patients suspected of having DIC. Both IPF and TPO levels were significantly increased in overt DIC patients and well correlated with DIC score. IPF also correlated with fibrin-related marker such as fibrinogen degradation product and D-dimer. Both IPF and TPO showed better mortality prediction than platelet count with the multivariate logistic regression and Kaplan-Meier survival analysis. These results suggest that IPF and TPO are new potential candidates to detect the severity of DIC and to predict DIC mortality.

Introduction: In disseminated intravascular coagulation (DIC), widespread activation of intravascular coagulation accompanied with florid endothelial activation results in release of unusually large von Willebrand factor (ULvWF) from endothelium. Circulating a disintegrin-like and metalloprotease with thrombospondin type 1 repeats (ADAMTS)-13 may be consumed through the ongoing cleavage of ULvWF, resulting in a secondary deficiency of ADAMTS-13 in DIC. We determined whether ADAMTS-13 activity showed a significant correlation with the activation status of the coagulation system and hospital mortality in DIC., Materials and Methods: ADAMTS-13 activity was assayed by fluorescence resonance energy transfer assay in 97 patients who were clinically suspected to have DIC., Results: ADAMTS-13 activity gradually decreased based on the DIC score and D-dimer levels and was correlated with the antithrombin level, representing the consumption of ADAMTS-13 during the ongoing coagulation process. There were no correlation between ADAMTS-13 activity and neutrophil CD64 expression as a neutrophil activation marker and circulating IL-6 level as an inflammatory marker. Patients with a low activity of ADAMTS-13 (< or = 56.4%) had a poor survival rate compared to patients with a high activity of ADAMTS-13., Conclusions: We conclude that ADAMTS-13 activity is strongly correlated with the severity of coagulopathy and hospital mortality. ADAMTS-13 may serve as a diagnostic and prognostic marker of DIC.

Background: Widespread coagulation activation and intravascular fibrin formation are clinical features of disseminated intravascular coagulation (DIC). The endogenous thrombin potential (ETP) has been shown to be a useful marker for hypo- or hypercoagulability. The factor Xa-activated clotting time (XACT) represents plasma levels of procoagulant phospholipids. We investigated whether the ETP and XACT would be good prognostic markers in patients suspected of having DIC and whether these markers would show a significant correlation with the thrombin-antithrombin complex (TAT), a marker of in vivo coagulation activation., Methods: One hundred twenty-nine patients suspected of having DIC were enrolled for the study. The TAT was measured by ELISA. The ETP and XACT were measured by calibrated automated thrombinography. The 28-day mortality was used as a predictor of clinical outcomes., Results: In overt DIC, higher XACT (9.67 vs. 7.33 min) and higher TAT (26.15 vs. 11.56 ng/ml) results were obtained from the nonsurvivors than from the survivors. ETP levels were lower in the overt DIC group than in the no overt DIC group. In receiver operating characteristic analysis, which was conducted to predict the 28-day mortality, the areas under the receiver operating characteristic analysis curve were as follows: 0.71 (95% CI: 0.62-0.78) for the XACT, 0.70 (0.61-0.77) for the TAT, and 0.64 (0.55-0.72) for the ETP. For the diagnosis of overt DIC, the area under the curve of XACT, TAT and ETP were 0.77 (0.69-0.84), 0.64 (0.55-0.72) and 0.73 (0.64-0.80), respectively. The odds ratio of the XACT for the relative risk of 28-day mortality was 9.60 (3.53-26.11), and that of the TAT was 5.18 (2.11-12.72) and that of the ETP 7.66 (1.67-35.17). For the diagnosis of overt DIC, the odds ratio of XACT, TAT and ETP were 37.35 (4.86-286.89), 4.89 (1.93-12.43) and 4.89 (1.98-12.09), respectively. There was a negative correlation between the TAT and ETP (r=-0.223, P=0.012) and a positive correlation between the TAT and XACT (r=0.251, P=0.004)., Conclusion: Our results suggest that the XACT and ETP may be useful diagnostic and prognostic markers for the DIC. Among various markers, the XACT serves as a good prediction of the 28-day mortality in patients suspected of having DIC.

Introduction: Although neutrophil can be activated by microcirculatory disturbances in DIC, its relation with the severity and prognosis of DIC has not been elucidated. We investigated the relationship between neutrophil activation and DIC severity and determined the prognostic value of neutrophil activation markers in patients with DIC., Materials and Methods: We measured two neutrophil activation markers, neutrophil CD64 expression and plasma neutrophil elastase, in 94 patients with suspected DIC and 55 healthy controls. Neutrophil CD64 expression and plasma neutrophil elastase were measured using CD64 quantitation kit, and PMN Elastase enzyme immunoassay kit., Results: Neutrophil CD64 expression and plasma neutrophil elastase level were significantly increased in patients with overt and non-overt DIC compared to normal controls (P<0.001, each). Neutrophil CD64 expression showed a significant linear trend of increase with increasing DIC score (P<0.001). In DIC patients, significant differences were observed between those with and without infection both in overt (P=0.003) and non-overt DIC (P=0.004). Neutrophil CD64 expression was significantly increased in 28-day non-survival group compared to survival group in both overt (P<0.001) and non-overt DIC (P=0.032). The 28-day survival rate showed a stronger association with the neutrophil CD64 expression (P<0.001) than with DIC score (P=0.028) or plasma neutrophil elastase level (P=0.246)., Conclusions: Neutrophil CD64 expression is significantly correlated with DIC severity and has a good predictive value for the 28-day mortality in patients suspected of having DIC. Neutrophil CD64 expression might be useful in monitoring the disease course and in predicting mortality in DIC patients.

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

Stromal cell-derived factor-1 (SDF-1) is a CXC chemokine that activates and directs the migration of leukocytes that have CXCR4, which is the unique receptor for SDF-1. Although SDF-1/CXCR4 interaction has been implicated in various inflammatory conditions, its role in modulating coagulation has not been determined. We studied the plasma SDF-1 levels in 90 patients with suspected disseminated intravascular coagulation (DIC) and we found that circulating SDF-1 was significantly increased in the overt DIC patients and was also increased in overt DIC patients who have a poor outcome. We then tested in vitro whether SDF-1 can affect the expression of monocyte tissue factor (TF) and endothelial thrombomodulin (TM), and both of these play important roles in coagulopathy. SDF-1 did not affect the expression of surface TF protein and its function and the TF mRNA level in both monocytes and the monocytic leukemia cell line THP-1. SDF-1 also did not change the surface TM expression of endothelial cells. SDF-1 could enhance low-dose ADP induced platelet aggregation, although it failed by itself to induce aggregation. These findings suggest that plasma SDF-1 might be closely associated with hypercoagulability though its action as a platelet activator.

Although the presence of decreased plasma fibrinogen has been regarded as an indicator of ongoing disseminated intravascular coagulation (DIC), fibrinogen, which is one of the acute phase reactants, is often increased in the patients with DIC. We investigated the diagnostic and prognostic utility of a new parameter [the fibrinogen/C-reactive protein (CRP) ratio] for predicting DIC in 1,056 patients with suspected DIC and who also had underlying disorders associated with DIC. Among the 535 patients with overt DIC, 46 patients (8.6%) showed low plasma fibrinogen (<100 mg/dl), suggesting that the plasma fibrinogen level is not a sensitive marker for DIC. There was a strong correlation between the increased DIC scores and increased number of patients with low (<104) fibrinogen/CRP ratios. Among the three groups with different serum fibrinogen/fibrin degradation product levels, the fibrinogen/CRP ratio showed a higher difference than did the fibrinogen level. The DIC score was highly correlated with the 28-day mortality and the number of patients with low fibrinogen/CRP ratios. The odds ratio (the relative risk of 28-day mortality) of the low fibrinogen/CRP ratio was 6.15, while the odds ratio of the low fibrinogen level was 2.13. The area under the receiver-operating characteristic curve of the fibrinogen/CRP ratio, when this was used for predicting mortality, showed significantly better discriminative power than did that of the fibrinogen level. This study demonstrates that the fibrinogen/CRP ratio may provide more discriminating power for identifying the patients with active coagulation consumption, and the fibrinogen/CRP ratio has a good predictive value concerning the 28-day mortality in the patients suspected of having DIC. The results of our study suggest that replacement of fibrinogen by the fibrinogen/CRP ratio for calculating the DIC score may lead to enhance diagnostic and prognostic power for DIC., (2007 S. Karger AG, Basel)