Systemically sustained thrombin generation in vivo is the hallmark of disseminated intravascular coagulation (DIC). Typically, this is in response to a progressing disease state that is associated with significant cellular injury. The etiology could be infectious or noninfectious, with the main pathophysiological mechanisms involving cross-activation among coagulation, innate immunity, and inflammatory responses. This leads to consumption of both pro- and anticoagulant factors as well as endothelial dysfunction and disrupted homeostasis at the blood vessel wall interface. In addition to the release of tissue plasminogen activator (tPA) and soluble thrombomodulin (sTM) following cellular activation and damage, respectively, there is the release of damage-associated molecular patterns (DAMPs) such as extracellular histones and cell-free DNA. Extracellular histones are increasingly recognized as significantly pathogenic in critical illnesses through direct cell toxicity, the promotion of thrombin generation, and the induction of neutrophil extracellular trap (NET) formation. Clinically, high circulating levels of histones and histone–DNA complexes are associated with multiorgan failure, DIC, and adverse patient outcomes. Their measurements as well as that of other DAMPs and molecular markers of thrombin generation are not yet applicable in the routine diagnostic laboratory. To provide a practical diagnostic tool for acute DIC, a composite scoring system using rapidly available coagulation tests is recommended by the International Society on Thrombosis and Haemostasis. Its usefulness and limitations are discussed alongside the advances and unanswered questions in DIC pathogenesis.
Blood Platelets/cytology/pathology ; Disseminated Intravascular Coagulation/*diagnosis/pathology ; Fibrin Fibrinogen Degradation Products/analysis ; Humans ; Immunity, Innate ; Laboratories, Hospital ; Partial Thromboplastin Time ; Prothrombin Time ; Thrombelastography

BACKGROUND/AIMS: This study investigated whether patients with acute promyelocytic leukemia (APL) truly fulfill the diagnostic criteria of overt disseminated intravascular coagulation (DIC), as proposed by the International Society on Thrombosis and Haemostasis (ISTH) and the Korean Society on Thrombosis and Hemostasis (KSTH), and analyzed which component of the criteria most contributes to bleeding diathesis. METHODS: A single-center retrospective analysis was conducted on newly diagnosed APL patients between January 1995 and May 2012. RESULTS: A total of 46 newly diagnosed APL patients were analyzed. Of these, 27 patients (58.7%) showed initial bleeding. The median number of points per patient fulfilling the diagnostic criteria of overt DIC by the ISTH and the KSTH was 5 (range, 1 to 7) and 3 (range, 1 to 4), respectively. At diagnosis of APL, 22 patients (47.8%) fulfilled the overt DIC diagnostic criteria by either the ISTH or KSTH. In multivariate analysis of the ISTH or KSTH diagnostic criteria for overt DIC, the initial fibrinogen level was the only statistically significant factor associated with initial bleeding (p = 0.035), but it was not associated with overall survival (OS). CONCLUSIONS: Initial fibrinogen level is associated with initial presentation of bleeding of APL patients, but does not affect OS.
Adult ; Aged ; Biomarkers/blood ; Chi-Square Distribution ; Disseminated Intravascular Coagulation/blood/diagnosis/*etiology/mortality ; Female ; Fibrinogen/analysis ; Hemorrhagic Disorders/blood/diagnosis/*etiology/mortality ; Humans ; Kaplan-Meier Estimate ; Leukemia, Promyelocytic, Acute/blood/*complications/diagnosis/mortality ; Logistic Models ; Male ; Middle Aged ; Multivariate Analysis ; Proportional Hazards Models ; Republic of Korea ; Retrospective Studies ; Risk Factors ; Young Adult

OBJECTIVETo study the effect of thrombelastography (TEM) in the diagnosis of disseminated intravascular coagulation (DIC) in children.

METHODThe data of 117 children suffering from DIC in the pediatric intensive care unit (PICU) and Cardiologic ICU (CICU) in the authors' hospital from January 2010 to June 2012 were collected. Ninety-four children without DIC were enrolled into the control group. The platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), D-dimers and TEM were determined. The sensitivity and specificity of TEM were measured and the relevance of TEM and DIC was investigated to evaluate the effect of TEM and the conventional tests of the coagulation system in the diagnosis of DIC in children.

RESULTThe average R reaction time in the DIC group was significantly longer than that in the control group[(13.3 ± 3.3)s vs. (4.5 ± 2.6)s, P = 0.000 5], and the average α-angle in the DIC group was smaller than that in the control group significantly (37.2° ± 1.4° vs. 55.6° ± 3.8°, P = 0.001 0). There was significant decrease in the maximal amplitude (MA) and amplitude (A) in the DIC group, compared with the control group. The OR value (95%CI) of the R reaction time,α-angle and MA was 3.538 (1.298-5.389), 2.472 (1.820-2.224) and 0.256 (0.263-0.831) respectively, which suggests good correlation with the existence of DIC (all P < 0.01). The specificity of R reaction time, α-angle and MA was higher than that of PT, APTT and D-dimers (85.7%, 73.5% and 72.9% vs. 27.0%, 42.1% and 68.2%) . The average R reaction time of children suffering from hemorrhage of severe liver disease(n = 36) was significantly longer than that of 40 healthy children [(9.2 ± 2.7) vs. (2.3 ± 1.8)s, P = 0.001 0], while the α-angle (42.8° ± 7.6° vs. 59.2° ± 10.8°, P = 0.040 0) and the MA value [(33.9 ± 5.1) vs.(56.0 ± 8.1) mm, P = 0.020 0] were significantly smaller. The average R reaction time of children suffering from congenital coagulopathy was significantly longer than that of healthy children [(6.8 ± 3.1) vs. (2.3 ± 1.8)s, P = 0.003 0], too.

CONCLUSIONTEM, which has high specificity, is beneficial to the diagnosis of DIC in children.

Blood Coagulation ; Case-Control Studies ; Child ; Child, Preschool ; Critical Illness ; Disseminated Intravascular Coagulation ; blood ; diagnosis ; Female ; Fibrin Fibrinogen Degradation Products ; analysis ; Humans ; Intensive Care Units ; Logistic Models ; Male ; Partial Thromboplastin Time ; Platelet Count ; Prothrombin Time ; ROC Curve ; Sensitivity and Specificity ; Thrombelastography

BACKGROUND: Dysfunctional natural anticoagulant systems enhance intravascular fibrin for mation 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 pro tein 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 phys iologic 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.
Adult ; Aged ; Anticoagulants/*blood ; Antithrombins/*blood ; Blood Platelets/cytology ; Blood Proteins/analysis ; Disseminated Intravascular Coagulation/complications/*diagnosis/mortality ; Female ; Fibrin Fibrinogen Degradation Products/analysis ; Humans ; Male ; Middle Aged ; Platelet Count ; Prognosis ; Protein C/*analysis ; Protein S/analysis ; Prothrombin Time ; Regression Analysis ; Sepsis/complications/*diagnosis ; Severity of Illness Index

Anticoagulants ; therapeutic use ; Blood Coagulation Tests ; Blood Component Transfusion ; methods ; Disseminated Intravascular Coagulation ; blood ; diagnosis ; etiology ; therapy ; Female ; Fibrin Fibrinogen Degradation Products ; analysis ; Fibrinolysis ; Fibrinolytic Agents ; therapeutic use ; Heparin, Low-Molecular-Weight ; therapeutic use ; Humans ; Infant, Newborn ; Intensive Care Units, Pediatric ; Male ; Platelet Count ; Predictive Value of Tests ; Sepsis ; complications

OBJECTIVEInflammation and coagulation occur concomitantly in severe pneumonia. The term non-overt disseminated intravascular coagulation (DIC) (pre-DIC state) refers to a state prevalent before the occurrence of overt DIC. It is suggested that initiation of treatment in non-overt DIC leads to better outcome than in overt DIC. The present study aimed at evaluating potential use of soluble P-selectin in diagnosis of pre-DIC state of children with severe pneumonia.

METHODThe laboratory findings (including soluble P-selectin, D-Dimer, platelet count, activated partial prothrombin time, prothrombin time and fibrinogen) of 226 children with severe pneumonia from Jan. 2010 to Jul. 2011 in pediatric intensive care unit (PICU), were analyzed in this prospective cohort study, and the ROC curve was plotted to evaluate the potential role of soluble P-selectin in diagnosis of pre-DIC state.

RESULTA total of 226 patients with severe pneumonia comprised of 75 positive and 151 negative pre-DIC state cases were enrolled. The mean value of soluble P-selectin, D-Dimer, and platelet count were 124.8 (26.9 - 608.3) µg/L, 1.3(0.7 - 16.0) mg/L and 91 (56 - 196)×10(9) for the positive cases, and 63.3 (2.8 - 302.1) µg/L, 0.5 (0.2 - 1.0) mg/L and 231 (120 - 680)×10(9) for the negative cases, respectively. There was a significant difference between the two groups. Coagulatory function in the positive cases, including activated partial prothrombin time, prothrombin time and fibrinogen which were (39.1 ± 3.5) sec, (14.8 ± 2.1) sec and (3.8 ± 0.5) g/L, respectively, were significantly higher than those in the negative cases [(37.2 ± 2.4) sec, (13.0 ± 0.5) sec and (3.3 ± 0.2) g/L] (P < 0.001). The area under ROC curve showed that D-dimer, soluble P-selectin for pre-DIC state had higher diagnostic value. The Optimal Operating Point of soluble P-selectin was determined and interpreted at 94.0 µg/L with a sensitivity of 0.824, a specificity of 0.887, and the Optimal Operating Point of D-dimer was determined and interpreted at 0.7 mg/L with a sensitivity of 0.905, a specificity of 0.867, systematic test of soluble P-selectin and D-dimer had a higher specificity of 0.920, determined at the same time.

CONCLUSIONTo improve the outcome of patients with DIC, there is a need to establish more useful and easily operative diagnostic criteria for pre-DIC state. Plasma levels of soluble P-selectin will be helpful in this respect. Systematic test of soluble P-selectin and D-dimer may be helpful in reducing misdiagnosis rate.

Child ; Child, Preschool ; Cohort Studies ; Disseminated Intravascular Coagulation ; blood ; complications ; diagnosis ; Female ; Fibrin Fibrinogen Degradation Products ; analysis ; Humans ; Infant ; Intensive Care Units ; Male ; P-Selectin ; analysis ; blood ; Partial Thromboplastin Time ; Platelet Count ; Pneumonia ; blood ; complications ; diagnosis ; Prospective Studies ; Prothrombin Time ; ROC Curve ; Sensitivity and Specificity

BACKGROUND: Fibrin-related markers (FRM) such as fibrin monomer (FM) and D-dimer (DD) are considered useful biological markers for the diagnosis of disseminated intravascular coagulation (DIC). However, no studies on the diagnostic performance of different FRMs have been published in Korea. The aim of this study was to evaluate the diagnostic performance of FM for DIC in comparison with DD. METHODS: The reference limit of FM was determined based on plasma sample data obtained from 210 control individuals. To evaluate diagnostic performance, FM data from the plasma samples of 139 patients with DIC-associated diseases were obtained for DIC scoring. FM was measured by immunoturbidimetry using STA-LIATEST FM (Diagnostica Stago, France). Patients were classified according to the DIC score as non-DIC, non-overt DIC, or overt DIC. ROC curve analyses were performed. RESULTS: The reference limit in the control individuals was determined to be 7.80 microg/mL. Patients with DIC-associated diseases were categorized as non-DIC (N=43), non-overt DIC (N=80), and overt DIC (N=16). ROC curve analyses showed that the diagnostic performance of FM was comparable to DD in both non-overt DIC and overt DIC (P=0.596 and 0.553, respectively). In addition, FM had higher sensitivity, specificity, positive predictive value, and negative predictive value than DD for differentiating overt DIC from non-DIC. CONCLUSIONS: This study demonstrated that the diagnostic performance of FM for DIC was comparable to DD. FM might be more sensitive and more specific than DD in the diagnosis of overt DIC, but not non-overt DIC.
Area Under Curve ; Biological Markers/blood ; Disseminated Intravascular Coagulation/blood/*diagnosis ; Fibrin Fibrinogen Degradation Products/*analysis/immunology/standards ; Humans ; Immunoassay/*methods/standards ; Nephelometry and Turbidimetry/*methods/standards ; ROC Curve ; Reagent Kits, Diagnostic ; Reference Values

BACKGROUND: Fibrin-related markers (FRM) such as fibrin monomer (FM) and D-dimer (DD) are considered useful biological markers for the diagnosis of disseminated intravascular coagulation (DIC). However, no studies on the diagnostic performance of different FRMs have been published in Korea. The aim of this study was to evaluate the diagnostic performance of FM for DIC in comparison with DD. METHODS: The reference limit of FM was determined based on plasma sample data obtained from 210 control individuals. To evaluate diagnostic performance, FM data from the plasma samples of 139 patients with DIC-associated diseases were obtained for DIC scoring. FM was measured by immunoturbidimetry using STA-LIATEST FM (Diagnostica Stago, France). Patients were classified according to the DIC score as non-DIC, non-overt DIC, or overt DIC. ROC curve analyses were performed. RESULTS: The reference limit in the control individuals was determined to be 7.80 microg/mL. Patients with DIC-associated diseases were categorized as non-DIC (N=43), non-overt DIC (N=80), and overt DIC (N=16). ROC curve analyses showed that the diagnostic performance of FM was comparable to DD in both non-overt DIC and overt DIC (P=0.596 and 0.553, respectively). In addition, FM had higher sensitivity, specificity, positive predictive value, and negative predictive value than DD for differentiating overt DIC from non-DIC. CONCLUSIONS: This study demonstrated that the diagnostic performance of FM for DIC was comparable to DD. FM might be more sensitive and more specific than DD in the diagnosis of overt DIC, but not non-overt DIC.
Area Under Curve ; Biological Markers/blood ; Disseminated Intravascular Coagulation/blood/*diagnosis ; Fibrin Fibrinogen Degradation Products/*analysis/immunology/standards ; Humans ; Immunoassay/*methods/standards ; Nephelometry and Turbidimetry/*methods/standards ; ROC Curve ; Reagent Kits, Diagnostic ; Reference Values

The authors report a case of acute kidney injury (AKI) resulting from menstruation-related disseminated intravascular coagulation (DIC) in an adenomyosis patient. A 40-yr-old woman who had received gonadotropin for ovulation induction therapy presented with anuria and an elevated serum creatinine level. Her medical history showed primary infertility with diffuse adenomyosis. On admission, her pregnancy test was negative and her menstrual cycle had started 1 day previously. Laboratory data were consistent with DIC, and it was believed to be related to myometrial injury resulting from heavy intramyometrial menstrual flow. Gonadotropin is considered to play an important role in the development of fulminant DIC. This rare case suggests that physicians should be aware that gonadotropin may provoke fulminant DIC in women with adenomyosis.
Acute Kidney Injury/*diagnosis/etiology ; Adult ; Creatinine/blood ; Disseminated Intravascular Coagulation/*chemically induced/complications ; Endometriosis/*complications/diagnosis/surgery ; Female ; Fertilization in Vitro ; Gonadotropins/*adverse effects ; Humans ; Magnetic Resonance Imaging ; Menstruation/*physiology ; Uterus/pathology/surgery

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.
Adult ; Aged ; Blood Coagulation Tests ; Disseminated Intravascular Coagulation/blood/*diagnosis/mortality ; Female ; Humans ; Infection/blood ; Interleukin-10/*blood ; Interleukin-6/*blood ; Male ; Middle Aged ; Prognosis ; Survival Analysis