Disseminated Intravascular Coagulation Score Research Articles

Clinical outcome of recombinant human soluble thrombomodulin (rTM) for patients with disseminated intravascular coagulation (DIC) complicating advanced solid cancer: Retrospective analysis.

e19611 Background: Disseminated intravascular coagulation (DIC) is a syndrome characterized by the activation of coagulation leading to systemic microvascular thrombosis. DIC is frequently observed in patients with hematologic malignancy and often in patients with advanced cancer. Recombinant human soluble thrombomodulin (rTM) has been introduced as a new type of anti-DIC agent for clinical use in patients with hematological cancer or infectious disease. However, the efficacy for advanced solid cancer has not been elucidated. Methods: All patients with DIC complicating advanced solid cancer who were treated by rTM in Tohoku university hospital from December 2009 to November 2011 were enrolled in this retrospective study. DIC was diagnosed and scored according to the diagnostic criteria established by the Japanese Ministry of Health and Welfare (JMHW DIC criteria). Change in DIC score and period of overall survival (OS) after treatment of rTM (380U/kg/day) were evaluated. The Kaplan-Meier method was used to calculate OS. Results: Twenty-two patients (32% female) were enrolled. The median age was 61.5 (r: 32-82). The primary organs were 7 stomach, 3 colorectal, 2 esophageal and 10 other cancers. DIC score (63.6%), FDP (54.5%), PT-INR (45.4%), FBG (36.4%) were kept or improved in these patients between day 1 and day 5 in rTM treatment. Median OS (mOS) was 30 days (r: 2–301). Subgroup analyses revealed that mOS was longer in patients who underwent chemotherapy following rTM treatment than in patients who did not (114 days vs. 10 days, p = 0.0083). Patients with better ECOG PS (<2 vs. >3; 114 days vs. 15 day, p = 0.018), smaller number of chemotherapy treated before DIC (<2 vs. >3; 69 days vs. 6 days, p = 0.0008) also showed better mOS. No critical complication was observed. Conclusions: This study showed that rTM was effective and safe for patients with DIC complicating advanced solid cancer. PS and number of chemotherapy regimens could be predictive factor of rTM. We considered that rTM yield the chance of chemotherapy to advanced cancer patients with DIC by preventing deterioration of DIC.

DIC Score: Statistical Relationship with PT, APTT, and Simplified Scoring Systems with Combinations of PT and APTT

We looked into the statistical association of prothrombin time (PT) and activated partial thromboplastin time (APTT) with disseminated intravascular coagulation (DIC) score calculated using the International society for thrombosis and haemostasis (ISTH) scoring system. The PT, APTT, PT + APTT, and PT/APTT ratios were evaluated against the DIC score by linear regression analysis in fifty inpatients with suspected DIC. The PT, PT + APTT, and PT/APTT ratios were all found to be statistically significant in predicting DIC scores with P values of 0.02, 0.03, and 0.02, respectively. The APTT alone was not found to be statistically significant in predicting DIC score and had a P value of 0.09. This scoring system does not need d-dimer levels and the platelet count.

A low TAFI activity and insufficient activation of fibrinolysis by both plasmin and neutrophil elastase promote organ dysfunction in disseminated intravascular coagulation associated with sepsis

IntroductionWe hypothesized that thrombin activatable fibrinolysis inhibitor (TAFI) and the activation of fibrinolysis by both plasmin and neutrophil elastase is insufficient to overcome fibrinolytic shutdown, contributing to multiple organ dysfunction syndrome (MODS) in sepsis-induced disseminated intravascular coagulation (DIC). Materials and MethodsFifty patients with sepsis were prospectively enrolled. The DIC was diagnosed based on the Japanese Association for Acute Medicine (JAAM) DIC and the International Society on Thrombosis and Haemostasis (ISTH) overt DIC criteria. ResultsThe JAAM DIC scores were independent predictors of patient death and MODS. The JAAM DIC patients, especially those who met the ISTH overt DIC criteria, showed lower TAFI activity, and higher levels of soluble fibrin, neutrophil elastase, fibrin degradation product by neutrophil elastase (EXDP), plasmin-alpha2 plasmin inhibitor complex (PPIC), tissue plasminogen activator-plasminogen activator inhibitor-1 complex (tPAIC) and D-dimer in comparison with non-DIC patients. There were differences in the levels of soluble fibrin, tPAIC, TAFI activity, and neutrophil elastase between the patients with and without MODS. However, no differences were observed in the levels of PPIC, D-dimer, or EXDP. Soluble fibrin negatively correlated with the TAFI activity. High neutrophil elastase, low TAFI activity and PPIC are independent predictors of patient death and MODS. tPAIC is an independent predictor of elevation of EXDP in DIC patients. ConclusionsActivation of fibrinolysis both by plasmin and neutrophil elastase cannot overcome fibrinolytic shutdown, leading to MODS and a poor outcome in sepsis-induced DIC. The systemic activation of neutrophils and a low TAFI activity are also involved in the pathogenesis of MODS.

Disseminated Intravascular Coagulation (DIC) at an Early Phase of Trauma Continuously Proceeds to DIC at a Late Phase of Trauma

The data from 254 patients with severe trauma were retrospectively analyzed. The patients were subdivided into disseminated intravascular coagulation (DIC) and non-DIC. There was a difference in the incidence of the continuous progression from the early to late phase of DIC between the patients with and without DIC on day 0. While 2 of 9 patients who newly developed late-phase DIC were complicated with sepsis, none of the 32 patients who showed a continuous progression of DIC from the early to late phase of trauma developed sepsis. The DIC and Sequential Organ Failure Assessment scores on day 0 were independent factors that predicted the continuous progression of the DIC from the early to late phase of trauma. Trauma itself, but not sepsis, contributes to the continuous progression of DIC from the early to late phase of trauma. The severity of DIC and organ dysfunction are involved in the pathogenesis of this continuous progression.

Safety of plasma‐derived protein C for treating disseminated intravascular coagulation in adult patients with active cancer

Cancer-related disseminated intravascular coagulation (DIC) is a life-threatening condition for which no effective treatment is currently available. Protein C (PC), a modulator of coagulation as well as the inflammatory system, has been successfully tested (in its activated recombinant form [a-rPC]) in sepsis-related coagulopathy, but with an increased risk for major bleeding. Plasma-derived PC (pd-PC) is more suitable than a-rPC in patients at high risk from bleeding due to its self-limiting process. We carried out a single-arm study evaluating the role of pd-PC in adult cancer patients with overt DIC. Over a period of 3 years, we treated 19 patients with overt DIC and a PC plasma concentration <50%; all received PC concentrate (Ceprotin(®), Baxter) for 72 hr in adjusted doses to restore normal PC values (70-120%). Blood coagulation, haematological tests, and the DIC score were recorded after 12, 24, 48 hr, 7 and 10 days, while clinical outcomes (bleeding, thrombosis and mortality) were recorded up to 28 days. Within 48 hr of starting pd-PC therapy, laboratory tests as well as the DIC score improved in all patients. At 28-days follow-up, no bleeding or thrombosis was observed. This is the first study to investigate the use of pd- PC for treatment of cancer-related overt DIC.

Usefulness of anti-PF4/heparin antibody test for intensive care unit patients with thrombocytopenia

BackgroundIt is critical to differentiate heparin-induced thrombocytopenia (HIT) from disseminated intravascular coagulation (DIC) in heparinized intensive care unit (ICU) patients with thrombocytopenia because the therapeutic approach differs based on the cause. We investigated the usefulness of PF4/heparin antibody tests in these patients.MethodsA total of 127 heparinized ICU patients whose platelet counts were <150×109/L or reduced by >50% after 5-10 days of heparin therapy were enrolled. PF4/heparin antibodies were measured using 2 immunoassays. We assessed the probability of HIT by using Warkentin's 4T's scoring system for antibody positive patients and compared routinely performed coagulation test results between patients with and without antibodies to evaluate the ability of these tests to discriminate between HIT and DIC.ResultsPositive results were obtained for 14 (11.0%) and 11 (8.7%) patients in the 2 assays. The analysis performed using the 4T's scoring system revealed that 11 of 20 (15.7%) patients with antibodies in at least 1 assay had intermediate or greater probability of HIT. Patients without antibodies had significantly higher levels of D-dimer than those with antibodies. However, there were no intergroup differences in platelet counts, PT, aPTT, fibrinogen, DIC score, and rate of overt DIC.ConclusionSeropositivity for PF4/heparin antibody was 8.7-11.0% in the patients with thrombocytopenia, and more than a half of them had an increased probability of HIT. Among the routine coagulation tests, only D-dimer was informative for differentiating HIT from DIC. PF4/heparin antibody test is useful to ensure appropriate treatment for thrombocytopenic heparinized ICU patients.

Analysis of the Cutoff Values in Fibrin-Related Markers for the Diagnosis of Overt DIC

Fibrin-related markers (FRMs) such as fibrin and fibrinogen degradation products (FDPs), d-dimer, and soluble fibrin monomer complex (SFMC) were prospectively evaluated in 522 patients using the overt disseminated intravascular coagulation (DIC) diagnostic criteria. The differences in all FRMs between the DIC group and the non-DIC group, and those between the survivors and nonsurvivors were significant in the patients with infections. In an analysis of all patients, DIC score cutoff values of 2 and 3 points for FDP, d-dimer, and SFMC were recommended to be 8.3 and 42.0 μg/mL, 2.4 and 22.0 μg/mL, and 3.4 and 138.0 μg/mL, respectively. In conclusion, the adequate cutoff value is thus considered to be useful for both making a diagnosis of DIC and for predicting the outcome. Fibrin-related markers are therefore thought to be more useful for making a diagnosis of DIC based on infections than based on any other underlying disorders.

Effects of antithrombin and gabexate mesilate on disseminated intravascular coagulation: a preliminary study

PurposeWe hypothesized that antithrombin is more effective for disseminated intravascular coagulation (DIC) than is gabexate mesilate, which is a protease inhibitor, suggested from the previous studies. Initially, we compared the effects of antithrombin and gabexate mesilate for treating infection-related DIC. MethodsSixteen adult patients with a diagnosis of DIC with infection who were assessed with an acute DIC score 4 or higher at the admission to the intensive care unit were divided into antithrombin-treated and gabexate mesilate–treated groups. White blood cell counts, C-reactive protein, platelet counts, antithrombin, fibrin and fibrinogen degradation product, d-dimer, fibrinogen, thrombin antithrombin complex, plasmin plasminogen complex, prothrombin time, and activated partial thrombin time were measured on the day of admission and on days 1, 3, 5, and 7 thereafter. Mortality over 28 days was also compared. ResultsPlatelet counts and antithrombin were significantly higher in the antithrombin group on day 7 and on days 5 and 7, respectively. Antithrombin increased to the normal level on day 1 in the antithrombin group but on day 7 in the gabexate mesilate group. C-reactive protein, fibrinogen degradation product, d-dimer, thrombin antithrombin complex, plasmin plasminogen complex, and prothrombin time were lower in the antithrombin group; but the differences were not significant. The 28-day mortality was 2 of 8 in the antithrombin group and 3 of 8 in the gabexate mesilate group, but they were not significantly different. ConclusionsAntithrombin may be a more effective treatment for coagulation and fibrinolysis disorders than gabexate mesilate in infection-related DIC, but there was no difference in 28-day mortality.

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

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

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

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

Disseminated Intravascular Coagulopathy in the First 24 Hours After Trauma: The Association Between ISTH Score and Anatomopathologic Evidence

Recent studies questioned "classical" concepts in trauma care, including whether disseminated intravascular coagulation (DIC) occurs in trauma. The knowledge on trauma DIC is limited to few studies built on diagnosing DIC with laboratory-based scores. This study explores whether DIC diagnosed by the well-established ISTH (International Society for Thrombosis and Hemostasis) score is corroborated by anatomopathologic findings. Prospective observational cohort study of severely injured (ISS ≥ 16) patients. DIC was diagnosed by the ISTH score throughout the first 24 hours after trauma. All organs surgically removed within 24 hours of trauma were reviewed by two independent pathologists. All autopsy reports were reviewed. Of 423 patients enrolled, ∼11% had "overt DIC" and 85% had "suggestive of non-overt DIC" scores throughout the 24 hours after trauma. "Overt DIC" patients had higher mortality and worse bleeding, receiving more blood and plasma transfusions. One hundred and sixteen patients underwent surgery within 24 hours of trauma, and all 40 excised organs were reviewed by two pathologists. Twenty-seven autopsies reports were reviewed. No anatomopathologic evidence of DIC was identified in the first 24 hours, even after additional histochemical staining. d-dimer was universally elevated after trauma. Common DIC features: platelet count, fibrinogen, clotting time, and factor VIII drop were mostly absent. d-dimer has a disproportional participation in trauma DIC scores. Within 24 hours of trauma, most severely injured patients have DIC scores "suggestive for" or of "overt DIC" but no anatomopathologic evidence of DIC. Considering pathologic findings as the gold standard diagnosis, then DIC is exceptionally uncommon and the ISTH score should not be used for trauma.

Delta neutrophil index as an early marker of disease severity in critically ill patients with sepsis

BackgroundThe immature granulocyte count has been reported to be a marker of infection and sepsis. The difference in leukocyte subfractions (delta neutrophil index, DNI) in ADVIA 2120 reflects the fraction of circulating immature granulocytes in the blood. This study evaluated the clinical utility of DNI as a severity and prediction marker in critically ill patients with sepsis.MethodsOne hundred and three patients admitted to the medical intensive care unit with sepsis were studied. DNI (the difference in leukocyte subfractions identified by myeloperoxidase and nuclear lobularity channels) was determined using a specific blood cell analyzer.ResultsForty four patients (42.7%) were diagnosed with severe sepsis/septic shock. Overt disseminated intravascular coagulation (DIC) occurred in 40 (38.8%). DNI was significantly higher in patients with severe sepsis/septic shock and overt DIC than in patients without (p < 0.05). DNI correlated with DIC score (r = 0.54, p < 0.001). We observed a monotonic increase in the proportion of overt DIC and severe sepsis/septic shock associated with increasing quartiles of DNI (p < 0.001). A DNI value > 6.5% was a better indicator of severe sepsis/septic shock than C-reactive protein, lactate, white blood cell count, and absolute neutrophil count (sensitivity, 81.3%; specificity, 91.0%; positive predictive value, 88.6%; and negative predictive value, 84.7%). In 36 (82%) of the 44 patients with severe sepsis/septic shock, DNI values were already elevated up to 12 hours before the onset of organ/circulatory failure.ConclusionsDNI may be used as a marker of disease severity in critically ill patients with sepsis. High levels of DNI may help to identify patients with an impending risk of developing severe sepsis/septic shock.

Evaluation of the Diagnostic Performance of Fibrin Monomer in Disseminated Intravascular Coagulation

BackgroundFibrin-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.MethodsThe 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.ResultsThe reference limit in the control individuals was determined to be 7.80 µg/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.ConclusionsThis 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.

Validating the incidence of coagulopathy and disseminated intravascular coagulation in patients with traumatic brain injury – analysis of 242 cases

Objectives: To estimate the incidence of coagulopathy and disseminated intravascular coagulation (DIC) in patients with traumatic brain injury (TBI) and to investigate its relationship to patient outcome.Design: A prospective observational study.Measurements and main results. From January 2007 to June 2009, 242 consecutive adult patients with TBI seen in three independent hospitals were recruited. Glasgow Coma Score (GCS) on admission, platelet counts (PLT), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), d-dimer (D-DT) and DIC scores were recorded for each case on admission. Clinical outcome was measured according to the Glasgow Outcome Scale (GOS) at 3 months after injury. Statistical analysis was carried using Student's t-test, one-way analysis of variance (ANOVA), and Tudey test. Coagulation abnormalities were present in approximately 50% of patients with TBI. Prolonged PT and increased D-DT and FIB levels occurred in patients with more severe brain injury and poorer outcome, and these findings were statistically significant.Conclusions: Coagulation changes, particularly the incidence of DIC, may occur within 6 h after TBI and are more pronounced in patients with severe injuries and poor outcome. PT, D-DT levels and more comprehensively a DIC scores may be useful prognostic indicators in patients with TBI.

Prospective external validation of the new scoring system for disseminated intravascular coagulation by Japanese Association for Acute Medicine (JAAM)

Introduction A new disseminated intravascular coagulation (DIC) scoring system was recently announced by Japanese Association for Acute Medicine (JAAM). We have conducted a prospective external validation study to assess the accuracy of this scoring system. Materials and methods All patients admitted to the ICU in a tertiary academic hospital in 2007 were prospectively observed. All patients younger than 15 years of age, those who stayed in the ICU for less than 24 hours, had cardiac surgery, hematological diseases, recent chemotherapy or radiotherapy or liver cirrhosis were excluded. The remaining patients were then screened using the JAAM DIC scoring system. Results DIC was diagnosed by the JAAM DIC scoring system in 45 of the 242 patients screened (18.6%). The DIC patients were older, had a higher Acute Physiology and Chronic Health Evaluation (APACHE) II score and stayed in the ICU longer in comparison to the non-DIC patients. However, hospital mortality was similar between the two groups (p = 0.98). There was no difference in the JAAM DIC score between the surviving and non-surviving DIC patients (p = 0.40). A multivariate logistic regression analysis revealed the DIC diagnosed by JAAM to have a non-significant low odds ratio for hospital mortality (OR 0.29, 95% CI 0.08-1.08, p = 0.066). Conclusion We have reported an external validation study of the JAAM DIC scoring system, which was conducted outside of the centers where data for developing the score were collected. DIC diagnosed by this scoring system was not related to hospital mortality.

Choline or CDP-choline attenuates coagulation abnormalities and prevents the development of acute disseminated intravascular coagulation in dogs during endotoxemia

Sepsis/endotoxemia causes platelet dysfunctions, abnormalities in coagulation and hemostatic mechanisms leading to organ dysfunctions and mortality. Choline prevents organ injury and improves survival during endotoxemia. The main objective of the present study was to determine the effects of choline or cytidine-5'-diphosphocholine (CDP-choline) on endotoxin-induced activation of coagulation and development of disseminated intravascular coagulation (DIC). Dogs were treated intravenously (i.v.) with saline, choline (20 mg/kg), or CDP-choline (70 mg/kg) three times with 4-h intervals starting 5 min before i.v. injection of endotoxin (1 mg/kg). Platelet counts and functions, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, coagulation factors, D-dimer and antithrombin (AT) were measured before and at 0.5-96 h after endotoxin. Circulating platelet, fibrinogen, coagulation factors and AT were decreased, whereas PT and aPTT were prolonged and serum D-dimer levels were elevated after endotoxin. Endotoxin-induced reductions in platelet counts and functions, fibrinogen, coagulation factors and AT were attenuated or blocked by choline or CDP-choline. Choline or CDP-choline blocked endotoxin-induced prolongation in PT and aPTT and enhancement in D-dimer. Elevated DIC scores were attenuated by choline and blocked by CDP-choline. Choline administration increased serum choline concentrations and caused bradycardia. Choline also increased choline and acetylcholine contents of circulating mononuclear cells and inhibited radioligand binding to their cholinergic receptors. These data show that choline administration, as choline chloride or CDP-choline, restores the abnormalities in the primary, secondary, and tertiary hemostasis and prevents the development of DIC during experimental endotoxemia in dogs probably by increasing both neuronal and non-neuronal cholinergic activity.

Massive pulmonary embolism leading to cardiac arrest is associated with consumptive coagulopathy presenting as disseminated intravascular coagulation.

A consumptive coagulopathy resembling disseminated intravascular coagulation (DIC) has been seen in patients with massive pulmonary embolism (PE). We hypothesized that a DIC-like condition is relevant in patients whose pulmonary embolism leads to cardiopulmonary arrest and cardiopulmonary resuscitation (CPR). This hypothesis was tested by the use of a database consisting of all cases of PE diagnosed at the Department of Emergency Medicine from June 1993 to October 2007. Out of 1018 cases with PE, 113 patients underwent CPR. In this cohort study, the resuscitated patients were compared with those with PE but without CPR. Patients with PE and CPR had 3-fold higher D-dimer, prolonged prothrombin time (PT), reduced platelet counts and lower fibrinogen and antithrombin (AT) levels compared with PE patients without cardiac arrest (P < 0.001 for all). Among patients with PE and CPR, D-dimer was abnormal in 100%, PT in 44%, AT in 53%, fibrinogen in 19% and platelets in 25%. In comparison, PE without CPR was associated with abnormal D-dimer in 99%, abnormal PT in 15%, low AT in 6%, low fibrinogen in 1% and low platelets in 2%. Nine per cent of the resuscitated patients had a DIC score >or= 5, indicating overt DIC. The DIC score highly correlated with 1-year and in-hospital mortality. Massive PE leading to CPR is associated with consumptive coagulopathy and overt DIC. In resuscitated patients, DIC markers may indicate pulmonary embolism as the underlying cause of arrest.

Anti-Heparin/PF4 Complexes by ELISA in Patients with Disseminated Intravascular Coagulation

Heparin-induced thrombocytopenia (HIT) is known to complicate disseminated intravascular coagulation (DIC), but rarely to be complicated by DIC. We measured the titers of anti-PF4/hepatin complex antibodies by ELISA (HIT-Elisa) and examined 4 parameters of coagulation and fibrinolysis [D-dimer, thrombin/antithrombin complex (TAT), plasmin/α2-plasmin inhibitor complex (PIC), and antithrombin levels] in 80 patients with DIC diagnosed by a DIC scoring system. Fourteen patients were HIT-Elisa-positive, 11 of whom received heparin. In 3 of these 11 patients, platelet counts were ≤10 × 10⁹/l and/or reduced by more than 50% for 5–10 days after the heparin (2 patients treated with renal replacement therapy for chronic uremia and postoperative renal failure, and 1 with DIC from a solid tumor). The 3 patients had an optical density reading of >1.0 and a high level of IgG for HIT antibodies, and were thus considered to have DIC complicated with HIT (DIC-HIT). The other 8 patients had optical density readings of 0.4–1.0, and it was unclear whether their thrombocytopenia was caused by HIT alone or by sustained DIC. There were no significant differences in platelet counts and the 4 parameters of coagulation and fibrinolysis between the patients with DIC-HIT and DIC patients with a weakly positive result (0.4–1.0). No differences were observed in platelet counts, or levels of D-dimer and antithrombin between HIT-Elisa-positive and -negative DIC patients. However, the HIT-Elisa-negative patients showed significantly higher levels of TAT and PIC, presumably reflecting DIC-related hypercoagulability. In conclusion, DIC patients treated with heparin occasionally showed HIT antibody seroconversion and developed HIT. HIT-Elisa could assist in the diagnosis of HIT.

Circulating hepatocyte growth factor as an independent prognostic factor of disseminated intravascular coagulation

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.

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.