Onset Of Disseminated Intravascular Coagulation Research Articles

Disseminated Intravascular Coagulation in Anaphylaxis.

Anaphylaxis is a life-threatening condition that involves severe cutaneous, respiratory, and cardiovascular symptoms. Disseminated intravascular coagulation (DIC) is an acquired, widespread activation of coagulation that can be caused by infectious conditions (e.g., sepsis) and noninfectious conditions. The onset of DIC following anaphylaxis is not commonly known, and information regarding the pathomechanism linking anaphylaxis to DIC is scarce. Further, demographic and clinical data in anaphylaxis-induced DIC are still missing to this day. Triggered by a case of anaphylaxis-induced DIC that seamlessly transitioned to lethal sepsis-induced DIC, we aimed to characterize the patient population affected by anaphylaxis-induced DIC by performing a review of existing literature and expand the discussion to underlying mechanisms. The overall mortality of the patient cohort (n = 30) identified by the literature review was 50%. All patients that died either suffered a bleeding event or a thrombotic event. The majority of patients (n = 25/30; 83%) had bleeding events; thrombotic events were only reported in nonsurvivors (n = 9/15 or 60% of nonsurvivors; vs. n = 0/15 in survivors; p < 0.001). Nonsurvivors of anaphylaxis-induced DIC were on average 25 years older than survivors (p = 0.068). In conclusion, DIC can complicate anaphylaxis and is expected to contribute to poor microvascular perfusion after anaphylaxis. Particularly, elderly patients with known cardiovascular disease and patients who develop thrombotic events are susceptible to lethal outcomes. As a rare and largely uncharacterized disease entity, further research is needed to investigate the link between DIC and anaphylaxis and to potentially identify better treatment strategies.

Identification of hemostatic markers that define the pre‐DIC state: A multi‐center observational study

BackgroundA limitation of diagnostic scoring systems for disseminated intravascular coagulation (DIC) is that once DIC is identified, it may be in a state of irreversible deterioration. ObjectivesTo identify hemostatic markers that can identify the pre‐DIC state. MethodsThis was a multi‐center observational study of 357 septic patients. The incidence of DIC was determined using the International Society on Thrombosis and Haemostasis (ISTH) DIC Score. Markers of interest include components of the DIC score: protein C (PC), antithrombin (AT), and citrullinated histones (H3Cit), which is a marker of NETosis. ResultsOut of 357 sepsis patients, 236 patients did not develop DIC (without‐DIC), 79 patients had DIC on Day 1 (overt‐DIC), and 42 patients developed DIC after Day 1 (pre‐DIC). Compared to without‐DIC patients, pre‐DIC patients had decreased platelet count, increased international normalized ratio (INR), decreased PC and AT, and increased H3Cit. In contrast, D‐dimer and fibrinogen levels did not differ between pre‐DIC and without‐DIC patients. Using receiver operating characteristics (ROC) analysis, we found that platelet count and INR in combination with PC and AT could discriminate pre‐DIC from without‐DIC. The area under the curve in the ROC analysis was 0.83 (95% confidence interval, 0.76 to 0.89). ConclusionOur study suggests that platelets and INR in combination with PC and AT can identify the pre‐DIC state in septic patients. In contrast, D‐dimer increased and fibrinogen decreased in the late (ie, overt) stages of DIC. Our data also suggest that NETosis contributes to the onset of DIC in sepsis.

Plasma Endothelial Glycocalyx Components as a Potential Biomarker for Predicting the Development of Disseminated Intravascular Coagulation in Patients With Sepsis.

Sepsis coagulopathy or disseminated intravascular coagulation (DIC) mainly due to progressive endothelial disruption and damage. The glycocalyx is expressed on the endothelial cell surface and contributes to anti-thrombogenicity, anti-inflammatory, and regulates vascular permeability. We aimed to evaluate the clinical utility of plasma glycocalyx components as biomarkers in predicting the onset of DIC in sepsis. This was a prospective observational study of 45 patients with sepsis (June to December 2018). Demographic, clinical (Acute Physiology, Age, Chronic Health Evaluation II [APACHE II], Sequential Organ Failure Assessment [SOFA]), and laboratory data from medical records were analyzed. Endothelial glycocalyx components (syndecan-1, heparan sulfate, hyaluronan) were measured using an ELISA kit. Among the 45 patients (23, sepsis; 22, septic shock), plasma syndecan-1, heparan sulfate, and hyaluronan levels were higher in those with septic shock and were positively correlated with disease severity as determined by the APACHE II and SOFA scores and lactate levels. Receiver operating characteristic curve analysis revealed high sensitivity and specificity of syndecan-1 for predicting septic shock. Further, these levels were compared between patients with or without the development of DIC. Plasma syndecan-1 and hyaluronan levels were significantly elevated in patients with DIC compared to those in patients without DIC and were strongly associated with activated partial thromboplastin time, prothrombin time, and platelet counts. Area under the curve values for predicting DIC based on syndecan-1 and hyaluronan levels measurements were 0.774 and 0.740, respectively. Increased plasma syndecan-1 and hyaluronan levels may be indicators of disease severity and useful predictors for DIC development in sepsis.

Drug-induced disseminated intravascular coagulation: a pharmacovigilance study on World Health Organization's database.

Disseminated intravascular coagulation (DIC) occurs in several clinical conditions, including drug therapy. We aim to investigate the association between the administration of several drug classes and the onset of DIC by using the reports of Adverse Drug Reactions (ADR) collected in Vigibase, the World Health Organization (WHO) database of ADR. We collected reports of drug-related DIC from 1968 to September 2015, classified in Vigibase according to the MedDRA (Medical Dictionary for Regulatory Activities) term "Disseminated intravascular coagulation". A disproportionality analysis using Reporting Odds Ratio (ROR) with 95% Confidence Interval (CI95%) was performed. Overall, 4653 reports of drug-associated DIC were retrieved and the 75.9% of them was serious according to WHO seriousness criteria. DIC was significantly (ROR > 1, lower limit of CI95% > 1) associated with 88 drugs, mainly antineoplastic agents, antithrombotic agents and antibacterials for systemic use. Among of the most frequently reported individual drugs we found dabigatran (94 reports) ROR = 1.34 (CI95% 1.08-1.67), oxaliplatin and bevacizumab both with 75 reports and ROR = 1.77 (1.38-2.27) and 2.02 (1.57-2.61), respectively. A substantial number of drugs, widely used in the clinical practice, may be associated with the potential occurrence of DIC. For many of these drugs, the ADR is not acknowledged in the corresponding Summary of Product Characteristics. The high number of drugs involved underlines the importance of evaluate this condition such as an ADR that might occur during drug therapy.

Neutrophil Extracellular Traps in the Development of Sepsis-Induced Disseminated Intravascular Coagulation

Introduction: Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by widespread intravascular activation of coagulation complicating many conditions including sepsis and traumatic injuries. Early recognition and treatment of DIC is of paramount importance. However, to date no useful markers have been identified that can differentiate “pre-DIC” (which is destined to lead to DIC) from “without-DIC” (in which the hypercoagulable state is transient and does not lead to DIC). Activation of neutrophils by inflammatory stimuli or microbes results in the release of neutrophil extracellular traps (NETs). NETs are web-like structures consisting of cell-free DNA (cfDNA), histones, myeloperoxidase (MPO), and anti-microbial proteins. Although NETs aid in the host response to infection by sequestering pathogens, excessive production of NETs can exert collateral damage to the host by activating coagulation, inhibiting fibrinolysis, and causing endothelial cell death. Recently, sepsis-induced DIC has been shown to correlate with circulating levels of DNA-associated MPO, suggesting that the release of NETs by neutrophils plays a critical role in the onset of DIC. Our objective was to attempt to identify a mechanistic role for NETosis in the development DIC in sepsis and use this information to identify ‘pre-DIC’ signatures.Methods: Clinical data and biological samples from 357 septic patients who were part of the DNA as a Prognostic Marker in ICU patient (DYNAMICS) study were used. Incidence of DIC was determined using the International Society on Thrombosis and Haemostasis (ISTH) scoring system on Day 1 and each subsequent day. We quantified levels of Citrullinated Histone H3 (H3Cit), a biomarker of NETosis, as well as levels of cfDNA. We also measured levels of Protein C (PC), a natural anticoagulant that prevents blood clotting in the microcirculation. Increased consumption of PC is a hallmark of sepsis and may lead to microvascular thrombosis and DIC.Results: Of the 357 patients included from the DYNAMICS study, 121 were classified as having DIC during the study period: 79 on Day 1 ('overt-DIC') and 42 on a subsequent day ('pre-DIC'). Baseline characteristics of patients are shown in Table 1. Those with DIC had significantly higher baseline APACHE II scores and were significantly more likely to be on vasopressors at admission or have a history of chronic liver disease. DIC was associated with significantly increased mortality (HR= 2.53; 95% CI = 1.62 - 3.93; p < 0.001) even when age and past medical history were controlled for. Levels of PC were significantly reduced in patients with DIC at all time points compared to those without DIC (p < 0.01). However, cfDNA levels did not differ between patients with and without DIC at any timepoint. As cfDNA may be released by multiple mechanisms and sources, H3 Cit was quantified on Day 1 as a marker of NETosis. Levels of H3 Cit on Day 1 were significantly higher in “pre-DIC” and “overt-DIC” patients compared to those 'without DIC' (p<0.05), non-septic, non-trauma ICU Controls (p<0.01), and healthy volunteers (p<0.001) (Figure 1). With respect to differentiating ‘pre-DIC’ from ‘overt-DIC’, using Day 1 H3 Cit provided an AUC of 0.66 (0.59-0.74). Higher H3 Cit levels were also correlated with lower PC levels in septic patients (r = -0.124; p = 0.02). In a comparison group of non-septic trauma patients also from the DYNAMICS study; (n=6) patients with DIC did not have significantly different Day 1 H3 Cit from (n=25) trauma patients without DIC (p=0.62) or ICU controls (p=0.99).Conclusion: In sepsis, DIC pathophysiology reflects a consumptive process as indicated by reduced PC levels. NETosis may contribute to this process by producing pro-coagulant stimuli and may prove useful in identifying patients who will develop DIC. As a regulated and targetable process investigations involving NETosis may yield therapies for early treatment of DIC in sepsis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Fibrinogen / CRP Ratio as a New Parameter for the Prediction of Disseminated Intravascular Coagulation in Patients with HELLP Syndrome

Background: The syndrome of Hemolysis, elevated Liver enzymes, and Low Platelet count (HELLP) is a life-threatening variant of preeclampsia, and may be accompanied by disseminated intravascular coagulation (DIC). Recently the fibrinogen/C-reactive protein (CRP) ratio has been suggested as a measurement that predicts onset of DIC. The authors sought to analyze the fibrinogen/CRP ratio among obstetric patients who developed DIC due to HELLP syndrome. Aim: the aim of this study is to determine if the fibrinogen/C-reactive protein (CRP) ratio could be used as a predictor for disseminated intravascular coagulation in obstetrics patients with the HELLP syndrome. Patients and Methods: this study was conducted as a prospective observational study at Ain Shams Maternity Hospital from November 2014 to November 2016 .The study included Patients diagnosed to have Severe Pre Eclamptic Toxemia SPET according to ACOG (2013).Patients was diagnosed with the HELLP syndrome according to the Martin classification of HELLP syndrome. Results: the results of our study suggest that replacing the use of fibrinogen levels alone with the fibrinogen/CRP ratio would enhance the diagnostic and prognostic power for DIC in patients with HELLP syndrome. Conclusion: in light of the physiologic changes of the coagulation cascade during gestation, the International Society on Thrombosis and Hemostasis ISTH score could not be implemented in pregnant women alone for the diagnosis and prediction of DIC. Recommendations: further evaluation of the fibrinogen/ CRP ratio is required to determine the generalizability of this marker’s use in DIC because of causes such as placental abruption, septic abortion, and failed abortion. Furthermore, prospective studies should be performed to determine the best method to predict if there any new method to predict DIC in patients with the HEELP syndrome.

Consumptive Coagulopathy after Commencement of Continuous Renal-Replacement Therapy in Patients with Decompensated Cirrhosis: A Case Series

Over a four-month period, three patients with ascites and hyponatraemia secondary to decompensated cirrhosis were admitted to the Intensive Care unit (ICU) of a quaternary referral centre for liver disease and transplantation for further management. Each had a stable documented coagulopathy without bleeding on ICU admission. Following commencement of anticoagulant-free continuous renal replacement therapy (CRRT), a severe bleeding diathesis developed in all three patients necessitating transfusion of large volumes of blood products. The clinical presentation and results of detailed coagulation profiles and thromboelastography (TEG) were consistent with the development of disseminated intravascular coagulation (DIC) with hyperfibrinolysis. The onset of DIC in all three cases was associated with significant morbidity. One patient went on to receive an orthotopic liver transplant (OLT) and death was the end result in the subsequent two cases. Due to the temporal relationship, we hypothesise that the initiation of CRRT may have contributed to the derangement in coagulation status in these patients. Though the exact mechanism is uncertain, it may be related to a higher rate of adsorption of high molecular weight kinins or the CRRT membrane’s ability to bind endogenous heparinoids. These cases highlight the precarious nature of the coagulation cascade in patients with decompensated cirrhosis. Initiation of CRRT may profoundly disrupt that tenuous balance and should be preceded by careful consideration of the potential complications including DIC and its associated morbidity.

Transgenic mice overexpressing arginase 1 in monocytic cell lineage are affected by lympho-myeloproliferative disorders and disseminated intravascular coagulation.

Arginase (ARG) is a metabolic enzyme present in two isoforms that hydrolyze l-arginine to urea and ornithine. In humans, ARG isoform 1 is also expressed in cells of the myeloid lineage. ARG activity promotes tumour growth and inhibits T lymphocyte activation. However, the two ARG transgenic mouse lines produced so far failed to show such effects. We have generated, in two different genetic backgrounds, transgenic mice constitutively expressing ARG1 under the control of the CD68 promoter in macrophages and monocytes. Both heterozygous and homozygous transgenic mice showed a relevant increase in mortality at early age, compared with wild-type siblings (67/267 and 48/181 versus 8/149, respectively, both P < 0.005). This increase was due to high incidence of haematologic malignancies, in particular myeloid leukaemia, myeloid dysplasia, lymphomas and disseminated intravascular coagulation (DIC), diseases that were absent in wild-type mice. Atrophy of lymphoid organs due to reduction in T-cell compartment was also detected. Our results indicate that ARG activity may participate in the pathogenesis of lymphoproliferative and myeloproliferative disorders, suggest the involvement of alterations of L-arginine metabolism in the onset of DIC and confirm a role for the enzyme in regulating T-cell homeostasis.

Soluble Recombinant Thrombomodulin Is a Potentially Promising Agent without Causing Severe Hemorrhagic Events for Hematological Malignancy-Induced Disseminated Intravascular Coagulation

AbstractAbstract 3413 Background:Disseminated intravascular coagulation (DIC) is a lethal complication in patients with hematological malignancies. Although standard therapy against DIC remains to be established, soluble recombinant thrombomodulin (rTM), which serves as a receptor for thrombin, has been developed and its effectiveness for DIC was recently reported (Saito et al, J Thromb Haemost 2006). We retrospectively analyzed 55 DIC episodes treated with rTM in patients with hematological malignancies. Patients and Methods:55 consecutive DIC episodes in 47 patients with hematological malignancies (AML except for APL, 21; APL, 8; ALL, 8; lymphoma, 8; myeloma, 2) hospitalized between November 2009 and July 2012 in University of Tsukuba Hospital were retrospectively analyzed. Diagnosis of DIC was based on DIC score of Japanese Ministry of Health and Labor Welfare criteria (Kobayashi et al, Bibl Haematol 1983). DIC was induced by hematological malignancy itself and severe infection secondary to hematological malignancy in 39 and 16 episodes, respectively. In every episode, 380 units/kg/day of rTM was administered intravenously from the onset of DIC for median of 7 (range, 2–22) days. The fibrin degradation products (FDP) level, DIC score, recovery time from DIC (recovery, the day when DIC score was decreased to 5 or less), and overall survival were analyzed. Results:Median DIC score at the onset was 7 (range, 6–11). 15 episodes were accompanied by bleeding tendency. Average of FDP level at the onset was 64.6 ƒE′g/dl (range, 20.6–202.4) in malignancy-induced DIC and 30.1 ƒE′g/dl (range, 13.2–72.0) in infection-induced DIC (P=0.03). FDP level 14 days after rTM administration was 10.1 ƒE′g/dl (SD: 3.7–27.9) and 20.3 ƒE′g/dl (SD: 9.3–44.3), respectively (P=0.04). Recovery rates from DIC 7 days after rTM administration were 72% in malignancy-induced DIC and 39% in infection-induced DIC (Fig. 1, P=0.02), and 100-day overall survival after the onset of DIC were 89% and 15% (Fig. 2, P<0.01), respectively. In multivariate analysis, infection-induced DIC was an only significant risk factor and presence of bleeding tendency, FDP level at the onset, DIC score at the onset, period of rTM administration, and number of rTM administration did not influence the recovery from DIC and overall survival. There were no severe hemorrhagic events after rTM administration or deterioration of bleeding tendency that led to discontinuation of rTM. Discussion and Conclusion:The recovery rate from hematological malignancy-induced DIC in the current cohort was comparable to that of rTM-treated DIC group (66%) and can be superior to that of heparin-treated DIC group (50%) in a previously reported phase III trial (Saito et al, J Thromb Haemost 2006). Although the use of heparin has fostered bleeding tendency in a number of previous DIC reports, bleeding tendency was reduced after rTM administration in all the DIC episodes analyzed with the current cohort. Therefore, this analysis traced the core conclusion of the previous phase III trial, emphasizing that rTM can be an effective anti-DIC agent without causing adverse hemorrhagic event even in DIC cases with preexisting bleeding tendency. However, the result was still significantly worse in infection-induced DIC secondary to hematological malignancies. [Display omitted] [Display omitted] Disclosures:Chiba:Asahi Kasei Pharma: Research Funding.

Diagnostic Criteria and Laboratory Tests for Disseminated Intravascular Coagulation

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

Frequency and hemostatic abnormalities in pre-DIC patients

Disseminated intravascular coagulation (DIC) sometimes has a poor outcome, and therefore early diagnosis and treatment are required. This study prospectively evaluated the hemostatic abnormalities and the onset of DIC in 613 patients with underlying diseases to identify a useful marker for diagnosing Pre-DIC. Pre-DIC was defined as the condition of patients within a week before the onset of DIC. Initially, 34.4% of patients were diagnosed with DIC, and about 8.5% of the patients without DIC were diagnosed as DIC within a week after registration (pre-DIC). The mortality of DIC, Pre-DIC and “without DIC” was 35.3%, 32.4% and 17.2%, respectively. All hemostatic parameters were significantly worse in “DIC” than “without DIC” and the values of the prothrombin time ratio, platelet count and fibrin monomer complex could classify the three groups; “DIC”, “pre-DIC” and “without DIC”. No useful marker was identified that provided an adequate cutoff value to differentiate “pre-DIC” from “without DIC”. A multivariate analysis identified clinical symptoms that were related to poor outcome. DIC must be treated immediately; there is no specific marker to identify pre-DIC.

Evaluation of Non Overt DIC Diagnostic Criteria.

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

A Rare Presentation of Gastric Adenocarcinoma with Acute Pulmonary Embolism and Fatal Acute Disseminated Intravascular Coagulation

Acute disseminated intravascular coagulation (DIC) is a rare but serious complication of malignancies. There are no standard treatment protocols to treat acute DIC in a setting of malignancy. However, there are some reports of using various combinations of chemotherapy with successful results. We report a rare case of poorly differentiated gastric adenocarcinoma initially complicated by deep vein thrombosis and pulmonary embolism (PE) with subsequent fatal acute DIC. Case report: A 57 year-old African American male presented with dysphagia, weight loss and left upper extremity swelling. His medical history included hypertension, chronic renal insufficiency and remote history of Billroth-type I gastrectomy for duodenal ulcer. Physical exam was significant for thin and malnourished male with an enlarged left supraclavicular lymph node. A bilateral upper extremity venous doppler ultrasonography showed thrombosis of the left internal jugular, left subclavian, and left brachiocphalic veins. The ventilation perfusion (VQ) scan was performed and confirmed abnormal ventilation and perfusion defect with high probability of PE involving the right middle lobe. Esophagogastroduodenoscopy (EGD) was subsequently performed and revealed distal esophageal ulceration along with marked thickening and erythema of the gastric mucosa. Gastric biopsies revealed poorly differentiated adenocarcinoma with signet cell features. He was started on coumadin treated symptomatically. Two months after initiation of oral anticoagulation, the patient developed hematemasis. His laboratory findings were significant for coagulopathy with elevated protrhombin time and partial thromboplastin time along with thrombocytopenia and marked hemolytic anemia. Acute DIC was confirmed on subsequent hematologic analyses. Anticoagulant was stopped and he was treated with blood and blood product transfusions. Moreover, high dose 5-fluorouracil (5-FU) and leucovorin was initiated to control DIC. Despite intensive medical interventions patient's expired eighth days after the onset of DIC. Our case illustrates the extremely rare presentation of gastric adenocarcinoma with both hypercoagulable state and subsequent acute DIC. Although high doses of 5-FU and leucovorin have previously been reported to successfully treat malignancy related acute DIC leading to prolong survival, the treatment was not helpful in our patient.

Plasma levels of heparin cofactor II (HCII) and thrombin-HCII complex in patients with disseminated intravascular coagulation.

Plasma levels of heparin cofactor II (HCII), thrombin-HCII complex (THC), antithrombin (AT), and thrombin-AT complex (TAT) were evaluated in patients with disseminated intravascular coagulation (DIC) associated with several underlying diseases. Plasma levels of AT were significantly reduced in almost all underlying diseases associated with DIC, but the plasma levels of HCII and HCII/AT ratio were significantly reduced only in patients with infections. While the plasma level of TAT was significantly increased in patients with all underlying diseases associated with DIC, the increase of THC was not significant. Plasma levels of AT were significantly reduced in DIC and pre-DIC associated with almost all underlying diseases, but those of HCII were significantly reduced only in DIC and pre-DIC patients with inflammatory diseases. The plasma levels of TAT were significantly increased in DIC, pre-DIC, and non-DIC patients with all underlying diseases, and those of THC were significantly increased in DIC and pre-DIC patients with inflammatory diseases. The plasma levels of THC were not significantly increased in non-DIC patients of any disease group. The decrease of AT may be caused by thrombin generation or inflammatory reaction that occurs in DIC associated with underlying diseases, while the decrease of HCII might be caused by both thrombin generation and inflammatory reaction. Finally, AT inhibits thrombin more strongly than HCII in several underlying diseases associated with DIC except for inflammatory diseases. In inflammatory diseases, HCII might play an important role in preventing the onset of DIC.

Hemostatic molecular markers before the onset of disseminated intravascular coagulation.

We retrospectively measured various hemostatic markers in 240 patients with disseminated intravascular coagulation (DIC) before the onset of DIC and in 110 non-DIC patients, and examined their usefulness for the diagnosis of pre-DIC. Changes in prothrombin time ratio and fibrinogen levels were not significant before the onset of DIC. The plasma levels of fibrinogen and fibrin degradation products before the onset of DIC were increased and the platelet count was gradually reduced in nonleukemic patients; these changes were already significant in the non-DIC state. The plasma levels of thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), D-dimer, and soluble fibrin monomer (sFM) were increased before the onset of DIC. In leukemic patients, the plasma levels of sFM on day 5, those of TAT on day 3, and D-dimer on day 1, were significantly increased before the onset of DIC. The levels of most hemostatic markers 7 days before the onset of DIC were not different from those observed in the non-DIC state. In nonleukemic patients, only D-dimer, sFM, and TAT levels were significantly increased 7 days before the onset of DIC compared with values in the non-DIC state. The positive rate of hemostatic markers for the diagnosis of DIC, TAT, and PPIC were high during the pre-DIC and non-DIC groups. The plasma levels of sFM and D-dimer were low in non-DIC and increased gradually during the pre-DIC state. These findings suggest that hemostatic molecular markers such as sFM, D-dimer, and TAT are useful for the diagnosis of pre-DIC, although their cutoff values were different among various diseases.

Changes in plasma tissue factor pathway inhibitor levels during the clinical course of disseminated intravascular coagulation.

In healthy volunteers, the plasma total tissue factor pathway inhibitor (TFPI) level was 68.7+/-14.1 ng/ml; the plasma free TFPI level, 17.7+/-5.4 ng/ml; the lipoprotein-associated TFPI (LP-TFPI), 51.1+/-12.0 ng/ml; the free TFPI/total TFPI ratio 0.26+/-0.07; and the plasma tissue factor levels were 149+/-46 pg/ml. Plasma tissue factor levels in patients with disseminated intravascular coagulation (DIC) were significantly higher than those in pre-DIC patients or in non-DIC patients. Plasma total-TFPI, free-TFPI and LP-TFPI levels were significantly higher in DIC patients than those in pre-DIC patients or in non-DIC patients. Before the onset of DIC, the plasma levels of tissue factor gradually increased, and 3 days before the onset of DIC they were significantly higher than those in non-DIC patients. The plasma levels of tissue factor reached their highest level 1 day before the onset of DIC and gradually decreased after the onset of DIC. Plasma levels of total-TFPI, free-TFPI, and LP-TFPI gradually increased before the onset of DIC, and the total-TFPI and LP-TFPI reached their highest levels at the onset of DIC. Plasma free-TFPI reached highest level one day after the onset of DIC. During the clinical course of DIC, the plasma level of tissue factor was the first to increase, then that of LP-TFPI and finally the free-TFPI plasma levels. These differences in the peak plasma levels of tissue factor, free-TFPI, and LP-TFPI might be related to the clinical course of DIC.

Hemostatic molecular markers before onset of disseminated intravascular coagulation in leukemic patients.

The changes in various hemostatic parameters were examined within a period from 7 days before the onset of disseminated intravascular coagulation (DIC) in 114 patients (i.e. in their pre-DIC state). The changes in prothrombin time (PT) ratio and fibrinogen levels were not significant before the onset of DIC. Plasma fibrinogen and fibrin degradation products (FDP) levels before the onset of DIC were high, but these changes were already significant in 110 non-DIC patients examined. Plasma thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), D-dimer and soluble fibrin monomer (SFM) levels were high before the onset of DIC. In the 110 leukemic DIC patients, the plasma SFM levels were significantly increased 5 days before, the plasma TAT levels were significantly increased 3 days before, and the D-dimer levels were significantly increased 1 day before the onset of DIC. The plasma tissue factor and plasminogen activator inhibitor-I levels were not significantly changed before the onset of DIC. The PT ratio, fibrinogen, FDP, platelet count, antithrombin, D-dimer, and PPIC levels at 7 days before the onset of DIC were not significantly different from the corresponding values in the non-DIC group, although the hemostatic molecular markers SFM, D-dimer, and TAT are useful for the diagnosis of pre-DIC. Plasma thrombomodulin levels were significantly increased in these patients who died, and plasma antithrombin and protein C activities markedly reduced in the patients who died. The outcome of the diseases underlying DIC is related to vascular endothelial cell injuries.

Plasma tissue factor and tissue factor pathway inhibitor levels in patients with disseminated intravascular coagulation.

We measured the plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with disseminated intravascular coagulation (DIC) to examine the relationship between TFPI and vascular endothelial cell injury. Plasma TF (273 +/- 90 pg/ml) and TFPI (252 +/- 125 ng/ml) levels were significantly increased in patients with DIC compared with non-DIC patients. Plasma TF antigen level was significantly increased in pre-DIC patients (285 +/- 85 pg/ml), while the plasma TFPI level (152 +/- 54 ng/ml) was not markedly increased in such a state. The plasma TF/TFPI ratio was high in the pre-DIC patients (2.10 +/- 0.90), and low in the DIC patients (1.40 +/- 0.87) and healthy volunteers (0.84 +/- 0.26). There was no significant difference between the DIC patients with a good outcome and those with a poor outcome in terms of plasma TF levels, although the plasma TFPI level in the DIC patients with a good outcome (289 +/- 133 ng/ml) was significantly higher than those with a poor outcome (187 +/- 75 ng/ml). During the clinical course of DIC, plasma TF antigen was increased first, and an increase of the plasma TFPI level followed the increase in plasma TF level. These findings suggest that plasma TFPI is released from vascular endothelial cells and it may reflect vascular endothelial cell injury. It is conceivable that TF and TFPI may play an important role in the onset of DIC.

Plasma tissue factor and tissue factor pathway inhibitor levels in patients with disseminated intravascular coagulation.

We measured the plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with disseminated intravascular coagulation (DIC) to examine the relationship between TFPI and vascular endothelial cell injury. Plasma TF (273 +/- 90 pg/ml) and TFPI (252 +/- 125 ng/ml) levels were significantly increased in patients with DIC compared with non-DIC patients. Plasma TF antigen level was significantly increased in pre-DIC patients (285 +/- 85 pg/ml), while the plasma TFPI level (152 +/- 54 ng/ml) was not markedly increased in such a state. The plasma TF/TFPI ratio was high in the pre-DIC patients (2.10 +/- 0.90), and low in the DIC patients (1.40 +/- 0.87) and healthy volunteers (0.84 +/- 0.26). There was no significant difference between the DIC patients with a good outcome and those with a poor outcome in terms of plasma TF levels, although the plasma TFPI level in the DIC patients with a good outcome (289 +/- 133 ng/ml) was significantly higher than that in those with a poor outcome (187 +/- 75 ng/ml). During the clinical course of DIC, plasma TF antigen was increased first, and an increase of the plasma TFPI level followed the increase in plasma TF level. These findings suggest that plasma TFPI is released from vascular endothelial cells and it may reflect vascular endothelial cell injury. It is conceivable that TF and TFPI may play an important role in the onset of DIC.

Changes in erythrocyte structure and in platelets in elderly patients with disseminated intravascular coagulation

We measured the platelet distribution width, the mean platelet volume, the volume percentage of platelets, and the platelet-to-large-cell ratio in 15 elderly patients with disseminated intravascular coagulation (DIC). Peripheral venous blood mixed with ehtylenediaminetetraacetic acid was analyzed with a Sysmex E-4000 analyzer. The underlying diseases were sepsis, pneumonia, pyelonephritis, and other inflammatory diseases. The mean duration of survival from the onset of DIC was 16.9 +/- 23.9 days. The distribution of red cell sizes before the onset of DIC did not differ significantly from that in patients without DIC, but fragmentation of erythrocytes on blood films was more common in the early stage of DIC (p < 0.01). Before the onset of DIC, the two groups did not differ significantly in the frequency of giant platelets on blood smears. At the onset of DIC, the platelet distribution width, the mean platelet volume, and the platelet-to-large-cell ratio were significantly higher than in patients without DIC. The concentration of glutamic-oxaloacetic transaminase and those of other serum enzymes did not change significantly, but the serum creatinine concentration and the blood urea nitrogen level increased as the platelet-to-large-cell ratio increased. No significant relation was evident between the levels of serum C-reactive protein and creatinine, between the platelet-to-large-cell ratio and the mean volume of red blood cells, or between the platelet-to-large-cell ratio and the distribution of red cell sizes. These data suggest that studies of platelets are more useful in the diagnosis of DIC at early stages of impaired organ function than are other indicators of inflammation such as the level of C-reactive protein.