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Staphylococci are responsible for many infections in humans, starting with skin and soft tissue infections and finishing with invasive diseases such as endocarditis, sepsis and pneumonia, which lead to high mortality. Patients with sepsis often demonstrate activated clotting pathways, decreased levels of anticoagulants, decreased fibrinolysis, activated endothelial surfaces and activated platelets. This results in disseminated intravascular coagulation and formation of a microthrombus, which can lead to a multiorgan failure. This review describes various staphylococcal virulence factors that contribute to vascular thrombosis, including deep vein thrombosis in infected patients. The article presents mechanisms of action of different factors released by bacteria in various host defense lines, which in turn can lead to formation of blood clots in the vessels., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interests., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Severe urinary tract infections occasionally cause sepsis and disseminated intravascular coagulation (DIC). We examined the efficacy of recombinant thrombomodulin (rTM) for treating DIC caused by urosepsis. We enrolled 40 patients who were diagnosed with DIC caused by urosepsis at our hospital between April 2018 and May 2022. Twenty-six patients were treated with rTM (rTM group), while 14 patients did not receive rTM (non-rTM group). The DIC score before treatment in the rTM group was significantly higher than that in the non-rTM group (P＜0.01). There was no significant difference in disease-specific survival between the two groups. There was a significant improvement in DIC scores on days 1-3 after administering rTM. However, the duration of DIC in the rTM group was significantly longer than that in the non-rTM group (P＝0.038). The administration of rTM may have benefits in patients with DIC caused by urosepsis.

Purpose: The prognostic impact of disseminated intravascular coagulation (DIC) in surgical patients with non-occlusive mesenteric ischemia (NOMI) is unclear. This study aimed to confirm the association between postoperative DIC and prognosis and to identify preoperative risk factors associated with postoperative DIC., Methods: This retrospective study included 52 patients who underwent emergency surgery for NOMI between January 2012 and March 2022. Kaplan-Meier curve analysis with the log-rank test was used to compare 30-day survival and hospital survival between patients with and without postoperative DIC. In addition, univariable and multivariable logistic regression analyses were performed to identify the preoperative risk factors for postoperative DIC., Results: The 30-day and hospital mortality rates were 30.8% and 36.5%, respectively, and the incidence rate of DIC was 51.9%. Compared to patients without DIC, patients with DIC showed significantly lower rates of 30-day survival (41.5% vs 96%, log-rank P < 0.001) and hospital survival (30.2% vs 86.4%, log-rank, P < 0.001). Logistic regression analyses showed that the Japanese Association for Acute Medicine (JAAM) DIC score (OR = 2.697; 95% CI, 1.408-5.169; P = 0.003) and Sequential Organ Failure Assessment (SOFA) score (OR = 1.511; 95% CI, 1.111-2.055; P = 0.009) were independent risk factors for postoperative DIC in surgical patients with NOMI., Conclusion: The development of postoperative DIC is a significant prognostic factor for 30-day and hospital mortalities in surgical patients with NOMI. In addition, the JAAM DIC score and SOFA score have a high discriminative ability for predicting the development of postoperative DIC., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: This study aimed to validate the performance of modified Japanese Association for Acute Medicine (m-JAAM) and simplified Japanese Society on Thrombosis and Hemostasis (s-JSTH) criteria in diagnosing coagulation disorders in sepsis and examine their prognostic value compared with sepsis-induced coagulopathy (SIC) and International Society on Thrombosis and Hemostasis (ISTH) criteria., Methods: This retrospective study included subjects diagnosed with sepsis (August 2020 to February 2021, n = 296). The m-JAAM, s-JSTH, SIC, and ISTH criteria were evaluated and compared using receiver operating characteristic (ROC) curves and areas under the curve (AUCs)., Results: There was no significant difference in AUC for predicting in-hospital 28-day mortality by m-JAAM, s-JSTH, SCI, and ISTH criteria (0.745, 0.763, 0.760, and 0.730, respectively). The proportion of patients fulfilling the m-JAAM and SIC criteria was higher than that of the s-JSTH and ISTH criteria (43.2%, 56.1% vs. 25.0%, 22.6%, P < .05)., Conclusion: The m-JAAM criteria might be more suitable for early-stage disseminated intravascular coagulation of sepsis than s-JSTH criteria., (© The Author(s) 2022. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Clinical characteristics and pathomorphological manifestations in 69 patients aged 18 to 86 years with a fatal outcome of the disease were examined in order to analyze the causes of severe course and high mortality of generalized forms meningococcal infection. It was found that the main clinical form was meningococcemia (90%), in the majority in combination with meningitis (52%). The fulminant course in 77% of patients with meningococcal sepsis manifested itself as a sudden onset, rapid development of typical symptoms. Hemorrhagic exanthema was detected on the first day of meningococcemia. The leading complications and critical conditions were infectious-toxic shock, disseminated intravascular coagulation and acute adrenal insufficiency (Waterhouse-Friederiksen syndrome). The severe course of meningitis (in 10%) led to the development of cerebral coma, the morphological substrate of which was edema - swelling of the brain.

Background: Hypomagnesemia reportedly has significant associations with poor clinical outcomes such as increased mortality and septic shock in patients with sepsis. Although the mechanism underlying these outcomes mostly remains unclear, some experimental data suggest that magnesium deficiency could potentiate coagulation activation in sepsis. However, in sepsis, the association between serum magnesium levels and coagulopathy, including disseminated intravascular coagulation (DIC), remains unknown. Thus, we aimed to investigate the relationship between serum magnesium levels and coagulation status and the association between hypomagnesemia and DIC in patients with sepsis., Methods: This retrospective observational study was conducted at the intensive care unit (ICU) of a university hospital from June 2011 to December 2017. Patients older than 19 years who met the Sepsis-3 definition were included. We categorized patients into three groups according to their serum magnesium levels: hypomagnesemia (< 1.6 mg/dL), normal serum magnesium level (1.6-2.4 mg/dL), and hypermagnesemia (> 2.4 mg/dL). We investigated the association between serum magnesium levels and overt DIC at the time of ICU admission according to the criteria of the International Society on Thrombosis and Haemostasis., Results: Among 753 patients included in this study, 181 had DIC, 105 had hypomagnesemia, 552 had normal serum magnesium levels, and 96 had hypermagnesemia. Patients with hypomagnesemia had a more activated coagulation status indicated by lower platelet counts, lower fibrinogen levels, higher prothrombin time-international normalized ratios, higher thrombin-antithrombin complex, and more frequent DIC than those with normal serum magnesium levels and hypermagnesemia (DIC: 41.9% vs. 20.6% vs. 24.0%, P < 0.001). The coagulation status in patients with hypomagnesemia was more augmented toward suppressed fibrinolysis than that in patients with normal serum magnesium levels and hypermagnesemia. Multivariate logistic regression revealed that hypomagnesemia was independently associated with DIC (odds ratio, 1.69; 95% confidence interval, 1.00-2.84; P = 0.048) after adjusting for several confounding variables., Conclusions: Patients with hypomagnesemia had a significantly activated coagulation status and suppressed fibrinolysis. Hypomagnesemia was independently associated with DIC in patients with sepsis. Therefore, the treatment of hypomagnesemia may be a potential therapeutic strategy for the treatment of coagulopathy in sepsis., (© 2022. The Author(s).)

Background: Patients with coronavirus disease 2019 (COVID-19) occasionally develop respiratory failure and coagulopathy. We aimed to determine whether coagulation abnormalities at admission and during the course of hospitalization can predict the liberation from respiratory support in critically ill patients with COVID-19 by combining the results of rotational thromboelastometry (ROTEM) with standard laboratory tests., Methods: This single-center, retrospective, observational study included 31 consecutive adult patients with COVID-19 who were admitted to the intensive care unit (ICU) and who required respiratory support between April 2021 and August 2021. We divided the patients into two groups according to the liberation from respiratory support and analyzed the differences between the groups., Results: There were 20 patients in the liberation group and 11 in the non-liberation group. There were no significant differences in the overt disseminated intravascular coagulation scores or abnormal counts in the ROTEM parameters at admission between groups, although there was a significant difference in the highest score in the ICU. The Sequential Organ Failure Assessment and sepsis-induced coagulopathy scores were significantly different between both groups at admission and at the time when the highest values were reported during the ICU stay., Conclusions: High sepsis-induced coagulopathy scores at admission to the ICU were found to be useful predictors of difficulties in the liberation from respiratory support in patients with severe COVID-19. However, increased overt disseminated intravascular coagulation scores and abnormal counts in the ROTEM parameters during the ICU stay were associated with difficulties in the liberation from respiratory support.

Sepsis is a systemic inflammatory response syndrome caused by viral infection. The circulatory dysfunction caused by sepsis is also called septic shock or septic shock. The main characteristics are rapid onset, rapid changes, and involvement. Multiple organs in the body make diagnosis difficult, which seriously threatens the survival of patients. As many as one million people worldwide die every year because of SIRS, it is also the leading cause of death among children in hospital ICUs. This article is aimed at studying the clinical characteristics of severe sepsis in children and the risk factors for death. Based on the analysis of the pathogenesis of sepsis and the treatment of septic shock, 65 cases of children with PICU sepsis admitted to a hospital were selected. Data, to study its clinical characteristics and risk factors for death. The results of the study showed that despite the interaction among the removal factors of the three indexes of serum lactic acid value, PCIS level, and the number of organs involved in MODS, they are still related to the mortality of children with severe sepsis., Competing Interests: There is no potential conflict of interest in our paper., (Copyright © 2022 Ying Zhang et al.)

Extremity gangrene is a fairly common pathology, which complicates systemic vascular and endocrine diseases. Most often, it is encountered in diseases like uncontrolled Diabetes Mellitus, presenting as diabetic foot gangrene, severe peripheral arteriosclerosis with gangrene of the extremity complicating severe uncontrolled systemic hypertension and meningococcal septicaemia with peripheral gangrene. It also occurs in some cases of snake bite as well as frost bite (in regions with extreme cold weather conditions). Some of them present as monolateral extremity gangrene. However, others present as bilateral symmetrical peripheral gangrene (SPG) characterized by bilateral extremity ischaemia resulting in gangrene in which there is no major vascular occlusive disease. There is disseminated intravascular coagulation with the gangrene being considered as a cutaneous marker and some of the patients that survive ultimately require amputation of the affected limb(s) in the severe cases. The mild cases end up losing some of the digits or just exfoliation of the dead cutaneous layer. The effects are generally more severe in the lower limbs than in upper limbs. Notable among these are some of those complicating meningococcal sepsis resulting from peripheral intravascular coagulation. We present here, five patients who presented with varying degrees of peripheral gangrene during an epidemic of meningitis and the treatments that were carried out depending on the severity of their cases.

Background:  Two different criteria for evaluating coagulopathy in sepsis were recently released: sepsis-induced coagulopathy (SIC) and sepsis-associated coagulopathy (SAC). Although both use universal haemostatic markers of platelet count and pro-thrombin time, significance and usefulness of these criteria remain unclear., Objective:  This article validates and evaluates the significance of SIC and SAC criteria compared with the International Society on Thrombosis and Haemostasis (ISTH) overt disseminated intravascular coagulation (DIC) and Japanese Association for Acute Medicine (JAAM) DIC criteria., Methods:  Clinical characteristics of patients from a nationwide Japanese cohort were classified by SIC, SAC or DIC status and relations between criteria were examined. We evaluated associations between in-hospital mortality and anticoagulant therapy according to the SIC, SAC or DIC status to clarify the significance of criteria for introducing anticoagulants. Intervention effects were analysed by Cox regression analysis adjusted by propensity scoring., Results:  Incidences of coagulopathy diagnosed by SIC and JAAM DIC were similar, whereas those of SAC and ISTH overt DIC were about half of the former two (61.4%, 60.8% vs. 45.3%, 29.3%). Severity and mortality of all criteria were almost comparable. For validating initiation of anticoagulation, favourable effects of anticoagulant therapy were observed only in sub-sets with, and not without, coagulopathy diagnosed by all four criteria. Slight non-significant differences between anticoagulant groupings were found in ISTH overt DIC- and SAC-negative populations, suggesting that some patients even 'without' these criteria may benefit from anticoagulant therapy., Conclusion:  Newly developed SIC diagnostic criteria for coagulopathy may be valuable in detecting appropriate candidates for anticoagulant therapy in sepsis and a useful alternative to conventional DIC scoring systems., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Rationale: This article describes a child with a life-threatening multiorgan failure with disseminated intravascular coagulation (DIC) and massive complement consumption. To our knowledge this therapeutic approach was for the first time effectively applied in a pediatric patient., Patient Concerns: A 14-month-old boy was presented with a severe, rapidly progressing, life-threatening disease because of sudden onset of fever, hemathemesis, hematuria, and bloody diarrhoea alongside fast spreading hematomas and general corporeal edema., Diagnosis: The most plausible diagnosis in our patient is Clostridium difficile sepsis-induced thrombotic microangiopathy alongside with DIC and consumption coagulopathy. The diagnosis was confirmed by positive C difficile bacteria strain in coproculture, clinical, and laboratory tests affirming DIC and global complement activation and consumption., Interventions: The patient was treated with antibiotics (Metronidazole, Vancomycin), plasmapheresis, dialysis, methylprednisolone, mycophenolate mofetil, and Eculizumab., Outcomes: The child is in fair overall condition in a 2 year follow-up with no complications save chronic renal failure., Lessons: In rare cases of sepsis with massive complement consumption, a case-sensitive Eculizumab therapy may be at least considered after the resolution of life-threatening multiorgan failure. The application of this drug can be performed only after sepsis induced disease is put under control. A fast withdrawal of Eculizumab after control of massive complement consumption is recommended to prevent triggering of second sepsis reactivation.

Severe sepsis is almost invariably associated with systemic activation of coagulation. There is ample evidence that demonstrates a wide-ranging cross-talk between hemostasis and inflammation, which is probably implicated in the pathogenesis of organ dysfunction in patients with sepsis. Inflammation not only leads to initiation and propagation of coagulation activity, but coagulation also markedly influences inflammation. Molecular mechanisms that play a role in inflammation-induced effects on coagulation have been recognized in much detail. Pro-inflammatory cells and cyto- and chemokines can activate the coagulation system and downregulate crucial physiological anticoagulant mechanisms. Initiation of coagulation activation and consequent thrombin generation is caused by expression of tissue factor on activated monocytes and endothelial cells and is ineffectually offset by tissue factor pathway inhibitor. At the same time, endothelial-associated anticoagulant pathways, in particular the protein C system, is impaired by pro-inflammatory cytokines. Also, fibrin removal is severely obstructed by inactivation of the endogenous fibrinolytic system, mainly as a result of upregulation of its principal inhibitor, plasminogen activator inhibitor type 1 (PAI-1). Increased fibrin generation and impaired break down lead to deposition of (micro)vascular clots, which may contribute to tissue ischemia and ensuing organ dysfunction. The foundation of the management of coagulation in sepsis is the explicit and thorough treatment of the underlying disorder by antibiotic treatment and source control measures. Adjunctive strategies focused at the impairment of coagulation, including anticoagulants and restoration of physiological anticoagulant mechanisms, may supposedly be indicated and have been found advantageous in experimental and initial clinical trials., (Copyright © 2016. Published by Elsevier Ltd.)

Disseminated intravascular coagulation (DIC) is a major complication in sepsis patients. We compared the performance of five DIC diagnostic criteria, focusing on the prediction of mortality. One hundred patients with severe sepsis or septic shock admitted to intensive care unit (ICU) were enrolled. Routine DIC laboratory tests were performed over the first 4 days after admission. The overall ICU and 28-day mortality in DIC patients diagnosed from five criteria (International Society on Thrombosis and Haemostasis [ISTH], the Japanese Association for Acute Medicine [JAAM], the revised JAAM [R-JAAM], the Japanese Ministry of Health and Welfare [JMHW] and the Korean Society on Thrombosis and Hemostasis [KSTH]) were compared. Both KSTH and JMHW criteria showed superior performance than ISTH, JAAM and R-JAAM criteria in the prediction of overall ICU mortality in DIC patients (odds ratio 3.828 and 5.181, P = 0.018 and 0.006, 95% confidence interval 1.256-11.667 and 1.622-16.554, respectively) when applied at day 1 after admission, and survival analysis demonstrated significant prognostic impact of KSTH and JMHW criteria on the prediction of 28-day mortality (P = 0.007 and 0.049, respectively) when applied at day 1 after admission. In conclusion, both KSTH and JMHW criteria would be more useful than other three criteria in predicting prognosis in DIC patients with severe sepsis or septic shock., Competing Interests: The authors have no potential conflicts of interest to disclose.

Introduction: The diagnostic and prognostic value of immature platelet fraction (IPF) in sepsis has not been determined. This study aimed to assess whether IPF is an early predictor of platelet decline due to coagulopathy and is associated with mortality in patients with sepsis., Materials and Methods: In total, 149 patients with a platelet count of ≥80×10(3)/μL on intensive care unit admission (101 with sepsis, 48 controls without sepsis) were prospectively evaluated. We measured IPF on admission and observed for development of subsequent platelet count decline (defined as a >30% decrease or <80×10(3)/μL) in 5days, and mortality at 28days. The absolute immature platelet count (AIPC) was calculated to evaluate thrombopoiesis., Results: Forty-seven patients with sepsis subsequently developed a decrease in platelet count. The IPF was highest in patients whose platelet count decreased, followed by patients without a decrease in platelet count and controls (median, 4.3% [3.1%-8.1%] vs. 3.7% [2.6%-4.6%] vs. 2.1% [1.6%-3.5%], respectively; P<0.0001). The AIPC was similar in patients with and without a decrease in platelet count (7.6 [4.2-10.0] vs. 5.9 [4.2-8.7]×10(3)/μL, respectively; P=0.32). Coagulation derangement was more severe in patients who did than did not subsequently develop a decreased platelet count. Cox regression and receiver operator characteristic curve analysis revealed that IPF was a strong independent predictor of mortality, with accuracy similar to a standard prognostic scoring system., Conclusions: The admission IPF in septic patients predicts a subsequent decrease in platelet count, indicating platelet consumption with ongoing coagulopathy and risk of poor prognosis., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Introduction: Recent studies have repeatedly reported the effectiveness of antithrombin (AT) supplementation for sepsis-associated disseminated intravascular coagulation (DIC). In this study, we intended to elucidate the usefulness of monitoring antithrombin activity during antithrombin supplementation., Methods: Data of 926 patients with sepsis-associated DIC who had been undergone AT substitution were retrospectively analyzed. All the patients had received 1500IU/day of AT concentrate for three consecutive days. The patients' demographic characteristics, including the age, body weight, baseline DIC score and baseline AT activity, and treatment-related markers such as the change in DIC score and the change in the AT activity with treatment were analyzed in relation to the 28-day mortality., Results: Logistic regression analysis revealed a significant association of the patients' age, baseline AT activity, Δ AT activity, baseline DIC score and Δ DIC score to the patients' outcomes. The cutoff values of the AT activities for death calculated by the ROC curve analysis were 41.3% for the baseline AT activity, 72.9% for the post-treatment AT activity and 37.0% for Δ AT activity. The area under the ROC curve (AUC) showed discriminative powers for the baseline AT activity, post-treatment AT activity and Δ AT activity of 0.58, 0.69 and 0.66, respectively., Conclusions: Monitoring of the AT activity is useful to predict the patients' outcome. Furthermore, the measurement of baseline AT activity may help in determining the appropriate dose for AT supplementation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Antithrombin III (ATIII) of low doses (1500-3000 units per day for 3-5 days) has been used for treatment of disseminated intravascular coagulation (DIC) for decades in Japan. In this study, we have examined the impact of ATIII practice change on outcome in critically ill patients with sepsis and DIC. From April 2005 to September 2008, all septic patients admitted to our ICU were divided into two groups: before withdrawing ATIII (period 1) and after withdrawing ATIII (period 2). Patients treated with ATIII in the period 1 and those not treated with ATIII in the period 2 were then matched according to the similar Acute Physiology and Chronic Health Evaluation II scores (± 3) and the same diagnosis grouping. Sensitivity analysis was also conducted for patients with DIC. Forty-one out of 98 patients (41.8%) in the period 1 and only one out of 80 patients (1.3%) in the period 2 were treated with ATIII. Thirty pairs of the patients were matched. There was no difference between the two groups regarding the platelet counts and Sepsis-related Organ Failure Assessment scores at day 1 and day 4. A subgroup analysis was conducted with 12 patients diagnosed with DIC out of the 30 pairs. There was no difference between the two DIC groups for platelet counts, Sepsis-related organ failure assessment scores and DIC score at day 1 and also day 4. Although not significant, hospital mortality tended lower in the period 2. This study found that withdrawing ATIII administration from management of septic patients with or without DIC did not influence outcome.

Background: The association between antithrombin use and mortality in patients with sepsis-associated disseminated intravascular coagulation (DIC) remains controversial., Objectives: To examine the hypothesis that antithrombin could be effective in the treatment of patients with sepsis-associated DIC following severe pneumonia., Methods: Propensity score and instrumental variable analyses were performed by use of a nationwide administrative database, the Japanese Diagnosis Procedure Combination inpatient database. The main outcome was 28-day mortality., Results: Severe pneumonia patients diagnosed with sepsis-associated DIC (n = 9075) were categorized into antithrombin (n = 2663) and control (n = 6412) groups. Propensity score matching created a matched cohort of 2194 pairs of patients with and without antithrombin use. Mortality differences were found between the two groups (antithrombin vs. control: unmatched, 40.8% vs. 45.7%; propensity-matched, 40.6% vs. 44.2%; inverse probability-weighted, 41.1% vs. 45.1%). Multiple logistic regression analyses showed an association between antithrombin use and 28-day mortality (unmatched with propensity score adjusted, adjusted odds ratio [OR] 0.87, 95% confidence interval [CI] 0.78-0.97; propensity-matched, adjusted OR 0.85, 95% CI 0.75-0.97; inverse probability-weighted, adjusted OR 0.85, 95% CI 0.79-0.90). An analysis with the hospital antithrombin-prescribing rate as an instrumental variable showed that receipt of antithrombin was associated with a 9.9% (95% CI 3.5-16.3) reduction in 28-day mortality., Conclusions: This retrospective, large, nationwide database study demonstrates that antithrombin administration may be associated with reduced 28-day mortality in patients with severe pneumonia and sepsis-associated DIC. A large, multinational randomized trial is required., (© 2014 International Society on Thrombosis and Haemostasis.)

The current management of disseminated intravascular coagulation (DIC) is based on aggressive treatment of the underlying condition and resuscitation with appropriate blood products. Anticoagulant therapy has appeared and disappeared in the different guidelines and important documents detailing the treatment of DIC. For example, Surviving Sepsis Campaign (SSC) guidelines, the 'global standard' for the management of severe sepsis, had recombinant activated protein C highly recommended in the original version, but this was withdrawn in the latest version due to the lack of evidence. In contrast, recent international guidance released from the International Society on Thrombosis and Haemostasis has introduced the potential efficacy of other agents. In sepsis-related DIC, the basis for anticoagulant therapy comes from the mounting evidence for the anti-inflammatory effects which these agents possess and can prove beneficial in septic situations. Several studies have clearly shown the important cross-talk between coagulation and inflammation in patients with sepsis. More recently, neutrophil extracellular traps and damage-associated molecular patterns (DAMPs), especially histones, have been demonstrated to play a crucial role in the coagulopathy of sepsis. Once again, the natural anticoagulants have an important function in neutralizing the effects of DAMPs and histones. In this review, in addition to examining the important role of anticoagulants in the septic milieu, the clinical studies examining antithrombin, recombinant thrombomodulin and plasma-derived activated protein C are detailed. However, large-scale randomized controlled trials are yet to be performed, with important consideration of the timing, dosage and duration of treatment., (© 2014 International Society on Thrombosis and Haemostasis.)

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

Purpose: Few reports have been made on the therapeutic effects as well as pathological features of an antithrombin preparation in patients diagnosed with septic disseminated intravascular coagulation (DIC) by the diagnostic criteria for acute DIC., Materials and Methods: A total of 88 sepsis patients who had received inpatient hospital care during the period from January 2000 through December 2008 were divided into two groups, an antithrombin group and a non-antithrombin group, to study the outcomes. Furthermore, the relationship between sepsis-related factors and DIC in 44 patients was studied., Results: The antithrombin group contained 34 patients, and the non-antithrombin group contained 54 patients. The outcomes were significantly better in the antithrombin group. The levels of protein C were low in DIC patients., Conclusion: Our results suggest that early administration of antithrombin might improve outcomes of septic DIC patients in the diagnostic criteria for Japanese Association for Acute Medicine acute DIC.

We prospectively studied (1) the relationships between angiogenic factors, their soluble receptors and organ dysfunction and (2) the effects of disseminated intravascular coagulation (DIC)-induced platelet consumption, thrombin generation, and tissue hypoxia on the expression of the factors and receptors. Fifty patients with sepsis were classified into two subgroups: 37 patients with DIC and 13 patients without DIC. DIC patients showed higher Sequential Organ Failure Assessment (SOFA) scores, the prevalence of multiple organ dysfunction syndrome (MODS) and more increased soluble fibrin and lactate levels. We observed lower levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor 2 (sVEGFR2), angiopoietin 1 (Ang1) and Ang1/Ang2, and higher sVEGFR1 and Ang2 levels in DIC patients, but not significant differences in soluble Tie2 expression during the study period. The levels of VEGF, sVEGFR1, and Ang2 in DIC patients correlated with the SOFA scores. Clear differences were observed in the levels of Ang2 in the DIC patients between survivors and nonsurvivors and between those with and without MODS. The area under receiver operating characteristic curves for predicting death and MODS by Ang2 were 0.710 and 0.784, respectively. The VEGF levels showed a marked correlation with the platelet counts. Soluble fibrin and lactate levels independently predicted increases in the levels of VEGF, sVEGFR1, and Ang2 in DIC patients. In conclusion, VEGF, sVEGFR1, Ang2, and Ang1/Ang2, especially Ang2, may have roles in the development of MODS in sepsis associated with DIC, and VEGF, sVEGFR1, and Ang2 serum levels correlated with the extent of DIC-induced platelet consumption, thrombin generation, and blood lactate levels.

Disseminate intravascular coagulation (DIC) is a clinical pathological syndrome associated to several diseases. Sepsis is the most common cause in infants and children. DIC results from the anomalous activation of blood coagulation, widespread formation of thrombi in the microcirculation, and consumption of clotting factors and platelets. Clinical findings are variable; the most common is bleeding, followed by purpura and acral gangrene (purpura fulminans). We report a patient with sepsis associated-DIC and concurrent deep venous thrombosis. The diagnostic evaluation allowed to discover inherited thrombophilia associated to protein C deficiency.

Background: Respiratory dysfunction associated with severe sepsis is a serious condition leading to poor prognosis. Activation of coagulation is a consequence of and contributor to ongoing lung injury in severe sepsis. The purpose of this study was to examine the efficacy of recombinant human soluble thrombomodulin (rhTM), a novel anticoagulant agent, for treating patients with sepsis-induced disseminated intravascular coagulation (DIC) in terms of mortality and respiratory dysfunction., Methods: This study comprised 86 consecutive patients with sepsis-induced DIC who required ventilator management. The initial 45 patients were treated without rhTM (control group), and the following 41 patients were given rhTM (0.06 mg/kg/d) for 6 days (rhTM group). Patients were followed up for 90 days after study entry. Sequential Organ Failure Assessment (SOFA) score and lung injury score were recorded until 7 days after entry., Results: The baseline characteristic of severity of illness was significantly higher in the rhTM group than in the control group. Nevertheless, 90-day mortality rate in the rhTM group was significantly lower than that in the control group (37% vs. 58%, p = 0.038). There was a significant difference in the serial change of SOFA score from baseline to day 7 between the two groups (p = 0.009). Both the respiratory component of the SOFA score and the lung injury score in the rhTM group were significantly lower compared with the control group (p = 0.034 and p < 0.001, respectively)., Conclusions: rhTM may have a significant beneficial effect on mortality and respiratory dysfunction in patients with sepsis-induced DIC., Level of Evidence: III, therapeutic study.

Cytokines trigger coagulant and fibrinolytic systems in sepsis to result in Disseminated Intravascular Coagulation (DIC) that is an important complication and leads to disseminated hemorrhages and multi-organ failure. High Mobility Group B1 DNA Binding (HMGB1) protein is a cytokine taking part in systemic inflammatory response. The objective of this study was to investigate HMGB1 levels in groups of septic patients with and without DIC.Twenty-one septic patients without DIC and 12 septic patients with DIC from the Intensive Care Unit (ICU) were included in the study. In addition, 20 patients admitted to the ICU without sepsis or DIC and 20 healthy volunteers served as controls. Levels of HMGB1, prothrombin time, activated partial thromboplastin time, fibrinogen, D-dimer, protein C, protein S, anti-thrombin III (ATIII), platelet (thrombocyte) and leukocyte count were determined. Levels of fibrinogen, protein C, ATIII and platelet count were significantly lower and D-dimer was significantly higher in the group with sepsis plus DIC compared to the group with sepsis without DIC. Levels of HMGB1 were higher in the group with sepsis and DIC compared to the group with sepsis; however, the difference was not statistically significant and the levels of HGMB1 of both groups were significantly higher compared to ICU and healthy control groups. HMGB1 levels were not significantly different in survivor and non survivor patients. HMGB1 levels did not differ in lower respiratory tract infection (LRTI) and urinary tract infection (UTI) in regard to the etiology of sepsis.

Tissue factor (TF) is a major initiator of extrinsic pathway of blood coagulation. A dual role of TF in the extensive crosstalk between blood coagulation and inflammation has recently become apparent. The majority of the cases of systemic inflammatory response syndrome, disseminated intravascular coagulation, and sepsis are accompanied by hyperactivation of TF in circulating monocytes and damaged tissue. Systemic Gram-negative infection induces expression of TF by vascular cells. In addition to extrinsic coagulation pathway, TF induces proinflammatory signaling cascade originating from activation of protease-activated receptors. Because TF-activated proteolytic cascade is placed in a nexus between coagulation and inflammation, early modulation of TF activity presently becomes a tempting experimental therapeutic strategy in systemic inflammatory response syndrome patients.

A 19-year-old male was admitted because of the trauma due to sepsis-induced disseminated intravascular coagulation (DIC) and multiple organ failure (MOF). We treated with antibiotics, danaparoid, and continuous hemodiafiltration (CHDF). Once he recovered, but after several days, he had septic shock and MOF again. With treatment, the inflammation and MOF improved but the platelet count was less than 1.0 × 10( 4)/μL. Because of the usage of heparin, we suspected heparin-induced thrombocytopenia (HIT) and measured the HIT antibody and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). Heparin-induced thrombocytopenia antibody was positive in the second sepsis but negative in the first sepsis. ADAMTS13 activity was low in both sepses. After stopping CHDF and the usage of heparin, his platelet count improved. Thrombocytopenia is the common and occasional condition for DIC. Heparin-induced thrombocytopenia and thrombotic thrombocytopenic purpura is rare but they must be ruled out in thrombocytopenia with nontypical clinical course, and the assays for HIT antibody and ADAMTS13 activity are useful tools.

Multiple organ infarctions are a very rare clinical event in children. We report a 3-month-old infant with sepsis and disseminated intravascular coagulation, who was diagnosed with cerebral ischemic stroke associated with middle cerebral artery stenosis and subsequent retinal infarction by magnetic resonance imaging, fundoscopy and magnetic resonance angiography. In addition, he suffered from renal infarction with hypertension and was treated until 1 year of age. We emphasize the importance of early recognition of organ infarctions, prophylaxis of risk factors and of optimized therapy of the underlying etiology., (Copyright © 2010 Elsevier. Published by Elsevier B.V. All rights reserved.)

Introduction: Sepsis is the most common disease associated with disseminated intravascular coagulation (DIC). To test the hypothesis that DIC diagnosed by the Japanese Association for Acute Medicine (JAAM) DIC scoring system (JAAM DIC) constitutes a dependent continuum to overt DIC diagnosed by the International Society on Thrombosis and Haemostasis (ISTH) overt DIC scoring system (ISTH overt DIC) in patients with sepsis, we conducted a retrospective study., Materials and Methods: The databases from two prospective, multicenter clinical investigations were analyzed. The inclusion criteria comprised patients with sepsis-related DIC, who met the JAAM DIC criteria., Results: The present study enrolled 166 patients, of whom 67 met the ISTH overt DIC criteria. All patients with sepsis who developed to overt DIC during the study period could be identified by the JAAM DIC diagnostic criteria in the first study. While the overall 28-day mortality was 31.3%, mortality (40.3%, p=0.0040) and the incidence of multiple organ dysfunction syndrome (70.1%, p=0.008) of the patients with the ISTH overt DIC was approximately one and a half times that of the patients associated with only the JAAM DIC. A stepwise increase in the ISTH overt DIC scores and the incidence of the ISTH overt DIC were also observed in accordance with the increase in the JAAM DIC scores., Conclusion: DIC diagnosed based on the JAAM DIC diagnostic criteria exists in a dependent continuum to the ISTH overt DIC in patients with sepsis, thus enabling them to receive early treatment.

Administration of high-dose antithrombin (AT) was investigated on a large collective of patients with severe sepsis in the KyberSept study. In the total study the administration of AT resulted in no significant reduction of the mortality rate in comparison to a placebo. However, in the protocol of this study subgroups were predefined, which when analyzed revealed that the group of patients who received AT but not simultaneously heparin did show a reduction of the mortality rate in comparison to the placebo group. The reduction of the absolute mortality rate of 15% reached statistical significance on day 90. Even patients classified as risk group grade II according to the Simplified Acute Physiology Score (SAPS), showed a significant reduction of the mortality rate of approximately 22% after 90 days without simultaneous administration of heparin. Such a positive result for administration of AT without simultaneous heparin treatment can also be found when severe sepsis complicated by disseminated intravascular coagulation (DIC) is present. Coagulation diagnostic assists the recognition of latent or fulminant DIC and also in surveillance of the course and development. The results of AT supplementation for severe sepsis and DIC are in agreement with earlier studies on smaller patient collectives and suggest that a randomized controlled clinical study should be carried out on a subcollective of severely ill patients.

This study investigated the relationship between calculated immature granulocyte (IG) counts and the severity of sepsis. Coagulation parameters, fibrinolytic indices, bacterial isolation rates in blood cultures, and mortality were observed in 237 patients with suspected sepsis. The difference in leukocyte subfractions (delta neutrophil index; DN) identified by a cytochemical myeloperoxidase reaction and by a nuclear lobularity assay was determined with a blood cell analyzer (ADVIA 120, Siemens, Inc.). DN was strongly correlated with manual IG counts (r = 0.75, p <0.05). Patients with high DN (>40%) averaged 40% lower in platelet count, 26% prolongation of prothrombin time (PT), and 35% diminution of antithrombin III (AT III) activity, vs those with low DN (5-20%). Overt disseminated intravascular coagulation was more prevalent as the DN increased, and reached a peak in patients with DN >40%. DN values were closely associated with PT (r = 0.35, p <0.05), AT III activity (r = -0.36, p <0.05), and platelet count (r = -0.27, p <0.05). Positive blood culture rate averaged 3.5-fold higher in patients with DN >40% vs the subgroup with low DN of 5-10%. The mortality rate of patients with DN >40% markedly exceeded the mortality rate of patients with DN of 5-10% (79% vs 15%, p <0.05). Thus, DN has implications for the severity of sepsis and may be valuable to assess the prognosis of patients with suspected sepsis.

In November 2001, drotrecogin alfa (activated) was approved by the US Food and Drug Administration; in August 2002 it was approved by the European Medicines Agency. Since the approval of drotrecogin alfa (activated), however, critical care physicians have been faced with several challenges, namely its costs, selection of patients who are more likely to benefit from it, and the decision regarding when to start drotrecogin alfa (activated) treatment. There are also operational issues such as how to manage the infusion to deliver an effective treatment while minimizing the risk for bleeding, particularly in patients with deranged clotting, at around the time of surgery or during renal replacement therapy. While addressing these issues, this review remains practical but evidence based as much as possible.

Sepsis-induced disseminated intravascular coagulation (DIC) is a serious condition because it is closely linked to the development of multiple organ dysfunctions. We compared molecular fibrinolysis markers for 117 patients with sepsis-induced DIC and 1627 patients with nonseptic DIC. Levels of fibrinogen and fibrin degradation products and D-dimer were significantly lower in sepsis-induced DIC cases than in nonseptic DIC cases. In septic DIC cases, plasma plasminogen activator inhibitor 1 (PAI-1) levels were significantly higher than in nonseptic DIC cases. D-dimer levels were negatively correlated with plasma PAI-1 levels in septic DIC cases. Multiple Organ Dysfunction Scores were significantly higher in septic DIC patients with PAI-1 levels >90 ng/mL than in the group with PAI-1 levels <30 ng/mL. The Kaplan-Meier survival functions until 28 days after DIC diagnosis were significantly lower in the group with PAI-1 levels >90 ng/mL than in the other groups. In a multivariate analysis, plasma PAI-1 levels at DIC diagnosis were an independent risk factor for mortality in sepsis-induced DIC (hazard ratio, 1.012; P = .008). These data suggest that plasma PAI-1 plays an important role in sustaining DIC in septic DIC cases and contributes to multiple organ failure and decreased survival in such patients.

We evaluated the score for disseminated intravascular coagulation (DIC) recently published by the International Society for Thrombosis and Haemostasis (ISTH) in a well-defined series of sepsis patients. Thirty-two patients suffering from severe sepsis and eight patients with septic shock were evaluated following the ISTH DIC score. Fibrin monomer and D-dimer were chosen as fibrin-related markers (FRM), respectively. DIC scores for nonsurvivors (n = 13) as well as for septic shock patients were higher (P < 0.04) compared with survivors and patients with severe sepsis, respectively. Using fibrin monomer and D-dimer, 30 and 25% of patients suffered from overt DIC. Overt DIC was associated with significantly elevated thrombin-antithrombin complexes and plasminogen activator inhibitor type-1 levels as well as with significantly lower factor VII clotting activity. Patients with overt DIC had a significantly higher risk of death and of developing septic shock. Since more than 95% of the sepsis patients had elevated FRM, the DIC score was strongly dependent on prolongation of the prothrombin time and platelet counts. The ISTH DIC score is useful to identify patients with coagulation activation, predicting fatality and disease severity. It mainly depends on the prolongation of the prothrombin time and platelet counts.

Pulmonary hemorrhage is a rare but well-known complication in preterm infants. We present a case of massive pulmonary hemorrhage in a 9-day-old male infant, successfully treated with intravenous recombinant activated factor VII (rFVIIa) (NovoSeven; Novo Nordisk). The infant was diagnosed with sepsis-related disseminated intravascular coagulation and required ventilator support for respiratory distress syndrome and blood transfusions due to active bleeding from endotracheal tube. After administration of the second dose of rFVIIa (120 microg/kg per dose, every 2 h), the active bleeding subsided dramatically and a significant improvement in the oxygenation index was seen 8 h after the third dose of rFVIIa treatment. There were also significant improvements in the prothrombin time, International Normalized Ratio, activated partial thromboplastin time and plasma fibrinogen levels after the third dose of rFVIIa treatment. The infant was discharged on day 82 of life and there was no finding of thrombosis during the hospitalization period. At month 18 of follow-up, there was no morbidity related to the pulmonary and central nervous systems. This case suggests that rFVIIa is effective as an alternative therapy in controlling massive pulmonary hemorrhage of preterm infants.

Localised and following systemic inflammatory reaction accompanying progression of infection causes generation of anti-inflammatory cytokines. They activate leucocytes, endothelium, coagulation and fibrinolysis. Sepsis is usually accompanied by already decompensated disseminated intravascular coagulation which significantly affects mortality of patients with this disease. The main cause of hypercoagulation state during sepsis seems to be inhibition of fibrinolysis as a result of overproduction of plasminogen activator inhibitor-1 in later stages of the disease. Some microorganisms have specific properties which affect individual components of hemostasis and thus increase their virulence. Because natural inhibitors of coagulation have not only anticoagulation but also strong anti-inflammatory effect, they seem to be an optimum remedy for fluorid coagulopathy during sepsis. Moreover, their use usually does not increase risk of bleeding.

A 31-year-old man who underwent chemotherapy and bone marrow transplantation to treat acute myeloblastic leukemia was admitted to our department complaining of high fever and hypotension. His physical examination revealed warm shock state, eruptions resembling that seen in systemic lupus erythematosus on his face and cyanosis in his fingers. We diagnosed septic shock and idiopathic skin eruption on his face. Following treatment with blood transfusion, anticoagulant, antibiotics, respirator and continuous arteriovenous hemofiltration and dialysis, the patient's condition gradually improved. The eruptions on his face first observed at admission progressed with a worsening of his disseminated intravascular coagulation (DIC), and subsided with an improvement in his DIC. A biopsy of the eruption was taken and pathological findings of the eruption revealed multiple micro-fibrin depositions of the dermis. The skin necrosis in purpura fulminans often begins in the distal extremities. But our patient developed this uncommon skin eruption on his face. Patients with an idiopathic skin eruption resembling a butterfly rash in a septic patient should be considered to complicate DIC as in the present case.

Disseminated intravascular coagulation (DIC) is a common phenomenon in patients with sepsis, but the clinical implications of this condition are not clear. Clinical trials with coagulation inhibitors have failed to show a significant benefit concerning survival. DIC is primarily a laboratory diagnosis, based on the combination of elevated fibrin-related markers (FRM), with decreased procoagulant factors and platelets. Non-overt DIC is observed in most patients with sepsis, whereas overt DIC is less frequent. Patients with overt DIC may display consumption coagulopathy and purpura fulminans. Consumption coagulopathy is a bleeding disorder caused by low levels of platelets and procoagulant factors associated with massive coagulation activation. Purpura fulminans is caused by widespread microvascular thrombosis, resulting in tissue necrosis. Treatment with drotrecogin alfa (activated) improves survival and other outcome parameters in severe sepsis, including a subgroup of patients fulfilling the laboratory criteria of overt DIC. No randomized trials demonstrating effective therapies in consumption coagulopathy have been published. Bleeding patients with consumption coagulopathy are most frequently treated with platelet transfusions and various plasma products including fresh frozen plasma and coagulation factor concentrates. Based on case reports, treatment with drotrecogin alfa (activated) or substitution of protein C have been recommended for adjuvant treatment of sepsis-related purpura fulminans.

Aim: To determine whether sequential change in coagulation parameters such as activated partial thromboplastin time (aPTT), prothrombin time (PT), platelets count and fibrinogen level may predict the outcome of patients in sepsis., Study Design: Cohort longitudinal study., Patients and Methods: Patients with positive two or more clinical criteria for sepsis were eligible for the study. Thirty patients were included, 24 male and 6 female. Eight patients survived, while 22 deceased. Median age of survivors was 66 years (range 23-77), and in non-survivors it was 69 years (range 48-79), p=0.37. In 9 patients malignancy was an underlying disease. APACHE II score was calculated at admittance, median value for survivors was 10 (range 7-15) and for non-survivors it was 26 (range 6-35), p=0.001. Calculated MODS score at the time blood cultures was 2 (range 0-9) for survivor and 6.5 (range 2-13) for non-survivors, p=0.007. Blood cultures were taken at the onset of sepsis, and in 29 patients they were positive. Coagulation parameters were measured at admittance, at the onset of sepsis and 48 hours after the introduction of the specific antimicrobial therapy., Results: Analysis of variance for repeated measurements between survivors and non-survivors has shown that there were no differences in values of coagulation parameters. The only significant difference between these groups of patients was APACHE II and MODS score. In 7 patients with severe thrombocytopenia (<33,000 x 10(9)/L) as a result of irreversible septic shock a clinically visible bleeding was present in only one patient., Discussion: Disseminated intravascular coagulation (DIC) is a clinical-pathological syndrome in which wide-spread intravascular coagulation is induced by procoagulants that are introduced or produced in the blood circulation and overcome the natural anticoagulant mechanisms. DIC causes tissue ischemia from occlusive microthrombi as well as bleeding from both the consumption of platelets and coagulation factors and the anticoagulant effect of products of secondary fibrinolysis. In sepsis, tissue factor which is the most common trigger of DIC can be generated and expressed on membranes of monocytes and endothelial cells during the systemic inflammatory response syndrome (SIRS). The wide-spread generation of thrombi in sepsis induces deposition of fibrin which leads to vessels obstruction and consumption of substantial amounts of haemostatic factors i.e. platelets, fibrinogen, factors V, VIII and others, protein C and antithrombin III (AT III). Intravascular thrombi trigger secretion of tissue plasmin activator (tPA) from endothelial cells which sets of compensatory thrombolysis which may reopen the occluded blood vessels. But byproducts of thrombolysis such as fibrin/fibrinogen degradation products may enhance bleeding by interfering with platelet aggregation, fibrin polymerization and thrombin activity. The typical feature of sepsis is depression of three powerful anticoagulant systems: protein C pathway, AT III pathway and tissue pathway factor inhibitor (TPFI). This sequence of events led us to hypothesize that alterations in coagulation parameters such as PT, aPTT, fibrinogen, platelets count may predict the outcome of disease, as it is well documented that the development of DIC confers prognosis of sepsis. The failure to distinguish survivors from non-survivors by the alteration in the coagulation parameters in this study may be due to a relatively low sample size or to the clinical necessity of an attending physician to substitute the deficient blood or coagulation product., Conclusion: The coagulation parameters PT, aPTT, platelet count and fibrinogen level can not serve as predictors of outcome in patients with sepsis. Further studies including more discerning coagulation parameters: AT III, D-dimer, soluble fibrin monomer, thrombin/antithrombin complex, plasmin/antiplasmin complex, fibrinopeptid A, fibrinopeptid B are necessary to evaluate whether these procoagulant and anticoagulant factors may help in predicting outcome and severity of sepsis.

Sepsis almost invariably leads to hemostatic abnormalities, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation (DIC). There is compelling evidence from clinical and experimental studies that DIC is involved in the pathogenesis of microvascular dysfunction and contributes to organ failure. In addition, the massive and ongoing activation of coagulation, may deplete platelets and coagulation factors, which may in turn cause bleeding. Recent insights into important pathogenetic mechanisms that may lead to DIC have resulted in novel preventive and therapeutic approaches to patients with sepsis and a derangement of coagulation. Thrombin generation proceeds via the (extrinsic) tissue factor/factor VIIa route and simultaneously occurring depression of inhibitory mechanisms, such as antithrombin III and the protein C system. Also, impaired fibrin degradation, due to high circulating levels of PAI-1, contributes to enhanced intravascular fibrin deposition. Supportive strategies aimed at the inhibition of coagulation activation may be justified on theoretical grounds and have been found to be beneficial in experimental and initial clinical studies. These strategies comprise inhibition of tissue factor-mediated activation of coagulation or restoration of physiological anticoagulant pathways, by means of the administration of antithrombin concentrate or recombinant human activated protein C.

Objectives: To assess the safety and effect on coagulopathy of a range of doses of recombinant human activated protein C (rhAPC). To determine an effective dose and duration of rhAPC for use in future clinical trials., Design: Double-blind, randomized, placebo-controlled, multicenter, dose-ranging (sequential), phase II clinical trial., Setting: Forty community or academic medical institutions in United States and Canada., Patients: One hundred thirty-one adult patients with severe sepsis., Interventions: Intravenous infusion of rhAPC (12, 18, 24, or 30 microg/kg/hr) or placebo for 48 or 96 hrs., Measurements and Main Results: No significant differences in incidence of serious bleeding events (4% rhAPC, 5% placebo, p >.999) or incidence of serious adverse events (39% rhAPC, 46% placebo, p = 0.422) between rhAPC- and placebo-treated patients were observed. One of 53 rhAPC-treated patients with suitable immunogenicity samples had a low level, transient, non-neutralizing anti-APC antibody response not associated with any clinical adverse event. Significant dose-dependent decreases in both D-dimer (p <0.001) and end of infusion interleukin 6 levels (p =.021) were demonstrated. No statistically significant effects on fibrinogen or platelet counts were observed. A nonstatistically significant 15% relative risk reduction in 28-day all-cause mortality was observed between rhAPC- and placebo-treated patients., Conclusions: rhAPC was safe and well-tolerated and demonstrated a dose-dependent reduction in D-dimer and interleukin 6 levels relative to placebo. The dose of 24 microg/kg/hr for 96 hrs was selected for use in future clinical studies.