Activation of the fibrinolytic system and utilization of the coagulation inhibitors in sepsis: comparison with severe sepsis and septic shock

OBJECTIVES: To determine whether the fibrinolytic system is activated and coagulation inhibitors are utilized in sepsis, to compare the findings detected in sepsis with those found in severe sepsis and septic shock, and to compare the role played by different infectious pathogens on fibrinolysis and coagulation inhibitors. DESIGN AND SETTING: Prospective study comparing patients with sepsis, severe sepsis, and septic shock and healthy volunteers in the general intensive care unit of a tertiary university hospital. PATIENTS: Eighty-two consecutive septic patients (47 with sepsis, 18 with severe sepsis, and 17 with septic shock), and 14 healthy volunteers (controls). MEASUREMENTS AND RESULTS: After blood sampling we measured activation markers of fibrinolysis [plasmin/alpha(2)-antiplasmin complexes (PAP), complexes of tissue plasminogen activator/plasminogen activator inhibitor (tPA/PAI), fibrin(ogen) degradation products (FDPs), D-dimmers fibrin degradation products (D-d)], the utilization marker of antithrombin III (ATIII) thrombin/antithrombin complexes (TAT), several factors of fibrinolysis [plasminogen, tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), alpha(2)-antiplasmin], and the natural coagulation inhibitors [ATIII, protein C (PrC), protein S (PrS)]. In sepsis, PAP, FDPs, D-d, and TAT were increased to 439.8+/-32.35 microg/l, 57% positive, 49% positive, and 3.46+/-0.27 microg/l, respectively, compared with control subjects (205.57+/-28.58 microg/l, 0% positive, 7% positive, and 1.61+/-0.1 microg/l, respectively). These markers further increased in severe sepsis and septic shock. With the exception of a decrease in ATIII and an increase in tPA and PAI-1, coagulation inhibitors and factors of fibrinolysis were not changed in sepsis. In severe sepsis and mainly in septic shock, coagulation inhibitors (ATIII, PrC) and plasminogen were markedly decreased, whereas tPA and PAI-1 were further increased. All changes were independent of the causative infectious pathogen. CONCLUSIONS: Fibrinolysis is strongly activated and ATIII is utilized in sepsis. These findings are further enhanced in severe sepsis and septic shock. In sepsis only ATIII is decreased. In contrast, in severe sepsis and mainly in septic shock plasminogen and the main coagulation inhibitors (i.e., ATIII, PrC) are depleted, indicating exhaustion of fibrinolysis and coagulation inhibitors. Finally, Gram-positive, Gram-negative and other micro-organisms produce identical impairment.     

Tissue factor production not balanced by tissue factor pathway inhibitor in sepsis promotes poor prognosis

OBJECTIVE: To determine the precise relationship among tissue factor, tissue factor pathway inhibitor (TFPI), and neutrophil elastase in sepsis, as well as to test the hypothesis that low TFPI concentrations are not sufficient to prevent tissue factor-dependent intravascular coagulation, leading to multiple organ dysfunction syndrome and death. DESIGN: Prospective, cohort study. SETTING: General intensive care unit of tertiary care emergency department. PATIENTS: Thirty-one consecutive patients with sepsis, classified as 15 survivors and 16 nonsurvivors. Ten normal, healthy volunteers served as controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Tissue factor antigen concentration (tissue factor), TFPI, neutrophil elastase, and global variables of coagulation and fibrinolysis were measured on the day of diagnosis of sepsis, severe sepsis, and septic shock and days on 1-4 after diagnosis. The number of systemic inflammatory response syndrome criteria that patients met and the disseminated intravascular coagulation score were determined simultaneously. The results of these measurements were compared between the survivors and the nonsurvivors. In the nonsurvivors, significantly higher concentrations of tissue factor and neutrophil elastase were found compared with the survivors and control subjects. However, the TFPI values showed no difference between the two groups. No correlation was found between the peak concentrations of tissue factor and TFPI. Disseminated intravascular coagulation scores and numbers of the SIRS criteria met by the survivors significantly decreased from day 0 to day 4, but those of the nonsurvivors did not improve during the study period. The nonsurvivors showed thrombocytopenia and higher numbers of dysfunctioning organs than did the survivors. CONCLUSIONS: We systematically elucidated the relationship between tissue factor and TFPI in patients with sepsis, severe sepsis, and septic shock. Activation of tissue factor-dependent coagulation pathway not adequately balanced by TFPI has important roles in sustaining DIC and systemic inflammatory response syndrome, and it contributes to multiple organ dysfunction syndrome and death. High concentrations of neutrophil elastase released from activated neutrophils may explain, in part, the imbalance of tissue factor and TFPI in sepsis.     

Coagulation dysfunction in sepsis and multiple organ system failure

In patients diagnosed with sepsis, severe sepsis or septic shock, cytokine-mediated endothelial injury, and TF activation initiate a cascade of events that culminate in the development of coagulation dysfunction characterized as procoagulant and antifibrinolytic. This abnormal state predisposes the patient to develop microvascular thrombosis, tissue ischemia, and organ hypoperfusion. Multiple organ dysfunction syndrome may be a product of this pertubation in coagulation regulation. Treatments aimed at correcting this coagulation dysfunction have met with mixed success. Current data suggest that AT III replacement therapy has limited efficacy in adults with severe sepsis. In contrast, adult patients diagnosed with severe sepsis and organ failure and treated with aPC (drotrecogin alfa activate) have a significantly reduced risk of death when compared with placebo-treated patients. A phase III trial examining the efficacy of protein C replacement therapy in pediatric patients with severe sepsis and organ failure is underway.     

Recognizing and managing severe sepsis: a common and deadly threat

Through a literature review, the epidemiology and pathophysiology, including alterations in inflammation, coagulation, and impaired fibrinolysis that occur in the course of severe sepsis, is presented. Treatment guidelines that are evidence-based and endorsed by 11 professional societies representing multispecialty groups are described. Severe sepsis is common; 750,000 cases are estimated to occur annually in the United States. The mortality rate for severe sepsis still ranges from 30 to 50%, and is as high as 80 to 90% for septic shock and multiple organ dysfunction. Severe sepsis exists along a continuum initiated by a localized infection that triggers a systemic response. A cascade of inflammation and activation of the coagulation system associated with impaired fibrinolysis leads to alterations in microvascular circulation associated with organ dysfunction, severe sepsis, multiple organ dysfunction syndrome, and death. In an attempt to improve care and reduce mortality, the Surviving Sepsis Campaign and The Institute for Healthcare Improvement (IHI) have created two sepsis treatment bundles.     

Differences in coagulation and fibrinolysis after traumatic and septic shock in man

In a prospective investigation of 19 patients with traumatic (n = 11) and septic (n = 8) shock admitted to the Intensive Care Unit of the University Hospital of Uppsala, differences in coagulation and fibrinolysis between the two conditions were evaluated. It was found that plasma coagulation variables such as thrombotest, normotest and antithrombin III were significantly lower in the septic patients, thus indicating a more intense and/or altered intravascular coagulation. Significantly higher levels of the von Willerbrand factor were found in septic patients, indicating a greater release from endothelial cells and platelets. The plasminogen activator inhibitor and the plasminogen-binding form of alpha 2-antiplasmin showed significantly higher values in septic patients, indicating a greater fibrinolysis inhibition in these patients. The greater disturbance in the protease-inhibitor balance in septicaemia was also verified by significantly lower levels of plasminogen and alpha 2-macroglobulin than after traumatic shock. Two out of 11 patients in traumatic shock developed the adult respiratory distress syndrome with a slow onset and benign course, whereas six out of eight septic shock patients developed a similar syndrome with a rapid onset and malignant course. These laboratory and clinical results lend further support to the hypothesis that the differences in coagulation and fibrinolysis systems reflect partly different pathogenic mechanisms underlying septic- and traumatic-induced adult respiratory distress syndrome.     

Activation of coagulation with concurrent impairment of anticoagulant mechanisms correlates with a poor outcome in severe melioidosis.

BACKGROUND: Melioidosis, which is caused by infection with the Gram-negative bacterium Burkholderia pseudomallei, is an important cause of sepsis in South-East Asia with a mortality of up to 40%. Knowledge of the involvement of coagulation and fibrinolysis in the pathogenesis of melioidosis is highly limited. OBJECTIVE: To define the involvement of the coagulation and fibrinolytic systems in patients with severe melioidosis. METHODS: Parameters of coagulation and fibrinolysis were measured in 34 patients with culture proven septic melioidosis and 32 healthy controls. RESULTS: Patients demonstrated strong activation of the coagulation system, as reflected by high plasma levels of soluble tissue factor, the prothrombin fragment F(1+2) and thrombin-antithrombin complexes (TATc), and consumption of coagulation factors resulting in a prolonged prothrombin time and activated partial thromboplastin time. Concurrently, anticoagulant pathways were downregulated in patients: protein C, protein S, and antithrombin levels were all decreased when compared to controls. Patients also demonstrated evidence of activation and inhibition of fibrinolysis, as reflected by elevated concentrations of tissue-type plasminogen activator (tPA), plasminogen activator inhibitor type 1, plasmin-alpha2-antiplasmin complexes (PAPc) and D-dimer. High TATc/PAPc ratios in patients pointed to a predominance of the prothrombotic pathway in melioidosis. Furthermore, soluble thrombomodulin levels were increased. The extent of coagulation activation correlated with mortality; patients who went on to die had higher TATc, F(1+2), tPA and PAPc and lower protein C and antithrombin levels on admission than patients who survived. CONCLUSIONS: The coagulation system is strongly activated during melioidosis. A high degree of activation of the coagulation system is an indicator of poor outcome in patients with melioidosis.     

Coagulation disorders in septic shock

Abnormalities in coagulation and fibrinolysis are frequently observed in septic shock. The most pronounced clinical manifestation is disseminated intravascular coagulation. Recent studies in human volunteers and animal models have clarified the early dynamics and route of activation of both coagulation and fibrinolytic pathways. In healthy subjects subjected to a low dose of either endotoxin or TNF an imbalance in the procoagulant and the fibrinolytic mechanisms is apparent, resulting in a procoagulant state. Also in patients with septic shock a dynamic process of coagulation and fibrinolysis is ongoing with evidence of impaired fibrinolysis. These abnormalities have prognostic significance; the extent of disturbances of coagulation and fibrinolysis is related to the development of multiple organ failure and death.     

Coagulation in sepsis: all bugs bite equally

Sepsis almost invariably leads to hemostatic abnormalities, ranging from insignificant laboratory changes to severe disseminated intravascular coagulation. There is compelling evidence from clinical and experimental studies that disseminated intravascular coagulation is involved in the pathogenesis of microvascular dysfunction and contributes to organ failure. Data from the PROWESS phase III clinical trial of recombinant activated protein C in patients with severe sepsis confirm this notion and demonstrate that the vast majority of patients with severe sepsis have increased markers for systemic coagulation activation, decreased physiological anticoagulant proteins and depressed fibrinolysis. There is no correlation between the type of microorganism that has caused the infection and the presence or severity of the coagulation disorder.     

Association between early glycemic control and improvements in markers of coagulation and fibrinolysis in patients with septic shock–induced stress hyperglycemia

Purpose

The purpose of this study is to evaluate the coagulation and inflammatory profiles in septic shock patients with baseline hyperglycemia under glycemic control.

Methods

Prospective, observational study conducted in an intensive care unit of a university hospital, including 41 septic shock nondiabetic patients with hyperglycemia (n = 21) or normoglycemia (n = 20) profiles at baseline. Hyperglycemic patients received a glucose control protocol (target glycemia, < 150 mg/dL). Metabolic, inflammatory, and coagulation markers were measured at baseline and after 24 hours.

Results

Median glycemic values between groups were different at baseline but not after 24 hours. Baseline coagulation profile was similar in both groups with elevated levels of coagulation markers, reduced factor VII, protein C, and antithrombin activities and fibrinolysis impairment. Normoglycemic patients had unchanged coagulation markers after 24 hours. After treatment, previously hyperglycemic patients exhibited increased plasminogen concentrations (P = .03) and reduced levels of plasminogen activator inhibitor 1 (P = .01) and tissue plasminogen activator (P = .03) as compared with baseline. They also had higher factor VII (P = .03), protein C (P = .04), and antithrombin (P = .04) activities than normoglycemic patients. Inflammatory markers were elevated in both groups and improved after 24 hours, independently of the glycemic profile.

Conclusions

Glycemic control during septic shock is associated with improvements in coagulation and fibrinolysis parameters compared with baseline and normoglycemic patients.     

Prognostic performance of disease severity scores in patients with septic shock presenting to the emergency department

BackgroundAn accurate disease severity score that can quickly predict the prognosis of patients with sepsis in the emergency department (ED) can aid clinicians in distributing resources appropriately or making decisions for active resuscitation measures. This study aimed to compare the prognostic performance of quick sequential organ failure assessment (qSOFA) with that of other disease severity scores in patients with septic shock presenting to an ED.MethodsWe performed a prospective, observational, registry-based study. The discriminative ability of each disease severity score to predict 28-day mortality was evaluated in the overall cohort (which included patients who fulfilled previously defined criteria for septic shock), the newly defined sepsis subgroup, and the newly defined septic shock subgroup.ResultsA total of 991 patients were included. All disease severity scores had poor discriminative ability for 28-day mortality. The sequential organ failure assessment and acute physiology and chronic health evaluation II scores had the highest area under the receiver-operating characteristic curve (AUC) values, which were significantly higher than the AUC values of other disease severity scores in the overall cohort and the sepsis and septic shock subgroups. The discriminative ability of each disease severity score decreased as the mortality rate of each subgroup increased.ConclusionsAll disease severity scores, including qSOFA, did not display good discrimination for 28-day mortality in patients with serious infection and refractory hypotension or hypoperfusion; additionally, none of the included scoring tools in this study could consistently predict 28-day mortality in the newly defined sepsis and septic shock subgroups.     

Effect of haemofiltration on pathological fibrinolysis due to severe sepsis: a case report.

Bleeding due to coagulopathy is a frequent complication of severe sepsis, especially in burn patients. The primary treatment is aimed at the underlying cause but additional supportive measures, consisting mainly of coagulation factor replacement, are frequently necessary. We describe the salutary effect of continuous veno-venous haemofiltration (CVVH) with predilution on diffuse haemorrhage in a patient with severe septic shock and renal failure. The diffuse haemorrhage was initially treated with replacement of coagulation factors. Prothrombin time and partial thromboplastin time became normal while diffuse bleeding continued and the thrombelastogram showed evidence of fibrinolysis. A short period of CVVH lead to the cessation of bleeding which was reflected by a normal thrombelastogram.     

The Italian SEPSIS study: Preliminary results on the incidence and evolution of SIRS,sepsis, severe sepsis and septic shock

This prospective, multicenter, epidemiological study was carried out in 99 Italian ICUs, distributed throughout the country, from April 1993 to March 1994. In the study, we applied the new ACCP/SCCM classification system for sepsis (SIRS, sepsis, severe sepsis and septic shock) and determined the prevalence, incidence, evolution and outcome of these categories in critically ill patients. The preliminary analysis of 1101 patients showed that on admission SIRS accounted for about half of the diagnoses (52%) with sepsis, severe sepsis and septic shock accounting for 4.5%, 2.1% and 3% of patients, respectively. Patients with severe sepsis or septic shock more frequently had high SAPS scores than patients without sepsis. Mortality rates were similar in patients with SIRS (26.5%) and without SIRS or infection (24%), but rose to 36% in patients with sepsis, to 52% in those with severe sepsis and to 81.8% in those with septic shock. Sepsis, severe sepsis and septic shock were more common in patients with medical diagnoses, and neither severe sepsis nor septic shock was observed in trauma patients. With respect to evolution, the incidence of septic shock was progressively higher in patients admitted with more severe “sepsis-related” diagnoses, while only a trivial difference in rates of incidence was observed between SIRS patients and those admitted without SIRS or any septic disorder (nil). The breakdown of the various ACCP/SCCM “sepsis-related” diagnoses at any time during the study was: SIRS in 58% of the population, sepsis in 16.3%, severe sepsis in 5.5% and septic shock in 6.1%. It seems reasonable to expect from the final evaluation of our study answers to the questions raised by the ACCP/SCCM Consensus Conference about the correlations between “sepsis-related” diagnosis, severity score, organ dysfunction score and outcome.     

Procalcitonin for early diagnosis and differentiation of SIRS,sepsis, severe sepsis,and septic shock

Objective To determine the value of procalcitonin (PCT) in the early diagnosis (and differentiation) of patients with SIRS, sepsis, severe sepsis, and septic shock in comparison to C-reactive protein (CRP), white blood cell and thrombocyte count, and APACHE-II score (AP-II). Design Prospective cohort study including all consecutive patients admitted to the ICU with the suspected diagnosis of infection over a 7-month period. Patients and methods A total of 185 patients were included: 17 patients with SIRS, 61 with sepsis, 68 with severe sepsis, and 39 patients with septic shock. CRP, cell counts, AP-II and PCT were evaluated on the first day after onset of inflammatory symptoms. Results PCT values were highest in patients with septic shock (12.89±4.39 ng/ml;P<0.05 vs patients with severe sepsis). Patients with severe sepsis had significantly higher PCT levels than patients with sepsis or SIRS (6.91±3.87 ng/ml vs 0.53±2.9 ng/ml;P<0.001, and 0.41±3.04 ng/ml;P<0.001, respectively). AP-II scores did not differ significantly between sepsis, severe sepsis and SIRS (19.26±1.62, 16.09±2.06, and 17.42±1.72 points, respectively), but was significantly higher in patients with septic shock (29.27±1.35,P<0.001 vs patients with severe sepsis). Neither CRP, cell counts, nor the degree of fever showed significant differences between sepsis and severe sepsis, whereas white blood cell count and platelet count differed significantly between severe sepsis and septic shock. Conclusions In contrast to AP-II, PCT appears to be a useful early marker to discriminate between sepsis and severe sepsis.     

Plasma platelet-activating factor acetylhydrolase activity in critically ill patients

OBJECTIVE: Platelet-activating factor (PAF) is a potent proinflammatory mediator in systemic inflammation and sepsis and is inactivated by the enzyme PAF-acetylhydrolase (PAF-AH). Recently, a large phase III clinical trial using recombinant PAF-AH to treat patients with severe sepsis was performed but failed to reduce 28-day mortality rate. To get more information on the activity of PAF-AH in sepsis, we repeatedly measured its activity in plasma in critically ill patients compared with healthy controls. DESIGN: Retrospective cohort study. SETTING: Intensive care unit. PATIENTS: Two hundred thirty-one patients who were admitted to an operative intensive care unit within 1 yr were enrolled and evaluated daily for American College of Chest Physicians/Society of Critical Care Medicine criteria. PAF-AH activity was measured as the release of [H]-acetate from [H]-acetyl-PAF. INTERVENTIONS: Analysis of plasma samples. MEASUREMENTS AND MAIN RESULTS: At the day of admission, PAF-AH activity of patients was below controls but markedly increased over time. Higher activities were seen in patients with severe sepsis or septic shock compared with those without organ failure. With respect to the clinical outcome, lower values were found in nonsurvivors only as long as they had not developed organ failure. In severe sepsis/septic shock, values of nonsurvivors exceeded those of survivors. PAF-AH activity was positively correlated with plasma levels of inflammatory mediators such as neopterine and tumor necrosis factor-alpha but not with acute phase reactants such as C-reactive protein, interleukin-6, or PCT. In addition, parenteral nutrition with lipid emulsions was seemingly associated with low PAF-AH activity compared with enteral nutrition. CONCLUSION: The data indicate severity- and time-dependent changes in PAF-AH activity and may help to explain the failure of recombinant PAF-AH treatment strategies that were not based on activity measurements.     

C1-inhibitor in patients with severe sepsis and septic shock: beneficial effect on renal dysfunction

OBJECTIVE: To investigate the efficacy and the safety of the parenteral administration of C1-inhibitor to patients with severe sepsis or septic shock. DESIGN: Double blind, randomized, and placebo-controlled trial. SETTING: Surgical and medical intensive care units of a tertiary care university hospital. PATIENTS: Forty consecutive patients (20 C1-inhibitor/20 placebo) who entered the intensive care unit with severe sepsis or septic shock. INTERVENTION: C1-inhibitor intravenously in a 1-hr infusion, starting with 6000 IU, followed by 3000 IU, 2000 IU, and 1000 IU at 12-hr intervals, compared with placebo. MEASUREMENTS AND MAIN RESULTS: C1-inhibitor administration significantly increased plasma C1-inhibitor antigen and activity levels during days 1-4 (p <.007). Patients in the C1-inhibitor group had significantly lower serum creatinine concentrations on day 3 (p =.048) and 4 (p =.01) than placebo patients. Multiple organ dysfunction assessed by logistic organ dysfunction and sepsis-related organ failure assessment scores was less pronounced in patients treated with C1-inhibitor. Mortality rate was similar in both groups. There were no C1-inhibitor-related side effects. CONCLUSIONS: C1-inhibitor administration attenuated renal impairment in patients with severe sepsis or septic shock.     

Time course and prognostic significance of hemostatic changes in sepsis: relation to tumor necrosis factor-alpha.

OBJECTIVES: To describe the time course and prognostic significance of tumor necrosis factor-alpha (TNF-alpha) levels and hemostatic abnormalities in clinical sepsis. DESIGN: Prospective, observational study with sequential measurements in an inception cohort. SETTING: An emergency department in a university teaching hospital. Patients were followed up until they either left the hospital or died. PATIENTS: During a 1-yr period, 43 adult patients were selected from all emergency department patients who met the established criteria for sepsis. Excluded were patients with either organ dysfunction or septic shock at the time of admission. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Blood samples were collected serially (day of admission and on days 3, 5, and 7) to determine TNF-alpha, platelet count, fibrinogen, factor VII, antithrombin III, tissue-type plasminogen activator activity, plasminogen activator inhibitor activity, plasminogen, and alpha2-antiplasmin. Fibrinopeptide A was measured only on the day of admission. Data were analyzed to determine whether admission values or serially obtained values within 7 days were useful in predicting outcome. Thirteen patients died and 30 survived. On admission, assay values indicated that platelet count and antithrombin III were significantly lower than normal (as observed in 50 healthy adults). Fibrinogen, plasminogen activator inhibitor type 1, tissue-type plasminogen activator, fibrinopeptide A, and TNF-alpha were higher than normal, whereas concentrations of factor VII, plasminogen, and alpha2-antiplasmin were in the normal range. No differences were detected in the admission values between survivors and nonsurvivors, except for antithrombin III. However, subsequent values of some variables demonstrated a difference between survivors and nonsurvivors. Survivors showed increasing platelet count and antithrombin III values compared with nonsurvivors, in whom the values remained low, with no significant changes during the study period. High TNF-alpha levels were found in both groups, but only survivors experienced progressive decrease during the observation period. CONCLUSIONS: Early clinical sepsis is characterized by high plasma levels of TNF-alpha and by activation of the coagulation and fibrinolysis systems. Longitudinal analysis of some variables (antithrombin III, platelet count, and TNF-ea) showed some differences with time between the survivor and nonsurvivor groups, but we feel that such differences were not large enough to be predictive in individual patients.     

Prognostic value of protein C concentrations in neutropenic patients at high risk of severe septic complications

OBJECTIVE: To assess the prognostic value of protein C, endogenous activated protein C, and D-dimer concentrations in patients at high risk of developing severe septic complications secondary to cytostatic chemotherapy. DESIGN: Prospective, comparative, single-center study. SETTING: Specialized ward for treating patients with acute leukemia and associated intensive care unit at a university hospital. SUBJECTS: Twenty-six consecutive patients who developed either severe sepsis (n = 13) or septic shock (n = 13) during chemotherapy-induced neutropenia (leukocytes <1,000/microL). INTERVENTION: None, other than standard care. MEASUREMENTS AND MAIN RESULTS: Baseline blood samples were obtained from 97 adult patients treated with intensive cytostatic chemotherapy. Serial blood sampling was performed in 62 of 97 patients who developed fever (>38.3 degrees C). Thirteen patients progressed to severe sepsis and 13 patients to septic shock. Protein C, endogenous activated protein C, and D-dimer were measured in these 26 patients. At fever onset, protein C concentrations decreased from normal baseline concentrations and were significantly lower in the group of patients who progressed to septic shock compared with those who developed severe sepsis (medians for protein C activity: 23.1% vs. 69.5%; p = .0003). The median elapsed time between detection of fever and the diagnosis of severe sepsis or septic shock was 16 hrs and 12 hrs, respectively. All septic shock patients died, whereas patients who progressed only to severe sepsis survived. CONCLUSIONS: Septic shock in neutropenic patients is associated with increased protein C consumption. The data demonstrate that the coagulation cascade is activated and produces a hypercoagulable state before the onset of clinical symptoms of severe sepsis and septic shock. Low protein C concentrations at the onset of fever and before the onset of clinical symptoms of severe sepsis or septic shock may have prognostic value in predicting an unfavorable outcome. Protein C measurements may help identify patients at risk in an early phase of neutropenic sepsis. It is also attractive to speculate that because low protein C concentrations were seen in these patients, protein C replacement may be beneficial in sepsis.     

Procalcitonin for early diagnosis and differentiation of SIRS, sepsis, severe sepsis, and septic shock

Objective: To determine the value of procalcitonin (PCT) in the early diagnosis (and differentiation) of patients with SIRS, sepsis, severe sepsis, and septic shock in comparison to C-reactive protein (CRP), white blood cell and thrombocyte count, and APACHE-II score (AP-II).¶Design: Prospective cohort study including all consecutive patients admitted to the ICU with the suspected diagnosis of infection over a 7-month period.¶Patients and methods: A total of 185 patients were included: 17 patients with SIRS, 61 with sepsis, 68 with severe sepsis, and 39 patients with septic shock. CRP, cell counts, AP-II and PCT were evaluated on the first day after onset of inflammatory symptoms.¶Results: PCT values were highest in patients with septic shock (12.89 - 4.39 ng/ml; P < 0.05 vs patients with severe sepsis). Patients with severe sepsis had significantly higher PCT levels than patients with sepsis or SIRS (6.91 - 3.87 ng/ml vs 0.53 - 2.9 ng/ml; P < 0.001, and 0.41 - 3.04 ng/ml; P < 0.001, respectively). AP-II scores did not differ significantly between sepsis, severe sepsis and SIRS (19.26 - 1.62, 16.09 - 2.06, and 17.42 - 1.72 points, respectively), but was significantly higher in patients with septic shock (29.27 - 1.35, P < 0.001 vs patients with severe sepsis). Neither CRP, cell counts, nor the degree of fever showed significant differences between sepsis and severe sepsis, whereas white blood cell count and platelet count differed significantly between severe sepsis and septic shock.¶Conclusions: In contrast to AP-II, PCT appears to be a useful early marker to discriminate between sepsis and severe sepsis.     

Coagulation system and platelets are fully activated in uncomplicated sepsis

OBJECTIVE: To test the hypothesis that the coagulation system and platelets are activated in sepsis, the uncomplicated and usually earliest stage of the septic process, and to compare the findings detected in sepsis with those found in severe sepsis and septic shock. DESIGN: Prospective study comparing patients with sepsis, severe sepsis, and septic shock, and healthy volunteers. SETTING: General intensive care unit in a tertiary university hospital. PATIENTS: Seventy-four consecutive septic patients (45 with sepsis, 15 with severe sepsis, and 14 with septic shock). Fourteen healthy volunteers served as control subjects. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: After blood sampling, molecular activation markers of coagulation (prothrombin fragments 1 and 2, fibrinopeptide A, thrombin-antithrombin complexes, and monomers of fibrin) and of platelets (beta-thromboglobulin and platelet factor 4), several coagulation factors, global tests of coagulation (prothrombin time and activated partial thromboplastin time), and platelet count (PTL) were measured. In sepsis, prothrombin fragments 1 and 2, fibrinopeptide A, thrombin-antithrombin complexes, and monomers of fibrin were increased to 2.52+/-0.21 nmol/L, 20.88+/-2.52 ng/mL, 33.8+/-2.9 microg/L, and 69% positive, respectively, compared with control subjects (0.86+/-063 nmol/L, 1.14+/-0.15 ng/mL, 16.07+/-1.01 microg/L, and 0%, respectively). Beta-Thromboglobulin and the beta-thromboglobulin-to-platelet factor 4 ratio were also increased to 107.87+/-11.87 IU/mL and 8.86+/-1.06, compared with controls (18.36 +/-2.99 IU/mL and 2.67+/-0.52, respectively). With the exception of a decrease in factor XII and an increase in fibrinogen, coagulation factors, global coagulation tests, and PTL were not changed in sepsis. In severe sepsis and mainly in septic shock, coagulation factors were markedly decreased, global coagulation tests were prolonged, and PTL was reduced. All changes were independent of the causative infectious pathogen. CONCLUSION: Coagulation system and platelets are strongly activated in sepsis. In this stage, only factor XII is decreased. In contrast, in severe sepsis and mainly in septic shock, most of the coagulation factors are depleted, PTL is decreased, and global coagulation tests are prolonged, indicating exhaustion of hemostasis. Finally, Gram-positive, Gram-negative, and other microorganisms produce identical impairment of coagulation.     

Fibrinolysis, thrombocytopenia, and coagulation abnormalities complicating high-dose interleukin-2 immunotherapy

High-dose interleukin-2 (IL-2) immunotherapy can cause hypotension, respiratory distress, interstitial edema, and thrombocytopenia, similar to endotoxic shock. We have observed that IL-2 has no direct effect on coagulation factors in vitro, but it has been observed to alter the coagulant properties of vascular endothelium. Accordingly, we investigated the possibility that IL-2 infusions initiate plasma fibrinolysis and disseminated intravascular coagulation (DIC). We studied the clinical course, platelet count, and coagulation profile in response to IL-2 infusion in seven patients, two with metastatic melanoma and five with metastatic renal cell carcinoma. Every patient experienced hemodynamic instability and thrombocytopenia, and one patient suffered an unusual complication, mesenteric thrombosis. No patient had appreciable changes in the prothrombin time or the partial thromboplastin time, nor did factors V or VIII decline in the two patients observed. In four patients examined, we found decreased titers of Hageman factor (factor XII), high molecular weight kininogen, prekallikrein, and plasma thromboplastin antecedent, as if these had been consumed by reactions of the intrinsic pathway of thrombin formation. Circulating D-dimer fragments were found in the plasma of every patient at some point during each infusion cycle, and we observed decreased titers of plasminogen in the four patients just mentioned, suggesting that IL-2 infusions initiated fibrinolysis. Taken together, the clotting factor derangements and related toxicity phenomena cannot be ascribed firmly to DIC. Activation of the intrinsic (contact) system of coagulation, however, may provide one link between the vascular endothelial surface alterations caused by IL-2 infusions and the development of the systemic toxicity that resembles septic shock.