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INTRODUCTION
Deficiency of von Willebrand factor-cleaving protease, a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) is thought to be responsible for platelet aggregation and microthrombi formation, which in turn cause the development of typical thrombotic microangiopathies (1). This deficiency is found in patients with thrombocytopenia-associated multiple organ failure such as thrombocytopenic purpura, hemolytic uremic syndrome, or sepsis (2-6). Disseminated intravascular coagulation (DIC) is a microangiopathic phenotype characterized by increased tissue factor (TF) and plasminogen activator inhibitor type I (PAI-1), unopposed by the anticoagulant proteins tissue factor pathway inhibitor (TFPI), protein C, antithrombin III, and prostacyclin (6, 7). The severest forms also have an ADAMTS 13 deficiency (8). We evaluated the clinical significance of ADAMTS13 deficiency in patients with sepsis-induced DIC.
MATERIALS AND METHODS
1, Study population
From September 2005 to December 2005, 19 patients with sepsis-induced DIC were enrolled at Konyang University Hospital, 813-bed teaching hospital located in Dajeon, Korea. Since the normal value of ADAMTS13 antigen level defined by manufacturer's instruction was less than 350 ng/mL, patients were categorized into two groups accordingly: the ADAMTS13 antigen level less than 350 ng/ml or above. Clinical characteristics and survival were compared between the two groups.
2. Diagnosis of sepsis and DIC
The diagnosis of sepsis was made according to the definition of the American College of the Chest Physicians/Society of Critical Care Medicine Consensus Conference Committee (9). The diagnosis of DIC was made according to the criteria established by the Japanese Ministry of Health and Welfare (1988), which are described elsewhere (10). Briefly, the presence of underlying diseases (infection or malignancies), specific clinical conditions (bleeding or organ dysfunction), and results of laboratory examinations (platelet counts, prothrombin time, fibrinogen, and/or fibrin degradation products) were quantified based on the score. If the score was 7 or more, the diagnosis of DIC was made. The severity of illness of the patients was evaluated according to the Acute Physiology and Chronic Health Evaluation II (APACHE II) (11).
3. Measurement of ADAMTS13
ADAMTS13 antigen levels were determined by IMUBIND® ADAMTS13 ELISA kit (America Diagnostica Inc, Stamford, CT, USA). ADAMTS13 activity levels were measured by fluorescence resonance energy transfer assay described previously (12).
4. Statistical analysis
The clinical characteristics were compared using the Mann-Whitney U test and Fisher's exact test depending on the scales of measurement. Survival was evaluated using Kaplan-Meier method. All P values were two-tailed, and P<0.05 was considered to be statistically significant. All analyses were performed using Statistical Package for the Social Sciences (SPSS) 11.0 (SPSS Inc., Chicago, IL, USA).
RESULTS
1. Demographic characteristics of patients
Among enrolled 19 patients, the level of ADAMTS-13 was below 350 ng/mL in 7 patients and above 350 ng/mL in 12 patients. Age, sex, and severity index of illness such as the presentation of septic shock and APACHE II score between the two groups did not show statistically significant differences (Table 1). The number of cases of microbiologically defined infections was 15 patients (79%). The causes of infections were pneumonia, intra-abdominal infections, and urinary tract infection in decreasing order of frequency; there were no differences in the cause of infection between the two groups (Table 1). The activity of ADAMTS-13 was below 70% in 6 patients; 3 patients (25%) were from the group whose level of ADMAMTS-13 was >350 ng/mL and 3 (42.9%) patients were from the group whose level of ADMAMTS-13 was ≤350 ng/ml. There were no differences between the two groups (Table 1).
2. Mortality according to the level of ADAMTS-13
Nine patients died of sepsis within 7 days after admission. Seven-day mortality rate was 25.0% (3 of 12) in the group with the levels of ADMAMTS-13 >350 ng/ml, and 85.7% (6 of 7) in the group with the levels of ADMAMTS-13 ≤350 ng/mL (Table 1). Log rank test using Kaplan-Meyer methods revealed that 7-day survival was much shorter in patients with ADAMTS13 antigen levels less than 350 ng/ml (P=0.023) (Fig. 1).
DISCUSSION
ADAMTS-13 activity is decreased in thrombotic thrombocytopenic purpura, sepsis, idiopathic thrombocytopenic purpura, heparin induced thrombocytopenia, liver cirrhosis, leukemia, and systemic lupus erythematosus (4, 13-15). In patients with sepsis, severe deficiency of ADAMTS-13 was associated with renal failure (8) and/or sepsis-induced thrombocytopenia and organ failure (15).
In this study, among patients with sepsis-induced DIC in intensive care unit, all patients whose level of ADAMTS13 was below 350 ng/mL died within 28 days, but only 3 patients (25%) from 12 patients whose levels of ADAMTS13 was above 350 ng/mL died. If cutoff value had been 500 ng/mL, the 28-day mortality rate of the patients with ADAMTS13 deficiency would be 75.0% (9/12) and the mortality rate of the patients without ADAMTS13 deficiency would be 14.3% (1/7). Therefore, the further study is needed to define the cutoff value of ADAMTS13 as a risk factor of mortality in patients with sepsis with DIC. Ono and colleague reported that severe secondary deficiency of ADAMTS13 in patients with sepsis-induced DIC was correlated with development of renal failure (8). Also, this study revealed that severe secondary deficiency of ADAMTS13 in patients with sepsis-induced DIC was associated with mortality. The underlying mechanism of sepsis-induced thrombocytopenia and organ failure is not well known, but it could be hypothesized that sepsis-associated thrombocytopenia results from widespread platelet aggregation and thrombotic microangiopathy caused, in part, by deficient proteolysis of ultra-large von Willebrand factor (ULVWF) (15). ULVWF is cleaved by ADAMTS13 (16). Therefore, ADAMTS13 deficiency may play a role in the sepsis-induced thrombocytopenia, organ failure, and subsequent mortality. The restoration from the deficient proteolysis of ULVWF could be achieved by plasma exchange (17) and it could attribute to clinical improvement in patients with severe sepsis if more studied are needed.
There are some prognostic indexes such as APACHE II score and Sequential Organ Failure Assessment (SOFA) score for severe sepsis. The difference in severity index of illness such as the presentation of shock and APACHE II score between the two groups was not observed. Therefore, the level of ADAMTS13 could be a significant prognostic factor in patients with sepsis-induced DIC.
This study has some limitations such as small number of subjects. However, this study revealed that secondary deficiency of ADMATS13 in patients with sepsis-induced DIC may be associated with unfavorable outcome. More studies are needed if the restoration from the status of deficient proteolysis of ULVWF could improve the survival rate of patients with sepsis.
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