Journal of Crohn's and Colitis
Volume 6, Issue 1 , Pages 13-20, February 2012

Activated thrombin activatable fibrinolysis inhibitor (TAFIa) is associated with inflammatory markers in inflammatory bowel diseases:

TAFIa level in patients with IBD

  • Danuta Owczarek

      Affiliations

    • Department of Gastroenterology, Hepatology and Infectious Diseases Jagiellonian University School of Medicine, Krakow, Poland
    • Corresponding Author InformationCorresponding author at: Department of Gastroenterology, Śniadeckich 5 31-531 Kraków, Poland.
    • ,
  • Anetta Undas

      Affiliations

    • Institute of Cardiology, Jagiellonian University School of Medicine, Krakow, Poland
    • ,
  • Jonathan H. Foley

      Affiliations

    • Department of Biochemistry, Queen's University, Kingston, Ontario, Canada
    • ,
  • Michael E. Nesheim

      Affiliations

    • Department of Biochemistry, Queen's University, Kingston, Ontario, Canada
    • Medicine, Queen's University, Kingston, Ontario, Canada
    • ,
  • Konrad Jabłonski

      Affiliations

    • Department of Gastroenterology, Hepatology and Infectious Diseases Jagiellonian University School of Medicine, Krakow, Poland
    • ,
  • Tomasz Mach

      Affiliations

    • Department of Gastroenterology, Hepatology and Infectious Diseases Jagiellonian University School of Medicine, Krakow, Poland

Received 7 February 2011; received in revised form 11 June 2011; accepted 12 June 2011. published online 15 July 2011.

Article Outline

Abstract 

Background

Thrombin activatable fibrinolysis inhibitor (TAFI) has been reported to be involved in the pathogenesis and progression of inflammatory bowel disease (IBD). Activated TAFI (TAFIa) attenuates fibrinolysis by cleaving C-terminal lysine residues thus down-regulating plasminogen activation. To date, no reports on TAFIa in IBD have been published.

Methods

Plasma levels of TAFIa were measured using a functional assay in 55 consecutive patients with ulcerative colitis (UC) and 50 with Crohn's disease (CD). Associations of TAFIa with disease activity, hemostatic variables and inflammatory markers were assessed.

Results

Plasma TAFIa was higher in CD patients than in those with UC. The disease activity correlated positively with TAFIa levels in the UC group, but not in the CD group. In UC patients, there were positive correlations of TAFIa with white blood cells, C-reactive protein and fibrinogen and an inverse correlation with albumin. In the CD group, a positive correlation was shown for C-reactive protein, fibrinogen and platelet count, while a negative correlation was noted for albumin.

Conclusions

This study is the first to show that TAFIa is increased in CD patients compared with UC and its levels are associated with inflammatory markers in both forms of IBD. These findings fit in the hypothesis that TAFIa may be a marker of active IBD, and in particular of active UC.

Highlights

► Thrombin activatable fibrinolysis inhibitor (TAFI) has been reported to be involved in the pathogenesis and progression of inflammatory bowel disease. ► This study is the first to show that TAFIa is increased in CD patients compared with UC and its levels are associated with inflammatory markers in both forms of IBD. ► TAFIa may be considered as a marker of exacerbated UC, but not CD.

Keywords: Inflammatory bowel disease, Inflammation, TAFI, Carboxypeptidase U

 

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1. Introduction 

Blood coagulation is linked with inflammation.1 While inflammatory processes are occurring, proteases originating from inflammatory infiltrate cells become activated as well as proteases involved in the coagulation and fibrinolytic pathways.1 Recently, much attention has focused on hemostatic abnormalities in the pathogenesis of inflammatory bowel disease (IBD) and its thromboembolic complications involving both venous and arterial vasculature.2 Thromboembolism is considered a relatively frequent extraintestinal manifestation of IBD that contributes to mortality associated with IBD.2 In IBD patients, thromboembolic complications occur mainly during disease exacerbation and are more common in patients with elevated markers of systemic inflammation.2 In approximately 60% of patients presenting with thromboembolic complications, pancolitis is observed.2 It has been suggested, however, that in contrast to Crohn's disease (CD), patients with ulcerative colitis (UC) have an increased risk of thromboembolic events which can occur in patients with low-activity disease or even during remission.2

Factors that contribute to thromboembolic complications in IBD patients include damage to vascular endothelium,3 hyperhomocysteinemia, genetic predisposition, vitamin deficiency, smoking and an imbalance of procoagulant, anticoagulant and fibrinolytic factors.2

Growing evidence indicates that elevated levels of thrombin activatable fibrinolysis inhibitor (TAFI) occur not only in coronary artery disease, ischemic stroke, diabetes, rheumatoid arthritis, Behcet's disease, but also in IBD.4, 5, 6, 7, 8 TAFI, a plasma zymogen, can be activated by thrombin, the thrombin-thrombomodulin complex, or plasmin.9, 10 The activated form of TAFI (TAFIa) removes C-terminal lysine residues from plasmin-modified fibrin which suppresses plasminogen activation, thereby attenuating fibrinolysis.11 Recently, it has been suggested that in addition to suppressing fibrinolysis, TAFIa may also be involved in inflammation. Its potential role as a natural anti-inflammatory molecule is currently being explored, with recognition of its ability to inactivate the potent anaphylatoxins, C3a and C5a, as well as the proinflammatory mediators, bradykinin and osteopontin.12

The available reports regarding plasma TAFI concentrations in IBD patients yielded conflicting results. Saibein et al.13 demonstrated that higher TAFI concentrations occur in IBD patients as compared to the controls, with no differences between the UC and CD patients. In another study published in 2008, TAFI concentrations were lower in UC and CD patients than in the healthy controls.14 To the best of our knowledge, there have been no studies on the presence of circulating TAFIa in IBD and its determinants. In view of the role of TAFI in hemostasis and its effect on inflammation, we sought to investigate the relationship between TAFIa concentrations in patients with UC or CD and both the activities of these diseases.

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2. Material and methods 

2.1. Study population 

We enrolled consecutive patients with UC and CD aged 18years or older diagnosed based on classic histopathological, endoscopic and radiological criteria.15 The exclusion criteria were pregnancy, concomitant inflammatory disorders, and concomitant severe diseases, because these disorders can raise risk of thromboembolic complications as well as influence the values of inflammatory and coagulation factors. The patients with a history of oral anticoagulation were also excluded.

The patients enrolled into the study were followed at the Department of Gastroenterology, Hepatology and Infectious Diseases, Jagiellonian University Medical College, Krakow, Poland. The study was approved by the Jagiellonian University Bioethics Committee. All participants gave their informed consent.

2.2. Clinical assessment 

In each patient, the following factors were assessed: disease duration, disease location, disease activity, complications, current pharmacotherapy, past surgical procedures, smoking habits and concomitant diseases. Body mass index (BMI) was calculated. Complications were defined as the presence of an abscess, fistulas, stenoses resulting in post-obstructive symptoms and IBD-associated extraintestinal diseases. In view of the employed pharmacotherapy, the patients were divided into groups administered 5-aminosalicylatate (5-ASA) alone, 5-ASA and steroids, 5-ASA and immunosuppressants, as well as 5-ASA, steroids and immunosuppressive drugs. To determine the location of lesions in UC and CD, the Montreal classification was employed.16

To assess the CD activity, the Crohn's Disease Activity Index (CDAI) was used. CDAI combined the evaluation of vital parameters, clinical findings and medical history as described in detail elsewhere.17 The activity of UC was evaluated using the disease activity index (DAI) that is a composite score based on the daily number of stools, visible blood in stool, appearance of the colonic mucosa at endoscopy, and the physician's global assessment. Each variable is scored from 0 to 3 so that the total index score ranges from 0 to 12.18

Depending on their CDAI score, the CD patients were divided into two subgroups, i.e. CD non-active (patients with CDAI <150) and CD active (patients with CDAI ≥150). The UC patients were also categorized into two subgroups based on their DAI scores, i.e. UC non-active (patients with DAI <6), and the active subgroup (patients with DAI ≥6).19

2.3. Laboratory tests 

Fasting blood samples were collected from the antecubital vein in the morning. On the same day, the following laboratory parameters were determined: blood cell count, hematocrit, blood platelets, albumin, fibrinogen, C-reactive protein (CRP), partial activated thromboplastin time (APTT), D-dimer, antithrombin and the protein C system components (thrombomodulin, protein C, free protein S). CRP and albumin were assayed using a Modular P clinical chemistry analyzer (Roche Diagnostics, Mannheim, Germany). A complete blood count was performed with a Sysmex XE-2100 hematology automated analyzer (Sysmex, Kobe, Germany). Fibrinogen and APTT were measured with a Behring Coagulation System (BCS, Dade Behring, Marburg, Germany). Protein C and antithrombin activities were measured using chromogenic assays (Siemens, Germany). Plasma soluble thrombomodulin concentrations were determined using an ELISA kit (Asserachrom Thrombomodulin; Roche, France). Free protein S levels were assayed using an ELISA with a rabbit polyclonal antibody against human protein S (Dako, Denmark). Plasma samples were treated 10.5% polyethylene glycol, which precipitates the protein S-C4b-binding protein complex, according to the method of Malm et al.20 Plasma D-dimer levels were measured using a VIDAS system (Roche, France).

Blood samples (9:1 of 3.2% trisodium citrate) for determination of TAFIa were immediately placed on ice and centrifuged at 4°C (20min, 2500g) within 30min of collection. Plasma samples containing TAFIa were stored at −80°C until analysis. TAFIa levels were determined using a previously described functional assay which is based on the ability of TAFIa to catalyze the removal of carboxyl-terminal lysine residues which bind a fluorescently labeled plasminogen derivative. Upon cleavage of the C-terminal lysine residues by TAFIa, the plasminogen becomes unbound and there is a concomitant increase in fluorescence. The rate of fluorescence increase is proportional to the TAFIa concentration.21 The assay was sensitive for TAFIa at a concentration of 12 pM. The inter- and intraassay variabilities were 8% and 6%, respectively. The values observed in healthy people of TAFI are 20.3±9.1 pM.21

TAFIa has been measured in duplicate and the mean of two values has been provided in the manuscript. A mean variability of the results is 8%.

All the measurements were performed by a technician blinded to the origin of the samples.

2.4. Statistical analysis 

The results were expressed as mean±SD. For asymmetric distribution median, lower and upper quartiles were used. The Shapiro–Wilk test was used to determine if the data were normally distributed. The intergroup data comparison was done using the Student's t-test for independent variables with normal distribution or the data were compared by the Mann–Whitney test. Multiple comparisons were done by one way ANOVA test with Scheffe's post-hoc test and nonparametric Kruskal Wallis test with Bonferroni/Dunn test. Associations between the variables with normal distribution were assessed using the Pearson correlation test, while the relationships of those without normal distribution were assessed using the Spearman rank correlation test. Relationships were presented graphically. A p-value <0.05 was considered statistically significant. Statistical analysis was performed using the Statistica software, v.9.0.

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3. Results 

We studied 105 patients, including 55 individuals with diagnosed UC and 50 with CD (Table 1).

Table 1. Characteristics of patients with ulcerative colitis and Crohn's disease.
CharacteristicsUlcerative colitis
N=55
/mean±SD/
/median (Q25; Q75)/		Crohn's disease
N=50
/mean±SD/
/median (Q25; Q75)/		p
Age37.1±13.2 36 (25; 46)30.1±10.5 29.5(22; 34)0.004
GenderFemale, n (%)28 (50.9)23 (46)0.615
Male, n (%)27 (49.1)27 (54)
BMI [kg/m2]22.75±3.4421.69±4.210.06
TAFIa [pM]51.49±32.82 51.6 (30.1; 66.7)65.93±34.12 60.25(37.7; 87.95)0.04
White blood cells [×103/μl]7.86±3.49 7.24(5.54; 8.75)7.37±3.24 6.73(5.47; 8.63)0.4
Hematocrit [%]40.05±4.4639.64±4.560.6
Platelet count [×103/μl]308.87±123.21 293(226; 354)329.9±100.44 317.5(275; 365)0.13
CRP [mg/l]16.53±32.55 5.8(1.6; 16.5)26.61±32.98 14.75(4.39; 31.1)0.012
Fibrinogen [g/l]4.35±1.975.21±2.080.02
Albumin [g/l]41.45±5.5939.74±5.670.1
aPTT [s]33.32±5.0534.06±4.020.17
D-dimer [ng/ml]258.43±211.36 181(115; 342)222.82±138.75 194(123; 257)0.9
Antithrombin [%]91.19±11.4989.34±10.670.4
Thrombomodulin [ng/ml]24.53±11.75 22.1(17.18; 29.32)21.35±10.25 21.31(12.98; 28.25)0.2
Protein C [%]120.24±27.76117.14±26.990.5
Protein S [%]84.83±23.7379.53±26.660.12

Data are presented as mean±SD. Abbreviations: BMI—body mass index, CRP—C-reactive protein, and aPTT—partial activated thromboplastin time. Median as well as lower and upper quartiles were added for the asymmetrical distribution.

In patients with UC and CD, we demonstrated higher TAFIa concentrations as compared to the values observed in healthy people, using the analytical method developed by Kim et al.21

The mean age of the CD patients was lower (p=0.0036). Higher CRP (p=0.012) and fibrinogen (p=0.02) were observed in CD patients. D-dimer, antithrombin, thrombomodulin, protein C and free protein S were lower in the CD group compared with the UC patients (Table 1). The concentration of TAFIa was higher in the CD than in the UC group (p=0.039).

Characteristics of patients with active and non-active UC and CD are presented in Table 2. Higher platelet count, CRP and fibrinogen were observed in the active subgroups of CD and UC as compared to the non-active subgroups for both diseases. In patients with UC, higher protein C was found in the active subgroup compared with the non-active subgroup (p=0.035). There was no such difference in the CD group. Plasma TAFIa concentrations were higher in the active vs. non-active subgroups only in the UC group (p=0.005). Graphically it is showed on the Fig. 3.

Table 2. Characteristics of patients with active and non-active ulcerative colitis and Crohn's disease.
CharacteristicsNon-active ulcerative colitis
N=23
/mean±SD/
/median(Q25; Q75)/		Active ulcerative colitis
N=32
/mean±SD/
/median(Q25; Q75)/		Non-active Crohn's disease
N=20
/mean±SD/
/median(Q25; Q75)/		Active Crohn's disease
N=30
/mean±SD/
/median(Q25; Q75)/
Age37.25±14.63 33.5(25; 50)37±12.28 38(26; 45)30.43±9.61 30(24; 34)29.81±11.32 28(21; 35)
GenderFemale, n (%)11 (46)17 (55)9 (39)14 (52)
Male, n (%)13 (54)14 (45)14 (61)13 (48)
BMI [kg/m2]22.99±3.522.56±3.4322.78±3.9520.75±4.27 #
TAFIa [pM]38.08±26.84 32.3(14.0; 61.15)62.22±33.58 ⁎ 60.25(39.8; 76.9)58.21±34.71 53.65(33.7; 80.4)72.46±32.87 74.7(44.798.9)
White blood cells [×103/μl]6.56±1.8 6.75(5.19; 7.76)8.86±4.14 ⁎ 8.2(5.59; 9.94)7.56±4.0 6.74(5.64; 8.47)7.21±2.48 6.72(5.01; 9.13)
Hematocrit [%]41.79±4.5438.7±3.9642.8±3.536.94±3.53 #
Platelet count [×103/μl]254.46±66 249(212.5; 305.5)351.0±140.64 ⁎ 326(252; 399)277±69.38 280(210; 338)374.96±101.76 # 341(296; 464)
CRP [mg/l]2.97±4.94 1.42(0.76; 2.45)27.03±40.34 ⁎ 11.2(7.22; 34.8)9.73±18.81 3.62(1.19; 8.68)40.99±35.83 # 28.5(16.4; 61)
Fibrinogen [g/l]3.1±1.255.31±1.89 ⁎4.14±1.556.13±2.07 #
Albumin [g/l]43.88±5.5539.58±4.93 ⁎42.87±3.7037.07±5.75 #
aPTT [s]33.67±4.9233.06±5.2134.4±4.333.78±3.82
D-dimer [ng/ml]231.38±218.22 143(111; 236)280.27±207.35 235(136; 360)208.44±140.29 176(117; 244)235.75±139.68 210(156; 263)
Antithrombin [%]92.34±9.6990.26±12.8489.8±9.8188.9±11.52
Thrombomodulin [ng/ml]24.76±10.18 22.27(17.45; 32.22)24.35±13.0 21.35(14.95; 28.68)21.07±10.46 22.18(12.98; 28.52)21.59±10.27 20.1(12.43; 28.25)
Protein C [%]111.08±20.94127.04 ±30.47 ⁎118.11±34.08116.31±19.8
Protein S [%]87.59±24.9782.79±22.9681.44±26.1877.92±27.47

Statistical analysis for HCT and antihrombin III was performed with parametric tests by using one way ANOVA and Scheffe's test. For the others parameters analysis was performed with nonparametric tests by using Kruskal–Wallis test with Bonferroni/Dunn test.

Bonferroni/Dunn test showed differences between groups for following parameters: TAFIa, PLT, CRP, Fibrinogen, and Albumin. Tests performed for p<0.05.

Median as well as lower and upper quartiles were added for the asymmetrical distribution.

Abbreviations see Table 1.

⁎p<0.05 active UC vs. nonactive UC.

#p<0.05 active CD vs. nonactive CD.

  • View full-size image.
  • Figure 3 

    Dispersion graphs of the TAFIa for: active Crohn's disesase (CDactive), nonactive Crohn's disease (CDnactiv), active ulcerative colitis (UCactiv) and nonactive ulcerative colitis (UCnactiv).

As shown in Table 3, in the UC patients, there were significant positive correlations of TAFIa with WBC, CRP, and fibrinogen as well as an inverse correlation with albumin. In the CD group, strong positive correlations were shown for CRP, fibrinogen, and platelet count, while a negative correlation was noted solely for albumin. The disease activity correlated positively with TAFIa levels in the UC group (r=0.39, p=0.004). No such association was demonstrated for CD. Graphically it is showed in Figure 1, Figure 2.

Table 3. Correlations TAFIa in ulcerative colitis and Crohn's disease.
Ulcerative colitisCrohn's disease
Correlationrprp
White blood cells0.290.037−0.050.73
Hematocrit−0.130.33−0.14a0.33
Platelet count0.230.090.380.009
C-reactive protein0.470.00040.460.001
Fibrinogen0.440.00090.61a<0.0001
Albumin−0.500.0001−0.39a0.005
D-dimer0.060.700.0020.98
Antithrombin0.070.630.04a0.78
Thrombomodulin0.210.120.090.55
Protein C0.220.110.070.65
Protein S−0.010.97−0.220.13
Disease activity0.390.0040.210.15

aPearson correlation coefficient (normal distribution), the remaining correlations calculated with Spearman coefficient.

Medication regimens did not affect plasma concentrations of TAFIa. In 4 treatment groups receiving 5-ASA alone, 5-ASA and corticosteroids, 5-ASA and immunosuppressive agents, and 5-ASA, corticosteroids and immunosuppressive agents, no between-groups differences in the TAFIa levels were observed. Other clinical features, i.e. disease location, disease duration and complications showed no significant association with plasma TAFIa levels (data not shown).

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4. Discussion 

Elevated plasma TAFI levels were previously observed in venous thrombosis, type 2 diabetes, nephrotic syndrome, rheumatoid arthritis, Behcet's disease, coronary artery disease, and neoplastic diseases.5, 6, 8, 22 In addition, increased TAFI concentrations were demonstrated to be associated with thromboembolic complications of these diseases.7, 8, 23, 24 The effect of TAFI on healing of cutaneous wounds and intestinal anastomoses has also been reported in mouse models.25

In patients with UC and CD, we demonstrated higher TAFIa concentrations as compared to the values observed in healthy people, using the analytical method developed by Kim et al.21 Interestingly, TAFIa levels were higher in the CD than in the UC groups. We provided additional evidence for the association between an increased activity of inflammatory disorders and elevated TAFIa. We demonstrated a correlation between the inflammatory markers, both CRP and fibrinogen, and TAFIa concentrations in the CD and UC patient groups. This finding is in agreement with previous studies reporting a significant correlation between TAFI levels and the acute phase response markers.5, 13 In the current study, significantly higher TAFIa was observed in patients with active UC than the non-active UC, but not in those with active CD vs. non-active CD. Analysis of the associations between TAFIa and clinical variables in IBD patients showed a significantly higher concentration of TAFIa in CD patients previously operated on as compared to the remaining CD patients, which might support the observation that increased TAFI levels is linked to a more severe course of chronic inflammatory diseases with complications in the history.8, 23 In the present study, no correlation was shown between CD location and TAFIa concentration, which is inconsistent with the results of Saibein et al. who however measured TAFI zymogen.13 This finding indicates that plasma TAFI levels may not correlate with activated TAFI levels. Further studies are needed to validate this hypothesis.

Increased TAFIa levels in CD vs. UC as well as active UC compared to non-active UC are an unexpected finding. It has been shown that TAFI might be activated by neutrophil elastase released from activated neutrophils.14, 26 This activation mechanism might contribute to the observations made in the present study.

A significant correlation was also noted between TAFIa concentration and platelet count in the CD group. Albumin, the so-called negative acute-phase protein, showed a significant inverse correlation with TAFIa in the CD and UC patients. This correlation demonstrates that there is a link between the activation of TAFI in circulating blood and the inflammatory response, which provides evidence of an additional link between coagulation and inflammation.

In the course of the inflammatory process, proteases originating from inflammatory infiltrate cells become activated and proteases of the coagulation and fibrinolytic systems become activated. Proinflammatory cytokines, such as interleukin-1, interleukin-8, and tumor necrosis factor α, also participate in blood coagulation activation.27, 28 TAFIa is a factor that not only bridges the coagulation and fibrinolysis systems, but it also potentially modulates the inflammatory process through its anti-inflammatory properties.29 The correlation between TAFIa and the inflammatory markers and the absence of such a correlation for most hemostatic markers assessed in the present study may support the notion that activation of blood coagulation and fibrinolysis in IBD is secondary to the inflammatory process 30 and effective IBD treatment suppresses elevated coagulation markers.31

The data presented by Marks et al.,32 although somewhat controversial33 is consistent with elevated TAFIa. Marks et al. demonstrated that acute inflammation is defective in CD and that this is in part due to a 79% reduction in neutrophil accumulation. TAFIa is elevated in IBD, but in CD the level is higher than UC and effectively cleaves C5a, which may result in decreased neutrophil activation and thus contribute to defective inflammation in IBD. The potential effect of TAFIa on inflammation and thrombosis in IBD may be confounded by many variables including the presence of soluble thrombomodulin,10 the TAFI genotype (Thr325 or Ile325)34 or the relatively short half-life of TAFIa.34 The TAFIa genotype is of particular interest since the Ile325 isoform has an increased half-life (16min) compared to the Thr325 isoform (8min). Individuals with the Ile325 isoform may be incapable of mounting an appropriate inflammatory response because of the prolonged TAFIa activity on the anaphylatoxins C5a and C3a. Previously, it has been shown that TAFI zymogen has the ability to cleave small substrates with approximately 2% of the catalytic efficiency of TAFI.34 As the size of the substrate increases the catalytic efficiency of TAFI also decreases to a point where no detectable activity is observed.35 This suggests that TAFI may have residual activity toward small substrates such as bradykinin but minimal activity toward larger substrates like C3a and C5a. As a result, TAFIa is potentially a key mediator of inflammation that should be considered with TAFI zymogen levels especially in the case of inflammation regulated by anaphylatoxins C3a and C5a.

Our study has several limitations. We did not evaluate a control group that should comprise patients suffering from an inflammatory bowel disease other than IBD. Recruitment of such population free of infections was not feasible. The current study focused on clinical and laboratory factors associated with TAFIa levels in CD and UC patients. The main aim of our study was to show differences both between CD and UC patients as well between active and non-active phase of these diseases. The number of study participants was limited. Therefore, analysis of subgroups in CD or UC patients should be interpreted with caution. We determined TAFIa on a single occasion. Hence, the current study did not address the issue of changes in TAFIa with time. Exclusion of anticoagulated patients and those with previous VTE episodes resulted in omission of subjects who could have even higher TAFIa concentrations. Finally, long-term follow-up to evaluate clinical outcomes, including thromboembolic events, wad beyond the scope of this study. A larger study is needed to assess clinical implications of our findings.

In conclusion, this study is the first to show that TAFIa is increased in IBD patients, with higher values for CD. Elevated TAFIa associated with inflammatory markers in both CD and UC patients. Our findings suggest that TAFIa may represent a better indicator of active UC. Further larger studies with long follow-up are needed to evaluate the links between TAFIa and exacerbation of IBD.

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PII: S1873-9946(11)00180-2

doi:10.1016/j.crohns.2011.06.005

Journal of Crohn's and Colitis
Volume 6, Issue 1 , Pages 13-20, February 2012

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