TIME COURSE OF C1-ESTERASE INHIBITOR AND ITS ROLE IN PREDICTION OF OUTCOME OF SEVERE TRAUMATIC BRAIN INJURY

TIME COURSE OF C1-ESTERASE INHIBITOR AND ITS ROLE IN PREDICTION OF OUTCOME OF SEVERE TRAUMATIC BRAIN INJURY

Borshchikova T.I., Epifantseva N.N., Kan S.L., Nikiforova N.V.

Novokuznetsk Institute of Medical Extension Course – the branch of Russian Medical Academy of Continuous Professional Education, Novokuznetsk, Russia 

C1-esterase inhibitor (C1I), the protein of α2-globulin fraction of the blood with molecular weight of 105 kDa, plays the important role in functioning of proteolytic systems of the blood and in regulation of homeostasis in critical states [1]. C1I protein is mainly synthesized in hepatocytes, and, in low amount, in monocytes, megakaryocytes, fibroblasts and endothelial cells [2]. The surface of the protein globule contains some chemically active centers which block the activity of proteases by means of formation of peptide association P1:Arg444-P1′:Thr445. The covalent complex protease-C1I is extracted from the blood flow by means of binding with serpin-specific receptors of hepatic cells, and, to lesser degree, through uptake by neutrophils and monocytes. The clearance time is 20-47 minutes [2]. Owing to proteolytic activity, C1I blocks the activation of complement proteins, and suppresses the activity of XI and XII clotting factors, formation of plasmin and kallikrein [1, 3]. C1I takes the active participation in regulation of vascular permeability, resulting in decreasing inflammatory exudation [4]. Other anti-inflammatory properties of C1I have been described: an ability to block the alternative way of activation of the complement system, to bind the endotoxin, to activate the phagocytosis and to suppress the migration of leukocytes into inflammation site [1, 5, 6, 7]. These properties of C1I allow its use for treatment of sepsis, gram-negative endotoxic shock, transplant rejection responses, ischemia-reperfusion syndrome and acute pancreatitis [1].
Severe traumatic brain injury (STBI) is characterized by activation of blood clotting and fibrinolysis, complement proteins and kallikrein-kinin system. C1I plays the important role in functioning of these systems (Fig. 1). Besides, the role of C1I in prediction of STBI outcome has not been studied previously. Therefore, the objective of our study was estimation of the time course of the C1-esterase inhibitor and its role in prediction of the outcome of severe traumatic brain injury.

Figure 1. Biological functions of the C1-esterase inhibitor [4]

MATERIALS AND METHODS

The study included 53 patients with STBI (the main group). The mean age of the patients was 42.1 ± 14.1. The main group included 46 (86.7 %) men and 7 (13.3 %) women. STBI was opened in 22 (41.5 %) patients and closed in 31 (58.5 %) patients [8]. In 45 (85 %) patients, the brain compression was associated with intracranial hematomas: subdural (24/44.4 %), epidural (4/7.2 %), intracerebral (12/23.3 %), multiple (5/10 %) hematomas. In 15 % of cases (8 patients), severe brain contusions were identified.
After admission to the clinic, Glasgow Coma Scale (GCS) was 6.9 ± 2.0, APACHE II – 19.7 ± 4.7. Surgical interventions (48/90.6 %) were carried out in presence of sign of brain compression. 5 patients (9.4 %) received only conservative techniques of treatment. In the early posttraumatic period, 27 (50.9 %) patients died. Severe pyoinflammatory complications were found in 30 (56.6 %) patients within the first two weeks of the posttraumatic period: pneumonia (23/76.7 %), meningitis (7/23.3 %).
The treatment of patients with STBI included the basic principles of intensive care of critical states: artificial lung ventilation, hemodynamics and intracranial pressure normalization, and correction of acid-base balance of the body. In the first day, the infusion therapy included mainly salt solutions: physiological solution, Ringer's solution and sterofundin. From the second day, the infusion therapy was reduced, and the enteral nutrition was added with nutrition mixtures. Considering the severity of condition at admission and artificial lung ventilation, hemoglobin was maintained within 96.7 ± 1.5 g/l, hematocrit – 0.29 ± 0.004.
On the days 1, 4, 7, 14 and 21, the venous blood was examined with the immunoturbidimetry technique (biochemical analyzer KONELAB-60i, Termoelectron) for C1I and other proteins: α1- antitrypsin (α1АТ), α2- antiplasmin (α2AP), α2-macroglobulin (α2MG). The reagents Spinreact (Spain) and Labsystems (Finland) were used. This technique was used for estimation of C-reactive protein (CRP) and complement proteins C3 (C3KK) and C4 (C4KK).
The nervous tissue protein S100 was estimated as the indicator of the cerebral injury severity. ELISA technique was used for this purpose (test-systems CanAg, Austria).
On the basis of physiological activity of C1I protein, the coagulation parameters of citrate venous peripheral blood were estimated: euglobulin (EGF), XII-kallikrein-dependent (XII-KDF) and streptokinase-induced fibrinolysis. Plasminogen reserve index (PRI) was calculated. The values of anticoagulation link of hemostasis were estimated: activity of antithrombin-III (AT-III), total activity of protein C with use of tool-sets Technology-Standard (Russia). The time course of D-dimers was estimated with solid-phase immunofluorescent assay (BioRad, USA) with test-systems Technoclon (Austria), soluble fibrin complexes – (SFC) with use of test-systems Technology-Standard (Russia).
The study did not include patients younger 18 and older 70, as well as patients with oncologic, endocrinologic and infectious diseases, and with organic pathology of the heart. The study did not include patients who had early postsurgical bleedings since they received the hemostatic therapy. The control group included 21 persons at the age of    41.8 ± 12.4. The control group included 17 men (80.9 %), 4 women (19.1 %).
On the basis of proteolytic activity of C1-I and active participation in functioning of kallikrein-kinin system, 16 patients of the main group and 14 patients of the control group received the examination of activity of prekallikrein (PK), high-molecular kininogen (HMK), clotting factors XII and XI. The immunodepleted plasma with coagulation activity < 1 % for determined factor (Technoclon, Austria) were used. Also activated partial thromboplastin time (APTT) was estimated.
The results of the study were analyzed with STATISTICA-7. The normalcy of data distribution was examined with Shapiro-Wilk’s test or Kolmogorov-Smirnov test. If distribution differed from normal values, Wilcoxon-Mann-Whitney test was used. The interdependence of values was estimated with Spearman correlation coefficient.
The study corresponded to the ethical principles of Helsinki Declare (2013) and to the Rules for Clinical Practice in the Russian Federation (the Order by Russian Health Ministry, 19 June 2003, No.266), with approval by the ethical committee of Novokuznetsk Institute of Medical Extension Course (the protocol No.1, 27 May 2019). 

RESULTS AND DISCUSSION

The time course of C1I and other serine proteases, clotting proteins and fibrinolysis are presented in the table 1. The level of C1I in STBI was lower than the normal value over the whole period of the follow-up, with the minimal value in the first 24 hours of the study.

Table 1. Dynamics of the proteins of the blood coagulation and fibrinolysis, serine protease inhibitors and inflammatory proteins in severe traumatic brain injury

Values

Indicators at study stages

Control group

Study stages (days)

1

4

7

10

14

21

 

 

Proteins-serine proteinase inhibitors

C1I, mg/dl

25.1 ± 0.7

16.9 ± 0.74♦

18.9 ± 0.74♦

22.4 ± 0.93♦

23.3 ± 0.93♦

22.3 ± 0.83♦

21.13 ± 0.83♦

α2AP, mg/dl

6.10 ± 0.42

4.23 ± 0.294♦

5.11 ± 0.31

5.51 ± 0.62

5.57 ± 0.34

5.90 ± 0.95

6.29 ± 1.35

α2MG, mg/dl

162.8 ± 3.4

144.3 ± 5.83♦

150.1 ± 5.64♦

155.4 ± 7.8

159.6 ± 7.8

161.4 ± 9.7

166.1 ± 15.8

α1AT, mg/dl

143.5 ± 3.7

183.3 ± 8.44♦

206.3 ± 9.14♦

218.1 ± 11.94♦

246.4 ± 11.6

230.6 ± 11.84♦

251.4 ± 18.94♦

 

 

Complement proteins

C3KK, g/l

1.04 ± 0.03

1.06 ± 0.06

1.32 ± 0.064♦

1.54 ± 0.083♦

1.89 ± 0.114♦

2.01 ± 0.094♦

2.04 ± 0.094♦

C4KK, g/l

0.26 ± 0.01

0.27 ± 0.02

0.32 ± 0.023♦

0.34 ± 0.043♦

0.40 ± 0.044♦

0.41 ± 0.063♦

0.40 ± 0.04 ♦

 

 

C-reactive protein and S100

CRP, mg/l

1.4 ± 0.3

85.0 ± 9.94♦

99.6 ± 9.24♦

105.4 ± 11.44♦

100.4 ± 12.24♦

93.2 ± 11.94♦

84.2 ± 10.74♦

S100  µg/l

0.130 ± 0,007

0.680 ± 0.0674♦

0.202 ± 0.0154♦

0.151 ± 0.009♦

0.148 ± 0.014

0.136 ± 0.009

0.130 ± 0.009

 

 

Blood clotting and fibrinolysis

EGF, min.

179.1 ± 8.9

270.6 ± 13.34♦

305.8 ± 9.14♦

324.5 ± 10.14♦

306.5 ± 16.24♦

342.4 ± 8.14♦

344.3 ± 11.64♦

XII-KDF, min.

8.2 ± 0.29

108.9 ± 18.34♦

161.2 ± 15.94♦

216.3 ± 16.44♦

131.6 ± 18.64♦

162.1 ± 18.54♦

184.9 ± 21.04♦

PRI, %

100.9 ± 2.5

91.3 ± 2.82♦

86.9 ± 2.14♦

79.9 ± 4.34♦

77.6 ± 4.34♦

76.7 ± 3.84♦

82.3 ± 5.34♦

AT-III activity, %

104.2 ± 2.4

88.5 ± 3.73♦

99.4 ± 3.9

88.9 ± 6.0

95.9 ± 5.9

110.4 ± 5.2

103.7 ± 3.5

SAPS, ratio

0.95 ± 0.04

0.78 ± 0.034♦

0.83 ± 0.023♦

0.81 ± 0.013♦

0.82 ± 0.022♦

0.80 ± 0.024♦

0.78 ± 0.033♦

SFC, mg/dl

0.78 ± 0.49

10.59 ± 1.044♦

15.15 ± 1.574♦

16.40 ± 1.084♦

17.66 ± 1.224♦

15.45 ± 1.024♦

15.40 ± 1.464♦

D-dimer, ng/ml

52 ± 8

1450 ± 4954♦

958 ± 2504♦

1029 ± 3124♦

3174 ± 9854♦

1164 ± 2264♦

-

Fibrinogen, g/l

3.14 ± 0.12

3.69 ± 0.114♦

4.63 ± 0.094♦

5.50 ± 0.164♦

5.94 ± 0.194♦

6.38 ± 0.224♦

6.04 ± 0.284♦

APTT, sec.

37.9 ± 0.4

38.9 ± 1.1

39.3 ± 1.5

37.3 ± 0.9

37.8 ± 0.9

38.2 ± 1.1

36.8 ± 1.2

Note: ♦ – statistically significant difference between the indicator and its value in the control group: ♦ – p < 0.05; 2♦ – p < 0.02; 3♦ – p < 0.01; 4♦ – p < 0.001.


Activation of complement system was estimated according to the time course of C3 and C4 proteins. In case of STBI, the level of C3KK did not differ from the values in the control group in the first day. On the days 4-14, C3 protein exceeded the values in the control group (p < 0.001), and it was higher than in the first day of the study. The maximal values of C3KK were identified only on the day 21 of the posttraumatic period. The level of C4KK increased on the day 4 and remained at the higher level over the whole period of the study. The increase in C3 and C4 components indicated the activation of the complement system through the standard way. It is known that activation of proteins of the complement system goes through the standard way with the antigen-antibody complex, and with the alternative and lectin pathways – with non-immunological molecules, including endotoxin [7]. The general direction of the time course of C3 and C4 proteins in the posttraumatic period was determined by their participation in protection of the body from injured cells, infectious agents, and anti-bodies released by specific immune cells [9]. The anti-inflammatory properties of C1I were related to inhibition of the activated form of the first component of the complement, which initiates the cascade of complement proteins through the standard pathway [10]. Since C1I suppresses two proteolytic enzymes of the first component of C1s and C1r complement, the efficiency of recombinant C1I for therapy of sepsis and septic shock is clear [3]. Albert-Weissenberger C. (2014) demonstrated the anti-inflammatory properties of C1I in the experimental model of STBI [11]. He found that introduction of recombinant C1I promoted the decrease in posttraumatic degeneration of the brain, stabilization of hematoencephalic barrier, and reduction of delivery of immune cells into cerebral parenchyma [11].
In case of STBI, a relationship between C1I level and severity of patients’ condition at the moment of admission was found, and some evident correlations between protein level, GCS and APACHE-II (C1I-GCS: r = 0.348, p < 0.001; C1I-APACHE-II: r = -0.234, p < 0.005). Moreover, the correlations between C1I and S100 protein showed the highest significance as the value of severity of cerebral cellular injury: r = -0.776 (p < 0.001). Intensive consumption of C1I in STBI is evident in activation of blood clotting system and fibrinolysis [12]. Within the first day after STBI, the decrease in plasma level of C1I showed its active consumption in internal pathway of coagulation, and the lineal relationship with severity of a traumatic injury. At the same time, the participation in the inflammatory response was shown by some reliable relationships between C1I, CRP (r = 0.175, p < 0.049), C3KK (r = 0.472, p < 0.001), C4KK (r = 0.295, p < 0.05) and fibrinogen (r = 0.308, p < 0.001).
The anti-inflammatory effect of C1I manifests itself by means of an ability to bind with various components of extracellular matrix, including collagen of type 4, laminin, entactin and fibrinogen [7]. Formation of the noncovalent association with C3b component promotes the suppression of an ability of leukocytes to migrate into the inflammation site [6]. It was found that C1I binding with gram-negative bacterial endotoxin prevents the influence of endotoxin on macrophages and further development of the inflammatory response [6].
The analysis of the time course of C1I in STBI, depending on an outcome (survived – deceased) and formation of inflammatory complications (patients with/without pyoinflammatory complications) showed the active consumption of the enzyme as result of proteolysis and in the second week of the posttraumatic period as result of the inflammatory response in development of pyoinflammatory complications (Fig. 2).

Figure 2. Dynamics of C1-esterase inhibitor in patients with severe traumatic brain injury depending on the outcome (a) of the disease and the occurrence of pyoinflammatory complications (b)

  

Note: * – significantly significant difference in the indicator compared to its level in the control group (Wilcoxon-Mann-Whitney test): * – p < 0.05; 2* – p < 0.02; 3* – p < 0.01; 4* – p < 0.001.


During the course of STBI, we reviewed the time courseof other proteins of the blood with proteolytic activity: α2-macroglobulin, α1antitripsin and α2-antiplasmin. The active consumption of these proteins was found in the early posttraumatic period, with subsequent increase at the background of secondary pyoinflammatory responses. So, the level of α1AT increased significantly (1.3 times on average) in the first day, achieving the maximal values on 14th day of the study, when its level exceeded the control values (1.7 times higher). The frequency analysis showed the increase in the control values of α1AT in 67.3 % of the cases in the first day, and in 100 % on 10th day. This important antiprotease takes the active participation in decreasing activity of thrombin, plasmin, kallikrein, activated factors X and XI and neutrophilic elastase [9].
In the first day with STBI, α2MG was lower than the value in the control group (p < 0.01). From 7th day, its level did not differ from the control group. The low level of this protein on the days 1-4 of the posttraumatic period was associated with its active consumption in proteolytic processes. It is known that α2-macroglobulin can bind any proteinases: metal-dependent, thiol, acid and serine proteolytic enzymes [9].
α2-antiplasmin, the direct inhibitor of plasmin, increased to the level of the lowest norm from 4th day of the posttraumatic period, showing its higher significance in regulation of fibrinolysis processes [9].
More significant correlations showed the primary role of C1I in regulation of complex proteolytic processes: C1I–α1AT: r = 0.391, p < 0.0001; C1I–α2MG: r = 0.171, p < 0.001; C1I–α1AP: r = 0.455, p < 0.005. The decrease in C1I showed its active participation in the processes of microclotting. Its sufficient level is required for prevention of inopexia [5].
In patients with STBI, the fibrinolytic activity (EGF, XII-KDF) was at the lower level during the whole period of the study (p < 0.001). Moreover, the degree of depression of EGF and XII-KDF was more intense during the second week of the posttraumatic period. The value of activity of clotting and fibrinolytic systems (SFC) increased from the first day, reaching the maximal level on the days 7-10 of the posttraumatic period. The correlations between C1I and PRI (r = -0.359, p < 0.001) and between C1I and total activity of CRP (r = 0.175, p < 0.048) were found.
Currently, the following anti-inflammatory properties of C1I have been acknowledged: blocking of the first component of the complement (C1r, C1s), blocking of MASP2 (mannan-binding lectin serine protease 2); inhibition of fibrinolytic proteases (plasmin, tissue plasminogen activator) and plasma proteins of kallikrein-kinin system (kallikrein, factors XI and XII) [1, 6, 9]. C1I can interact not only with kallikrein, plasmin and factor XII, but also with the precursor of plasma thromboplastin [1]. Binding with plasmin does not require for any intact molecule of C1I. The enzyme is equally activated by the intact molecule and by the partially split molecule [1, 9]. According to the literature data, the main inhibitor of plasma kallikrein is C1I. It blocks approximately 57 % of its plasma form [12]. Moreover, the “versatile” protein-inhibitor α2-macroglobulin binds only 43 % of kallikrein [12].
Since C1I plays the important role in regulation of the internal mechanism of blood clotting and vascular permeability by means of interaction with proteins of kallikrein-kinin system [4], the next stage of our study was estimation of the time course of proteins of kallikrein-kinin system in STBI (the table 2). From the first day of the posttraumatic period, the evident decrease in proteins of kallikrein-kinin system was observed: factor XI, high-molecular kininogen, prekallikrein (1.6 times on average); factor XII (1.3 times). Factor XII in STBI was 30 % lower (on average) than the values in the control group. The lowest values were observed on 10th day (57.5 ± 13.5 %). The lowest values of factor XI were noted in the first day (p < 0.001). It increased subsequently and corresponded to the level in the control group on the days 10-14. For the whole period of the study, prekallikrein and high molecular kininogen were 1.6 times lower the values in the control group (p < 0.05).

Table 2. Dynamics of the activity contact factors in the acute period of the severe traumatic brain injury

Value

Indicators at study stages

Control group
(n = 14)

Study stage, days (n = 16)

1

7

10

14

Factor XII, %

101.48 ± 2.80

79.4 ± 10.2♦

68.6 ± 9.74♦

57.5 ± 13.53♦

70.8 ± 11.13♦

Factor XI, %

99.19 ± 3.51

63.9 ± 3.74♦

76.1 ± 5.94♦

106.5 ± 4.5

93.6 ± 10.9

Prekallikrein, %

98.62 ± 3.12

61.6 ± 6.04♦

60.7 ± 7.64♦

67.0 ± 16.0♦

71.1 ± 11.7♦

High-molecular-weight kininogen, %

103.29 ± 3.15

64.3 ± 3.74♦

73.9 ± 7.84♦

56.0 ± 1.04♦

67.2 ± 8.44♦

Note: ♦ – statistically significant difference between the indicator and its value in the control group (tests of Mann-Whitney-Wilcoxon): ♦ – p < 0.05; 2♦ – p < 0.02; 3♦ – p < 0.01; 4♦ – p < 0.001.


The most intense correlations of C1I were identified in relation to factor XI (XI-C1I; r = 0.407, p < 0.027). The correlation coefficients between C1I, factor XII, prekallikrein and high molecular kininogen were 0.179, 0.100 and 0.037 correspondingly (p > 0.05). At the same time, a correlation between C1I and the values of activity of external and internal mechanisms of fibrinolysis were found (C1I–EGF: r = 0.490, p < 0.050; C1I–XII-KDF: r = -0.305, p = 0.032; C1I–D-dimer: r = -0.395, p < 0.05). These correlations show the direct anti-plasmin action of C1I in the blood flow. The less important correlations between C1I and proteins of kallikrein-kinin system show the active consumption of Hageman factor in the processes of microvascular clotting in response to an injury. It is confirmed by the high level of the correlation between C1I and factor XI (XI–C1I: r = 0.521, p < 0.008) in development of pneumonia in the acute period of STBI. It is known that activity of the contact factors is blocked (to lesser degree) by other inhibitors of serine proteases: antithrombin-III, α1AT, α2AP, α2MG, proteins of protein C system [6]. In our study, factor XI showed a significant correlation with α2MG (XI–α2MG: r = 0.406, p < 0.031) and α1AT (XI–α1AT: r = 0.398, p < 0.05). The results show the contribution of C1I into inactivation of XI factor that is important for regulation of the processes of intravascular clotting and inflammation [9].
Therefore, in case of STBI, C1I has the important role in regulation of balance of cascade systems of homeostasis. Due to its biological activity it can maintain the balance of kallikrein-kinin system, blood clotting, fibrinolysis and complement proteins since their excessive activation can cause some life-threatening disorders in critical states. In case of STBI, we found the proteolytic consumption of C1I in microclotting responses in the first days after STBI and in later period – in inflammatory responses during development of secondary pyoinflammatory complications. Active consumption of C1I in inflammatory responses and in coagulation cascade gives the features of the marker of prediction of the disease outcome.
In our previous work, we have shown the role of C1I in prediction of development of pyoinflammatory complications. We found some efficient prediction models including C1I, blood level of lymphocytes and platelets, CRP, and S100 [13]. These variables also showed their significance in the multiple regression analysis of early prediction of STBI. The table 3 demonstrates the most significant equations of multiple regression. The frequency analysis showed the actual accuracy of the prediction models in the first day after trauma. It was 77-86 %. The probability of the poor outcome of STBI increased to 98 % after addition of the immune suppression value (white cell count in the peripheral blood) to the selected variables. The real accuracy of identification of the poor outcome of STBI was 75-95 %. The use of C1I in combination with S100, immune suppression level (absolute count of lymphocytes) and clotting values (a decrease in count of lymphocytes, an increase in fibrinogen) with probability up to 95 % allows predicting the poor outcome of STBI.

Table 3. Indicators and multiple regression equations for different sets of independent variables in early prediction of outcome from severe traumatic brain injury

Values

Values of multiple regression in dependence on selected independent variables

1

2

3

C1I
S100 protein
Fibrinogen

C1I
S100 protein
Fibrinogen
Platelets

C1I
S100 protein
C-reactive protein
Platelets
Lymphocytes

Multiple R

0.880

0.920

0.991

Determination coefficient (R2)

0.774

0.857

0.982

Standardized determination coefficient (standardized R2) 

0.638

0.571

0.953

Number of cases

32

30

25

CONCLUSION

Despite of active research of body’s responses to the traumatic brain injury, understanding of these processes at the molecular level require for further detailed searching. Our study has shown the predictive value of C1I for estimation of a probability of the poor outcome of STBI. Considering the above-mentioned facts, one can suppose that the use of recombinant C1I can be the perspective therapeutic strategy in treatment of STBI. 

Information on financing and conflict of interest

The study was conducted without sponsorship. The authors declare the absence of any clear or potential conflicts of interest relating to this article.

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