Журнал «Медицина неотложных состояний» 6 (61) 2014

Introduction

The VTE prophylaxis in thoracic surgery is considered separately at the Ukrainian, Europeans and the America’s national guidelines by the thromboprophylaxis. Lung volume reduction caused by the pneumonectomy, trauma of the large pulmonary vessels, the use of a diathermocoagulation, malignant nature of the underlying disease, elderly patients' age and the presence of chronic comorbidities leads to an increased risk of thrombotic complications.

One of the areas to reduce intraoperative bleeding, including background on the pharmacological prevention of VTE low molecular weight heparin (LMWH) is used as fibrinolysis inhibitor tranexamic acid [4].

To date, the clinicians do not have a consensus on the start, the dose and the mode of administration ofthromboprophylaxis in patientsof onco-pulmonological profile.There are no consensus about the methods to reduce the risk of LMWH provoked intraoperative bleeding.

The aim of this work was to optimize methods of thromboprophylaxis in operational onco – pulmonology, which are based on the recommendations of the domestic and foreign, as well as our own researches.

Materials and Methods

During 2012 - 2013 years we examined 54 patients aged 26 to 79 years, who were examined to the II - III functional class according to ASA. Patients with lung tumors were subjected to thoracotomy from enucleation or atypical resection of lung lobe to pneumonectomy.

General anesthesia during thoracotomy was performed by the standard technique of inhalation anesthesia with sevoflurane or total intravenous propofol-based anesthesia with using a double-lumen endobronchial intubation and one-lung ventilation.

The first group included 21 patients with moderate to high risk of VTE (by Caprini at al.), who were underwent mechanical (elastic bandaging of the lower limbs) and pharmacological VTE prophylaxis (low (2500 IU) or high (3500 IU) prophylactic doses of Zibor, respectively). LMWH administered 12 hours before surgery. Subsequently - 1 time every 24 hours until complete restoration of motor activity of the patient (usually 3 - 5 days).

The second group included 18 patients with moderate to high risk of VTE (by Caprini at al.), who were underwent the mechanical (elastic bandaging of the lower limbs) and pharmacological VTE prophylaxis (low or high doses of prophylactic Zibor, respectively). LMWH administered 12 hours before the surgery, as in the first group. At the same time for 30 minutes before surgery was administered the tranexamic acid (Tranexam) 10 mg/kg intravenously once, in order to reduce perioperative blood loss.

The control group consisted of 15 patients I - II class ASA with low and moderate risk of VTE who received only mechanical prophylaxis.

Blood sample were taken from the cubital vein in standard vakuteyner sodium citrate. The 1 st time - in the ward (prior to administration of tranexamic acid and transport the patient to the operating room), the 2nd time - at the end of the operation on the operating table.

XIIa-kallikrein-dependent fibrinolysis was determined by a set "Fibrinolysis test" by "TECHNOLOGIYA STANDARD", Barnaul (Russian Federation). Anti-Xa activity of heparin is determined by coagulologic method usinga reagent kit NGO "RENAM" (Russian Federation) "ReaKlot heparin-test." The activity of antithrombin III in human plasma were determined by U.Abildgaard using a reagent kitNGO "RENAM" (Russian Federation) «ReaKlot -АТIII». The activity of protein C blood plasma was determined by using a reagent kit NGO "RENAM" "Protein C - test".

Statistical analysis was performed using the program MedStat [5].

Results and discussion

Changes occurring with anti Xa activity of heparin plasma in patients under the influence of thoracotomy, lung resection and general anesthesia were studied in a group of patients in the control group who did not receive pharmacological VTE prophylaxis using LMWH. Results: preoperatively 0,14 ± 0,07 U/ml, after the operation 0,03 ± 0,02 U/ml, p = 0.001. Takes place expressed, a statistically significant reduction of anti-Xa activity of heparin plasma under the influence of surgical trauma, enhanced thrombus formation with subsequent depletion of anticoagulant hemostasis. This indicates the tension in the coagulation and anticoagulation systems in organisms patients caused by an operating trauma. These data show that it is optimal way to start preoperative pharmacological thromboprophylaxis.

The speed of XIIa-dependent fibrinolysis was investigated before and during surgery in patients in the control group. It was revealed a significant initial elongation time XIIa-dependent fibrinolysis in this group of patients compared with reference values ​​(240 - 600).It is observed in the state of "pre-thrombosis": 974 ± 531 seconds preoperatively, 616 ± 342 seconds postoperatively, p = 0.013.This proves once again the advantage in preoperative launch of pharmacological thromboprophylaxis. Under the influence of the operating trauma the fibrinolysis time significantly decreased.

Thus, thoracotomy with resection of the lung in a state of general anesthesia leads to a simultaneous decrease in anti-Xa activity of heparin and shortening the XIIa-dependent fibrinolysis time of blood plasma in patients (increase in the activity of the fibrinolytic system).

Based on these data, and given that one of the areas to reduce intraoperative bleeding is used as fibrinolysis inhibitor tranexamic acid, it can be concluded that simultaneous use of LMWH and tranexamic acid in operational pulmonology is useful.

In the study of XIIa-dependent fibrinolysis time of blood plasma in patients treated with LMWH 12 hours before the operation was indicate the shortening the time of fibrinolysis with returning to normal data (240 - 600) compared with patients not receiving LMWH:411 ± 208 seconds preoperatively, 435 ± 183 seconds postoperatively. This can be explained by the fact that the heparin through the system of activated protein C indirectly promotes fibrinolysis by inhibition of endothelial cell production of plasminogen activator inhibitor-1 by the feedback mechanism is complexed with plasmin, fibrinogen and epinephrine, what provide fibrinolytic activity[8]. Apparently LMWH are shown the same characteristic. The effect of surgical trauma did not lead to a further shortening of the XIIa-dependent fibrinolysistime, as in patients not receiving LMWH before surgery.

In Group 2, who received both LMWH and tranexamic acid, XIIa-dependent fibrinolysis was not significantly different from the indicator of patients in group 1. However, immediately after the operation there was a significant decrease in the fibrinolytic activity (elongation time of fibrinolysis), compared with the preoperative level: preoperatively 372 ± 86 s after operation 433 ±135 s, p = 0.037.

Thus, LMWH did not affect the effectiveness of tranexamic acid. In order to ascertain the effect of tranexamic acid on the efficacy of LMWH was investigated anti-Xa activity of heparin plasma in patients studied groups: LMWH group - before surgery 0,25 ± 0,016 U / mL after surgery 0,22 ± 0,014 U / ml; LMWH + T group - 0,3 ± 0,05 U / ml before surgery and 0,28 ± 0,07 U / ml after surgery.

Thus, the use of tranexamic acid does not reduce the effectiveness of LMWH. The values ​​of anti-Xa activity of heparin inpatients’blood plasma remain within a "prophylactic" range (0.1 - 0.3 IU/ml) during the surgical intervention. Reducing anti Xa activity after surgery in both groups compared to baseline due to the time factor - the more time has passed since the introduction.

To more fully explore the possible impact of joint use of LMWH and tranexamic acid on the anticoagulant potential of the hemostatic system, the antithrombin III activity and protein C system activitywere investigated.

Results of research of activity of antithrombin III: LMWH group - before surgery 73,7 ± 8,5%, after surgery 64,6 ± 6,2%, p = 0.023; LMWH group + T - before surgery 80,7 ± 16,3%, after surgery 78,6 ± 14,7%. As seen from these data, tranexamic acid on the background of LMWH did not reduce the activity of antithrombin III.

On the contrary, there is no significant decrease in the activity of antithrombin III after surgery in patients treated with LMWH. Perhaps this is due to the fact that are decreases consumption of antithrombin III to inhibition of plasminogen because fibrinolytic activity is reduced under the influence of tranexamic acid.[9].

Results of research of protein C activity: LMWH group - before surgery 0,98 ± 0,23 nd after surgery 0,84 ± 0,16 nd, p = 0.009; LMWH group + T - before surgery 0,86 ± 0,24 nd after surgery 0,92 ± 0,31 nd. Listed the lack significant reduction in activity of protein C at the end of surgery in patients treated with LMWH and tranexamic acid, and having such as in patients of group 1 (see Figure 6). Perhaps this is due to anti-inflammatory effects of tranexamic acid, which leads to less stress in the protein C system under the influence of surgical trauma [9].

Explanation of the mechanisms of influence of tranexamic acid on antithrombin III and protein C systems requires the deeper research. However, it is safe to say that on the background of LMWH administration, tranexamic acid does not lead to a decrease in LMWH activity.

Currently, the Department of Anesthesiology of the Donetsk regional clinical territorial medical association introduced protocol of the thromboprophylaxis during planned operations on the lungs, which is based on the risk assessment and recommendations by Joseph Caprini et al [10], as well as the order of 329 the MoH of Ukraine and our own research, which are cited above.

Conclusions

1.   In patients with lung cancer observed the initial weakening of blood plasma fibrinolytic activity.
2.   In patients undergoing lung resection there is a decrease anti Xa activity of heparin, and shortening the XIIa-dependent fibrinolysis time of blood plasma compared to baseline.
3.  The administration of Zibor in 12 h before surgery leads to intraoperative increase of anti Xa heparin activity to the prophylaxis level. Alsoisnormalizedfibrinolyticactivityofbloodplasma.
4.  The use of tranexamic acid, on the background of Zibor action, increases the XIIa-dependent fibrinolysis during resection of the lung, compared with the preoperative level.
5.    The use of tranexamic acid on the background of Ziboraction does not reduce the anticoagulant potential of the hemostatic system, because it does not lead to a decrease in anti-Xa activity, protein C system activity and activity of antithrombin III.
6.   Simultaneous use of tranexamic acid and Zibor not lead to mutual inefficiencies and may be used in the scheme of thromboprophylaxis in patients with an increased risk of intraoperative hemorrhage.