Federal Scientific Clinical Center of Miners’ Health Protection,

Leninsk-Kuznetsky, Russia

 

During knee joint endoprosthetics (KJE) a patient loses the greatest amount of his/her blood as draining or occult blood loss (in the form of hematoma) in the postsurgical period [1]. Postsurgical blood loss 3-5 times increases intrasurgical one, resulting in different complications. Generally, during the first 24 hours the total blood loss often increases 20-25 % of the circulating blood volume (CBV) that leads to worsening the postsurgical period and treatment outcomes. One of the main causes of postsurgical bleeding is fibrinolysis activation [2, 3]. Primarily this reaction has compensatory characteristics and is a response to increase in hemostatic potential of the blood in the region of injured tissues. However, because of significant release of cytokines and other substances into the blood which intensify proteolysis processes directly or indirectly this reaction can be excessive and impediment for final hemostasis. At that, during bleeding the level of fibrinolytic activity in the blood is higher compared to the period without bleeding [4]. In the greatest amount of the patients such bleeding has no systemic character and is noted only in the wound; however, this fact does not exclude its clinical significance. Considering these circumstances the drugs inhibiting excessive fibrinolysis are used in some clinics for decreasing blood loss volume in surgery, gynecology and orthopedics. However, resulting changes in hemostasis can increase already high risk of thromboembolic complications. It is conditioned by characteristics of surgical intervention and frequent use of the tourniquet for the hip of a patient during surgery [5, 6]. The risk of development of thromboembolic complications during this pathology is not studied completely.

Objective – to examine the efficiency and safety of intrasurgical use of fibrinolysis inhibitor tranexam in patients with planned surgical blood loss and high risk of venous thrombosis.

 

MATERIALS AND METHODS

The study included 107 patients with gonarthrosis admitted for KJE (24 men and 83 women). The age of the patient was 47-69 (61 ± 5.7). Based on the preliminary examinations [6], with the aim of reducing risk of postsurgical venous thrombosis all patients did not have hip tourniquet during surgery.

The exclusion criteria were (contraindications to tranexam):

1) myocardial infarction and its consequences,

2) thrombophlebitis and postthrombophlebitic syndrome,

3) disorders of colored vision,

4) hematuria and renal insufficiency.

 

The patients were randomly divided into 2 groups depending on the method of infusion transfusion therapy in KJE and use of tranexam. The study group included the patients (n = 55) with intrasurgical infusion of tranexam. All patients were informed about the aim of tranexam administration and gave the informed consent for its use. The tranexam dose was 10 mg/kg and was infused during 20 minutes in the beginning of surgery [1, 7]. Blood loss was compensated with hydroxyethyl starch drugs (6 % voluven – 500 ml) and polyionic solutions 10-15 ml/kg. The use of the donor blood components was maximally limited for decreasing risk of hemotransfusion complications.

The control group included the patients (n = 52) who received intrasurgical hemodilution with autoplasma. Preliminarily 1-2 sessions of double discrete plasmapheresis (500-600 ml for one session) were performed with the minimal 3 day interval between the sessions. Autoplasma was frozen and stored at -20° C. Autoplasma reinfusion was performed at the most traumatic moment of surgery. Low molecular heparin was administrated percutaneously for all patients 12 hours before surgery, with the aim of reducing basic hypercoagulative syndrome. The repetitive injection was 8-10 hours after surgery, and then 1 time a day. All patients received spinal anesthesia (SA) with 0.5 % marcaine 2-3 ml at the level of L2-L4 and monitored sedation with propofol, 100-200 mg/h with continuous instrumental infusion. After surgery the patients were transferred to the intensive care unit for controlling general state, draining contents and further treatment. Hemoglobin level decrease below 80 g/L was considered as an indication for hemotransfusion. For the patients with concurrent ischemic heart disease and postsurgical ECG signs of disorders of myocardial perfusion and trophism the low accessible limit for transfusion of donor red blood cells was hemoglobin level 100 g/L.

For general assessment of hemostasis system state the technique of thromboelastography (TEG) was used which is common for integral estimation of processes in the blood and in plasma during clotting and sequent thrombolysis (Fig.) [8]. The study was performed with the thromboelastograph by Haemoscope corporation (USA). The following TEG values were registered and analyzed:

R – time (min.) from the moment of placement of sample into the analyzer till formation of the first fibrin fibers.

K – time (min.) from clot formation till achievement of fixed level of clot transparence (amplitudes = 20 mm).

MA – maximal amplitude (mm) describes lots of dynamic properties of composition of fibrin and thrombocytes, as well as reflects maximal strength of a clot.

A60 – TEG amplitude after 60 min.

IL – lysis index (%) defined by the formula: IL = A60/MA × 100, it is characteristics of clot dissolution process – lysis; at that, decrease in IL value indicates fibrinolysis increase.    

  The following indices of coagulation part of hemostasis were examined: prothrombin time as international normalized ratio (INR) and prothrombin ratio (PTR); activated partial thromboplastin time (APTT, sec.); fibrinogen level (Fg, g/L) using STA Compact coagulometer (France). Soluble fibrin complexes (SFC × 10^-2, g/L) were defined using orthofenantren test at the plate. The venous blood was examined 24 hours before surgery, before klexan administration and 24 hours after surgery.

Intrasurgical ECG and arterial pressure (AP) monitoring were performed with the monitors by SpaceLabs, Inc. (USA), measurement of oxygen saturation (SpO₂) - with Oxisat 2, Drager )Germany).

Ultrasound color mapping for identification of thrombotic lesions in the veins of lower extremities was realized with the MyLab Class C ultrasound scanner (Italy). The examinations were performed before surgery and 7 days after it.

The committee for ethics and substantiation of medical scientific studies of Scientific Clinical Center of Miners’ Health Protection confirmed that the methodology of the performed study did not contradict the moral ethic standards, legal, regulatory and recommended documents. The study used the common research methods. The performed researches can be recognized as acceptable and evidentiary.

The study results were analyzed with Biostat and STATISTICA 6.1. The normalcy of distribution of values in the groups was assessed with Kolmogorov-Smirnov test. As far as sample distribution tended to normality, the results of the study were presented as mean (M) and standard deviation (δ). For examination of intragroup and intergroup differences Student t-test and χ² were used. The differences were statistically significant with p < 0.05.

Figure

The scheme of calculation of thromboelastogram  values  

 

RESULTS

The duration of surgeries did not differ in the groups and it was 78.2 ± 9.1 minutes. For the patients of the study group tranexam was infused in isotonic solution with dose of 10 mg/kg body mass (on average, 806.5 ± 98.3 mg) at the start of surgery. At the final stage of surgery the additional electrocoagulation hemostasis was performed, as well as draining, wound closure and application of compressing bandage.

In the study the blood loss was comparable in the groups, while intrasurgical blood loss was little lower after hemodilution with autoplasma. Administration of tranexamic acid resulted in statistically significant more than two time decrease in postsurgical blood loss degree (Table 1). It is in concordance with the results by other authors [1, 9]. 

Table 1
Postsurgical blood loss in the groups of patients with knee joint endoprosthesis (M ± δ)

Blood loss			Study group  (n = 55)			Control group  (n = 52)
During surgery (ml)			438.2 ± 72.8			365.8 ± 69.6
Draining losses (ml)			158.6 ± 82.2 *			349.9 ± 162.7
Note: * – reliability of difference in indices between the groups (p < 0.05).

There was a statistically significant decrease in cell composition of the blood during 5 days after surgery. It was associated with blood loss. Hemoglobin decreased from 130.8 ± 10.1 till 98.2 ± 14.7 (g/L) in the study group and from 128.5 ± 17.5 till 99.2 ± 21.1 (g/L) in the control group, red blood cells – from 4.38 ± 0.39 till 3.03 ± 0.47 (×10¹²/L) in the study group and from 4.41 ± 0.35 till 3.08 ± 0.55 (×10¹²/L) in the control group. Some researchers used hemoglobin level (4-5 days after surgery) for assessment and calculation of occult blood loss [1]. However, in both groups no patients required donor hemotransfusion. It is possibly related to the relatively high basic level of hemoglobin in most patients (> 130 g/L). However, there were no statistically significant intergroup differences in indices of cell composition of the blood at day 5. This proves that the blood-saving effect of tranexam is comparable to intrasurgical administration of reserved fresh-frozen autoplasma with abundant amount of the clotting factors.

The results of hemostasis examinations showed statistically significant increase of INR in both groups after surgery (Table 2). PTI has reverse changes. Hemodilution, using low molecular heparin and premedication can explain it. There was a statistically significant increase in SFC and D-dimer in the patients of both groups. However, after administration of tranexam increase in products of fibrin lysis is truly lower than in the control group. It supports efficiency of its action as fibrinolysis inhibitor.

Table 2
Hemostasis in patients before and after knee joint endoprosthetics in the groups (M ± δ)

Indicators		Study group (n = 55)				Control group (n = 52)
		Before surgery		After surgery		Before surgery		After surgery
Fg, g/L		3.78 ± 0.42		4.81 ± 0.67 *		3.81 ± 0.54		4.88  ± 0.7 *
APPT, sec.		35.3 ± 4.2		37.6 ± 6.4		34.9 ± 5.1		35.6 ± 6.4
INR		0.88 ± 0.05		1.02 ± 0.07 *		0.89 ± 0.04		1.01 ± 0.07 *
PTI, %		106.2 ± 4.5		99.3 ± 3.7		107.1 ± 8.3		105.7 ± 5.8
SFC õ 10-2, g/L		9.8 ± 4.27		16.2 ± 3.6 #		8.2 ± 2.42		23.8 ± 4.26 *
D-dimer, mg/L		0.3 ± 0.12		0.7 ± 0.09 *#		0.3 ± 0.11		1.8 ± 0.3 *
Note: * – reliability of difference with basic values (p < 0.05);
# – reliability of difference in values between the groups (p < 0.05).

The results of thromboelastography supported efficiency of influence of tranexam on fibrinolysis (Table 3). If fibrinolytic activity in the patients of the control group increased by 20 % (decrease of IL from 56 ± 6.7 % to 32 ± 7.2 %), then in the patients after tranexam administration this increase was only by 5 % (p = 0.048). At that, fibrinolysis trends were different; in some patients fibrinolysis activity decreased, but not more than by 10 %. It is possibly associated with changes in maximal hardness of a clot (MA) after surgery. Therefore, these results allow to conclude that tranexam does not block fibrinolytic activity completely, but only hinder its excessive development.

Table 3
Thromboelastogram values in patients before and after
knee joint endoprosthetics in the groups (M ± δ)

Indicators		Study group				Control group
		(n = 55)				(n = 52)
		Before surgery		After surgery		Before surgery		After surgery
R, min.		8.6 ± 1.72		8.2 ± 1.23		8.5 ± 1.81		8.3 ± 1.58
K, min.		4.7 ± 1.2		3.8 ± 1.12		4.5 ± 1.72		3.9 ± 0.93
MA, mm		44.2 ± 3.81		39.4 ± 5.42		45.6 ± 5.58		48.4 ± 6.64
IL, %		53 ± 6.1 %		48 ± 5.8 % #		56 ± 6.7 %		32 ± 7.2 % *
Note: * – reliability of difference with basic values (p < 0.05);
# – reliability of difference between the groups (p < 0.05).

During duplex scanning after KJE only two cases of deep venous thrombosis (sural vein and one of the paired posterior tibial veins) were found. Both cases were identified in the group without tranexam administration. There were no significant intergroup differences on frequency of thrombotic complications (χ² = 0.569, df-1, p = 0.451). It is known that tranexam inhibits both plasmin and other proteases including the clotting factors and many biologic active substances. During traumatic surgery, as total knee joint endoprosthetics, in the region of alteration the inflammatory mediators, neuropeptides and catecholamines release immediately which increase sensitivity of nociceptors to mechanic and thermal stimulants (primary hyperplasia). Therefore, some authors offer use of tranexamic acid with glucocorticosteroids and non-steroidal anti-inflammatory drugs as inhibitors of local and systemic inflammation [10], particularly for prevention of clot formation. Administration of tranexam may have similar action, intensifying anesthesiologic protection. However, further study is needed.

It is possible that frequency of venous thrombosis is associated with exclusion of the patients with underlying thrombophlebitis and postthrombophlebitic syndrome. In the laboratory conditions the patients after tranexam administration did not show increase of hypercoagulation syndrome. During surgery stable hemodynamics persisted. There was no need for transfusion of the components of homological and allogenic blood.

Therefore, the results of this open prospective randomized study show that tranexamic acid can be used for decrease of blood loss during knee joint endoprosthetics in patients without previous thrombophilia. During planned surgery for achieving this effect the single 20 minutes infusion with 10 mg/kg is sufficient in the beginning of operation. It is possible that tranexamic acid decreases excessive development of fibrinolysis and other inflammatory mediators, and by means of decrease in systemic inflammatory response it hinders development of venous thrombosis after knee joint endoprosthetics.

 

CONCLUSION:

1. During knee joint endoprosthetics administration of tranexam, 10 mg/kg, allows statistical significant reducing postsurgical blood loss and excluding donor hemotransfusion by means of correction of pathologic increase of fibrinolytic activity of the blood.

2. Tranexamic acid, 10 mg/kg, does not increase risk of thromboembolic complications after knee joint endoprosthetics.