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UDC 616.151.511:616.15-008.1-07-08 doi.org:10.31684/2541-8475.2019.1(13).62-67
THE COURSE OF DEEP VEIN THROMBOSIS OF LOWER LIMBS DEPENDING ON THE CONTENTS OF D-DIMERS AND C-REACTIVE PROTEIN IN THE ACUTE PHASE
1Altai State Medical University, Barnaul 2Diagnostic Center of Altai Krai, Barnaul 3City Hospital No. 5, Barnaul
A.S. Petrikov12, D.V. Dudin13, L.N. Popkova3, I.V. Volodin13, Ya.N. Shoikhet13
The article concentrates on the evaluation of the course and progression of deep vein thrombosis of lower limbs (DVT of lower limbs) in the acute phase, taking into account the dynamics of clinical and laboratory blood values against a background of anticoagulant therapy. It also studies the odds ratios of development of proximal and distal DVT of lower limbs depending on the contents of the markers of coagulation hemostasis and inflammation - D-dimers and C-reactive protein (CRP).
Key words: proximal and distal deep vein thrombosis of lower limbs, acute phase, course of venous thrombosis, D-dimers, C-reactive protein, inflammation.
The development of deep vein thrombosis of lower limbs (DVT of lower limbs) remains a significant problem of medicine and is one of the main causes of mortality and disability of the population [1, 2, 3, 4, 5], so timely diagnosis of DVT of lower limbs determining the nature of the disease and the possible risk for the patient is of paramount importance. Today, in the diagnosis of DVT of lower limbs, along with ultrasonic techniques, laboratory tests are widely used, among which the detection of D-dimers is important [5, 6, 7]. It is known that D-dimers are products of fibrin decay and integral indicators of activation of the coagulation hemostasis system, and their high concentration in blood plasma is an indispensable indicator of thrombotic state [8]. At the same time, the content of D-dimers can be a prognostic sign of the course of venous thrombosis [9].
Many researchers in the pathogenesis of venous thromboembolic complications (VTEC) development assign a significant role to systemic and local inflammation along with multidirectional disorders in the hemostasis system [10, 11, 12]. A significant marker of inflammatory response is C-reactive protein (CRP), which belongs to the group of acute phase proteins [12]. E.A. Thomas, M.J. Cobby et al. proved that CRP is highly sensitive and reliable acute phase protein contributing to the diagnosis of DVT of lower limbs [13]. It was found that the use of CRP in the diagnosis of venous thrombosis has 100% sensitivity (95% CI; 78-100%) with the method specificity of 52% (95% CI; 3470%). According to modern ideas, the content of CRP can reflect local inflammation in the vessel intima and prospectively determine the risk of vascular complications. Its increased content in the blood serum can also affect endothelium and lead to its destruction, loss of thromboresistance, loss of
ability to resist thrombocyte aggregation and fibrin formation [14].
In recent years, there have been works on determining the content of acute phase inflammation proteins and coagulation hemostasis markers, as well as on evaluation of associative relationships in the acute phase in DVT of lower limbs [9, 14, 15, 16, 17, 18, 19]. However, the issue of the course of venous thrombosis in the acute phase remains insufficiently studied taking into account the dynamics of D-dimers and CRP content depending on the prevalence of thrombotic process. Analysis of the interrelations of inflammatory and hemostatic reactions in the acute phase in patients with DVT of lower limbs may allow to determine the prognostic course of thrombosis against the background of the studied clinical and laboratory markers and conducted ACT. All of the above was a prerequisite for determining the quantitative content of D-dimers and CRP in the blood serum in the acute phase, studying the relationships between them and their associative influence on the course of DVT of lower limbs against the background of treatment.
The research objective is to study the odds ratio of development of DVT of lower limbs, the character of the lesions and its course depending on the content of D-dimers and CRP in the acute phase against the background of anticoagulant therapy.
Materials and methods
The comparative prospective study from November, 2015 to May, 2017 included 62 patients with documented DVT of lower limbs, aged from 25 to 69 years (the mean age was 55.1±1.5), being treated in the Department of Vascular Surgery of RSBIH City Hospital No. 5, Barnaul - it is a clinical base of the Department of Faculty Surgery, Hospital
Surgery with the course of FVE of FSBEI HE ASMU of the Ministry of Health of the Russian Federation. Depending on the nature of damage of the deep veins, patients were randomized into 2 groups. The first group consisted of 37 patients - 27 men (73.0%) and 10 women (27.0%) with proximal DVT of lower limbs (the mean age was 55.9±1.8 years). The second group consisted of 25 patients - 14 men (56.0%) and 11 women (44.0%) with distal deep vein thrombosis (the mean age was 53.9±2.6 years). There were no statistically significant differences between the analyzed groups of patients by sex and age (p#0.05).
In the first group, isolated proximal thrombosis was diagnosed in 30 patients (81.1%), the combination of DVT of lower limbs with PATE was found in 6 patients (16.2%), and the combination
Inclusion criteria are as follows: deep vein thrombosis of lower limbs documented by ultrasound angiography (USAG), age from 25 to 69, duration of the disease no more than 14 days. Exclusion criteria are the following: oncology diseases, acute infections, skeletal traumas and fractures, operative interventions, prolonged immobilization, air travels, age under 25 and over 69, presence of contraindications to the use of anticoagulant therapy (ACT), severe concomitant diseases of the kidneys, liver, and heart in the stage of decompensation.
A control group was formed by the case-control method, it included 74 relatively healthy people (45 men and 29 women) with no signs of any disease, aged between 23 and 67 years (the mean age was 52.2±1.7 years). Study inclusion criteria are as follows: absence of acute vascular events in the anamnesis (venous or arterial thrombosis, PATE, myocardial infarction, apoplectic attack, etc.), absence of pathology of bronchopulmonary and cardiovascular systems, joint diseases, oncology diseases, skeletal traumas, and prolonged immobilization. There were no statistically significant differences between the analyzed groups of patients and the control group by sex and age (p>0.05).
In the in-patient hospital, along with the generally accepted clinical and laboratory blood indicators (indicators of general blood analysis, 58
with superficial vein thrombosis (SVT) was found in 1 patient (2.7%). In 18 patients of the first group, long thrombosis of the femoral vein in combination with lesions of the popliteal and pedidial veins (48.7%) prevailed. 13 patients showed thrombosis of the iliofemoral popliteal pedidial segment (35.1%), and 6 patients (16.2%) had iliofemoral popliteal phlebothrombosis. In the second group, isolated distal DVT of lower limbs was found in 20 patients (80.0%), the combination of distal DVT of lower limbs with PATE was found in 2 patients (8.0%), and the combination with SVT was found in 3 patients (12.0%). Thrombosis with lesion of the popliteal pedidial segment was diagnosed in 18 patients (72.0%), and isolated lesion of the pedidial segment was diagnosed in 7 patients (28.0%) (Table 1).
basic biochemical indicators, APTT, MNO, PTI, SFMC, fibrinogen), according to standard methods, on the 1-3, 5-7, and 12-14 days of hospitalization, blood was taken from the cubital vein to quantify the content of CRP and D-dimers. Evaluation of CRP concentration in blood serum was carried out by immunoturbidimetric method using the automatic biochemical analyzer Sapphire 400 (Hirose Electronic System, Japan) with a set of CRP reagents - Vital of DAC - SpectroMed firm. Determination of D-dimers content in blood serum was carried out by chemiluminescent two-stage immunoenzymatic method on the automatic coagulometer Instrumentation Laboratory ACL Elite Pro (USA) using D-Dimer, HemosIL reagents. The mean content of D-dimers in serum in the control group was 143.2±9.2 ng/ml, and the content of CRP was 1.4±0.2 mg/l (Table 2).
In the acute phase, treatment of patients was carried out according to Russian clinical recommendations [5]. All patients were prescribed un-fractionated heparin (UFH) as a starting drug. Further, 8 patients (12.9%) were transferred to vitamin K antagonists (VKA), and 54 patients (87.1%) were transferred to new oral anticoagulants (NOAC). In the first group, 6 patients (16.2%) were selected a dose of warfarin, 29 patients (78.4%) were transferred to dabigatran etexilate (DE) at a dose of 150 mg 2 times a day from day 5, and 2 patients (5.4%) were assigned rivaroxaban. In the second group,
Table 1
The nature of clinical implications in patients with DVT of lower limbs
Nature of First group (n=37) Second group (n=25)
clinical implications Abs number % Abs number % p <8
Isolated DVT of lower limbs 30 81.1 20 80.0 0.05
DVT of lower limbs + PATE 6 16.2 2 8.0 0.05
DVT of lower limbs + SVT 1 2.7 3 12.0 0.05
Total: 37 100.0 25 100.0 -
warfarin was assigned to 2 patients (8.0%), DE to 21 patients (84.0%), and rivaroxaban to 2 patients (8.0%). No statistically significant differences were
Statistical processing of the obtained data was carried out using licensed programs MicrosoftOffice and Statistica, version 10 (USA), which included an assessment of the statistical significance between two compared data groups: for parametric variation series - Student's t-test, for dichotomous (qualitative) data - Z-test, as well as calculation of the Pearson's correlation coefficient (r). To estimate the normality of the distribution, a visual evaluation of the frequency distribution (histogram and normality graph) was applied with the subsequent use of the Shapiro-Wilk W test. Differences were considered statistically significant at p<0.05.
Results and discussion
It was found that the average content of CRP and D-dimers in patients with DVT of lower limbs and PATE in the acute phase in both proximal and distal thrombosis was statistically significantly higher than in the control group (Table 2). The average content of D-dimers in patients of the first group on days 1-3 from hospitalization was statistically significantly higher than in the control group by 2666 ng/ml (p<0.01), on days 5-7 - by 2188 ng/ml (p<0.01), and on days 12-14 - 1371 ng/ml (p<0.01). In patients of the second group, the concentration of D-dimers on days 1-3 from hospitalization was statistically significantly higher than the mean values of the control group by 1421 ng/ml (p<0.01),
noted taking into account the drug used in the analyzed groups.
2
on days 5-7 - by 1043 ng/ml (p<0.01), and on days 12-14 - 305 ng/ml (p<0.01).
In intragroup comparison, it was found that in patients with proximal DVT of lower limbs against the background of ACT on days 12-14 the average content of D-dimers was statistically significantly lower by 1295 ng/ml (p<0.01) compared to days1-3, and by 817 ng/ml compared to days 5-7 (p<0.001). There was also a statistically significant decrease in the average content of D-dimers on days 12-14 in patients with distal DVT of lower limbs by 1116 mg/ml (p<0.01) compared to days 1-3, and by 378 ng/ml (p<0.05) compared to days 5-7.
On days 1-3 from hospitalization, the content of D-dimers in patients of the first group was statistically significantly higher than in patients of the second group by 1245 ng/ml (p<0.01), on days 3-5 - by 1145 ng/ml (p<0.01), and on days 12-14 -by 1066 ng/ml (p<0.01).
On days 1-3 from hospitalization, the average content of CRP in patients with proximal thrombosis of the group was statistically significantly higher than in the control group by 56.6 mg/l (p<0.01), on days 5-7 - by 31.6 mg/l (p<0.01), and on days 1214 - by 15.8 mg/l (p<0.01). In patients with distal DVT of lower limbs, the level of CRP on days 1-3 from hospitalization was statistically significantly higher than the control data by 27.0 mg/l (p<0.01), on days 5-7 - by 13.0 mg/l (p<0.01), and on days 12-14 - by 4.6±0.7 mg/ml (p<0.01).
Table
Dynamics of D-dimers and CRP content in patients with DVT of lower limbs in acute phase
Dynamics of D-dimers content (ng/ml)
period of observation first group (n=37) second group (n=25) control group (n=74) P1-2< P1-c< P2-c<
1-3 days 2809±346.7 1564±202.8 0.01 0.01 0.01
5-7 days 2331±391.3 1186±200.5 0.01 0.01 0.01
12-14 days 1514±221.3 448±79.5 143.2±9.3 0.01 0.01 0.01
p (1-3) - p (5-7) >0.05 <0.05
p (1-3) - p (12-14) <0.01 <0.01 - - -
p (5-7) - p (12-14) <0.01 <0.01
Dynamics of C-reactive protein content (mg/l)
period of observation first group (n=37) second group (n=25) control group (n=74) P1-2< P1-c< P2-c<
1-3 days 58.0±6.4 28.4±7.4 0.01 0.01 0.01
5-7 days 33.0±7.1 14.4±2.6 0.01 0.01 0.01
12-14 days 17.2±4.3 6.0±0.7 1.4±0.2 0.01 0.01 0.01
p (1-3) - p (5-7) <0.01 <0.01
p (1-3) - p (12-14) <0.01 <0.01 - - -
p (5-7) - p (12-14) <0.01 <0.01
In intragroup comparison, it was found that in patients of the first group against the background of ACT, there is a statistically significant decrease in the average content of CRP on days 5-7 by 25.0 mg/l (p<0.01), and on days 12-14 by 40.8 mg/l (p<0.01) in comparison with days 1-3. There was also a statistically significant decrease in the average content of CRP in patients with distal DVT of lower limbs - by 14.0 mg/l (p<0.05) on days 5-7, and by 22.4 mg/l (p<0.01) on days 12-14 compared to days 1-3.
On days 1-3 from hospitalization, the content of CRP in patients of the first group was statistically significantly higher than in patients of the second group by 29.6 mg/l (p<0.01), on days 3-5 - by 18.6 mg/l (p<0.01), and on days 12-14 - by 11.2 ng/ml (p<0.01).
Thus, the average content of D-dimers and CRP in blood serum in patients with proximal DVT of lower limbs was statistically significantly higher than in distal venous thrombosis, which indicates more significant and long lesion of the venous bed.
In the first group, the correlation analysis established the presence of associative relations of average strength between the content of D-dimers and CRP on days 5-7 (r=0.55; p=0.012) and on days 12-14 (r=0.46; p=0.0042). In patients of the second group, the correlation of the average strength between the content of D-dimers and CRP was established on days 1-3 (r=0.58; p=0.0092) and on days 12-14 (r=0.53; p=0.0204).
In the acute phase in patients with DVT of lower limbs against the background of ACT, there was a tendency to decrease in both the average content of D-dimers and the mean concentration of CRP on days 5-7 and 12-14 in comparison with the initial indicators (p<0.01). In the first group, on days 12-14, a synchronous decrease in the content of D-dimers and CRP was observed in 27 patients (73.0%), a decrease in one indicator was observed in 8 patients (21.6%), and a synchronous increase in D-dimers and CRP in 2 patients only (5.4%). Among them, a 45-year-old man with acute occlusal femoropopliteal pedidial phlebothrombosis on the left, who was transferred to VKA, died of PATE on the 13th day of hospitalization. At the same time, there was a significant increase in the content of CRP on days 5-7 and 12-14 (100 mg/l and more) against the background of treatment, the level of D-dimers was sharply increased (7500 ng/ml and more) during the entire period of hospitalization.
In the second group, on days 12-14, a synchronous decrease in the content of D-dimers and CRP was observed in 23 patients (92.0%), a decrease in D-dimers against the background of CRP growth was observed in 1 patient (4.0%), and a synchronous increase in D-dimers and CRP in only one woman aged 35 (4.0%). She was diagnosed with acute popliteal pedidial phlebothrombosis on the left. After UFH therapy, the patient was transferred
to VKA (warfarin) at a daily dose of 5 mg. During the acute phase, there was a tendency to increase in the content of CRP (more than 50 mg/l) and D-dimers (more than 3000 ng/ml) by days 12-14. Four months after release against the background of taking warfarin, the patient was hospitalized again with an acute recurrent femoropopliteal pedidial phlebothrombosis on the left.
The influence of different levels of CRP and D-dimers in blood serum on the odds ratio (OR) of development of DVT of lower limbs was studied. It was found that serum CRP content up to 5.0 mg/l was not accompanied by an increase in the odds ratio of development of distal [0R=0.104; 95% CI: 0.382-6.735, p>0.05] and proximal DVT of lower limbs [0R=0.021; 95% CI: 0.721-3.774, p>0.05]. The CRP concentration in the range from 5.01 to 10.0 mg/l also did not affect the increase in the OR of development of distal [OR=1.612; 95% CI: 0.133-37.260, p>0.05] and proximal thrombosis [OR=1.672; 95% CI: 0.251-33.071, p>0.05], whereas CRP content in the blood serum of more than 10.0 mg/l is associated with the OR of development of distal thrombosis by 8.7 times [0R=8.7; 95% CI: 4.031-18.576, p<0.05] and proximal thrombosis by 16.8 times [OR=16.8; 95% CI: 5.592-50.545, p<0.05].
It was found that the content of D-dimers in blood serum ranging up to 250 ng/ml was not accompanied by an increase in the odds ratio of development of both distal [OR=0.022; 95% CI: 0.001-0.087, p>0.05] and proximal [OR=0.007; 95% CI: 0.001-0.055, p>0.05] DVT of lower limbs. The D-dimers concentration from 251 to 500 ng/ ml also did not affect the OR of development of distal [0R=0.207; 95% CI: 0.026-1.676, p>0.05] and proximal [OR=0.132; 95% CI: 0.017-1.055, p>0.05] thrombosis, while an increase in the D-dimers content of more than 500 ng/ml was associated with an increase in the OR of development of distal thrombosis by 35.9 times [0R=35.9; 95% CI: 9.11141.17, p<0.05] and proximal thrombosis by 36.5 times [0R=36.5; 95% CI: 9.27-143.3, p<0.05].
Thus, the increase in the content of D-dimers in blood serum of more than 500 ng/ml is associated with the increase in the 0R of development of both distal and proximal DVT of lower limbs by 35.9 and 36.5 times respectively. The increase in CRP concentration of more than 10.0 mg/l is associated with the increase in the 0R of development of distal thrombosis by 8.7 times and proximal thrombosis by 16.8 times.
Conclusion
Determination of D-dimers and CRP content in patients with DVT of lower limbs allows to assess its course and prognosis, as well as the effectiveness of ACT in the acute phase. The use of adequate ACT in the acute phase, accompanied by a synchronous decrease in the content of D-dimers and CRP by days 12-14 from the moment of
hospitalization, testifies to the favorable course of DVT of lower limbs. At the same time, the increase in laboratory markers on days 5-7 and 12-14 against the background of the use of anticoagulants, in particular, D-dimers and CRP, can be considered as a prognostically unfavorable sign of the course of DVT of lower limbs with the development of lethal outcome or the progression of thrombosis.
It was established that the content of D-dimers in serum of more than 500 ng/ml is associated with the increase in the OR of development of proximal and distal DVT of lower limbs by 36.5 and 35.9 times respectively. The increase in the CRP level in serum of more than 10 mg/l is associated with the increase in the OR of development of proximal and distal thrombosis by 16.8 and 8.7 times respectively. It was revealed that in patients with proximal and distal DVT of lower limbs in the acute phase during days 12-14, the average content of D-dimers and CRP in blood serum is statistically significantly higher than in healthy people. In the acute period, the average values of D-dimers and CRP in proximal thrombosis are statistically significantly higher compared to distal thrombosis. There is a moderate correlation between the content of D-dimers and CRP in serum on days 5-7 and 12-14 of hospitalization in patients with proximal DVT of lower limbs, on days 1-3 and 12-14 in patients with distal DVT of lower limbs against the background of ACT.
Conflict of interest. The authors declare that there is no conflict of interest.
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Contacts
Corresponding author: Petrikov Aleksei Sergeevich, Doctor of Medical Sciences, Associate Professor of the Department of Faculty Surgery named after Professor I.I. Neimark, Hospital Surgery with the course of FVE, Altai State Medical University, Barnaul.
656045, Barnaul, Zmeinogorsky Tract, 75. Tel.: (3852) 685144. E-mail: petricov@asmu.ru
Author information
Dudin Denis Valeryevich, Assistant (ext. parttimer), Regional Clinical Hospital, Barnaul. 656024, Barnaul, ul. Lyapidevskogo, 1. Tel.: (3852) 268233. E-mail: ya.denis-dudin@yandex.ru
Popkova Lyubov Nikitichna, Head of the
Laboratory, Doctor of Clinical Laboratory Medicine,
City Hospital No. 5, Barnaul.
656045, Barnaul, Zmeinogorsky Tract, 75.
Tel.: (3852) 268277.
E-mail: gb5_barnaul@mail.ru
Volodin Ilya Vladimirovich, Doctor of Clinical Laboratory Medicine, City Hospital No. 5, Barnaul. 656045, Barnaul, Zmeinogorsky Tract, 75. Tel.: (3852) 268277. E-mail: gb5_barnaul@mail.ru
Shoikhet Yakov Nakhmanovich, Doctor of Medical Sciences, corresponding member of RAS, Head of the Department of Faculty Surgery named after Professor I.I. Neimark, Hospital Surgery with the course of FVE, Altai State Medical University, Barnaul.
656045, Barnaul, Zmeinogorsky Tract, 75. Tel.: (3852) 685023. E-mail: starok100@mail.ru
