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Aim. To investigate the prognostic value of renal function and to estimate glomerular filtration rate (GFR) changes during a 5-year follow-up of patients receiving warfarin therapy. Subjects and methods. 200 patients (124 men, 76 women) mainly from a group at high risk for thromboembolic events (mean CHA2DS2-VASc scores, 3.25±1.89) were examined. The patients’ mean age was 62.3±9.4 years; the follow-up period was 5 years. 74% of the patients received warfarin monotherapy (international normalized ratio (INR) 2.0 to 3.0); 36% took vitamin K antagonists in combination with one or two antiplatelet agents. The CKD-EPI formula was used to estimate GFR in all the patients at baseline and throughout the investigation once a year. Results. GFR less than 70.9 ml/min/1.73 m2 was found to be a predictor of fatal and nonfatal thrombotic events. The decreased GFR was unassociated with the development of major and clinically relevant hemorrhagic complications within 5 years of warfarin therapy. The initial decline in renal function (GFR

The following paper presents an analysis of fibrinogen and D-dimer levels and global index characterizing the anticoagulant function of protein C (TromboPas). 1104 people (25–64 years of age) of Tomsk adult unorganized population were examined within the framework of ECCE-RF-2012 (Epidemiology of cardiovascular diseases and their risk factors in the Russian Federation) project. The relationships of these parameters with the main demographic and clinical characteristics were analyzed. The presence of at least one of the markers of hypercoagulability, which include fibrinogen level higher than 3,7 g/l D-dimer – 500 ng / ml, and the index of inhibition of thrombin formation in the TromboPas (PICI%) test, that islower or equal to 84%, was found in 55,44% of the patients. At the same time, in 2,72% of the surveyed population a combination of all three hypercoagulation markers was observed, whereas a combination of at least one of the mentioned markers and / or risk factors such as arterial hypertension (AH) and obesity (BMI≥30 kg/m2) was observed in 36,87% of patients. Hypercoagulation markers, hypertension and obesity were absent only in 19,47% of patients. Thus, the results suggest a high risk of thrombotic complications of cardiovascular disease (CVD) in the studied population and justify the feasibility of developing adequate methods to prevent them.

Aim. To study effects of thrombin-activated fibrinolysis inhibitor (TAFI) on efficacy and safety of long-term anti-coagulant treatment in patients with venous thromboembolic complications (VTEC). Material and methods. A total of 111 patients with a history of an episode of deep vein thrombosis (DVT) and/or pulmonary artery thromboembolism (PATE) entered the study. All the patients received unfractionated or low-molecular heparin for at least 5 days than switch on warfarin (target values of INR 2,0-3,0). Baseline blood levels of TAFI were measured. The patients were followed up for 18 months. Recurrent (DVT/TAFI and hemorrhagic complications (HC) were end points. Also, frequency of complete lysis of deep vein thrombi was assessed after 12 months of treatment. Results. A TAFI level varied from 50 to 217% (median 106%, interquartile rage 90-133%). TAFI concentration positively correlated with fibrinogen and thromb size. The patients were divided into two groups depending on TAFI content: group 1 patients had low TAFI (under 25th percentile; < 90%); patients of group 2 had high TAFI (above 25th percentile; > 90%). Group 1 patients were characterized by less stable anticoagulation. This association did not depend on genetic characteristics which determine sensitivity to warfarin (CYP2C9 and VKORC1). Low TAFI was associated with reduced risk of DVT for 18 months and higher probability of complete lysis of the thrombi after 12 months of anticoagulant therapy compared to VTEC patients with high TAFI. No differences were found by TAFI level in patients with HC and without HC, but in HC patients low TAFI was associated with spontaneous hemorrhages and bleeding in therapeutic INR values. Conclusion. The results of this pilot study evidence that a TAFI level can be one of the factors influencing efficacy and safety of long-term anticoagulant therapy in patients with VTEC on warfarin treatment.

Aim. To compare effects of prolongation of the treatment with therapeutic doses of enoxaparin to 1 month on recanalization of occlusively thrombosed deep veins (OTDV) of the limbs with results of standard therapy with unfractionated heparin (UFH). Both treatments were followed by warfarin administration. Material and methods. Thirty patients were selected from 111 patients with a history of deep vein thrombosis (DVT) and/or pulmonary artery embolism according to the following criteria: the presence of occlusive thrombosis of one deep vein minimum; the absence of DVT for 12 months of follow-up. Patients of group 1 (n = 15) received standard therapy (UFH for at least 5 days) with switch to warfarin. Patients of group 2 (n = 15) received therapeutic doses of enoxaparin (1 mg/kg each 12 hours) for 30 days minimum with switch to warfarin. Follow-up was 12 months. Ultrasonic duplex angioscanning of the limbs was made at baseline, 1, 3, 6 and 12 months after treatment start. Results. After follow-up month 1, 3 and 6 number of patients with occlusive DVT was significantly less in group 2. All the patients given enoxaparin achieved recanalization of OTDV within 3 months of treatment. OTDV recanalization was not achieved in 20% patients of group 1 even 12 months after treatment start. Conclusion. Prolongation of enoxaparin treatment to 1 month followed by warfarin treatment is superior to standard UFH treatment followed by warfarin in providing recanalization of OTDV within 3 months of treatment. Moreover, this treatment predicts persistence of recanalization within 12 months of anticoagulant therapy.

Aim. To investigate frequency of carriage of genetic polymorphisms CYP2C9 and VKORC1 in patients with venous thromboembolic complications (VTEC) in Moscow population given warfarin treatment and effects of this carriage on stability of anticoagulation and frequency of hemorrhagic complications (HC) in warfarin treatment. Material and methods. The study included 111 patients with the history of deep vein thrombosis and/ or pulmonary artery thromboembolism. All the patients received non-fractionated or low-molecular heparin for at least 5 days, then warfarin (target INR 2.0-3.0). Warfarin dose was selected empirically. Gene CYP2C9 and VKORC1 polymorphisms were studied. HC were end points. Results. Genotype CYP2C9*1/*1 (a "wild" type) was detected in 94 (84.7%) patients. Of other genotypes - heterozygotes CYP2C9*1/*2 (4.5%) and CYP2C9*1/*3 (10.8%). Genotyping by VKORC1 detected genotype GG (a wild type) in 42.3%, genotype GA - in 48.6%, genotype AA - in 9.1% patients. A mean warfarin dose, supporting an adequaite INR, was asspciated with both genotype CYP2C9 and VKORC1. Warfarin doses were highest in carriers of wile genotypes CYP2C9 and VKORC1 (6,9 and 8,8 mg/day), the lowest - in patients with genotypes CYP2C9*1/*3 and __ VKORC1 (4,5 and 4,0 mg/day). The carriers of polymorphisms CYP2C9*1/*3 and VKORC1 showed less stable anticoagulation vs carriers of allele variants CYP2C9*1/*1, CYP2C9*1/*2 and genotypes GG, GA VKORC1. An HC rate depended, as a rule, on carriage of genotypes CYP2C9*1/*3 and AA VKORC1. The highest risk of HC was associated with genotype CYP2C9*1/*3. The results of multifactorial regression analysis also indicated that carriage of genotype CYP2C9*1/*3, a female gender and the range of INR in warfarin treatment ≥ 2,66 are independent predictors of HC in VTEC patients on warfarin treatment. Conclusion. Carriage of gene CYP2C9 and VKORC1 polymorphisms affects suppoting dose of warfarin and rate of hemorrhage in patients with VTEC in Moscow population. Frequency of HC is the highest in carriers of genotypes CYP2C9*1/*3 and AA VKORC1, they need minimal supporting dose of warfarin. Carriage of genotype CYP2C9*1/*3 in line with a female gender and instability of INR is an independent predictor of HC in VTEC patients in Moscow population on warfarin treatment.

Aim: to reveal the frequency of clopidogrel resistance in patients with acute coronary syndrome (ACS) and its impact on prognosis in these patients. Subjects and methods. Seventy-five clopidogrel-treated patients with ACS were followed up. Optical aggregometry was conducted using ADP 20 μmol. The resistance criteria were baseline platelet aggregation, platelet aggregation on day 7, % < 10%. Inflammatory markers (IL-6, IL-10, and C-reactive protein) were determined. Genetic polymorphisms (the IIIa subunit gene - Leu33Pro, the receptor P2Y12 C18T and G36T gene, and the CYP3*A4(A-293G) gene) were studied. Results. According to the accepted resistance criteria, 54 (72%) patients were sensitive to clopidogrel and 21 (28%) were resistant to the agent. The resistance was revealed in 7 (23%) of the patients with ECG ST-segment elevation and in 14 (31%) of those with ST-segment elevation. Before admission to the clinic, the unresponsive patients had significantly more frequently received the loading clopidogrel dose of 300 mg while that latter was 600 mg in the responsive patients. As compared with the responsive patients, the unresponsive ones showed a significantly lower baseline antibody level that was increased on day 7. The clopidogrel resistance determined by this criterion had no impact on prognosis. On dividing the patients by aggregation quartile values, poor manifestations insignificantly more frequently occurred in the third and fourth quartiles. No clear correlation was found between the occurrence of clopidogrel resistance and the activation of an inflammatory process. The monozygous variant of the receptor P2Y12 CT18T gene was insignificantly more frequently encountered in the unresponsive patients. Conclusion. The laboratory phenomenon of clopidogrel resistance exists. Large multicenter studies of this issue are needed to identify simple and least expensive resistance methods and clear diagnostic criteria that enable the findings to be compared.

Aim: to study the prevalence of various risk factors (RF) for venous thromboembolic events (VTEE) and their association with D-dimer levels. Subjects and methods. The clinical, demographic, anthropometric, anamnestic, and laboratory data were analyzed in 106 patients (73 men and 33 women) aged 18 to 78 years admitted to hospital with the first or recurrent episode of VTEE. Results. RF and VTEE-associated diseases were identified in all patients. Over 90% of the patients had more 2 RFs. The most common RFs were the age above 40 years (85%) and overweight (82%), including obesity (42%). There was a preponderance of cardiovascular diseases in the pattern of VTEE-associated diseases. The direct causes (precipitating factors) of thrombosis were revealed in 57% of cases; the thrombotic episode was classified as idiopathic in 43%. Elevated D-dimer levels were found in 74% of the patients. Higher D-dimer content was seen in women, non-smokers, patients operated on for thrombosis, those who had 2 precipitating factors or more, and those who had a less than 30-day history of thrombosis. There was an inverse correlation between the elevated level of D-dimer and the duration of thrombosis by the moment of its identification (thrombus age). Conclusion. All patients who have experienced a venous thrombotic episode have various RFs for VTEE. The content of D-dimer exceeds the normal value in most patients with VTEE. Among the RFs studied, thrombus age is the most important factor associated with elevated D-dimer levels in patients with VTEE.

Aim. To compare efficacy and safety of warfarin and enoxaparin used in the first month of treatment of patients with an episode of deep vein thrombosis (DVT) and/or pulmonary artery thromboembolism (PATE). Material and methods. Sixty patients (34 males, 26 females, age 18-76 years) after the DVT/PATE episode were divided into two groups. Patients of group 1 received standard therapy (non-fractionated heparin -NFH followed by warfarin), patients of group 2 instead of NFH received enoxaparin (1 mg/ kg each 12 hours for at least 30 days). Ultrasonic scanning of the limbs and determination of D-dimer were conducted before and after 1 month of treatment. End points were the following: recurrent DVT/ PATE, death due to PATE, hemorrhagic complications. Results. Improvement of deep vein patency after 1 month of anticoagulant treatment was observed in both the groups. Enoxaparin proved more effective in relation to reduction of the number of venous occlusions (9 and 50, respectively, after 1 month treatment (p < 0.001). Hemorrhagic complications were seen in both the groups with equal frequency (13.4%). These hemorrhagic episodes did not require discontinuation of the drugs. Baseline D-dimer was significantly higher in the enoxaparin group - 1.51 (0.73-2.44) mcg/ml vs 0.93 (0.42-1.33) mcg/ml (p = 0.019). After treatment D-dimer level and number of patients with high D-dimer diminished in both groups. Conclusion. Enoxaparin proved more effective than warfarin in the first treatment month. In the same safety and prophylactic effect enoxaparin is more effective in recanalization of occusions in the deep veins.

Aim. To evaluate the prognostic value of GDF-15 in relation the development of bleeding and events in stable CAD patients, receiving combined antithrombotic therapy. Materials and methods. The data was obtained from the prospective registry REGATA, 343 CAD patients (249 males), median age 68 [IQR 62; 75] years) were enrolled. Patients with sinus rhythm and concomitant PAD received acetylsalicylic acid in combination with rivaroxaban 2.5 mg bid (31.8%) or clopidogrel (24.8%). Other 43.4% with concomitant atrial fibrillation (AF) received direct oral anticoagulants in combination with antiplatelet therapy after elective percutaneous coronary interventions. Median follow-up was 12 months [IQR 9.0; 18.0]. The safety end point was major and clinically relevant bleedings (type 2–5) according to the BARC classification. Plasma samples for GDF-15 identification were taken at the inclusion and analyzed using ELISA assay. Results. Frequency of BARC 2–5 bleedings was 16% (BARC 2 – 46; BARC 3 – 9; BARC 4–5 – 0), median GDF-15 level was 1185.0 pg/ml [850.0; 1680.0]. In patients with AF and concomitant MFA, the level of GDF-15 was significantly higher than in the subgroups of patients with only AF or MFA (p=0.0022). According to the quintile analysis, GDF-15 values in the top three quintiles of distribution (cut-off value 943 pg/ml) were associated with higher frequency of bleeding events: 23.2% versus 5.1%; p=0.0001. The multivariable logistic regression model demonstrated that bleeding events were independently associated with GDF-15 level943 pg/ml (OR 2.65, 95% CI 1.11–6.30; p=0.0275), AF (OR 2.61, 95% CI 1.41–4.83; p=0.0023) and chronic kidney disease (OR 1.92, 95% CI 1.03–3.60; p=0.0401). Clinical factors determining the risk of bleeding events also determined a GDF-15 elevation. Conclusion. Assessment of GDF-15 level may improve bleeding risk stratification in CAD patients with concomitant AF and/or PAD receiving combined antithrombotic therapy.

Introduction. The secretome of mesenchymal stem cells (SMSC) is widely used in medicine. It is most often used due to its immune-modulating and regenerative properties in the treatment of autoimmune, immuno-mediated and other diseases due to its anti-inflammatory, neuroprotective and regenerating action. In many studies, exosomes isolated from SMSC are used as a therapeutic agent. In recent years, the interest in the development of products containing SMSC for external use has increased. Similar drugs are planned to be used in the treatment of diabetic wounds, for skin regeneration, the treatment of inflammatory diseases, as well as alopecia. There are multiple studies on increasing collagen secretion and reducing skin photosensitivity in preclinical studies, which confirms the significant potential for the use of SMSC in dermatology and cosmetology. The purpose of this review was to study the potential of using conditioned medium in medicines for external use, approaches to standardization of SMSC as a pharmaceutical substance and methods of increasing percutaneous delivery.Text. SMSC as an active pharmaceutical ingredient is a transparent liquid from yellow to orange in color with a characteristic odor. The pH of the ready-to-use SMSC composition ranges from 7.0 to 7.5, which allows it to be used in topical and external applications without the addition of stabilizers or pH correctors. Problems of delivery of SMSC through the epidermis are most often solved by placing the secretome in hydrogels, using exosomes or technology using microneedles. Since 2022, after legislative changes, measures have been taken to register and introduce into clinical practice domestic drugs based on cellular products. However, as the analysis showed, it will take some time before the appearance of original medicines based on SMSC, and today in the Russian Federation only products related to cosmetics and veterinary drugs, as well as zoocosmetics, are produced so far.Conclusion. SMSC may also prove to be a safer and more effective substance for the potential treatment of a wide range of acute and chronic diseases. But despite the large number of positive results of using SMSC for wound healing in animals, as well as clinical studies on skin regeneration, there are no studies of its safety and effectiveness, as well as standardization of the production process.

Aim. To study the effect of exercise on markers of endothelial impairment, platelet activation, thrombin formation, fibrinolysis in patients who survived myocardial infarction (MI) at young age. Material and methods. The levels of fibrinogen (F), Willebrand factor (WF), beta-thromboglobulin (BTG), fragment 1+2 of prothrombin activation (F 1+2), antigen of tissue plasminogen activator (TPA), D-dimer at rest as well as BTG, F 1 = 2, WF, TPA antigen and its activity in treadmill test (TT) were compared in 25 patients younger than 35 years who survived Q-myocardial infarction (Q-MI) > 6 months before (group 1), 10 of whom had unaffected or little affected coronary arteries as shown by coronaroangiography (subgroup Ш) while 15 had stenosing coronary atherosclerosis (subgroup 1A); in 20 patients who had Q-MI at the age of 40-55 years (group 2); in 10 healthy patients under 35 years of age (group 3). Results. Initial concentrations of F, F 1 + 2 and TPA antigen were significantly higher than in healthy subjects. F and TPA antigen were higher in subgroup 1A than in subgroup 1H. D-dimer was higher in group 2 vs 1. TT raised concentration of BTG in all the groups, induced a stable trend of F 1+2 rise in patients of subgroup IE (p = 0.059), raised WF only in group 3, TPA antigen at peak stress in all the patients being in group 1 higher than in healthy controls and in subgroup 1A than in subgroup 1H. TPA antigen was more active at the peak stress in group 1 than in group 2 but the differences became insignificant in analyzing only patients who reached submaximal load by heart rate. Conclusion. Stenosing coronary atherosclerosis in patients after MI at young age is associated with high F and TPA levels. Elevated F 1+2 was registered at exercise test in young patients free of coronary obstruction. TPA levels were raised higher by exercise in patients with stenosing atherosclerosis of the coronary arteries. TPA activity induced by exercise depended more on exercise intensity than on the age of the patients.

Introduction. Patients undergoing elective myocardial revascularization require 6 months of dual antiplatelet therapy (DAPT), including aspirin and clopidogrel. In patients with multifocal atherosclerotic lesion (MFA), it may be reasonable to extend the DAPT. Additional consideration of laboratory parameters, which reflect sensitivity to clopidogrel, may be useful in assessing the effectiveness and safety of prolongation DAPT.Aim. To determine the significance of laboratory parameters reflecting sensitivity to clopidogrel in assessing the prognosis of patients with MFA receiving long-term DAPT after myocardial revascularization.Materials and methods. 128 patients with coronary artery disease (CAD) and MFA were included from the prospective register of antithrombotic therapy (REGATTA-1), ClinicalTrials NCT04347200. Inclusion criteria were elective myocardial revascularization, the use of DAPT planned for at least one year and additional determination sensitivity to clopidogrel – residual platelet reactivity and polymorphisms of the CYP2C19* gene. Thrombotic events (TO) in any vascular beds and hemorrhagic complications(GO) (BARC 2–5).Results. The median of DAPT was 380 days, IQR (346. 447). The total incidence of thrombotic events and hemorrhagic complications (the majority – BARC 2) were 9.9 and 4.4 cases per 100 patient-years. The frequency of bleeding events was 4.4 cases per 100 patient-years. There was no association of TO with the PRU and pharmacogenetic parameters. CYP2C19*17 allele carriers tended to have a higher frequency of GO rates compared compared to wild genotype carriers (63% versus 29%, p = 0.05). The frequency of GO in patients with PRU 147 (two lower quintiles) was higher compared with the frequency of GO in the three upper quintiles of the distribution: 12% vs. 3%, p = 0.041. PRU lost significance in multivariate analysis and an independent laboratory predictor of GO was the carriage of CYP2C19*17 alleles (HR 4.8).Conclusion. In patients with MFA who are candidates for long-term DATT after myocardial revascularization, an additional pharmacogenetic assessment of the effect of clopidogrel (allelic variants of CYP2C19*17) can be discussed in order to predict bleeding

Background. The role of albuminuria as a marker of the atherosclerosis burden and a predictor of prognosis in patients with polyvascular disease (PD) has been little studied. Aim. To evaluate the prevalence, association with atherosclerosis burden, and prognostic value of albuminuria in relation to cardiovascular and bleeding complications in patients with PD. Materials and methods. The data was obtained from the prospective registry REGATA-1 (NCT04347200). Seventy four patients (75.7% males, median age 67 [6169] years) with PD (CAD and peripheral arterial disease) were enrolled. All patients received aspirin and rivaroxaban 2.5 mg. The albumin-creatinine ratio in a single morning urine sample, estimated glomerular filtration rate (eGFR), and von Willebrand factor levels were determined. Results. Mild albuminuria (1029 mg/g) was detected in 45.9% of patients, moderate and severe (30 mg/g) in 29.7%; eGFR60 ml/min in 21.7%, chronic kidney disease (CKD) according to the full KDIGO criteria (eGFR and/or albuminuria 30 mg/g) twice as often (39.2%). The frequency of nephroprotective therapy prescription was insufficient. The level of albuminuria did not correlate with von Willebrand factor (endothelial dysfunction marker), but was associated with affecting of 45 vascular beds (ROC AUC 0.775; p=0.011). During the follow-up (12 [818] months) 3 patients developed MACE, 11 BARC 23 bleedings. Neither albuminuria nor eGFR were predictors of MACE, bleeding, or net clinical benefit. CKD (KDIGO) was also not associated with bleedings. CKD (KDIGO) was independent predictor of MACE (in significant multiple regression model beta coefficient for CKD was 0.097; p=0.042), however, the small number of end points allows us to speak only of a hypothesis-generating trend. The implementation of CKD (KDIGO) has increased the predictive value of the REACH score. Conclusion. Albuminuria is highly prevalent in patients with PD. It is a marker of atherosclerosis burden. CKD, diagnosed taking into account the level of albuminuria, can be used in a comprehensive assessment of cardiovascular risk in this category of patients.

Introduction. Lengthening the period of direct oral anticoagulant (DOAC) withdrawal before intervention is not allowed. Chronic kidney disease (CKD), impaired liver function, extremely low or high body mass, chronic heart failure (CHF), and age > 90 years can increase blood DOAC levels. DOAC therapy does not require routine laboratory monitoring. However, there are coagulation tests that can be used to detect the presence of a drug in blood. Duration of DOAC discontinuation and the appropriateness of assessing residual anticoagulant concentrations before intervention with a high bleeding risk in a special category of patients is to be defined.Aim. To measure residual concentrations of anticoagulants and their association with perioperative bleeding risk in patients with AF using DOACs in blood samples collected immediately before TAVI.Materials and methods. The 94 patients with atrial fibrillation (AF) included in the study were characterized by senile age, a high risk of thromboembolic complication (ТС), many comorbidities, and a high prevalence of senile asthenia. The apixaban and rivaroxaban concentrations were measured according to the value of anti-Xa activity and control plasmas with normal levels of coagulation factors (Diagnostica Stago, France).Results. The median time of DOAC withdrawal before TAVI was 60 hours [47.5; 72]. However, the DOAC concentration exceeded 30 ng/ml in 1/5 patients (19.2%), and stage 3 or more CKD was more common in these patients. Our study showed the relationship between DOAC concentration and the duration of DOAC withdrawal period. However, the relationship between DOAC concentration and bleeding that occurred in the perioperative period could not be found. Patients with signs of CKD were older and had a lower BMI as compared to patients without CKD.Conclusion. Our data showed the relationship between the DOAC concentration and the duration of DOAC withdrawal period. No relationship was found between DOAC concentrations and bleeding.

Introduction. Increased expression of tissue factor by tumor cells, formation of procoagulant microparticles and secretion of proinflammatory cytokines that activate leukocytes and endothelial cells are considered to be the main factors provoking blood coagulation activation in cancer patients.The aim of the investigation was to study the peculiarities of hemostasis activation markers and endothelial damage in patients with active cancer.Materials and methods. Patients with active cancer were included in the study. We determined the following biomarkers: fibrinogen (Fg), von Willebrand factor (vWF), D-dimer (D-d), growth differentiation factor 15 (GDF-15), vascular endothelial growth factor A (VEGF-A).Results. Twenty-two patients with active cancer were included in the study. The median follow-up of the patients was 180 days (minimum 90, maximum 240). The presence of metastatic lesion was found in 62% of patients. At the end of the follow-up period (after 6 months) remission of the underlying disease was observed in 45.5% of patients, and 54.5% of patients were found to have progressed oncoprocess. GDF-15 levels ranged from 1486 to 11,722 pg/ml and were above normal values in all patients. Significant variability was also revealed in the level of VEGF-A - from 1 to 2944 pkg/ml, and only in 7 (32%) patients its level corresponded to normal values (0-66 pkg/ml). High levels of Fg (>3.6 g/L), D-d (>500 ng/ml), and vWF (>160%) were detected in 19 (86%), 18 (82%), and 17 (77%) patients, respectively.Conclusions. The pilot study demonstrates a pronounced activation of the blood coagulation system and endothelial damage in patients with active cancer receiving chemotherapy and having a high risk of venous thromboembolic complications. The detected relationship of markers characterizing blood coagulation activation (D-d) and endothelial damage (vWF) with the progression of oncoprocess necessitates their further study in this category of patients.

Currently, direct oral anticoagulants (DOACs) should be preferred when prescribing anticoagulant therapy to atrial fibrillation patients because of their lower potential for interactions and risk of bleeding than warfarin. However, in the absence of standardized laboratory tests and a specific antidote (except dabigatran), prescribing and monitoring DOAC therapy remains a challenge for clinicians and patients. The present review focuses on the problems of DOAC laboratory evaluation, indications, and prospects for its use. Routine coagulation tests including activated partial thromboplastin time, prothrombin time and thrombin time are not recommended for DOAC therapy. Currently, there are specific coagulation tests (anti-Xa activity factor determination for apixaban/ rivaroxaban and diluted thrombin time for dabigatran) that allow judging the presence of the drug in the blood. According to current recommendations, these tests should be used only to assess anticoagulant concentrations and not to adjust doses and decide on the timing of withdrawal before invasive intervention. Nevertheless, the issue of determining DOAC concentration during invasive interventions, the need for which only increases with age, is most relevant. Also a possible additional factor that may alter the bioavailability and pharmacokinetics of DOAC and be taken into account in the evaluation of laboratory activity is the presence of chronic renal disease, hepatic insufficiency, low or excess body weight. The use of specific coagulation tests for patients undergoing elective and urgent surgery among special categories of patients (with chronic kidney disease, low or excess body weight, renal failure) is promising.

Activated platelets are involved in blood coagulation by exposing phosphatidylserine (PS), which serves as a substrate for assembling coagulation complexes. Platelets accelerate fibrin formation and thrombin generation, two final reactions of the coagulation cascade. We investigated the effects of antiplatelet drugs on platelet impact in these reactions and platelet ability to expose PS. Washed human platelets were incubated with acetylsalicylic acid (ASA), ticagrelor, ASA in combination with ticagrelor, ruciromab (glycoprotein IIb-IIIa antagonist), or prostaglandin E1 (PGE1). Platelets were not activated or activated by collagen and sedimented in multiwell plates, and plasma was added after supernatant removal. Fibrin formation (clotting) was monitored in a recalcification assay by light absorbance and thrombin generation in a fluorogenic test. PS exposure was assessed by annexin V staining using flow cytometry. Ticagrelor (alone and in combination with ASA), ruciromab, and PGE1, but not ASA, prolonged the lag phase and decreased the maximum rate of plasma clotting and decreased the peak and maximum rate of thrombin generation. Inhibition was observed when platelets were not treated with exogenous agonists (activation by endogenous thrombin) and pretreated with collagen. Ticagrelor (alone and in combination with ASA), ruciromab, and PGE1, but not ASA, decreased PS exposure on washed platelets activated by thrombin and by thrombin + collagen. PS exposure on activated platelets in whole blood was lower in patients with acute coronary syndrome receiving ticagrelor + ASA in comparison with donors free of medications. These results indicate that antiplatelet drugs are able to suppress platelet coagulation activity not only in vitro but also after administration to patients.

Introduction. The direct oral anticoagulants (DOC) therapy does not require alaboratory control; however, it may be required to determine the anticoagulationlevel to choose a treatment strategy if alarge bleeding is developing or emergency surgery is needed.The objective of this experimental study was to investigate the relationship between the residual factor Xa (FXa) activity, anti-Xa activity units oflow molecular weight heparins (LMWH), and the apixaban and rivaroxaban plasma concentrations in a chromogenic anti-Xa assay.Material and methods. Concentrated DOC solutions were prepared by extracting apixaban and rivaroxaban from crushed tablets using methanol and dimethyl sulfoxide, respectively. The resulting solutions were added to the donor plasma pool until final inhibitor concentrations are achieved in the range from 10 to 100 ng/ml plasma. Anti-Xa activity was determined using an STA-compact analyser and the Liquid anti-Xa reagent kit, an analysis protocol, and calibrators designed to control the LMWH therapy. The effect on the thrombin formation dynamics was investigated using the thrombin generation test (TGT) and the PPR reagent as a trigger (final concentrations of tissue factor are 5 pM, and those of phospholipids are 4 μM). TGT curves were analysed using the Thrombinoscope program.Results. It was shown that in the anti-Xa activity test version designed to control the LMWH therapy, there is a high correlation (R2 > 0.98) between thelogarithm of the residual factor Xa activity and the content of apixaban and rivaroxaban in the range from 10 to 80 ng/ml. Rivaroxaban shows about 1.5 times more anti-Xa activity than apixaban at equal concentrations. It was also shown that apixaban and rivaroxaban at doses equal both in concentration and in anti-Xa activity differ in their effect on the thrombin formation dynamics and thrombin inactivation in the TGT.Conclusion. In the LMWH anti-Xa activity test version, the measured range of apixaban and rivaroxaban includes 30 ng/ml and 50 ng/ ml concentrations taken as “cut-off points” to determine the treatment tactics in emergency cases. However, thelack of certified DOC calibratorslimits the use of this test in clinical practice.

Aim. To study the predictive value of growth differentiation factor 15 (GDF-15) in patients with atrial fibrillation (AF) after elective percutaneous coronary intervention (PCI).Material and methods. The study included 150 patients (men, 69,3%) with AF receiving direct oral anticoagulants in combination with two (89,3%) or one antiplatelet agent (10,7%) after elective PCI. Median age was 71,0 [interquartile range, 66,0; 77,0] years. The median follow-up was 11,5 months [interquartile range, 8,0; 12,0]. The efficacy endpoint was the sum of cardiovascular events (CVEs), including cardiovascular death, ischemic stroke, venous thromboembolism, peripheral arterial thrombosis, acute coronary syndrome, and the need for emergency PCI. The safety endpoint was considered to be BARC type 2-5 bleeding. Prior to PCI, blood plasma samples were taken from patients to determine GDF-15 and D-dimer by enzyme immunoassay.Results. The incidence of CVEs was 16%. The incidence of BARC type 2-5 bleeding was 24,7%. The median GDF-15 level was 1270,0 pg/ml [953,0; 1778,0]. According to multiple regression, the GDF-15 level is associated with D-dimer (t=3,20; p=0,0018), diabetes (t=3,97; p=0,0001) and SYNTAX score II (t=4,77; p1191 pg/ml (p=0,0076) increases the likelihood of CVE (area under the curve, 0,647; confidence interval (CI), 0,5650,723). According to Kaplan-Meier survival curves, significant differences were found in terms of absence of CVEs during the follow-up period between the groups of patients with a GDF-15 >1191 and those with GDF-15

Atrial fibrillation (AF) is the most common indication for the long-term oral anticoagulation therapy. For several decades, vitamin K antagonists have been the mainstay of routine clinical practice.A prospective 10-year follow-up of patients with atrial fibrillation receiving warfarin therapy showed that the incidence of all cerebral circulation disorders was 2.59 per 100 patient-years. The warfarin therapy contributed to the prevailing of non-fatal events among the cerebral circulation disorders which occurred during the therapy. The incidence of fatal ischemic strokes was 0.91 per 100 patient-years over the 10-year follow-up study.If the duration of a patient within the target therapeutic range (TTR) was

Despite the long-term clinical experience, bleeding remains the greatest danger for patients taking vitamin K antagonists. Moreover, even the presence of risk factors for hemorrhagic complications in a patient should not be the only reason for cancelling anticoagulant therapy. The challenge in assessing the frequency of hemorrhage is primarily explained by different approaches to hemorrhage classification. For patients receiving long-term anticoagulant therapy, along with fatal and life threatening hemorrhages, minor and clinically significant small hemorrhages should be taken into account to assess the safety of treatment. The 15-year prospective follow-up of patients receiving warfarin found that the frequency of all hemorrhagic complications was 8.66/100 patient-years, major hemorrhage — 2.98/100 patient-years, and clinically significant hemorrhage — 2.62/100 patient-years. According to the results of the discriminant analysis, the predictors for the development of major and clinically significant hemorrhagic complications in patients receiving long-term therapy with warfarin are administration of proton pump inhibitors, labile INR during therapy, recurrent minor hemorrhage in history and amiodarone therapy. The 15-year prospective follow-up of patients receiving warfarin demonstrated that minor hemorrhagic complications account for one third of all bleedings and are not associated with the subsequent development of clinically significant and major bleeding in patients. The prospective follow-up also found an increase in the frequency of hemorrhagic complications if one or two antiplatelet agents were added to warfarin therapy. The incidence of major and minor clinically significant hemorrhagic complications during triple antithrombotic therapy was 24/100 patient-years, which was higher than in the warfarin monotherapy subgroups and in the case of combining warfarin with an antiaggregant (4.4 and 8.47%, respectively). The localization of bleeding was analyzed to reveal that in triple antithrombotic therapy the greatest number of bleedings occurred in the upper or lower gastrointestinal tract. The relative risk was calculated to confirm that triple antithrombotic therapy significantly increased the risk of gastrointestinal bleeding by 3.02 times.

The article presents a comparative evaluation of the current clinical angiographic scales in the risk stratification for patients with stable coronary artery disease undergoing elective percutaneous coronary interventions. The article discusses the prospects for improving the prognostic value of scales by adding two laboratory markers reflecting the degree of coagulation cascade activation and the adequacy of antiplatelet therapy — D-dimer and residual platelet reactivity to adenosine diphosphate.

Despite the development of new oral anticoagulants, vitamin K antagonists (VKA) continue to be widely used for the treatment and prevention of throm-boembolic complications. On top of that, they have no alternative in patients with artificial heart valves. Receiving AVC results in the synthesis of modified factors of pro-thrombin-converting complex (prothrombin, factor X, IX and VII, as well as two components of the anticoagulant system — protein C and protein S) without capacity to bind with the phospholipid surface, which significantly reduces the likelihood of intravascular thrombosis, but the degree of anti-coagulation is individual and requires monitoring for each patient. Prothrombin test (PT test) is used to monitor the degree of anti-coagulation, which is based on determining the plasma clotting time in a patient after addition of thromboplastin and calcium chloride (prothrombin time). Tromboplastin is animal tissue extract containing tissue factor and phospholipids. In practice, the determination of the anti-coagulation degree by prothrombin time is no easy task. The fact of the matter is that various thromboplastin drugs have different sensitivity to the reduction of factors of prothrombin-converting complex; clotting time of normal and pathologic plasma depends on used thromboplastin and differs even for different series of thromboplastin supplied by the same manufacturer. In addition, prothrombin time depends on the method used (coagulometer). WHO had adopted a system of reporting the PT test results in the form of INR (International normalized ratio) specifically to measure the degree of anti-coagulation in patients who receive oral anticoagulant therapy.

Aim. To study social and economic gradients — educational and occupational statuses, wealth level, behavioral risk factors (FR) in Russian population by the ESSE-RF data.Material and methods. The data for the analysis consisted of representative selections of 13 regions of RF (n=22906) participants of the study, incl. men (n=8353) and women (n=13553) of 25-64 y.o., with response 80%. We calculated the odds ratios for the presence of behavioral FR: smoking, excessive alcohol consumption, insufficient physical activity (IPA), nonrational food consumption, anxiety and depressive disorders, — in persons from different social and economic groups by education level, type of inhabitation, professional status, wealth level.Results. Higher education was associated with better FR profile, except IPA (negative association) and alcohol consumption (absence of association). "White in general had less FR probability than Blue, excl. IPA and psychoemotional deviations (in men). As for the wealth association with the FR there is backward gradient, i.e. lesser the income, higher the risk of FR presence, excl. IPA and excessive alcohol intake in women. For example, in very wealthy men the odds ratio for depressive states was 3,09 [95% CI 2,08-4,57] comparing to the persons with low income. The type of territory of inhabitance was associated with less behavioral FR in Russian population, as significant associations are found only for depression and excessive salt consumption in both genders and IPA in men. Conclusion. The significant social and economic gradients of behavioral FR prevalence are found, the direction of those is not necessary the same as in European countries. The analysis of association with social and economic parameters would help to develop the directed preventive interventions.

Current guidelines recommend use of anticoagulants (preferably fondaparinux) until hospital discharge in non-invasively treated patients (pts) with non-ST-segment elevation acute coronary syndrome (NSTEACS). however, some evidence exists that anticoagulants may be safely stopped earlier in low-risk aspirin-treated pts. Aim. To assess markers of hemostasis activation and in-hospital events rate after very early discontinuation of fondaparinux in non-invasive treatment of low-risk pts hospitalized with NSTEACS. Material and methods. 53 pts admitted with NSTEACS at median 2,3 h after last episode of chest pain were included into prospective non-comparative study. All pts had GRACE score ≤108, negative tn t (cut-off 0,03 ng/ml), and no st-segment deviation >0,1 mV. Aspirin and beta-blockers were used in all cases while clopidogrel in 35 (66,0%) only. After single subcutaneous injection of fondaparinux at presentation no anticoagulants were used. Plasma thrombin-antithrombin (tAt), d-dimer (dd), plasmin-antiplasmin (PAP) levels, plasminogen activator inhibitor-1 (PAI-1) activity and its complex with tissue plasminogen activator (tPA/PAI-1) level were measured at median 18,0 and 42,5 hours after fondaparinux. 12-lead ECG monitoring was started at median 21,2 h after fondaparinux and continued for median 38,6 h. Treadmill stress test was performed on days 4-18 (median 9) after hospitalization. Pts were followed until hospital discharge (median 14 days). Results. Plasma tAt , dd and PAP levels increased after discontinuation of fondaparinux: medians 3,1 and 3,3 ng/l (p=0,002), 359 and 486 ng/l (p=0,002), 471 and 498 ng/l (p=0,052), respectively. Increase at least one of these markers of hemostasis activation was revealed in 49 (92,5%) pts. Ischemic st-segment deviations on ambulatory ECg were found in 13 pts (24,5%). First episode appeared at median 51,8 hours after fondaparinux and only one was symptomatic. tAt , dd and PAP levels as well as their changes were not associated with recurrence of ischemia. Positive result of treadmill test was obtained in 12 Conclusion. While in non-invasive treatment of low-risk nstEACs pts very early discontinuation of fondaparinux was associated with activation of coagulation this laboratory finding was not related to recurrence of ischemia and clinical events rate was low. (25,0%) pts (5 with and 7 without ischemic st-segment deviations on ambulatory ECg; p=0,25). during hospital stay, no patient died or had myocardial infarction; 3 had recurrent angina.

The review takes into consideration the diagnostic significance of the main screening coagulologic tests under the light of modern views on the role of vessel wall, plasma proteins and blood cells in the dynamics of thrombin formation and its activities regulation.

Aim. to study the significance of residual platelet reactivity (RPR) to adenosine diphosphate (ADP) and carriage of the gene cythochrome P450 CyP2C19 polymorphisms in relationship to the bleeding risk in stable CHD patients, undergoing planned PCI and receiving double antiplatelet therapy with aspirin and clopidogrel. Material and methods. In stable CHD patients after planned PCI we studied genotypes of polymorphic gene markers, related to clopidogrel metabolism (CyP2C19*1,*2,*3,*17) and studied RPR to ADP at clopidogrel treatment with Verifynow P2y12 analyzer (Accumetrics, США, San Diego, USA) at planned clinic visit in 5-12 months of treatment. Results. In CHD patients receiving double antiplatelet therapy for panned PCI during 12 months, minor clinically non-significant bleedings (MCNS) were the most prevalent, 51,1% noted them during follow-up, and major bleedings (MB) occured in 3,2%, minor clinically significant (MCs) — 9%. MCNS are the reason for DAT interruption in 14-15% patients after planned PCI. the value of RPR to ADP less than 205 PRU in stale CHD with aspirin and clopidogrel after planned PCI 7,8 times increases the risk of MCNS bleedings. In stable CHD with DAT after planned PCI during 12 months there was no any relationship of thrombotic outcomes and revascularization with the value of RPR to AdP. there was relationship noted between the value of RPR to ADP and carriage of slowly functioning alleles of clopidogrel metabolism. MCNS are not related to major bleedings and reflect effectiveness of antiplatelet therapy, that is confirmed also by significantly lower rate of recurrent revascularizations due to restenosis and absence of stent thrombosis in the group of MCNSB.

Aim. To evaluate the prevalence of aspirin resistance, its clinical features, potential solutions, and prognostic role in patients with acute coronary syndrome (ACS). Material and methods. The study included 51 patients with ACS and ST segment elevation (STEACS) and 49 ACS patients without ST segment elevation (non-STEACS). All participants received aspirin in a standard dose of 100 mg/d. Platelet aggregation (PA) was measured with a laser assay method and arachidonic acid (0,5 mg/dl) as an inductor. Aspirin resistance was diagnosed if PA was at least 20% at Day 7 of aspirin treatment. Results. Aspirin resistance was observed in 11% of the patients receiving aspirin in a standard dose of 100 mg/d. The majority of aspirin-resistant patients had STEACS, therefore, the data for this group were analysed in detail. Major clinical characteristics of aspirin-resistant and aspirin-responding patients were similar. After the in vitro test with aspirin, to determine the pharmacokinetic type of aspirin resistance, the medication dose was increased to 300 mg/d. The comparison group included 10 patients with STEACS, receiving aspirin in the dose of 100 mg/d. Thirty days later, PA was significantly reduced in both aspirin-resistant groups, therefore, the aspirin dose increase did not affect PA dynamics. In aspirin-resistant patients, prognosis was slightly worse than in their aspirinresponding peers. Conclusion. Aspirin resistance was more prevalent in STEACS patients. By Day 30, PA was substantially reduced. Increasing aspirin dose to 300 mg/d did not affect PA dynamics.

Aim. To identify the factors determining homocysteine (HMC) levels in Russian patients with stable coronary heart disease (CHD). Material and methods. The study included 506 patients (388 men; mean age 59,4±12,2 years) with stable CHD. Classical risk factors (RFs) of cardiovascular disease (CVD), renal function (creatinine clearance by Cockroft-Gault formula), and atherosclerotic pathology of other localizations were assessed. The levels of plasma HMC, folate, and cobalamin were measured. Genetic analysis was performed using the real-time polymerase chain reaction method. Results. In 432 patients (85,4 %), hyperhomocysteinemia was diagnosed. The mean HMC level was 14,3±4,6 mkmol/l. According to multifactor analysis results, HMC level was independently associated with folate level (beta coefficient -3,86, p