Hemostasis Parameters Research Articles

Coagulation hemostasis disorders and elevated lipoprotein (a) levels in patients with arterial hypertension and multifocal atherosclerosis

Introduction. Hemostatic disorders may act as additional risk factors in patients with arterial hypertension (AH) and multifocal atherosclerotic lesion (MFAL). Elevated lipoprotein (a) (Lp(a)) levels may exacerbate procoagulant shifts.Aim. To identify disorders in the coagulation link of hemostasis in patients with AH and MFAL, depending on the level of Lp(a).Materials and methods. The study included 219 patients with hypertension and MFAL, median age 59 (53; 66) years, of which 110 patients with stage I–II controlled hypertension (group 1) and 109 patients with stage III controlled hypertension with a history of ischemic stroke. Depending on the level of Lp(a), patients in each group were divided into 2 subgroups with Lp(a) levels < 50 mg/dl and with Lp(a) levels above 50 mg/dl. Patients of both groups received antihypertensive, lipid-lowering, antiplatelet therapy and had comparable values of blood pressure and lipid spectrum.Results. In group 2 patients, procoagulant shifts were significantly more often recorded, despite the constant use of antiplatelet therapy. Violations of hemostasis parameters depending on the level of Lp(a) were observed in subgroups 1b and 2b. According to the results of multiple a posteriori comparisons, the most significant hypercoagulation changes were observed in patients with stroke, as well as with Lp(a) levels > 50 mg/dl.Conclusions. Thus, in some patients with hypertension and MFAL, despite taking antihypertensive, lipid-lowering and antiplatelet therapy, coagulation hemostasis disorders may occur. Elevated Lp(a) levels are combined with more pronounced hemostatic disorders, especially in the presence of a previous stroke. Intensification of antithrombotic therapy may be considered in such patients to prevent cardiovascular complications.

Pulmonary artery thrombosis in Behcet's syndrome: a case series

Abstract Background Behçet's syndrome (BS) is a complex multisystemic vasculitis that affects vessels of all sizes and kinds, with a high tendency towards thrombosis. Arterial disease is rare and manifests primarily in the form of pulmonary artery aneurysms (PAA), but also of pulmonary artery thrombosis (PAT) in 1/3 of the cases. Purpose Our work aims to depict the profile and outcomes of BS patients presenting with PAT. Methods This retrospective, descriptive, and monocentric study was conducted between 2000 and 2022, among 531 adult patients diagnosed with BS (ISG and/or ICBD criteria). All cases of documented PAT were included. Results 16 cases of PAT were recorded (3%). The mean age of the patients was 34 ± 6 years (19-58), and the sex ratio (M/F) was 4.7:1. Cardiovascular risk factors were mainly active smoking (12%) and high blood pressure (6%). PAT was the revealing manifestation of BS (30%), or occurred after a median of 4.5 years following BS onset. Patients were mostly asymptomatic (69%), or presented with dyspnea (35%), hemoptysis (31%), and thoracic pain (25%). On chest CTA, PAT was often bilateral (78%) and proximal (46%). PAA were frequently observed (25%), being consistently bilateral, multiple, proximal and distal at the same time. Deep venous thrombosis was found in the lower extremities (19%), superior vena cava (27%), and inferior vena cava (6%). Cardiac involvement was also commonly associated (40%), mostly consisting of right intracardiac thrombosis (37%). Concomitant extracardiovascular involvements included mucocutaneous (87%), ocular (26%), articular (25%), and digestive (6%) lesions. Inflammatory parameters were raised in most patients (80%). Hemostasis parameters were within normal ranges and screening for inherited and acquired thrombophilia was negative in all cases. Patients were treated with colchicine (97%), glucocorticoids (93%), cyclophosphamide (47%), azathioprine (47%), and a TNF-a-inhibitor (6%). Curative anticoagulation with low-molecular-weight heparin followed by oral antivitamin K was often prescribed (60%). No surgery or endovascular procedure was performed. Relapse and death were recorded in respectively 15% and 26% of the cases. Conclusion In contrast to common thrombotic diseases, PAT in BS is attributed to vasculitis rather than hypercoagulability, resulting in distinct clinical features. The diagnosis should be promptly considered in young men who present with concurrent thrombotic lesions and PAA. Early and appropriate management is imperative to enhance patient outcomes.Left proximal PAT in a BS patient

Vascular thrombosis and relapse-associated factors in Behcet's syndrome: a comprehensive analysis of 136 patients

Abstract Background Vascular thrombosis in Behçet syndrome (BS) is frequent and associated with high morbidity and mortality rates. Purpose To investigate BS patients presenting with a thrombotic event (TE) and identify the factors associated with relapse. Methods We retrospectively conducted a single-center, descriptive, and analytic study, from 2000 to 2022, enrolling all BS patients presenting TE, including venous thrombosis (VT) and/or arterial thrombosis (AT). Results TE was observed in 136/531 patients (25%), mostly men (83%), aged 29 ± 9 years (11-50) at BS onset. TE was the initial presentation of BS (32%) or occurred after a median of 4 years [0;25]. It included VT (92.5%), AT (18%), and both (13%). VT mostly consisted of DVT in the lower extremities (60%), vena cava (30%), and cerebral (15%) veins. It involved one (55%), two (27%), and multiple (16%) veins (Figure 1). AT mainly affected the pulmonary (42%), femoral (21%), coronary (17%), cerebral (8%) arteries, and aorta (8%). Arterial aneurysms were common (18%), especially in the pulmonary arteries (11%). Intracardiac thrombosis was also visualized (10%). Noncardiovascular manifestations mainly included aphthous ulcers (96%), pseudofolliculitis (36%), ocular lesions (41%), and arthralgias (22%). Hemostasis parameters were within normal ranges. Patients were treated with colchicine (98%), corticoids (98%), and immunosuppressants (80%). Anticoagulation and anti-platelet aggregation were administered in 90% and 15% of the cases, respectively. Six patients underwent vascular surgery. Post-thrombotic syndrome was noted in 14% of the patients. Relapse was common (25%), mainly occurring in men (81%), of younger age (24 ± 6) at first TE. Relapse consisted of one (55%), two (32%), or multiple episodes (13%). It occurred in the same vascular system initially affected (69%), a different one (12%), and both at the same time (19%). Multivariable analysis revealed TE at onset (OR= 2.99, 95% CI[1.14 ; 7.82], p=0.02), arterial thrombosis (OR= 2.91, 95% CI[1.10 ; 8.40], p=0.04), and arterial aneurysms (OR= 2.58, 95% CI [1.09 ; 8.45], p=0.02) as factors significantly associated with TE relapse (Figure 2). Conclusion Our study highlights several particularities of TE in BS, with TE at onset, arterial thrombosis, and arterial aneurysms emerging as significant relapse factors.

Impact of a new coronavirus infection on the level of inflammatory, haemostasis markers and microcirculatory parameters of patients with arterial hypertension

Relevance. The COVID-19 pandemic and its consequences have significantly affected the health of the population as a whole. Persons who have undergone coronavirus infection against the background of chronic cardiovascular diseases and obesity deserve special attention. Aim. To study and compare the main indicators of carbohydrate and lipid metabolism the level of inflammatory and haemostasis markers, microvascular changes in obesity AH patients and in AH patients with normal body weight 1 month after a new coronavirus infection in moderate to severe form. Materials and methods. The study included 87 patients of both sexes, aged from 18 to 55 years, from which three groups were formed: the first group included people with AH and normal body weight (BMI<25 kg/m²) who had undergone COVID-19 within a month, the second group included people with AH and obesity (BMI≥30 kg/m²) who had undergone COVID-19 within a month, the control group consisted of 20 people with AH and obesity without COVID-19. The parameters of height, weight, waist circumference, and BMI were assessed in all subjects. The parameters of lipid profile, glucose level were determined, inflammatory markers and haemostasis parameters. All participants underwent laser Doppler flowmetry (LDF) on the forearm with constrictor and dilator functional tests, and single-photon emission computed tomography (SPECT) in combination with x-ray computed tomography (SPECT/CT). Results. Patients of groups 1 and 2 naturally differed from each other in anthropometric indicators. Lipid and carbohydrate metabolism rates were also significantly higher in group 2 patients compared to group 1 patients (p < 0.05). The CRP level in the group of people with hypertension and obesity who underwent COVID-19 was significantly higher than in people with hypertension without obesity (p < 0.001) and than in people with hypertension and obesity without a history of COVID-19. When comparing microcirculation parameters by LDF, there was a decrease in tissue hemoperfusion (M), blood flow reserve (RK) in all three groups (p < 0.001), the most pronounced dysfunction of neurogenic and myogenic blood flow regulation was detected in the group of people with hypertension andobesity who underwent COVID-19. Conclusion. The study of microcirculation indicators by LDF method in persons with hypertension and obesity after suffering a coronavirus infection indicates the predominance of the spastic type of microcirculation, which, together with an increase in the levels of inflammatory markers, indicates a higher risk of thrombosis and cardiovascular complications, requiring more careful monitoring and treatment of this group of patients.

The Correlation between Interleukin-6 and D-dimer in Severe and Critical COVID-19 Patients

Severe and critical COVID-19 patients are known to experience hyperinflammatory conditions and endothelial damage primarily characterized by increased levels of IL-6 and D-dimer. This group of patients is also considered at risk of experiencing hemostasis disorders including decreased platelet counts, prolonged PT and APTT, as well as increased fibrinogen. Therefore, this study aimed to determine the correlation between IL-6 and D-dimer in severe and critical COVID-19 patients. The relationship between IL-6 and other hemostasis parameters such as platelet count, PT, APTT, and fibrinogen were also analyzed. A descriptive-correlative observational design was used with a retrospective cross-sectional approach. The subjects were severe and critical COVID-19 patients at Hasan Sadikin Hospital, Bandung treated between January to December 2021 and met the inclusion and exclusion criteria. Secondary data were taken from medical records and the Laboratory Information System (LIS). Correlation analysis between IL-6 and D-dimer as well as hemostasis parameters was carried out using the Spearman test. The results showed that among the total 167 subjects, the median age was 60 years. The number of male subjects was 110 (65.86%), while the most common comorbidity was hypertension (45.51%). The analysis showed a very weak and insignificant correlation between IL-6 and platelets (r= -0.044; p=0.571), IL-6 and PT (r=0.115; p=0.137), IL-6 and APTT (r=0.109; p=0.159), as well as IL-6 and fibrinogen (r= -0.087; p=0.264). However, the correlation between IL-6 and D-dimer was significant (r= 0.199; p=0.010). Interleukin-6 did not correlate with hemostasis parameters but correlated with D-dimer. This means that IL-6 and D-dimer may provide information about the inflammatory response in COVID-19 patients and help monitor disease progression.

PREDICTION OF THE STATE OF CRITICAL PATIENTS WITH SARS-CoV-2 INFECTION (LABORATORY ASPECT)

The aim of the study: to establish potential hematological markers for predicting mortality and recovery in patients with severe disease. Research metods. Demographic data, comorbidities, and blood parameters in patients with COVID-19 were analyzed. Critically ill COVID-19 patients have been divided into two research groups: those who recovered from a severe course of the disease (group 0) and deceased (group 1). Results and Conclusions. Clinical and laboratory hematocytological, biochemical, and hemostasis blood tests have been carried out. Diagnostic accuracy of several hematological indices has been established for prognostic stratification of the fatal outcome of the disease course in critical patients, namely the neutrophil-to-lymphocyte ratio (NLR > 5.57), the systemic immune- inflammation index (SII > 1914), enzyme activity determination (SPK > 137) and hemostasis parameters evaluation (D-dimer > 243; SFC > 6.5).

Dynamics of hemostasis system parameters in assessing the risk of complications in the patients with acute myocardial infarction receiving antiplatelet therapy

Background. Current treatment of patients with myocardial infarction is based on the strategy of early invasive coronary intervention in combination with dual antiplatelet therapy - with acetylsalicylic acid and a P2Y12 blocker of platelet adenosine diphosphate receptors. In patients with thrombosis of the infarct-related artery, the phenomenon of “slow/ no reflow” (slowing of blood flow due to distal embolization of the artery), inhibitors of glycoprotein IIb/IIIa platelet receptors are administered as additional disaggregant therapy. In patients undergoing standard antiplatelet therapy in combination with glycoprotein IIb/IIIa inhibitors, there is a risk of hemorrhagic complications, therefore, monitoring of hemostasis parameters is necessary. Currently, there are no standard approaches to monitor the antiplatelet therapy.Objective. To study the dynamics of hemostatic system parameters in patients with acute myocardial infarction during antiplatelet therapy.Material and methods. We assessed platelet aggregation with 10 µmol of adenosine phosphate as an inducer in patients with ST-segment elevation myocardial infarction with different options of standard antiplatelet therapy in combination with GPIIb/IIIa inhibitors. Group 1 included 20 patients on dual antiplatelet therapy (clopidogrel 75 mg + acetylsalicylic acid 100 mg) + GPIIb/IIIa inhibitor (tirofiban). Group 2 included 15 patients on dual antiplatelet therapy (ticagrelor 180 mg + acetylsalicylic acid 100 mg) + GPIIb/IIIa inhibitor.Results. While on antiplatelet therapy the patients in both groups 1 and 2 demonstrated a decrease in platelet aggregation ability under the impact of adenosine phosphate, relative to the norm: 38 (21;43) % and 14 (11;15) %, respectively, the norm being 79 (73;84) % (p<0.05). Meantime, no thrombotic events in the form of stent thrombosis were noted, which indicated antiplatelet therapy efficacy. In an intragroup comparison, the decrease in the platelet aggregation ability was most pronounced in group 2 (p<0.05). By the 7th day of myocardial infarction, the platelet aggregation had continued to decrease to 26 (17;43) % in group 1, to 10 (7;11) % in group 2. The most pronounced effect of antiplatelet therapy was observed in group 2 (p<0.05), which was manifested by a statistically significant decrease in platelet aggregation ability under the impact of 10 µmol of adenosine phosphate.Conclusions. While studying the hemostasis system changes over time in patients with myocardial infarction receiving antiplatelet therapy, we have found that making the platelet aggregation ability assessment with 10 µmol of adenosine phosphate as an inducer is possible to identify the effect of medications. However, further studies including larger patient groups are needed to determine the target values of platelet aggregation with 10 µmol of adenosine phosphate and assess the therapy efficacy.

Stability of Hemostasis Parameters in Whole Blood, Plasma, and Frozen Plasma: Literature Review and Recommendations of the SFTH (French Society of Thrombosis and Haemostasis).

Preanalytical sample management is critical for a proper assessment of hemostasis parameters, and may differ depending on prescribed tests or additional tests considered to be necessary after initial results. Although there is quite vast literature on this issue, the Working Group of the French Society of Thrombosis and Haemostasis (SFTH) deemed it necessary to make an in-depth literature review and propose recommendations for the proper handling of samples prior to hemostasis assays. This extensive assessment is accessible on-line in French at the SFTH website. Here, a more synthetic view of these recommendations is proposed, supported by easy-to-use tables. The latter respectively deal with the stability of whole blood or fresh plasma, frozen samples, and proper handling of samples forwarded on dry ice. Procedures are classified as recommended, acceptable, not conformed and lacking data. This work involved the retrieval of 125 references, first screened by a working group of 6 experts, then reviewed by 20 other experts in the field. The highly detailed conditions summarized in these tables will hopefully help hemostasis laboratories to secure the conditions recommended for sample collection and transportation. Moreover, as some conditions clearly lacked recommendations, this review can open new fields of investigation for hemostasis preanalytics.

Fibrin clot permeability (Ks) in patients on left ventricular assist device

Patients on left ventricular assist devices (LVAD) are prone to excessive hemostasis disturbances due to permanent contact of artificial pump surfaces with blood components. We aimed to investigate if fibrin clot permeability is altered in patients on long-term continuous-flow LVAD therapy and if the clot permeability is associated with clinical characteristics and adverse events. We investigated 85 end-stage heart failure patients (90.6% men, age 48.6–63.8 years) scheduled for continuous flow long-term LVAD support according to current clinical indications. The patients were assessed periodically: prior to LVAD implantation (T1), 3–6 months (T2) after LVAD implantation, 6–12 months after (T3) and then every 6 months. We tested the first three blood samples (T1-T3) and the last available blood sample (T4), but no longer than 5 years after LVAD implantation. We assessed hemostasis parameters (Activated Partial Thromboplastin Time (APTT) Prothrombin Time, Activated Partial Thromboplastin Time, Fibrinogen, d-dimer, Antithrombin, Thrombin Time, Factor VIII, and von Willebrand Factor, aspirin-induced platelet inhibition, adenosine-diphosphate test) changes during the study period. Fibrin Clot Permeability was evaluated using a pressure system and Permeability Coefficient (Ks) was calculated. We observed a decrease in fibrin clot permeability (Ks) between T1, T2, T3 and T4 time periods; P < 0.01 for each comparison. Fibrin clot permeability was negatively correlated with fibrinogen concentration: r = − 0.51, P < 0.001, factor VIII activity r = − 0.42, P < 0.001. There was no association of Ks with age, Left Ventricular Ejection Fraction (LVEF) and medications P > 0.001, however cumulative measurements in patients on aspirin showed shortening of Ks in this group P = 0.0123. Major adverse cardiac and cerebrovascular events (MACCE) occurred in 36.5% patients, bleeding events in 25.9%, Net Adverse Clinical Events (NACE) in 62.4%; 31.7% patients died, and 17.6% underwent transplantation. The transplantation was considered as the endpoint. Discrepancies in Ks were observed between patients with MACCE, bleeding, and NACE, and patients without adverse events. Ks showed a constant trend towards normalization (P < 0.01) only in patients without adverse events. Patients with advanced heart failure have disturbed clot structure. A trend towards normalization of the Ks values is associated with fewer thromboembolic and bleeding complications in this group of patients.

Sex-Specific Associations between Thyroid Status, Inflammation and Hemostasis Biomarkers in Patients with Subacute Thyroiditis.

Background: Subacute thyroiditis (SAT) is characterized by profound inflammation and fluctuations in thyroid hormones which may affect the hemostasis balance. This study investigates sex-specific associations between thyroid status, inflammation and hemostasis biomarkers in SAT. Methods: We included 52 patients (40 women and 12 men) treated with non-steroidal anti-inflammatory drugs (NSAID) or methylprednisolone (MPS). Free thyroxine (fT4), thyroid stimulating hormone, C-reactive protein, complete blood count and routine hemostasis parameters were assessed. Results: Both men and women were in hyperthyroid state and had comparable levels of inflammatory biomarkers. A shortened activated partial thromboplastin time (aPTT) was observed in 16.7% of the men and 10% of the women (p = 0.562), and a shortened prothrombin time (PT) was observed in 33% of the men and 12.5% of the women (p = 0.094). In men, aPTT positively correlated with fT4 (r = 0.627; p < 0.05), while PT positively correlated with leukocyte-based inflammatory indices in women (p < 0.05). NSAID-treated patients had lower aPTTs and platelet counts than those treated with MPS (p < 0.05). Principal component analysis extracted "proinflammatory", "prothrombotic" and "antithrombotic" factors, but the "proinflammatory" factor was the independent predictor of elevated fT4 in women (OR = 2.705; p = 0.036). Conclusions: Our data demonstrated sex-specific associations of thyroid status and inflammatory biomarkers with hemostasis parameters in SAT. Routine hemostasis screening tests may help in monitoring the changes in the hemostasis system over the course of SAT.

Anti-Platelet Activity of Sea Buckthorn Seeds and Its Relationship with Thermal Processing.

Sea buckthorn (Hippophae rhamnoides L.) is a tree or shrub with small, orange berries. Sea buckthorn seeds have shown many properties beneficial to human health, including antioxidant, anti-hypertensive, anti-hyperlipidemic, and retinoprotective activities. Seeds, as a component of food, are often exposed to high temperatures, which can increase or decrease their biological activity. In our previous study, we showed that both raw and roasted sea buckthorn seeds had significant antioxidant activity, which was measured in human plasma in vitro. In this paper, we evaluated the effect of extracts from raw and roasted sea buckthorn seeds on several parameters of hemostasis in vitro, including thrombus formation in full blood (measured by the Total Thrombus formation Analysis System-T-TAS), blood platelet activation (based on the exposition of P-selectin, the active form of GPIIb/IIIa on their surface and platelet-derived microparticles formation), aggregation (measured with impedance aggregometry), adhesion to fibrinogen and collagen, arachidonic acid metabolism in washed platelets stimulated by thrombin, and COX-1 activity. We also measured the levels of free 8-isoprostane in plasma and the total non-enzymatic antioxidant status of plasma. The extract from roasted seeds (50 µg/mL) significantly prolonged the time of occlusion measured by T-TAS-the AUC10 (area under the curve) value was decreased by approximately 18%. Both extracts decreased the exposition of the active form of GPIIb/IIIa on the surface of platelets activated with 10 μM ADP (by 38.4-62.2%) and 20 μM ADP (by 39.7-51.3%). Moreover, the extract from raw seeds decreased the exposition of P-selectin on the surface of platelets stimulated with 20 μM ADP (by 31.2-34.9%). The adhesion of thrombin-stimulated platelets to fibrinogen and collagen was inhibited only by the extract from roasted sea buckthorn seeds (by 20-30%). Moreover, the extract from raw seeds inhibited the level of TBARS (thiobarbituric acid-reactive substances, an indicator of enzymatic peroxidation of arachidonic acid) in washed platelets stimulated with thrombin; the activity of COX-1 was inhibited by both extracts, although the effect of the extract from raw seeds was stronger. These results indicate that sea buckthorn seeds have anti-platelet activity that is not decreased by thermal processing, but more research is needed to determine which exact chemical compounds and mechanisms are responsible for this phenomenon.

Interrelation of plasma haemostasis and heart rate variability in patients with chronic coronary syndrome in combination with COVID-19

The aim of the study was to identify the relationship between activated partial thromboplastin time, prothrombin time, fibrinogen, D-dimer and indicators of N-N interval deviations, heart rate, on the one hand, and to identify the relationship between parasympathetic and sympathetic heart rate activity and dynamic blood viscosity, on the other hand. The COVID-19 pathogen affects the functioning of the parasympathetic and sympathetic nervous systems, which also changes the heart rate. To study this process, a group of 10 patients with chronic coronary syndrome in combination with COVID-19 without comorbidities aged 35-48 years was observed in a hospital. To study this relationship, plasma haemostasis parameters (activated partial thromboplastin time, prothrombin time, fibrinogen, D-dimer) and heart rate variability were taken at the time of admission to the hospital and after discharge from the hospital. A direct correlation between the indicators was found: in patients 1 and 4, at the time of admission to the hospital, there was an increase in activated partial thromboplastin time, prothrombin time, D-dimer and a decrease in fibrinogen, which coincides with an increase in heart rate, 5-10 minute and long-term deviation of the N-N segments. That is, changes in blood plasma affect the rhythm of the heart already at the onset of COVID-19 in combination with chronic coronary syndrome. Patients 1 and 4 had an increase in D-dimer at the time of discharge from the hospital, which coincided with an increase in heart rate. Patients require further follow-up, as these are signs of a cautious prognosis. All other plasma haemostasis parameters are normal in all patients, with minor changes. It is necessary to monitor plasma haemostasis and heart rate variability to adjust treatment during hospitalization of patients with chronic coronary syndrome in combination with COVID-19 and after discharge from hospital

Comparison of thrombodynamic methods and routine hemostasis tests in the evaluation of hypercoagulable syndrome in chronic glomerulonephritis

Nephrotic syndrome (NS) is associated with a high risk of thrombotic complications. In this group of patients, routine local tests for assessing hemostasis do not accurately reflect hypercoagulable state. Global functional tests for assessing hemostasis, including thrombodynamics (TD), are considered promising for assessing disorders in the blood coagulation system of these patients. To compare the rate of hypercoagulability according to routine hemostatic tests and TD and to evaluate the factors associated with increased risk of thrombotic complications in patients with chronic glomerulonephritis (CGN). The study included 94 patients with active CGN who were not receiving anticoagulant therapy; 63 (80.3%) patients had NS, and 31 (19.7%) had active CGN without NS. Hemostasis parameters were assessed using local coagulation tests and TD test. Using logistic regression analysis, factors associated with the risk of thrombosis were assessed. Of the 94 patients with active CGN in 63 without preventive anticoagulant therapy, hypercoagulability according to routine tests was detected in 6 (9.5%) patients with NS and in 3 (9.7%) patients without NS (p<0.05). Hypercoagulability according to the TD test was detected in 24 (53.9%) patients with NS and in 5 (32.2%) without NS (p<0.05). The formation of spontaneous clots was observed in 29 (30.9%) of patients with CGN, most of them 24 (83%) with NS. 10.6% of patients in our cohort experienced thromboembolic events. The risk of thromboembolic events according to the univariate regression analysis was associated with older age, higher lipid levels, use of glucocorticosteroids and detection of spontaneous clots by the TD test. No association of thromboembolic events with abnormalities in routine hemostasis tests was obtained. In patients with CGN with nephrotic syndrome, hypercoagulability is detected in 9.5% of cases with routine coagulation tests and in 53.9% of cases with TD test. Detection of spontaneous clots by TD test is associated with a risk of thromboembolic events.

Efficacy and safety of the combination of estetrol 15 mg/drospirenone 3 mg in a cyclic regimen for the treatment of endometriosis-associated pain and objective gynecological findings: a multicenter, placebo-controlled, double-blind, randomized study

To evaluate the efficacy and safety of 24-week cyclic administration of estetrol (E4) 15 mg/drospirenone (DRSP) 3 mg in Japanese patients with endometriosis. A 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. A total of 162 Japanese women diagnosed with endometriosis. Participants were randomly allocated to the E4/DRSP group or the placebo group. In the E4/DRSP group, participants were orally administered one tablet containing E4 15 mg and DRSP 3 mg daily for 24 days, followed by one placebo tablet for 4 days for a hormone-free interval, constituting a one-cycle regimen. One placebo tablet was administered once daily for 28 days to participants in the placebo group. The treatments were continued for six cycles (24 weeks) throughout the confirmatory period. Changes in visual analog scale scores for the most severe pelvic pain (lower abdominal and back pain) from baseline to six treatment cycles at the end of the confirmatory study period. E4/DRSP showed changes in average visual analog scale scores for the most severe pelvic pain (-33.2 mm) from baseline to the end of the six-cycle treatment. The between-group difference was significant (-8.5 mm, two-sided 95% confidence interval: -16.1 to -0.9 mm), showing superiority to placebo (p=0.028). Responder rates, ≥30% and ≥50% reduction in visual analog scale scores from baseline, were larger in the E4/DRSP group than in the placebo group: 53.2% versus 29.6% (p=0.004) and 36.4% versus 12.3% (p<0.001). Objective gynecological findings (induration of the cul-de-sac, pelvic tenderness, limited uterine mobility) were significantly improved by E4/DRSP treatment, and the proportions of stable and worsened participants were significantly lower than in the placebo group. E4/DRSP reduced the size of endometriomas and improved quality of life, based on quality of life-related questionnaires and global impression scores. No safety concerns were observed with E4/DRSP treatment. Few differences were observed in the proportion of participants with hemostasis parameters outside the reference range between the E4/DRSP and placebo groups. E4/DRSP effectively treats endometriosis-associated pain and improves gynecological findings. E4/DRSP may be a safe, new option for endometriosis treatment with a potentially reduced risk of thromboembolic events.

Recommendations on Monitoring and Replacement of Antithrombin, Fibrinogen, and Von Willebrand Factor in Pediatric Patients on Extracorporeal Membrane Oxygenation: The Pediatric Extracorporeal Membrane Oxygenation Anticoagulation CollaborativE Consensus Conference.

To derive systematic review informed, modified Delphi consensus regarding monitoring and replacement of specific coagulation factors during pediatric extracorporeal membrane oxygenation (ECMO) support for the Pediatric ECMO Anticoagulation CollaborativE. A structured literature search was performed using PubMed, Embase, and Cochrane Library (CENTRAL) databases from January 1988 to May 2020, with an update in May 2021. Included studies assessed monitoring and replacement of antithrombin, fibrinogen, and von Willebrand factor in pediatric ECMO support. Two authors reviewed all citations independently, with conflicts resolved by a third reviewer if required. Twenty-nine references were used for data extraction and informed recommendations. Evidence tables were constructed using a standardized data extraction form. Risk of bias was assessed using the Quality in Prognosis Studies tool. The evidence was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation system. A panel of 48 experts met over 2 years to develop evidence-based recommendations and, when evidence was lacking, expert-based consensus statements. A web-based modified Delphi process was used to build consensus via the Research And Development/University of California Appropriateness Method. Consensus was defined as greater than 80% agreement. We developed one weak recommendation and four expert consensus statements. There is insufficient evidence to formulate recommendations on monitoring and replacement of antithrombin, fibrinogen, and von Willebrand factor in pediatric patients on ECMO. Optimal monitoring and parameters for replacement of key hemostasis parameters is largely unknown.

New Findings Regarding the Effects of Selected Blue Food Colorants (Genipin, Patent Blue V, and Brilliant Blue FCF) on the Hemostatic Properties of Blood Components In Vitro.

Natural and synthetic colorants present in food can modulate hemostasis, which includes the coagulation process and blood platelet activation. Some colorants have cardioprotective activity as well. However, the effect of genipin (a natural blue colorant) and synthetic blue colorants (including patent blue V and brilliant blue FCF) on hemostasis is not clear. In this study, we aimed to investigate the effects of three blue colorants-genipin, patent blue V, and brilliant blue FCF-on selected parameters of hemostasis in vitro. The anti- or pro-coagulant potential was assessed in human plasma by measuring the following coagulation times: thrombin time (TT), prothrombin time (PT), and activated partial thromboplastin time (APTT). Moreover, we used the Total Thrombus formation Analysis System (T-TAS, PL-chip) to evaluate the anti-platelet potential of the colorants in whole blood. We also measured their effect on the adhesion of washed blood platelets to fibrinogen and collagen. Lastly, the cytotoxicity of the colorants against blood platelets was assessed based on the activity of extracellular lactate dehydrogenase (LDH). We observed that genipin (at all concentrations (1-200 µM)) did not have a significant effect on the coagulation times (PT, APTT, and TT). However, genipin at the highest concentration (200 µM) and patent blue V at the concentrations of 1 and 10 µM significantly prolonged the time of occlusion measured using the T-TAS, which demonstrated their anti-platelet activity. We also observed that genipin decreased the adhesion of platelets to fibrinogen and collagen. Only patent blue V and brilliant blue FCF significantly shortened the APTT (at the concentration of 10 µM) and TT (at concentrations of 1 and 10 µM), demonstrating pro-coagulant activity. These synthetic blue colorants also modulated the process of human blood platelet adhesion, stimulating the adhesion to fibrinogen and inhibiting the adhesion to collagen. The results demonstrate that genipin is not toxic. In addition, because of its ability to reduce blood platelet activation, genipin holds promise as a novel and valuable agent that improves the health of the cardiovascular system and reduces the risk of cardiovascular diseases. However, the mechanism of its anti-platelet activity remains unclear and requires further studies. Its in vivo activity and interaction with various anti-coagulant and anti-thrombotic drugs, including aspirin and its derivatives, should be examined as well.

Estetrol: a new word in modern hormonal contraception. A review

The concept of the demographic policy of the Russian Federation is to increase the birth rate, preserve citizens' health, and increase life expectancy. One of the priority areas is the reproductive health of women. The pleiotropic effect of the components of combined hormonal drugs is successfully used in clinical practice by obstetricians-gynecologists not only for contraception but also for conditions requiring prophylaxis and drug therapy. Estrogens have a protective effect on the reproductive and extragenital organs; however, evidence of the effect of estrogen-containing drugs on breast tissue and hemostasis remains debatable. We analyzed the data published in the international databases PubMed, Google Scholar, and MEDLINE (search depth – 5 years). Estetrol (E4) is a native fetal estrogen produced by the fetal liver during pregnancy. The key difference from other estrogens is its highly selective and differentiated effect on various tissues and its unique antiproliferative properties. The review presents the results of studies on estrogenic and antiestrogenic effects of E4 and the combination of E4 with progestogen (Esteretta drug product approved in Russia), with particular attention paid to the oncoprotective effect of E4. Research data suggest that E4 may have different effects on breast epithelial cells and breast cancer cells compared to other estrogens. Clinical data indicate that E4 has a more selective pharmacological profile compared to other estrogens, which is reflected in a low estrogenic effect on the liver, including the production of sex hormone binding globulin, hemostasis parameters, and lipid profile.

Indicators of plasma hemostasis in hypertensive patients of different age groups

Background. Scientific works of several authors determine age-related differences in hemocoagulation hemostasis. Thus, in older people, changes in hemovascular hemostasis are noted with impaired vasomotor, anticoagulant and fibrinolytic activity of the endothelium. Anticoagulant system disorders increase with age. There are few studies on plasma hemostasis in arterial hypertension patients, especially in older age groups. Aim: The study aimed at a complex research and comparative assessment of the plasma state hemostasis parameters in older and middle-aged hypertensive patients. Materials and methods. 134 patients who were divided into 2 groups were examined. Group I (n = 65) – the older hypertensive patients (60 - 74 years); group II (n = 69) – the middle-aged hypertensive patients (45 - 59 years) respectively. 15 people were involved in the control for each of the studied groups (group III – the older persons and group IV – the middle-aged persons) comparable to the main in terms of age and sex. They were divided into 2 groups of 24-hour day profile of blood pressure: dippers and non-dippers. Fibrinogen (g/l) was determined on an Amelung KC 1A hemocoagulometer to assess the plasma hemostasis state. The fibrinolytic activity of plasma (min) was according to the Kowalski method, antithrombin III (%) with the help of Humalyzer Junior filter photometer. Results. When comparing the plasma hemostasis indicators in the older and the middle-aged patients the value of antithrombin III in the middle-aged persons exceeded the similar indicator in the older persons. That is, in older patients, on the contrary, suppression of fibrinolytic and anticoagulant activity is noted. A significant slowing of the indicator of fibrinolysis activity was found in the middle-aged patients of the dipper group compared to the control group. A significant decrease in the fibrinogen level was found in the older patients in the dipper group and its increase in the non-dipper group relative to the control. The level of the antithrombin III significantly decreased in the non-dipper group compared to normative indicators. Conclusions. 1. The significant decrease in anticoagulant activity against the background of suppressed fibrinolysis according to indicators of the plasma hemostasis of the older patients was noted. 2. The thrombogenicity of blood plasma revealed by us during the study of plasma hemostasis indicates the high probability of thrombotic complications developing in patients. _________________________________________________________________________________________ Keywords: arterial hypertension; essential hypertension; plasma hemostasis; fibrinogen; fibrinolytic activity of plasma; antithrombin III

Clinical significance for assessing adaptive hemostasis changes during multiple pregnancy after in vitro fertilization

Aim: to assess adaptive hemostasis changes in multiple dichorionic pregnancy after in vitro fertilization (IVF). Materials and Methods. A prospective observational randomized controlled trial was conducted by examining 58 and 46 pregnant women with multiple dichorionic diamniotic twins resulting from applying assisted reproductive technologies (ART) and spontaneous delivery (comparison group), respectively. Hemostasis parameters were studied as follows: activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen, antithrombin, protein C, protein S, functions of protein С (РrоС Global test), D-dimer, platelet aggregation with adenosine-5-diphosphate (ADP), ristocetin, and collagen. Results. A high coagulation potential was revealed, more prominent after using ART (p &lt; 0.05). Fibrinogen level gradually increased while gestation age increased, whereas APTT, PT and TT level decreased. In the group with natural conception, fibrinogen increased by 22 % in the second trimester, reaching 4.5 g/L (95 % CI = 4,2–4,8) and by 6 % in the third trimester, reaching 4.8 g/L (95 % CI = 4,3–5,4), whereas in the IVF group – by 26 %, reaching 5.3 g/L (95 % CI = 4,7–5,6) and by 21 %, reaching (6.5 g/L; 95 % CI = 5,2–6,8) in relevant trimester of pregnancy, respectively. Antithrombin level was lower in IVF patients – 76.8 % (95 % CI = 72.6 – 81.0) in the second trimester, reaching 70.6 % (95 % CI = 64.8–76.4) in the third trimester (p &lt; 0.001). Protein C level did not differ significantly between groups and was low within the reference range. The aggregatogram demonstrated a high platelet hemostatic potential in IVF patients (p &lt; 0.05) as early as in the first trimester: ADP-induced aggregation – 68.3 % (95 % CI = 62.9–73.7), ristocetin-induced aggregation – 53.1 % (95 % = CI 48.7–58.5), collagen-induced aggregation – 58.4 % (95 % CI = 52.1–64.7). In the third trimester, both platelet aggregation and functional activity (ADP-induced aggregation – 64.5 % [95 % CI = 59.3–69.7], ristocetin-induced aggregation – 68.4 % [95 % CI = 63.2–73.6], collagen-induced aggregation – 50.7 % [95 % CI = 44.3–57.1]; p &lt; 0.05) and D-dimer level persistently increased, also more prominently in the IVF group (1.60 ± 0.46 ng/ml; p &lt; 0.05). Conclusion. Gestational adaptation in induced multiple pregnancies is at high risk of breach in compensatory mechanisms and requires monitoring for timely detection of decompensation signs and their correction to prolong pregnancy till optimal delivery time frame.

COAGULATION AND ANTICOAGULATION PARAMETERS IN MULTIPLE SCLEROSIS PATIENTS WITH AND WITHOUT COVID-19

The aim. To investigate plasma levels of main coagulation and fibrinolytic factors in MS patients with and without COVID-19 history. Materials and methods. A total of 127 participants were enrolled in this study, including 97 MS patients and 30 healthy controls (HC). Patients with MS were divided into two groups: MS+Covid group (n=41) – patients with MS, who had a laboratory-verified diagnosis of COVID-19 in the past 3-6-month period and MS group (n=56) – patients with MS, who did not suffer from COVID-19 previously. Determination of plasma levels of prothrombin, plasminogen, tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), protein C (PC), soluble thrombomodulin (TM) was performed by means of enzyme-linked immunosorbent assay. Spectrophotometric techniques were used to determine concentrations of fibrinogen, soluble fibrin monomeric complexes (SFMC) as well as plasminogen activity and inhibitory potential of α-2-antiplasmin. Results. The MS group was characterized by elevated levels of plasma prothrombin, fibrinogen, D-dimer, SFMC, soluble TM compared to HC, while PC concentration did not differ between MS and HC groups. Plasma plasminogen level as well as plasma level of the potential plasmin activity were significantly decreased in MS patients compared to HC group. The plasma tPA level was significantly reduced while plasma PAI-I level was significantly increased in MS patients compared to HC. Patients of MS group had an increased level of plasma α-2-antiplasmin activity compared with HC group. To note, most of studied parameters did not differ between two MS groups, except protein C, soluble thrombomodulin levels and plasma α-2-antiplasmin activity. Conclusions. The results of our study showed that MS patients have got altered hemostasis parameters; however, further study is necessary to find out the relationship between particular components of coagulation and fibrinolytic systems and pathophysiology of MS. Additionally, our findings demonstrated that a SARS-CoV-2 infection had a limited effect on hemostasis parameters in MS patients, causing changes in only a few parameters, including thrombomodulin and protein C levels as well as α-2-antiplasmin activity.