RESUMO
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 level>943 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.
Assuntos
Fator 15 de Diferenciação de Crescimento , Hemorragia , Sistema de Registros , Humanos , Masculino , Feminino , Idoso , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Hemorragia/etiologia , Pessoa de Meia-Idade , Fator 15 de Diferenciação de Crescimento/sangue , Estudos Prospectivos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/sangue , Quimioterapia Combinada , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/complicações , Fibrinolíticos/administração & dosagem , Fibrinolíticos/efeitos adversos , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Clopidogrel/administração & dosagem , Clopidogrel/efeitos adversos , Prognóstico , Federação Russa/epidemiologia , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/efeitos adversos , Rivaroxabana/administração & dosagem , Rivaroxabana/efeitos adversos , Intervenção Coronária Percutânea/métodos , Intervenção Coronária Percutânea/efeitos adversosRESUMO
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 [61-69] 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 (10-29 mg/g) was detected in 45.9% of patients, moderate and severe (≥30 mg/g) - in 29.7%; eGFR<60 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 4-5 vascular beds (ROC AUC 0.775; p=0.011). During the follow-up (12 [8-18] months) 3 patients developed MACE, 11 - BARC 2-3 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.
Assuntos
Aterosclerose , Insuficiência Renal Crônica , Masculino , Humanos , Idoso , Feminino , Albuminúria/diagnóstico , Albuminúria/epidemiologia , Albuminúria/etiologia , Fator de von Willebrand , Insuficiência Renal Crônica/complicações , Aterosclerose/diagnóstico , Aterosclerose/epidemiologia , Aterosclerose/complicações , Taxa de Filtração GlomerularRESUMO
Aim Searching for clinical, angiographic, and biochemical predictors of cardiovascular complications (CVC) and hemorrhagic complications in patients with atrial fibrillation (AF) receiving a multicomponent antithrombotic therapy (MAT) for an elective percutaneous coronary intervention (PCI). Patients with ischemic heart disease (IHD) and AF who require MAT for PCI are at a high risk of thrombotic complications (stroke, systemic embolism, coronary events) and hemorrhage. This warrants searching for new risk factors determining prediction of the outcome.Materials and methods This study included 207 patients (146 males aged 70.1±8.3 years) with IHD and AF who received direct oral anticoagulants (DOAC) as a part of their MAT therapy. Median duration of the follow-up was 12 [8.0; 12.0]âmonths. The efficacy endpoint was a sum of CVCs combining cardiovascular death, ischemic stroke, venous thromboembolic complications, acute coronary syndrome (ACS), and requirement for an unscheduled PCI. "Coronary events", including ACS and requirement for an unscheduled PCI were analyzed separately. The safety endpoint was BARC type 2-5 bleeding. Upon admission, biomarkers (growth-differentiation factor 15 (GDF-15), D-dimer, thrombin-activated fibrinolysis inhibitor (TAFI), and plasminogen activator inhibitor-1 (PAI-1)) were measured for all patients. Searching for prognostically significant indexes was performed with the Cox proportional hazards regression.Results Incidence of all CVCs was 16.4â%. Independent predictors of CVC included the DOAC treatment at a reduced dose (odds ratio (OR) 2.5 at 95â% confidence interval (CI) 1.02-6.15; p=0.0454), GDF-15 >1191âpgâ/ml (OR 3.76 at 95â% CI, 1.26-11.18; p=0.0172), PAI-1 >13.2 U/ml (OR 2.67 at 95â% CI, 1.13-6,26; p=0.0245). Incidence of coronary complications was 9.2â%. Independent predictors of coronary complications included a SYNTAX index >26.5 (OR 4.5 at 95â% CI, 1.45-13.60; p=0.0090), PCI for chronic coronary occlusion (OR 3.21 at 95â% CI, 1.10-9.33; p=0.0326), a GDF-15 >1191âpg/ml (ÐR 4.70 at 95â% CI, 1.32-16.81; p=0.0172). Incidence of BARC type 2-5 bleeding was 26.1â%. The only independent predictor for hemorrhage complications was the total PRECISE-DAPT score >30 (ÐR 3.22; 95â% CI, 1.89-5.51; Ñ<0.0001).Conclusion Three independent predictors of CVC were identified for patients with IHD and AF treated with MAT following an elective PCI: treatment with a reduced dose of DOAC, GDF-15 >1191âpgâ/ml, and PAI-1>13.2 U/ml. Independent predictors of coronary complications included a SYNTAX index >26.5, PCI for chronic coronary occlusion, and GDF-15 >1191âpg/ml. The factor associated with a risk of bleeding was the total PRECISE-DAPT score >30.
Assuntos
Fibrilação Atrial , Intervenção Coronária Percutânea , Idoso , Anticoagulantes , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Fibrinolíticos/efeitos adversos , Hemorragia , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária , Fatores de Risco , Resultado do TratamentoRESUMO
DNA aptamers (oligonucleotides) interacting with thrombin exosite I contain G-quadruplex, two T-T, and one T-G-T loops in their structure. They prevent exosite I binding with fibrinogen and thrombin receptors on platelet surface, thereby suppressing thrombin-stimulated formation of fibrin from fibrinogen and platelet aggregation. Earlier, we synthesized original antithrombin aptamer RE31 (5'-GTGACGTAGGTTGGTGTGGTTGGGGCGTCAC-3') that contained (in addition to G-quadruplex) a hinge region connected to six pairs of complementary bases (duplex region). In this study, we compared properties of RE31 aptamer and its analogues containing varying number of bases in the duplex region and nucleotide insertions in the hinge region. Reduction in the number of nucleotides in the duplex region by 1 to 4 pairs (in comparison with RE31 aptamer) resulted in the decrease of the structural stability of aptamers (manifested as lower melting temperatures) and their ability to inhibit thrombin-stimulated fibrin formation in human blood plasma in tests of thrombin, prothrombin, and activated partial thromboplastin times. However, an increase in the number of bases by 1 to 2 pairs did not cause significant changes in the stability and antithrombin activity of the aptamers. Insertions into the hinge region of RE31 aptamer decreased its antithrombin activity. Investigation of RE31 antithrombotic properties demonstrated that RE31 (i) slowed down thrombin formation in human blood plasma (thrombin generation test), (ii) accelerated lysis of fibrin clot by tissue plasminogen activator in in vitro model, and (iii) suppressed arterial thrombosis in in vivo model. Based on the obtained data, RE31 aptamer can be considered as a potentially effective antithrombotic compound.
Assuntos
Antitrombinas/farmacologia , Aptâmeros de Nucleotídeos/farmacologia , Trombina/efeitos dos fármacos , Aptâmeros de Nucleotídeos/química , Sítios de Ligação , Testes de Coagulação Sanguínea , Humanos , Agregação Plaquetária/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Activity of tissue factor (TF) in membrane microparticles (MPs) produced in vitro by endothelial cells (ECs), monocytes, THP-1 monocytic cells, granulocytes, and platelets was investigated. ECs were isolated from human umbilical vein, and monocytes, granulocytes, and platelets - from the blood of healthy donors. ECs, monocytes, and THP-1 cells were activated by bacterial lipopolysaccharide, granulocytes - by lipopolysaccharide or phorbol myristate acetate, and platelets - by SFLLRN, thrombin receptor-activating peptide. MPs were sedimented from the culture medium or supernatant of activated cells at 20,000g for 30 min. Coagulation activity of MPs was analyzed in a modified recalcification assay by assessing their effects on coagulation of donor plasma depleted of endogenous MPs (by centrifuging at 20,000g for 90 min). MPs from all cell types accelerated plasma coagulation. Antibodies blocking TF activity prolonged coagulation lag-phase in the presence of MPs from ECs, monocytes, and THP-1 cells (by 2.7-, 2.0-, and 1.8-fold, respectively), but did not influence coagulation in the presence of MPs from granulocytes and platelets. In accordance with these data, TF activity measured by its ability to activate factor X was found in MPs from ECs, monocytes, and THP-1 cells, but not in MPs from granulocytes and platelets. The data obtained indicate that active TF is present in MPs produced in vitro by ECs, monocytes, and THP-1 cells, but not in MPs derived from granulocytes and platelets.
Assuntos
Células Sanguíneas/química , Micropartículas Derivadas de Células/química , Células Endoteliais/química , Tromboplastina/metabolismo , Células Sanguíneas/citologia , Células Sanguíneas/metabolismo , Linhagem Celular , Micropartículas Derivadas de Células/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Humanos , Tromboplastina/análiseRESUMO
The VerifyNow assay is based upon the ability of activated platelets to cross-link beads coated with fibrinogen. However, fibrinogen is an abundant protein of blood, and therefore it may affect test results by competing with fibrinogen of beads for binding to platelets. To test this assumption, we assessed the influence of artificial alteration of fibrinogen level in blood samples obtained from donors (n = 9) and patients on clopidogrel therapy (n = 8) on the results of the VerifyNow P2Y12 assay. Fibrinogen level was altered by adding to blood samples 1/10 volume of fibrinogen solution (10.56 g/liter) or corresponding buffer. Relative to baseline, addition of buffer significantly increased platelet reactivity, whereas addition of fibrinogen decreased it. Analysis of the relationship between change in platelet reactivity values (dBase and dPRU) and change in fibrinogen concentration (dFg) revealed strong negative correlations: dBase = -63.3 × dFg - 27.1 (r = -0.924, p < 0.0005) and dPRU = -54.4 × dFg - 21.8 (r = -0.764, p < 0.0005). Thus, the results of our experiments suggest that: (i) blood fibrinogen strongly influences results of the VerifyNow P2Y12 assay, and (ii) correcting for fibrinogen effect may be needed to improve the accuracy of the test in the measuring of antiplatelet effect of clopidogrel therapy.
Assuntos
Plaquetas/metabolismo , Fibrinogênio/metabolismo , Testes de Função Plaquetária/métodos , Receptores Purinérgicos P2Y12/metabolismo , Aterosclerose/tratamento farmacológico , Plaquetas/citologia , Clopidogrel , Fibrinogênio/química , Humanos , Proteínas Imobilizadas/química , Proteínas Imobilizadas/metabolismo , Nefelometria e Turbidimetria , Agregação Plaquetária/efeitos dos fármacos , Receptores Purinérgicos P2Y12/química , Análise de Regressão , Ticlopidina/análogos & derivados , Ticlopidina/farmacologia , Ticlopidina/uso terapêuticoRESUMO
AIM: to investigate parameters of fibrinolysis in patients on long-term warfarin (W) therapy, and assess their relation to the risk of recurrent bleeding occurring at therapeutic international normalized ratio (INR). MATERIALS AND METHODS: Our prospective study involved 78 W-naive patients (40 men, age 64.3+/-12.2 years). Follow up period was 5.6+/-3.4 months. INR was measured monthly; determination of coagulation parameters (D-dimer, fibrinogen, complex plasmin-2-antiplasmin [PAP] and thrombin-activatable fibrinolysis inhibitor [TAFI] was performed before and after at least 3 months of W therapy. RESULTS: During follow-up bleedings occurred in 47 (60.3%) patients, 26 patients (33.3%) had recurrent bleedings at therapeutic INR and 21 patients (26.9%) had single bleeding. Mean time in therapeutic range (TTR) was >70.
Assuntos
Anticoagulantes , Hemorragia , Varfarina , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Coagulação Sanguínea , Produtos de Degradação da Fibrina e do Fibrinogênio , Fibrinolisina , Humanos , Coeficiente Internacional Normatizado , Masculino , Estudos Prospectivos , Recidiva , Fatores de Risco , Varfarina/administração & dosagem , Varfarina/efeitos adversos , Varfarina/uso terapêutico , alfa 2-AntiplasminaRESUMO
UNLABELLED: Aim of the study was to elucidate value of HAS-BLED and HEMORR2HAGES scales for prediction bleedings in patients receiving long-term warfarin (W) therapy. MATERIAL AND METHODS: The study involved 119 patients (72 men) aged 60.9 ± 9.6 years with atrial fibrillation or venous thromboembolic complications. Follow up period was 5.6 ± 3.4 years. All bleedings were categorized as 1) single bleeding with INR > 4.0 during the 1st month of W therapy; 2) any single bleeding after 1st month of W therapy; 3) recurrent bleedings. CYP2C9 and VKORC1 (G3673A) genotypic variants were determined by PCR. Patients were divided into low (< 3 points of HAS-BLED scale, n = 58; < 4 points of HEMORR2HAGES scale, n = 109) and high (3 points of HAS-BLED scale, n = 61, ≥ 4 points of HEMORR2HAGES scale, n = 10) bleeding risk groups. RESULTS: There was no relationship between total HAS-BLED, HEMORR2HAGES scores and numbers of all as well as category 1 and 2 bleedings. The difference in bleeding frequency between high and low risk groups was significant only for recurrent bleedings. There were 22 (36.1%) and 5 (8.6%) recurrent bleedings among 61 and 58 patients with high and low-risk HAS-BLED score, respectively (p = 0.0048). Recurrent bleedings also occurred more frequently among patients with high risk (7/10, 70%) compared with low risk (20/109, 18.35%) HEMORR2HAGES score (p = 0.018). Subgroups of high and low bleeding risk according to HAS-BLED and HEMORR2HAGES scores differed only by proportion of patients with recurrent bleedings. High W sensitivity represented by 2*/2*, 2*/3*, 3*/3* CYP2C9 and/or AA VKORC1 homozygosis was detected in 25 of 119 patients. Six of 8 patients (75%) with category 1 bleedings were carriers of any polymorpism. CONCLUSION: HAS-BLED and HEMORR2HAGES scales performed best in predicting recurrent bleedings in patients on long term W therapy. Single bleedings with INR > 4.0 during 1st month of W therapy were associated with reduced W metabolism (AA VKORC1 or/and CYP2C9 allelic variants 2*/2*, 2*/3*, 3*/3*).
Assuntos
Hemorragia/epidemiologia , Medição de Risco/métodos , Tromboembolia/prevenção & controle , Varfarina/efeitos adversos , Adulto , Idoso , Anticoagulantes/efeitos adversos , Feminino , Seguimentos , Hemorragia/induzido quimicamente , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Federação Russa/epidemiologia , Fatores de TempoRESUMO
Aim of the study was to elucidate value of HAS-BLED and HEMORR2HAGES scales for prediction bleedings in patients receiving long-term warfarin (W) therapy. MATERIAL AND METHODS: The study involved 119 patients (72 men) aged 60.9+/-9.6 years with atrial fibrillation or venous thromboembolic complications. Follow up period was 5.6 +/-3.4 years. All bleedings were categorized as 1) single bleeding with INR>4.0 during the 1st month of W therapy; 2) any single bleeding after 1st month of W therapy; 3) recurrent bleedings. CYP29 and VKORC1 (G3673A) genotypic variants were determined by PCR. Patients were divided into low (<3 points of HAS-BLED scale, n=58; <4 points.
RESUMO
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.
Assuntos
Anticoagulantes/administração & dosagem , Enoxaparina/administração & dosagem , Trombose Venosa/tratamento farmacológico , Anticoagulantes/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Enoxaparina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/sangue , Embolia Pulmonar/etiologia , Embolia Pulmonar/prevenção & controle , Resultado do Tratamento , Trombose Venosa/sangue , Trombose Venosa/complicações , Varfarina/administração & dosagem , Varfarina/uso terapêuticoRESUMO
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 endpoints. 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 > or = 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.
Assuntos
Anticoagulantes/efeitos adversos , Hidrocarboneto de Aril Hidroxilases/genética , Hemorragia/genética , Oxigenases de Função Mista/genética , Tromboembolia Venosa/tratamento farmacológico , Varfarina/efeitos adversos , Adolescente , Adulto , Idoso , Anticoagulantes/uso terapêutico , Citocromo P-450 CYP2C9 , Feminino , Hemorragia/induzido quimicamente , Hemorragia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Moscou/epidemiologia , Polimorfismo Genético , Vitamina K Epóxido Redutases , Varfarina/uso terapêutico , Adulto JovemRESUMO
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 endpoints. 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.
Assuntos
Anticoagulantes/uso terapêutico , Carboxipeptidase B2/sangue , Embolia Pulmonar/tratamento farmacológico , Trombose Venosa/tratamento farmacológico , Varfarina/uso terapêutico , Adolescente , Adulto , Idoso , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Hemorragia/induzido quimicamente , Hemorragia/enzimologia , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Projetos Piloto , Estudos Prospectivos , Embolia Pulmonar/sangue , Embolia Pulmonar/enzimologia , Análise de Regressão , Risco , Fatores de Tempo , Trombose Venosa/sangue , Trombose Venosa/enzimologia , Varfarina/administração & dosagem , Varfarina/efeitos adversos , Adulto JovemRESUMO
Characteristics of a new antithrombin DNA-aptamer RE31 were studied. This aptamer inhibited thrombin formation in human plasma catalyzed by exogenous (lengthening of thrombin time) and endogenous thrombin (lengthening of partial prothrombin time and activated partial thromboplastin time). In addition, the aptamer completely suppressed thrombin-induced aggregation of human platelets. On the other hand, RE31 did not reduce amidolytic activity of thrombin towards the short peptide substrate, in other words, did not modify the state of enzyme active center. By the capacity to inhibit clotting reactions, RE31 was superior to the previously described highly effective 31-component antithrombin aptamer 31TBA (thrombin binding aptamer, TBA). The effect of RE31 was species-specific: it inhibited human thrombin activity more effectively than activities of rat and rabbit thrombins.
Assuntos
Antitrombinas/farmacologia , Aptâmeros de Nucleotídeos/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Trombina/antagonistas & inibidores , Animais , Coagulação Sanguínea/efeitos dos fármacos , Coagulação Sanguínea/fisiologia , Humanos , Inibidores da Agregação Plaquetária/farmacologia , Coelhos , Ratos , Trombina/metabolismoRESUMO
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
Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Tromboembolia Venosa/sangue , Tromboembolia Venosa/etiologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Moscou/epidemiologia , Fatores de Risco , Tromboembolia Venosa/epidemiologia , Adulto JovemAssuntos
Aspirina , Resistência a Medicamentos , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , Fator de Ativação de Plaquetas/metabolismo , Tromboxano B2/análogos & derivados , Idoso , Aspirina/administração & dosagem , Aspirina/efeitos adversos , Aspirina/farmacocinética , Angiografia Coronária , Monitoramento de Medicamentos , Ecocardiografia Transesofagiana , Eletrocardiografia , Teste de Esforço , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/fisiopatologia , Fatores de Risco , Índice de Gravidade de Doença , Tromboxano B2/urina , Resultado do TratamentoRESUMO
We followed for 18 months 90 patients who had had deep vein thrombosis (DVE) and/or pulmonary embolism (PE) and received therapy with anticoagulants either for 3-12 months or for indefinitely long time. During follow-up rate of recurrent DVE was 16.7%, no recurrences of PE were registered. Predictors of recurrent PE were selected among 165 demographic, anthropometric, anamnestic, clinical, genetic, instrumental, and laboratory parameters, as well as risk factors of development of thromboembolic complications. According to results of multifactorial regression analysis we established the following independent predictors recurrent DVE during 18 months of follow-up: elevated level of DAdimer after 1 month of anticoagulant therapy (p=0.005; relative risk--relative risk [RR] 8.1, 95% confidence interval [CI] 1.9 to 34.8), homozygosity for C249T polymorphism in beta-fibrinogen gene (p=0.044; RR 8.4 95% CI 1.1 to 65.7), and percentage of all values of international normalized ratio within therapeutic interval 2.0-3.0 (p=0.009; RR 0.94, 95 CI 0.89 to 0.98).
Assuntos
Anticoagulantes/uso terapêutico , Ultrassonografia Doppler Dupla , Trombose Venosa/diagnóstico , Adolescente , Adulto , Idoso , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Recidiva , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Trombose Venosa/sangue , Trombose Venosa/tratamento farmacológico , Adulto JovemRESUMO
OBJECTIVE: The study was aimed at comparing efficacy and safety of two diferent approaches to initial anticoagulant therapy: a standard approach (non-fractionated heparin [NFH]for not less than 5 days followed by changing over to warfarin) and an alternative one, i. e., prolongation of treatment with therapeutic doses of enoxaparinfor up to one month with switching to warfarin, also assessing the effect of initial anticoagulant therapy on the "outcomes" of venous thromboembolic complications (VTECs) during 12 months of treatment. MATERIAL AND METHODS: We followed up a total ofone hundred and eleven patients after endured episodes of deep vein thrombosis (DVT) and/or pulmonary artery thromboembolism (PATE). Group One patients (n=80) received the standard therapy (NFH for not less than 5 days followed by changing over to warfarin). For Group Two patients (n=31), NFH was replaced by therapeutic doses of enoxaparin (1 mg/kg each 12 hours) for at least 30 days, with the patients then transferred to warfarin according to the standard regimen. Ultrasonographic duplex scanning of limb vessels was performed at baseline, 1, 3, 6 and 12 months after initiation of therapy. The patients were followed up for 12months. The following end points were taken into account: DVT/PATE relapses, haemorrhagic complications. RESULTS: Improved patency ofdeep veins one month after initiation of treatment was observed in the both groups, however efficacy of enoxaparin turned out to be superior to that of the standard therapy in relation to a decreased number of occlusive thrombosis of veins - 9 versus 41 (p=0.005). Commencing from month two of treatment patients from the both groups began taking warfarin, however the number of occlusive thromboses of deep veins during 12 months of treatment was considerably lower as compared with that in the enoxaparin group, i. e. I versus 21 (p=0.013) after 3 months; with 1 vs 11 (p=0.009) after 6 months, and 0 vs 8 (p=0.013) after 12 months. The rate of DVT relapses and haemorrhagic complications during the first month of treatment was similar in the both groups. Startingfrom month two of therapy there were no DVT relapses in the enoxaparin group. Conclusions. Enoxaparin within the first month of treatment in patients having developed VTEC, with similar DVT complication rate, appeared to be superior to the standard therapy with NFH and warfarin in achieving recanalization of occlusively thrombosed veins, with its advantages in improving patency of deep veins preserving within 12 months. The use of enoxaparin was also associated with lower rate of DVT relapses during 12 months of treatment.
Assuntos
Anticoagulantes/administração & dosagem , Enoxaparina/administração & dosagem , Tromboembolia Venosa/induzido quimicamente , Trombose Venosa/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticoagulantes/efeitos adversos , Enoxaparina/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Risco , Federação Russa/epidemiologia , Terapia Trombolítica/efeitos adversos , Terapia Trombolítica/métodos , Fatores de Tempo , Ultrassonografia Doppler Dupla , Tromboembolia Venosa/diagnóstico por imagem , Tromboembolia Venosa/epidemiologia , Trombose Venosa/diagnóstico por imagem , Adulto JovemRESUMO
PURPOSE: To study the factors associated with an elevated content of D-dimer in patients diagnosed as having cardiovascular diseases (CVD) with no apparent thromboembolic complications. MATERIAL AND METHODS: A retrospective analysis of 1,000 case histories of patients (624 men and 376 women) aged from 19 to 93 years and undergoing treatment at the Institute of Cardiology named after A.L. Myasnikov in 2009. The sole criterion for inclusion into the study was the fact of hospitalization for any CVD and an altered content of D-dimer. The D-dimer levels were determined by latex agglutination using reagent kits «ST ALIATES® D-DF¼ (Diagnostica Stago). The upper limit of the normal distribution of the D-dimer amounted to 0.5 µg/ml. RESULTS: Thromboembolic complications were encountered in 13% of patients. Search for increased D-dimer predictors was carried out amongst a total of 867 CVD patients with no manifest thromboembolic complications. The D-dimer levels ranged widely from 0.01 to 16.97 (median 0.32, interquartile range 0.20-0.63) mg/ml and exceeded the upper limit of the normal distribution in 32% of the patients. Based on the findings of the univariate analysis we selected 14 parameters with the level of significance P<0.05, associated with an elevated D-dimer content. These parameters included but were not limited to: female gender, age >68 years, a history of venous thromboembolic events, no cardiac angina, the presence of ciliary arrhythmia and functional class III-IV chronic cardiac insufficiency (CCI), decompensated CCI, the presence of a permanent artificial pacemaker, an acute inflammatory process, chronic obstructive pulmonary disease, active cancer, pulmonary hypertension, and dilatational cardiomyopathy. The subsequent multivariate analysis showed that female gender, age >68 years, an acute inflammatory process, pulmonary hypertension, and decompensated CCI were independent predictors of an elevated D-dimer level in patients with CVD without apparent thromboembolic complications. CONCLUSIONS: The D-dimer level exceeded the upper limit of the normal distribution in 32% of CVD patients without manifest thromboembolic complications. Independent predictors of elevated D-dimer in CVD patients with no visible thromboses are as follows: female gender, age >68 years, acute inflammation, pulmonary hypertension, and decompensation of CCI.
Assuntos
Doenças Cardiovasculares/sangue , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Testes de Fixação do Látex , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Tromboembolia , Adulto JovemRESUMO
The effects of two DNA aptamers (oligonucleotides) 15TBA and 31TBA (15- and 31-mer thrombin-binding aptamers, respectively) on thrombin activity were studied. Both aptamers added to human plasma dose-dependently increased thrombin time (fibrin formation upon exposure to exogenous thrombin), prothrombin time (clotting activation by the extrinsic pathway), and activated partial thromboplastin time (clotting activation by the intrinsic pathway). At the same time, these aptamers did not modify amidolytic activity of thrombin evaluated by cleavage of synthetic chromogenic substrate. Aptamers also inhibited thrombin-induced human platelet aggregation. The inhibitory effects of 31TBA manifested at lower concentrations than those of 15TBA in all tests. These data indicate that the studied antithrombin DNA aptamers effectively suppress its two key reactions, fibrin formation and stimulation of platelet aggregation, without modifying active center of the thrombin molecule.
Assuntos
Antitrombinas/farmacologia , Aptâmeros de Nucleotídeos/farmacologia , Aptâmeros de Nucleotídeos/química , Sequência de Bases , Relação Dose-Resposta a Droga , HumanosRESUMO
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.