RESUMEN
The risk of thrombosis in individuals with rare compound thrombophilias, homozygous factor V Leiden (FVL) plus heterozygous prothrombin G20210A (PTM), homozygous PTM plus heterozygous FVL, and homozygous FVL plus homozygous PTM, is unknown. We identified, worldwide, individuals with these compound thrombophilias, predominantly through mailing members of the International Society on Thrombosis and Haemostasis. Physicians were sent a clinical questionnaire. Confirmatory copies of the genetic results were obtained. One hundred individuals were enrolled; 58% were female. Seventy-one individuals had a venous thrombosis (includes superficial and deep vein thrombosis, and pulmonary embolism), 4 had an arterial thrombosis and 6 had both. Nineteen individuals had never had a thrombotic event. Thrombosis-free survival curves demonstrated that 50% of individuals had experienced a thrombotic event by 35 yrs of age, while 50% had a first venous thromboembolic event (VTE; includes all venous thrombosis except superficial thrombosis) by 41 yrs of age; 38.2% of first VTEs were unprovoked. 37% of patients had at least one VTE recurrence. Seventy percent of first pregnancies carried to term and not treated with anticoagulation were thrombosis-free. In conclusion, patients with these rare compound thrombophilias are not exceedingly thrombogenic, even though they have a substantial risk for VTE.
Asunto(s)
Factor V/genética , Predisposición Genética a la Enfermedad , Polimorfismo Genético , Protrombina/genética , Trombofilia/epidemiología , Trombofilia/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Alelos , Coagulación Sanguínea , Pruebas de Coagulación Sanguínea , Niño , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Embarazo , Riesgo , Trombofilia/diagnóstico , Trombofilia/mortalidad , Adulto JovenRESUMEN
During surgery and childbirth, patients with hereditary antithrombin (AT) deficiency are at high risk for thrombosis, and heparin prophylaxis may not be sufficiently efficacious. In these patients, exogenous AT may be used in association with heparin. A recombinant human AT (generic name: antithrombin alfa) has been developed. This multi-center study assessed the efficacy and safety of prophylactic intravenous administration of antithrombin alfa to hereditary AT deficient patients in high risk situations, including elective surgery, childbirth, or cesarean section. Antithrombin alfa was administered prior to and during the high risk period for restoration and maintenance of AT activity at 100% of normal. Heparin, low-molecular-weight heparin, and/or vitamin K antagonists were used according to standard of care. The primary efficacy endpoint was the incidence of acute deep vein thrombosis (DVT) from baseline up to day 30 post dosing as assessed by independent central review of duplex ultrasonograms and/or venograms. Safety was assessed based on adverse events (AEs) and laboratory evaluations. Five surgical and nine obstetrical hereditary AT deficiency patients received antithrombin alfa for a mean period of seven days. No clinically overt DVT occurred. Central review of ultrasonograms identified signs of acute DVT in two out of 13 evaluable patients. No antithrombin alfa-related AEs were reported. No patient developed anti-antithrombin alfa antibodies. In conclusion, this study suggests that antithrombin alfa is a safe and effective alternative to human plasma-derived AT for treating hereditary AT deficiency patients at high risk for thromboembolic events.
Asunto(s)
Anticoagulantes/administración & dosificación , Antitrombinas/administración & dosificación , Trastornos de la Coagulación Sanguínea Heredados/tratamiento farmacológico , Trombosis de la Vena/prevención & control , Adulto , Anciano , Anticoagulantes/efectos adversos , Antitrombinas/efectos adversos , Antitrombinas/deficiencia , Antitrombinas/genética , Artroplastia de Reemplazo de Cadera/efectos adversos , Coagulación Sanguínea/efectos de los fármacos , Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de la Coagulación Sanguínea Heredados/complicaciones , Trastornos de la Coagulación Sanguínea Heredados/genética , Cesárea/efectos adversos , Parto Obstétrico/efectos adversos , Esquema de Medicación , Europa (Continente) , Femenino , Heparina/uso terapéutico , Humanos , Infusiones Intravenosas , Masculino , Mamoplastia/efectos adversos , Persona de Mediana Edad , Flebografía , Estudios Prospectivos , Proteínas Recombinantes/administración & dosificación , Factores de Tiempo , Resultado del Tratamiento , Ultrasonografía Doppler Dúplex , Estados Unidos , Trombosis de la Vena/sangre , Trombosis de la Vena/etiología , Trombosis de la Vena/genética , Trombosis de la Vena/patologíaRESUMEN
Activated protein C resistance (APCR), measured using the original assay described by Dahlbäck, is a risk factor for venous thrombosis independent of the factor V Leiden (FVL) mutation. This assay is based on the activated partial thromboplastin time (APTT) after plasma exposure to activated protein C (APC). As this assay was sensitive to numerous interferences, new assays have been developed for FVL screening. The objectives of the study were to investigate the association of second generation assays for APCR with venous thrombosis in FVL non-carriers. One hundred ninety-seven subjects with a history of venous thrombosis and 211 controls were explored using 3 APCR assays, the original APTT-based assay (test A), an APTT-based assay with factor V depleted plasma pre-dilution (test B) and a direct factor X activation-based assay with the same pre-dilution (test C). We found that subjects with results in the lowest quartile of the APTT-based assays are at increased risk, compared to those in the highest quartile (test A Odds Ratio = 6.39; 95% CI 3.23-12.63; test B OR = 2.72; 95% CI 1.50-4.94). There was no significant risk increase associated with test C results. After adjusting for FVIII levels, the ORs of tests A and B were similar (test A OR = 3.22; 95% CI 1.47-7.08; test B OR = 3.10; 95% CI 1.54-6.21). In conclusion, APTT-based assays, but not direct factor X activation-based assays, effectively detect the risk for venous thrombosis independent of FVL. Pre-dilution in factor V depleted plasma is an effective way to directly assess the risk independent of FVIII levels.
Asunto(s)
Resistencia a la Proteína C Activada/metabolismo , Pruebas de Coagulación Sanguínea/métodos , Factor V/genética , Mutación , Trombosis de la Vena/patología , Adulto , Estudios de Casos y Controles , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Trombosis de la Vena/genéticaRESUMEN
INTRODUCTION: Recent ex vivo platelet aggregometry data indicate that clopidogrel 75 mg/day plus acetylsalicylic acid (ASA) 75 mg/day is a more potent antiplatelet regimen than the marketed combination of dipyridamole+ASA. The present study was designed to assess the antithrombotic effect of both dual antiplatelet regimens using a human ex vivo model of arterial thrombosis. MATERIALS AND METHODS: This was a randomized, double-blind, placebo-controlled, crossover study. During two 10-day treatment periods separated by a 14-day washout period, 23 healthy male volunteers received once-daily clopidogrel 75 mg plus acetylsalicylic acid 75 mg, or twice-daily extended-release dipyridamole 200 mg plus acetylsalicylic acid 25 mg. Assessments were made at baseline and on Day 10 of each period. Arterial thrombus formation was induced ex vivo by exposing a collagen-coated surface in a parallel-plate perfusion chamber to native blood for 3 min (arterial wall shear rate 2600 s(-1)). Total platelet and fibrin deposition was determined by immunoenzymatic methods. RESULTS: Compared with baseline values, the mean inhibition of total platelet deposition was 63.9+/-5.9% with clopidogrel plus acetylsalicylic acid, compared with 18.4+/-5.6% for extended-release dipyridamole plus acetylsalicylic acid (67% reduction; 95% CI, 49-79%; p<0.0001). Corresponding figures for fibrin deposition were 64.9+/-4.8% and 18.3+/-9.7%, respectively (58% reduction; 95% CI, 45-67%; p<0.0001). Both treatments were well tolerated. CONCLUSIONS: Clopidogrel plus acetylsalicylic acid showed significantly superior antithrombotic efficacy compared with extended-release dipyridamole plus acetylsalicylic acid in preventing arterial thrombogenesis in humans.
Asunto(s)
Aspirina/administración & dosificación , Dipiridamol/administración & dosificación , Trombosis/prevención & control , Ticlopidina/análogos & derivados , Adolescente , Adulto , Arterias , Clopidogrel , Colágeno , Estudios Cruzados , Preparaciones de Acción Retardada , Quimioterapia Combinada , Fibrina/metabolismo , Humanos , Técnicas para Inmunoenzimas , Masculino , Perfusión , Adhesividad Plaquetaria/efectos de los fármacos , Pruebas de Función Plaquetaria , Trombosis/tratamiento farmacológico , Trombosis/economía , Ticlopidina/administración & dosificaciónAsunto(s)
Anticoagulantes/uso terapéutico , Heparina/uso terapéutico , Tromboembolia/tratamiento farmacológico , Tromboembolia/prevención & control , 4-Hidroxicumarinas , Anticoagulantes/efectos adversos , Heparina/efectos adversos , Humanos , Enfermedad Iatrogénica , Indenos , Vitamina K/antagonistas & inhibidoresRESUMEN
The use of von Willebrand factor [VWF antigen (WF:Ag)] measurement as a marker of endothelial cell activation for monitoring hypertensive pregnancies is limited by the poor definition of reference values. We reassessed these reference values using different assays, and those of the propeptide (VWF:Ag II) and factor VIII coagulant activity (factor VIII:C), in a large population of normal pregnancies, at 3-week intervals of gestational age. Plasminogen activator inhibitors (PAI-1 and PAI-2) were measured in parallel. Blood was collected at single time points between 12 weeks and delivery in 306 women undergoing normal singleton pregnancy. For clinical purposes, the VWF:Ag reference values were assay independent and the influence of ABO blood group on VWF:Ag or factor VIII:c was found to be limited during the third trimester. VWF:Ag II was not influenced by the ABO blood group. The ratio, VWF:Ag/factor VIII:C was close to 1.0 throughout pregnancy. In contrast, VWF:Ag II increased more slowly than VWF:Ag and the ratio of VWF:Ag II to VWF:Ag in plasma decreased from 1.00 to 0.5 at term. PAI-1 and PAI-2 increased with gestational age, but PAI-2 decreased during the last 2 weeks, indicating physiological placental regression at the very end of pregnancy.
Asunto(s)
Factor VIII/análisis , Inhibidor 1 de Activador Plasminogénico/análisis , Inhibidor 2 de Activador Plasminogénico/análisis , Embarazo/sangre , Factor de von Willebrand/análisis , Femenino , Humanos , Valores de ReferenciaRESUMEN
OBJECTIVE: To assess the pharmacokinetics and effects on blood coagulation of dermatan sulfate (DS), a glycosaminoglycan with antithrombotic properties, following intravenous and single and repeated intramuscular administrations. The mean molecular weight of DS is currently 22kD, i.e. 5kD lower than batches used in the early development of the compound. SUBJECTS AND METHODS: Each of 14 male healthy volunteers received DS 300mg as an 8-hour intravenous infusion and as single and repeated (once daily for 9 days) intramuscular injections. Nine of the same subjects were also given DS 100mg and 200mg as single intramuscular doses. Plasma DS concentrations were measured with a specific chromogenic assay. Activated partial thromboplastin time (aPTT) and thrombin clotting time (TCT) responses were also determined. RESULTS: The mean +/- SD volume of distribution and terminal half-life of DS were 6.0 +/- 1.4L and 0.9 +/- 0.2h after intravenous infusion. Maximum plasma concentration (C(max)) and area under the plasma concentration-time curve after single intramuscular injections were dose-proportional. After repeated intramuscular administration, steady state was reached by day 3. On day 9, plasma DS fluctuated between 4.3 +/- 1.5 (C(max)) and 0.9 +/- 0.4 (minimum plasma concentration at steady state) mg/L, time to C(max) was 3.4 +/- 0.8h, terminal half-life was 12.2 +/- 4.1h and the accumulation factor was 2.0 +/- 0.5. Geometric mean bioavailability of intramuscular DS was 54% and 79% after single and repeated 300mg administration, respectively. aPTT and TCT responses were both linearly related to plasma DS concentrations, with TCT showing greater responsivity. CONCLUSION: As compared with earlier DS studies, the present data showed a greater extent of DS absorption after single intramuscular administration and a faster absorption rate after repeated dosing, and provided evidence of dose-response predictability. These findings may explain the improved antithrombotic efficacy of DS observed in a recent clinical trial.
RESUMEN
We have investigated the effect of moderate and strenuous exercise on experimental arterial thrombus formation in men. Thrombogenesis was measured in 15 sedentary healthy male volunteers at rest or immediately after two standardized exercise tests performed for 30 min on a bicycle ergometer. The exercises were performed at a constant load corresponding to either 50 or 70% maximal oxygen uptake. Thrombus formation was induced ex vivo by exposing a collagen-coated coverslip in a parallel plate perfusion chamber to native nonanticoagulated blood for 3 min. The shear rate at the collagen surface was 2,600 s(-1). Platelet and fibrin deposition was quantified by immunoenzymatic methods. The results show that moderate exercise did not affect arterial thrombus formation. In contrast, platelet thrombus formation on collagen was increased on the average by 20% after 30 min at 70% maximal oxygen uptake (P = 0.03). Fibrin deposition on collagen remained unchanged with exercise, regardless of its intensity. Thus, with the use of a clinically relevant human experimental model of thrombosis, the present study suggests that exercise of heavy intensity may increase the risk for arterial thrombogenesis in sedentary young healthy male volunteers.
Asunto(s)
Ejercicio Físico/fisiología , Estilo de Vida , Resistencia Física/fisiología , Trombosis/etiología , Adulto , Arterias , Coagulación Sanguínea/fisiología , Fenómenos Fisiológicos Sanguíneos , Humanos , Masculino , Agregación Plaquetaria/fisiologíaRESUMEN
Tissue factor (TF) and its specific inhibitor TF pathway inhibitor (TFPI) are produced by vascular smooth muscle cells (SMCs) in vitro and are increased in vivo in atherosclerotic compared to normal vessels. Besides local regulation of the hemostatic balance, this may be related to non-hemostatic TF/protease dependent functions such as SMC proliferation, adhesion and migration. The aim of the study was to compare the expression of both proteins between the contractile (normal adult) and synthetic (neo-intimal) SMC phenotypes. Primary cultures of SMCs isolated from rat thoracic aorta before and 10 days after balloon injury displayed stable characteristics of the contractile and synthetic phenotype, respectively. Synthetic SMCs expressed more TF mRNA than contractile SMCs, but released excess TF in the conditioned medium, so that the cell-associated TF activity measured by a factor Xa generating assay remained similar in the two subtypes. Accordingly, cell surface thrombogenicity measured under blood flow conditions was also similar. The production and release of functional TFPI was enhanced by a factor 3 to 6 (p < 0.01) in synthetic SMCs. A difference in the quantitative expression of TF and TFPI is a new distinctive feature of SMC phenotypes. Matrix-associated TFPI derived from synthetic SMCs may serve as an anchorage for their migration and regulate protease-activated processes during neo-intima formation.
Asunto(s)
Lipoproteínas/biosíntesis , Músculo Liso Vascular/citología , Tromboplastina/biosíntesis , Animales , Aorta/lesiones , Técnicas de Cultivo de Célula , Modelos Animales de Enfermedad , Fibrina/metabolismo , Lipoproteínas/análisis , Masculino , Músculo Liso Vascular/metabolismo , Perfusión , Fenotipo , Ratas , Ratas Wistar , Tromboplastina/análisis , Trombosis/etiología , Regulación hacia ArribaRESUMEN
We report the pharmacodynamic properties of tinzaparin (175 U/kg antifactor Xa) given as a single daily administration for 5 consecutive days to 14 healthy volunteers as a known safe, effective treatment of deep vein thrombosis and pulmonary embolism. The Cmax for antifactor Xa (0.87 +/- 0.15 U/ml) was associated with a 2.4 +/- 0.5-fold prolongation of the activated partial thromboplastin time (APTT) and a high antithrombin activity (0.38 +/- 0.1 U/ml). The Cmax value of antifactor Xa was 1.5- and twofold lower than those generated by similar doses of nadroparin and enoxaparin respectively. The clearance of antifactor Xa activity (1.29 +/- 0.2 l/h) was 1.5- and twofold greater than those reported for nadroparin and enoxaparin respectively. These results indicated that the antithrombotic and prohaemorrhagic effects of a low molecular weight heparin were independent from the absolute levels of antifactor Xa activities and from the prolongation of the APTT.