RESUMEN
The association between hypercoagulability and use of drospirenone (DRSP) and ethinylestradiol (EE) containing combined oral contraceptives (COCs) is an important clinical concern. We have previously reported that the two formulations of DRSP combined with EE (namely, DRSP/20EE and DRSP/30EE) bring about a prothrombotic state in hemostatic traits of female users. We report here the serum metabolomic changes in the same study cohort in relation to the attendant prothrombotic state induced by COC use, thus offering new insights on the underlying biochemical mechanisms contributing to the altered coagulatory profile with COC use. A total of 78 healthy women participated in this study and were grouped as follows: control group not using oral contraceptives (n = 25), DRSP/20EE group (n = 27), and DRSP/30EE group (n = 26). Untargeted metabolomics revealed changes in amino acid concentrations, particularly a decrease in glycine and an increase in both cysteine and lanthionine in the serum, accompanied by variations in oxidative stress markers in the COC users compared with the controls. Of importance, this study is the first to link specific amino acid variations, serum metabolites, and the oxidative metabolic profile with DRSP/EE use. These molecular changes could be linked to specific biophysical coagulatory alterations observed in the same individuals. These new findings lend evidence on the metabolomic substrates of the prothrombotic state associated with COC use in women and informs future personalized/precision medicine research. Moreover, we underscore the importance of an interdisciplinary approach to evaluate venous thrombotic risk associated with COC use.
Asunto(s)
Androstenos/efectos adversos , Biomarcadores/sangre , Coagulación Sanguínea/efectos de los fármacos , Anticonceptivos Orales Combinados/efectos adversos , Etinilestradiol/efectos adversos , Metaboloma , Adolescente , Adulto , Androstenos/administración & dosificación , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Plaquetas/ultraestructura , Anticonceptivos Orales Combinados/administración & dosificación , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Eritrocitos/ultraestructura , Etinilestradiol/administración & dosificación , Femenino , Cromatografía de Gases y Espectrometría de Masas , Humanos , Metabolómica/métodos , Activación Plaquetaria/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Trombosis/sangre , Trombosis/diagnóstico , Trombosis/etiología , Adulto JovenRESUMEN
Venous thrombosis is associated with combined oral contraceptive (COC) use. We investigated the impact of two ethinyl estradiol (EE) and drospirenone (DRSP) containing COCs (3 mg DRSP/20 µg EE and 3 µg DRSP/30 µg EE) on the viscoelasticity of whole blood clots along with the biophysical and biochemical characteristics of erythrocytes. Thromboelastography (TEG) analysis showed a tendency toward a hypercoagulable state in the COCs groups that was more pronounced with higher EE concentrations. Light microscopy and scanning electron microscopy (SEM) showed rouleaux formation of erythrocytes and alterations to the erythrocyte shape for both COC groups, which was attributed to membrane damage. SEM analysis showed spontaneous activation of fibrin and platelets in the COC groups, along with interactions between erythrocytes and platelets and/or fibrin. Confocal microscopy confirmed compromised membrane integrity in the COC groups compared to controls. Global thrombosis test analysis showed increased platelet activation and low thrombolysis in both COC groups when compared to controls. In conclusion, DRSP/EE formulations impact erythrocytes' biophysical and biochemical properties to cause a shift in hemostasis to a prothrombotic state. Although these effects are mostly subclinical the long-term effects and risks involved with the use of these hormones should be considered carefully for each individual.
Asunto(s)
Androstenos/farmacología , Anticonceptivos Orales Combinados/farmacología , Módulo de Elasticidad/efectos de los fármacos , Agregación Eritrocitaria/efectos de los fármacos , Eritrocitos/efectos de los fármacos , Etinilestradiol/farmacología , Activación Plaquetaria/efectos de los fármacos , Trombosis de la Vena/inducido químicamente , Viscosidad/efectos de los fármacos , Plaquetas/efectos de los fármacos , Membrana Celular/fisiología , Forma de la Célula/efectos de los fármacos , Eritrocitos/química , Femenino , Humanos , Microscopía Electrónica de Rastreo , TromboelastografíaRESUMEN
Combined oral contraceptive (COC) use is a risk factor for venous thrombosis (VT) and related to the specific type of progestin used. VT is accompanied by inflammation and pathophysiological clot formation, that includes aberrant erythrocytes and fibrin(ogen) interactions. In this paper, we aim to determine the influence of progesterone and different synthetic progestins found in COCs on the viscoelasticity of whole blood clots, as well as erythrocyte morphology and membrane ultrastructure, in an in vitro laboratory study. Thromboelastography (TEG), light microscopy, and scanning electron microscopy were our chosen methods. Our results point out that progestins influence the rate of whole blood clot formation. Alterations to erythrocyte morphology and membrane ultrastructure suggest the presence of eryptosis. We also note increased rouleaux formation, erythrocyte aggregation, and spontaneous fibrin formation in whole blood which may explain the increased risk of VT associated with COC use. Although not all COC users will experience a thrombotic event, individuals with a thrombotic predisposition, due to inflammatory or hematological illness, should be closely monitored to prevent pathological thrombosis.
Asunto(s)
Coagulación Sanguínea/efectos de los fármacos , Eritrocitos/efectos de los fármacos , Eritrocitos/ultraestructura , Congéneres de la Progesterona/efectos adversos , Progesterona/efectos adversos , Adolescente , Adulto , Pruebas de Coagulación Sanguínea , Anticonceptivos Orales Combinados/efectos adversos , Agregación Eritrocitaria , Congéneres del Estradiol/farmacología , Estrógenos/farmacología , Hormonas/sangre , Humanos , Hierro/sangre , Masculino , Microscopía , Microscopía Electrónica de Rastreo , Progestinas/efectos adversos , Factores de Riesgo , Tromboelastografía , Trombosis/inducido químicamente , Trombosis/prevención & control , Trombosis de la Vena , Adulto JovenRESUMEN
As erythrocyte and estrogens interact so closely and erythrocytes can indicate the healthiness of an individual, it is essential to investigate the effects of natural estrogens as well as synthetic estrogens on these cells. Whole blood samples were used for thromboelastography (TEG), light microscopy (LM), and scanning electron microscopy (SEM) investigation. Viscoelastic investigation with TEG revealed that estrogens affected the rate of clot formation without any significant effect on the strength or stability of the clot. Axial ratio analysis with LM showed a statistically significant increase in number of erythrocytes with decreased roundness. Morphological analysis with SEM confirmed the change in erythrocyte shape and revealed both ultrastructural membrane changes and erythrocyte interactions. As erythrocyte shape and membrane flexibility correlates to physiological functioning of these cells in circulation, these changes, indicative of possible eryptosis brought on by estrogens, when experienced by individuals with an underlying inflammatory or hematological illness, could impair erythrocyte functioning and even result in obstructions in circulation. In conclusion, we suggest that whole blood analysis with viscoelastic and morphological techniques could be used as assessment of the hematological healthiness of individuals using estrogens.
Asunto(s)
Coagulación Sanguínea/efectos de los fármacos , Eritrocitos/efectos de los fármacos , Eritrocitos/ultraestructura , Congéneres del Estradiol/farmacología , Estrógenos/farmacología , Trombosis/prevención & control , Adolescente , Adulto , Viscosidad Sanguínea , Elasticidad , Eriptosis , Humanos , Masculino , Microscopía Electrónica de Rastreo/métodos , Tromboelastografía/métodos , Adulto JovenRESUMEN
BACKGROUND: The effect of endogenous hormone concentrations, specifically 17ß-estradiol and progesterone, on fibrin network formation has not been established. OBJECTIVES: It is essential to understand natural hormone mechanisms since these hormones are still present in circulation while hormonal contraceptives, which are associated with increased risk of venous thromboembolism, are used. METHODS: Due to the fact that these hormones are known to increase hypercoagulability and the prothrombotic state scanning electron microscopy (SEM), atomic force microscopy (AFM), thromboelastography (TEG) and turbidimetry were employed to investigate the morphology, surface roughness, viscoelastic properties and formation and lysis of fibrin. RESULTS: 17ß-estradiol and progesterone showed hypercoagulable viscoelastic properties and decreased the diameter and surface roughness of fibrin while increasing dense matted deposit occurrence. Our results suggest that the additional burden of hormonal load, together with the presence of endogenous estrogen and progesterone, may result in a prothrombotic and hypercoagulable state in females with an inflammatory predisposition. CONCLUSION: Our results are of clinical importance when considering hormones as either pathological agent or therapeutic intervention as will be assessed in future investigation.