RESUMEN
Inherited blood disorders comprise a large spectrum of diseases due to germline mutations in genes with key function in the hematopoietic system; they include immunodeficiencies, anemia or metabolic diseases. For most of them the only curative treatment is bone marrow transplantation, a procedure associated to severe complications; other therapies include red blood cell and platelet transfusions, which are dependent on donor availability. An alternative option is gene therapy, in which the wild-type form of the mutated gene is delivered into autologous hematopoietic stem cells using viral vectors. A more recent therapeutic perspective is gene correction through CRISPR/Cas9-mediated gene editing, that overcomes safety concerns due to insertional mutagenesis and allows correction of base substitutions in large size genes difficult to incorporate into vectors. However, applying this technique to genomic disorders caused by large gene deletions is challenging. Chromosomal transplantation has been proposed as a solution, using a universal source of wild-type chromosomes as donor, and induced pluripotent stem cells (iPSCs) as acceptor. One of the obstacles to be addressed for translating PSC research into clinical practice is the still unsatisfactory differentiation into transplantable hematopoietic stem or mature cells. We provide an overview of the recent progresses in this field and discuss challenges and potential of iPSC-based therapies for the treatment of inherited blood disorders.
Asunto(s)
Trastornos de la Coagulación Sanguínea Heredados/sangre , Edición Génica/métodos , Terapia Genética/métodos , Células Madre Hematopoyéticas/metabolismo , Células Madre Pluripotentes/metabolismo , Diferenciación Celular , HumanosRESUMEN
Osteonecrosis of the femoral head (ONFH) is a debilitating disease with major social and economic impacts. It frequently affects relatively young adults and has a predilection for rapid progression to femoral head collapse and end-stage hip arthritis. If not diagnosed and treated properly in the early stages, ONFH has devastating consequences and leads to mandatory total hip arthroplasty. The pathophysiology of non-traumatic ONFH is very complex and not fully understood. While multiple risk factors have been associated with secondary ONFH, there are still many cases in which a clear etiology cannot be established. Recognition of the prothrombotic state as part of the etiopathogeny of primary ONFH provides an opportunity for early medical intervention, with implications for both prophylaxis and therapy aimed at slowing or stopping the progression of the disease. Hereditary thrombophilia and hypofibrinolysis are associated with thrombotic occlusion of bone vessels. Anticoagulant treatment can change the natural course of the disease and improve patients' quality of life. The present work focused on highlighting the association between hereditary thrombophilia/hypofibrinolysis states and ONFH, emphasizing the importance of identifying this condition. We have also provided strong arguments to support the efficiency and safety of anticoagulant treatment in the early stages of the disease, encouraging etiological diagnosis and prompt therapeutic intervention. In the era of direct oral anticoagulants, new therapeutic options have become available, enabling better long-term compliance.
Asunto(s)
Susceptibilidad a Enfermedades , Necrosis de la Cabeza Femoral/etiología , Trombofilia/sangre , Trombofilia/complicaciones , Animales , Biomarcadores , Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de la Coagulación Sanguínea Heredados/complicaciones , Trastornos de la Coagulación Sanguínea Heredados/etiología , Terapia Combinada , Manejo de la Enfermedad , Necrosis de la Cabeza Femoral/terapia , Predisposición Genética a la Enfermedad , Humanos , Trombofilia/etiología , Resultado del TratamientoAsunto(s)
Trastornos de la Coagulación Sanguínea Heredados/sangre , COVID-19/sangre , SARS-CoV-2 , Trombosis/prevención & control , Adolescente , Adulto , Anciano , Trastornos de la Coagulación Sanguínea Heredados/complicaciones , Trastornos de la Coagulación Sanguínea Heredados/tratamiento farmacológico , Factores de Coagulación Sanguínea/uso terapéutico , COVID-19/complicaciones , Niño , Preescolar , Femenino , Humanos , Lactante , Irán/epidemiología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Trombosis/epidemiología , Trombosis/etiología , Adulto JovenRESUMEN
Tissue factor (TF) is the primary initiator of blood coagulation in vivo and the only blood coagulation factor for which a human genetic defect has not been described. As there are no routine clinical assays that capture the contribution of endogenous TF to coagulation initiation, the extent to which reduced TF activity contributes to unexplained bleeding is unknown. Using whole genome sequencing, we identified a heterozygous frameshift variant (p.Ser117HisfsTer10) in F3, the gene encoding TF, causing premature termination of TF (TFshort) in a woman with unexplained bleeding. Routine hematological laboratory evaluation of the proposita was normal. CRISPR-edited human induced pluripotent stem cells recapitulating the variant were differentiated into vascular smooth muscle and endothelial cells that demonstrated haploinsufficiency of TF. The variant F3 transcript is eliminated by nonsense-mediated decay. Neither overexpression nor addition of exogenous recombinant TFshort inhibited factor Xa or thrombin generation, excluding a dominant-negative mechanism. F3+/- mice provide an animal model of TF haploinsufficiency and exhibited prolonged bleeding times, impaired thrombus formation, and reduced survival following major injury. Heterozygous TF deficiency is present in at least 1 in 25,000 individuals and could limit coagulation initiation in undiagnosed individuals with abnormal bleeding but a normal routine laboratory evaluation.
Asunto(s)
Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de la Coagulación Sanguínea Heredados/genética , Mutación del Sistema de Lectura , Tromboplastina/deficiencia , Tromboplastina/genética , Animales , Secuencia de Bases , Codón sin Sentido , Modelos Animales de Enfermedad , Femenino , Edición Génica , Haploinsuficiencia , Heterocigoto , Humanos , Células Madre Pluripotentes Inducidas , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Terminación de la Cadena Péptídica Traduccional , FenotipoRESUMEN
Inherited platelet function disorders are rare hemorrhagic diseases. The gold standard for their exploration is optical aggregometry; however, investigations by flow cytometry (FCM) are being increasingly used. In this review, the physiology of platelets is first recalled, setting the stage for the compartments of platelets that can be apprehended by specific and appropriate labeling. As this requires some pre-analytical precautions and specific analytical settings, a second part focuses on these characteristic aspects, based on literature and on the authors' experience in the field, for qualitative or quantitative explorations. Membrane labeling with antibodies to CD42a or CD41, respectively, useful to assess the genetic-related defects of Glanzmann thrombocytopenia and Bernard Soulier syndrome are then described. Platelet degranulation disorders are detailed in the next section, as they can be explored, upon platelet activation, by measuring the expression of surface P-Selectin (CD62P) or CD63. Mepacrin uptake and release after activation is another test allowing to explore the function of dense granules. Finally, the flip-flop anomaly related to Scott syndrome is depicted. Tables summarizing possible FCM assays, and characteristic histograms are provided as reference for flow laboratories interested in developing platelet exploration.
Asunto(s)
Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de las Plaquetas Sanguíneas/sangre , Citometría de Flujo , Inmunofenotipificación , Trastornos de la Coagulación Sanguínea Heredados/tratamiento farmacológico , Trastornos de la Coagulación Sanguínea Heredados/genética , Trastornos de la Coagulación Sanguínea Heredados/inmunología , Trastornos de las Plaquetas Sanguíneas/tratamiento farmacológico , Trastornos de las Plaquetas Sanguíneas/inmunología , Trastornos de las Plaquetas Sanguíneas/patología , Plaquetas/efectos de los fármacos , Plaquetas/inmunología , Plaquetas/patología , Humanos , Activación Plaquetaria/genética , Activación Plaquetaria/inmunología , Quinacrina/uso terapéuticoAsunto(s)
Síndrome Coronario Agudo/genética , Trastornos de la Coagulación Sanguínea Heredados/genética , Coagulación Sanguínea/genética , Variación Genética , Infarto del Miocardio/genética , Síndrome Coronario Agudo/sangre , Síndrome Coronario Agudo/epidemiología , Síndrome Coronario Agudo/prevención & control , Adolescente , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de la Coagulación Sanguínea Heredados/tratamiento farmacológico , Trastornos de la Coagulación Sanguínea Heredados/epidemiología , Niño , Preescolar , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/sangre , Infarto del Miocardio/epidemiología , Infarto del Miocardio/prevención & control , Fenotipo , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Adulto JovenAsunto(s)
Betacoronavirus , Trastornos de la Coagulación Sanguínea Heredados/sangre , Infecciones por Coronavirus/sangre , Pandemias , Neumonía Viral/sangre , Trombofilia/sangre , Adulto , Trastornos de la Coagulación Sanguínea Heredados/complicaciones , COVID-19 , Infecciones por Coronavirus/complicaciones , Resistencia a la Enfermedad , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Humanos , Masculino , Persona de Mediana Edad , Neumonía Viral/complicaciones , Embolia Pulmonar/etiología , Factores de Riesgo , SARS-CoV-2 , Trombocitopenia/etiología , Trombofilia/etiología , Trombosis de la Vena/etiologíaAsunto(s)
Trastornos de la Coagulación Sanguínea Heredados , Hemorragia , Caolín/química , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de la Coagulación Sanguínea Heredados/complicaciones , Trastornos de la Coagulación Sanguínea Heredados/diagnóstico , Niño , Preescolar , Femenino , Hemorragia/sangre , Hemorragia/diagnóstico , Hemorragia/etiología , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Tiempo de Tromboplastina Parcial , Factores de RiesgoRESUMEN
INTRODUCTION: Inherited factor VII (FVII) deficiency is the most common of the rare bleeding disorders and shows a heterogenous distribution of bleeding phenotypes independent of factor activity level. The bleeding score (BS) evaluates the phenotype of patients with rare bleeding disorders. Thromboelastography (TEG) and thrombin generation assays (TGAs) are 2 methods to evaluate global hemostasis, and controversially both tests are useful for identifying different bleeding tendency phenotypes. The purpose of this study was to investigate the use of the BS and global assays (TEG and TGAs) to predict the bleeding phenotype of inherited FVII deficiency. MATERIALS AND METHODS: A total of 27 patients with FVII deficiency were evaluated with the BS and global hemostasis assays. RESULTS: The BS was compatible with disease severity according to the FVII activity level (P<0.05) but the BS and bleeding grade of patients did not show a statistically significant correlation with factor activity level (P>0.05). No significant correlation was observed between the factor activity level and any TEG parameter (P>0.05). The factor activity level was negatively correlated with the lag time of the TGA on the contrary positively correlated with the peak thrombin time of the TGA (P<0.05). CONCLUSIONS: The global assays do not successfully predict the bleeding phenotype. The BS is a more suitable tool than conventional and global assays for predicting the bleeding phenotype.
Asunto(s)
Trastornos de la Coagulación Sanguínea Heredados/diagnóstico , Pruebas de Coagulación Sanguínea/métodos , Deficiencia del Factor VII/diagnóstico , Índice de Severidad de la Enfermedad , Tromboelastografía/métodos , Trombina/análisis , Adolescente , Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de la Coagulación Sanguínea Heredados/metabolismo , Estudios de Casos y Controles , Niño , Preescolar , Deficiencia del Factor VII/sangre , Deficiencia del Factor VII/metabolismo , Femenino , Estudios de Seguimiento , Hemostasis , Humanos , Masculino , Fenotipo , Valor Predictivo de las PruebasRESUMEN
Background Inherited thrombophilias are well-established predisposing factors for venous thromboembolism, but their role in arterial thrombosis, such as arterial ischemic stroke, remains uncertain. We aimed to evaluate the association between inherited thrombophilia (factor V Leiden, prothrombin G20210A mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency) and risk of arterial ischemic stroke in adults. Methods and Results We searched PubMed, EMBASE, and Cochrane Library Databases from inception to December 31, 2018. We included case-control or cohort studies of adults reporting the prevalence of inherited thrombophilias in those with arterial ischemic stroke and subjects without arterial ischemic stroke. Two reviewers (T.C., E.D.) independently searched the literature and extracted data. Pooled odds ratios (ORs) and 95% CIs were calculated using random-effects model. We identified 68 eligible studies, which collectively enrolled 11 916 stroke patients and 96 057 controls. The number of studies reporting factor V Leiden, prothrombin G20210A mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency were 56, 45, 15, 17, and 12, respectively. Compared with controls, patients with arterial ischemic stroke were significantly more likely to have the following inherited thrombophilias: factor V Leiden (OR, 1.25; 95% CI, 1.08-1.44; I2=0%), prothrombin G20210A mutation (OR, 1.48; 95% CI, 1.22-1.80; I2=0%), protein C deficiency (OR, 2.13; 95% CI, 1.16-3.90; I2=0%), and protein S deficiency (OR, 2.26; 95% CI, 1.34-3.80; I2=8.8%). Statistical significance was not reached for antithrombin deficiency (OR, 1.25; 95% CI, 0.58-2.67; I2=8.8%). Conclusions Inherited thrombophilias (factor V Leiden, prothrombin G20210A mutation, protein C deficiency, and protein S deficiency) are associated with an increased risk of arterial ischemic stroke in adults. The implications of these findings with respect to clinical management of patients with ischemic stroke require further investigation.
Asunto(s)
Trastornos de la Coagulación Sanguínea Heredados/genética , Coagulación Sanguínea/genética , Isquemia Encefálica/epidemiología , Accidente Cerebrovascular/epidemiología , Trombofilia/genética , Adulto , Anciano , Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de la Coagulación Sanguínea Heredados/diagnóstico , Trastornos de la Coagulación Sanguínea Heredados/epidemiología , Isquemia Encefálica/sangre , Isquemia Encefálica/diagnóstico , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Pronóstico , Medición de Riesgo , Factores de Riesgo , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/diagnóstico , Trombofilia/sangre , Trombofilia/diagnóstico , Trombofilia/epidemiologíaAsunto(s)
Trastornos de la Coagulación Sanguínea Heredados , Plaquetas/metabolismo , Fibrinólisis/genética , Eliminación de Gen , Hemorragia , alfa 2-Antiplasmina/deficiencia , Adolescente , Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de la Coagulación Sanguínea Heredados/genética , Hemorragia/sangre , Hemorragia/genética , Humanos , Masculino , TromboelastografíaRESUMEN
BACKGROUND: Congenital disorders of glycosylation are rare inherited diseases affecting many different proteins. The lack of glycosylation notably affects the hemostatic system and leads to deficiencies of both procoagulant and anticoagulant factors. OBJECTIVE: To assess the hemostatic balance in patients with multiple coagulation disorders by using a thrombin generation assay. METHOD: We performed conventional coagulation assays and a thrombin generation assay on samples from patients with congenital disorder of glycosylation. The thrombin generation assay was performed before and after activation of the protein C system by the addition of soluble thrombomodulin. RESULTS: A total of 35 patients were included: 71% and 57% had low antithrombin and factor XI levels, respectively. Protein C and protein S levels were abnormally low in 29% and 26% of the patients, respectively, whereas only 11% displayed low factor IX levels. Under baseline conditions, the thrombin generation assay revealed a significantly higher endogenous thrombin potential and thrombin peak in patients, relative to controls. After spiking with thrombomodulin, we observed impaired involvement of the protein C system. Hence, 54% of patients displayed a hypercoagulant phenotype in vitro. All the patients with a history of stroke-like episodes or thrombosis displayed this hypercoagulant phenotype. CONCLUSION: A thrombin generation assay revealed a hypercoagulant in vitro phenotype under baseline condition; this was accentuated by impaired involvement of the protein C system. This procoagulant phenotype may thus reflect the risk of severe vascular complications. Further research will have to determine whether the thrombin generation assay is predictive of vascular events.
Asunto(s)
Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de las Proteínas de Coagulación/sangre , Trastornos Congénitos de Glicosilación/sangre , Trombina/metabolismo , Adolescente , Coagulación Sanguínea/genética , Trastornos de la Coagulación Sanguínea Heredados/diagnóstico , Trastornos de la Coagulación Sanguínea Heredados/genética , Niño , Preescolar , Trastornos de las Proteínas de Coagulación/diagnóstico , Trastornos de las Proteínas de Coagulación/genética , Trastornos Congénitos de Glicosilación/diagnóstico , Trastornos Congénitos de Glicosilación/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Paris , Fenotipo , Estudios Retrospectivos , EspañaAsunto(s)
Antitrombinas/administración & dosificación , Trastornos de la Coagulación Sanguínea Heredados , Resistencia a Medicamentos/genética , Trastornos Hemorrágicos , Protrombina , Trombosis de la Vena , Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de la Coagulación Sanguínea Heredados/tratamiento farmacológico , Trastornos de la Coagulación Sanguínea Heredados/genética , Trastornos de la Coagulación Sanguínea Heredados/patología , Femenino , Humanos , Masculino , Mutación , Protrombina/genética , Protrombina/metabolismoRESUMEN
Essentials A carboxylase mutation that impairs splicing to delete exon 2 sequences was previously reported. We found that the mutant was inactive for vitamin K-dependent (VKD) protein carboxylation. An incomplete splicing defect likely accounts for VKD clotting activity observed in the patient. The results indicate the importance of proper carboxylase embedment in the membrane for function. BACKGROUND: Mutations in the γ-glutamyl carboxylase (GGCX), which is required for vitamin K-dependent (VKD) protein activation, can result in vitamin K clotting factor deficiency (VKCFD1). A recent report described a VKCFD1 patient with a homozygous carboxylase mutation that altered splicing and deleted exon 2 (Δ2GGCX). Only Δ2GGCX RNA was observed in the patient. OBJECTIVES: Loss of exon 2 results in the deletion of carboxylase sequences thought to be important for membrane topology and consequent function. Carboxylase activity is required for life, and we therefore tested whether the Δ2GGCX mutant is active. METHODS: HEK 293 cells were edited by the use of CRISPR-Cas9 to eliminate endogenous carboxylase. Recombinant wild-type GGCX and recombinant Δ2GGCX were then expressed and tested for carboxylation of the VKD protein factor IX. A second approach was used to monitor carboxylation biochemically, using recombinant carboxylases expressed in insect cells that lack endogenous carboxylase. RESULTS AND CONCLUSIONS: Δ2GGCX activity was undetectable in both assays, which is strikingly different from the low levels of carboxylase activity observed with other VKCFD1 mutants. The similarity in clotting function between patients with Δ2GGCX and these mutations must therefore arise from a novel mechanism. Low levels of properly spliced carboxylase RNA that produce full-length protein would not have been observed in the previous study. The results suggest that the splicing defect is incomplete. Δ2GGCX RNA has been detected in normal human liver, and has been designated carboxylase isoform 2; however, Δ2GGCX protein was not observed in normal human liver. The lack of activity and protein expression suggest that isoform 2 is not physiologically relevant to normal VKD protein carboxylation.
Asunto(s)
Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de la Coagulación Sanguínea Heredados/genética , Coagulación Sanguínea/genética , Ligasas de Carbono-Carbono/genética , Ligasas de Carbono-Carbono/metabolismo , Exones , Mutación , Empalme del ARN , Trastornos de la Coagulación Sanguínea Heredados/diagnóstico , Sistemas CRISPR-Cas , Factor IX/metabolismo , Edición Génica , Predisposición Genética a la Enfermedad , Células HEK293 , Homocigoto , Humanos , Fenotipo , Procesamiento Proteico-PostraduccionalRESUMEN
The best-known inherited mild bleeding disorders (MBDs), i.e. type 1 von Willebrand disease (VWD), platelet function disorders (PFDs), and mild to moderate clotting factor deficiencies, are characterized clinically by mucocutaneous bleeding, and, although they are highly prevalent, still pose difficult diagnostic problems. These include establishing the pathological nature of bleeding, and the uncertainties surrounding the clinical relevance of laboratory results. Furthermore, the high frequency of bleeding symptoms in the normal population and the subjective appraisal of symptoms by patients or parents makes elucidating the pathological nature of bleeding difficult. Standardized bleeding assessment tools and semiquantitative bleeding scores (BSs) help to discriminate normal from abnormal bleeding. However, as most MBDs have similar bleeding patterns, for example, bleeding sites, frequency, and severity, BSs are of little help for diagnosing specific diseases. Global tests of primary hemostasis (bleeding time; PFA-100/200) lack sensitivity and, like BSs, are not disease-specific. Problems with the diagnosis of type 1 VWD and PFD include assay standardization, uncertain definition of von Willebrand factor cut-off levels, and the lack of universal diagnostic criteria for PFD. Regarding clotting factor deficiencies, the bleeding thresholds of some coagulation factors, such as factor VII and FXI, are highly variable, and may lead to misinterpretation of the clinical relevance of mild to moderate deficiencies. Remarkably, a large proportion of MBDs remain undiagnosed even after comprehensive and repeated laboratory testing. These are tentatively considered to represent bleeding of undefined cause, with clinical features indistinguishable from those of classical MBD; the pathogenesis of this is probably multifactorial, and unveiling these mechanisms should constitute a fertile source of translational research.
Asunto(s)
Trastornos de la Coagulación Sanguínea Heredados/diagnóstico , Pruebas de Coagulación Sanguínea , Coagulación Sanguínea/genética , Trastornos de las Plaquetas Sanguíneas/diagnóstico , Pruebas de Función Plaquetaria , Animales , Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de la Coagulación Sanguínea Heredados/genética , Trastornos de las Plaquetas Sanguíneas/sangre , Trastornos de las Plaquetas Sanguíneas/genética , Diagnóstico Diferencial , Predisposición Genética a la Enfermedad , Humanos , Fenotipo , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Enfermedad de von Willebrand Tipo 1/sangre , Enfermedad de von Willebrand Tipo 1/diagnóstico , Enfermedad de von Willebrand Tipo 1/genéticaRESUMEN
BACKGROUND: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF. METHODS: We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events. RESULTS: We identified 13 novel genome-wide significant ( P≤2.5×10-8) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk. CONCLUSIONS: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.
Asunto(s)
Arteriopatías Oclusivas/genética , Trastornos de la Coagulación Sanguínea Heredados/genética , Coagulación Sanguínea/genética , Factor VIII/análisis , Sitios Genéticos , Trombosis de la Vena/genética , Factor de von Willebrand/análisis , Arteriopatías Oclusivas/sangre , Arteriopatías Oclusivas/etnología , Biomarcadores/sangre , Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de la Coagulación Sanguínea Heredados/etnología , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Análisis de la Aleatorización Mendeliana , Fenotipo , Proteína Ribosomal L3 , Factores de Riesgo , Trombosis de la Vena/sangre , Trombosis de la Vena/etnologíaRESUMEN
OBJECTIVES: The relationship between chronic kidney disease and cardiovascular disease is complex and bidirectional. This relationship may be partially linked to thrombophilic genetic anomalies that may predispose to the progression of both diseases. MATERIALS AND METHODS: We analyzed blood samples from 102 Lebanese patients with end-stage renal disease and undergoing hemodialysis and 20 randomly selected healthy volunteers for frequencies of 12 cardiovascular disease gene mutations and traditional risk factors. The frequencies of these mutations were calculated and compared in both groups. We stratified patients by quartiles according to their mean score of genetic mutations and traditional risk factors, as well as their mean age at dialysis initiation. Correlation analyses were performed on the various patient groups. RESULTS: We observed a high frequency of mutations in patients on dialysis. Homozygous mutations (> 10% of patients) were observed in the PAI-1 (11%), MTHFR A1298C sequence variant (12.7%), and ACE genes (12%); in addition, the FXIII V34L and PAI-1 4G/5G genotypes were significantly associated with early dialysis initiation (P < .001 and P = .004, respectively). We observed a strong linear relationship between the different scores and age at dialysis initiation, with older patients exhibiting the highest genetic, traditional, and total scores versus those shown in the youngest patients (R2 = 0.72 and P < .001; R2 = 0.98 and P < .001; and R2 =0.96 and P < .001, respectively). CONCLUSIONS: Our results revealed a polygenic thrombophilic profile in our population of Lebanese patients with end-stage renal disease. This profile showed a strong association between early dialysis initiation and specific homozygous cardiovascular disease gene mutations. The cumulative load of these genetic and traditional risk factors may be partly responsible for the increased risk of cardiovascular disease and risk of progression to end-stage renal disease in patients with chronic kidney disease.
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Trastornos de la Coagulación Sanguínea Heredados/genética , Coagulación Sanguínea/genética , Fallo Renal Crónico/terapia , Mutación , Polimorfismo de Nucleótido Simple , Diálisis Renal , Trombofilia/genética , Adulto , Factores de Edad , Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de la Coagulación Sanguínea Heredados/diagnóstico , Estudios de Casos y Controles , Estudios Transversales , Femenino , Predisposición Genética a la Enfermedad , Homocigoto , Humanos , Fallo Renal Crónico/diagnóstico , Líbano , Masculino , Persona de Mediana Edad , Tasa de Mutación , Fenotipo , Factores de Riesgo , Trombofilia/sangre , Trombofilia/diagnóstico , Factores de TiempoRESUMEN
Patient registry is a powerful tool for planning health care and setting groundwork for research. This survey reports a detailed registry of inherited bleeding disorders (IBD) and their management at a not-for-profit organization in a developing country to form the basis for planning development and research. We reviewed medical records of patients with IBD from 8 hemophilia treatment centers of Fatimid Foundation located in various cities. Information collected included sociodemographic data, diagnostic tests, severity of hemophilia A and B, number of bleeding episodes per year, site and frequency of hemarthrosis, and seropositivity for viral diseases. We analyzed 1497 patients from November 1, 2015, to April 30, 2016. There were 1296 (87%) males and 201 (13%) females with a mean age of 24.5 (11) years (range, 6 months to 65 years). Hemophilia A constituted the bulk of IBD (848, 57%) followed by von Willebrand disease (172, 11%), hemophilia B (144, 10%), platelet function defect (106, 7%), and rare bleeding disorders (70, 5%). Mucocutaneous bleeding (1144, 76%) and hemarthrosis (1035 patients, 69%) were the main complications. There were 1026 (69%) patients who received only blood components for treatment of any bleeding episode while the remaining 464 (31%) were on combination therapy (blood components and factor concentrate). Seroreactivity for hepatitis C was frequent (28%), while hepatitis B (1%) and human immunodeficiency virus (0.01%) were less commonly seen. This study was an important step toward a patient registry in a hemophilia treatment center in Pakistan. Hemophilia A is the most common bleeding disorder and hepatitis C is the most frequent treatment-related complication.
Asunto(s)
Trastornos de la Coagulación Sanguínea Heredados , Hemartrosis , Hemorragia , Hepatitis C , Adolescente , Adulto , Anciano , Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de la Coagulación Sanguínea Heredados/complicaciones , Trastornos de la Coagulación Sanguínea Heredados/epidemiología , Trastornos de la Coagulación Sanguínea Heredados/terapia , Niño , Preescolar , Estudios Transversales , Femenino , Hemartrosis/sangre , Hemartrosis/epidemiología , Hemartrosis/etiología , Hemartrosis/terapia , Hemorragia/sangre , Hemorragia/epidemiología , Hemorragia/etiología , Hemorragia/terapia , Hepatitis C/sangre , Hepatitis C/epidemiología , Hepatitis C/etiología , Hepatitis C/terapia , Humanos , Lactante , Masculino , Persona de Mediana Edad , Pakistán/epidemiologíaRESUMEN
OBJECTIVE: This article estimates the interaction between types of combined hormonal contraception (CHC) and factor V Leiden (FVL) mutation on the risk of venous thrombosis event (VTE). SUBJECTS AND METHODS: All premenopausal women with first incident VTE who were referred to our unit (Paris, France) between 2000 and 2009 were included in this case-only study. Differences in interactions by progestin type were assessed on a multiplicative scale, assuming the independence of genotype and prescription of type of CHC. RESULTS: Among 2,613 women with VTE, 15.9% had a FVL and 69% used CHC. The interaction between CHC use and presence of FVL on VTE risk was statistically significant (1.37, 1.06-1.77 95% confidence interval [CI]). This interaction appeared higher for drospirenone 1.99 (1.18-3.38 95% CI) (n = 98) or cyproterone acetate users 1.71 (1.20-2.45 95% CI) (n = 326), but not significant for 1st or 2nd or norgestimate CHC users. The results were similar when excluding women with a family history of VTE or with provoked VTE. In this sub-group of women, these interactions appeared higher for third generation, cyproterone acetate and drospirenone CHC users as compared with 1st or 2nd or norgestimate CHC users (odds ratio [OR], 1.68 [1.04-2.70; 95% CI], 2.91 [1.71-4.95 95% CI], 3.22 [1.54-6.73 95% CI], respectively). CONCLUSION: Our results show that the interaction between FVL and CHC use differ by progestin type, which is higher in CHC containing third-generation progestin, drospirenone or cyproterone acetate, compared with second generation. Further studies are needed to assess the cost-effectiveness of biological thrombophilia screening (FVL) when such prescription of CHC is planned.
Asunto(s)
Trastornos de la Coagulación Sanguínea Heredados/genética , Anticonceptivos Orales Combinados/efectos adversos , Anticonceptivos Hormonales Orales/efectos adversos , Factor V/genética , Progestinas/efectos adversos , Tromboembolia Venosa/inducido químicamente , Tromboembolia Venosa/genética , Adolescente , Adulto , Androstenos/efectos adversos , Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de la Coagulación Sanguínea Heredados/diagnóstico , Trastornos de la Coagulación Sanguínea Heredados/epidemiología , Acetato de Ciproterona/efectos adversos , Femenino , Humanos , Incidencia , Persona de Mediana Edad , Paris/epidemiología , Premenopausia/sangre , Factores de Riesgo , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiología , Adulto JovenRESUMEN
Thromboembolic disease is a complex disorder with a multifactorial aetiology and a severe outcome. In newborns and children it may be missed or diagnosed late, thus worsening the prognosis. The neonatal disease is different from the disorder affecting older children and adults. However, scant epidemiological data and few randomised clinical trials regarding paediatric patients are available, and treatment recommendations are largely based on adult guidelines. Younger patients then have several decades over which they will suffer from the complications of thrombosis and risk of a new thrombotic episode. Current knowledge about neonatal thromboembolic disease and its prevention is reviewed here along with maternal, foetal, neonatal, pharmacological, environmental, lifestyle and occupational contributing factors. Additional data are urgently needed to improve diagnostic and therapeutic strategies and patient outcomes.