RESUMEN
Heritable dysfibrinogenaemia (HD) is a rare qualitative disorder of fibrinogen (FGN). To better describe the clinical, laboratory and genotypic spectrum of HD, we evaluated 35 subjects identified at two UK centres using laboratory criteria. 12/35(34%) subjects with HD experienced bleeding (bleeding score >1 at any site), 3/35(9%) thrombosis and 20/35(57%) were asymptomatic. Amongst subjects with bleeding, symptoms were typically mild, at one anatomical site and seldom occurred after invasive procedures. All subject showed dry clot weight within or above laboratory reference interval (median 3·2 g/l; range 1·9-5·1), reduced Clauss fibrinogen (median 0·52 g/l; range 0·21-1·3), and prolonged thrombin (median 30·7 s; range 21·3-45·7) and reptilase (median 42·0 s; range 20·0-68·0) times. In all subjects, the prothrombin time ratio (PTR), determined by Sysmex CA-1500 coagulometer and Innovin activator, was abnormal (median 1·42; range 1·22-1·61). The activated partial thromboplastin time ratio and PTR with other coagulometers and activators were comparatively insensitive to HD. All subjects with HD harboured heterozygous candidate nucleotide variations within known hotspots in the FGN genes. The HD variants identified in this cross-sectional study seldom have significant clinical manifestations and show similar laboratory features irrespective of genotype. Selection of coagulometer and PT activator may markedly affect the detection of new HD cases using coagulation screening tests.
Asunto(s)
Afibrinogenemia/epidemiología , Fibrinógenos Anormales/genética , Adolescente , Adulto , Afibrinogenemia/sangre , Afibrinogenemia/genética , Anciano , Alelos , Pruebas de Coagulación Sanguínea/instrumentación , Pruebas de Coagulación Sanguínea/métodos , Niño , Estudios Transversales , Análisis Mutacional de ADN , Inglaterra/epidemiología , Femenino , Frecuencia de los Genes , Genotipo , Hemorragia/epidemiología , Hemorragia/etiología , Humanos , Masculino , Tamizaje Masivo , Persona de Mediana Edad , Fenotipo , Mutación Puntual , Polimorfismo de Nucleótido Simple , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
We report a kindred with heritable protein C (PC) deficiency in which two siblings with severe thrombosis showed a composite type I and IIb PC deficiency phenotype, identified using commercial PC assays (proband: PC antigen 42 u/dl, amidolytic activity 40 u/dl, anticoagulant activity 9 u/dl). The independent PROC nucleotide variations c.669C>A (predictive of Ser181Arg) and c.131C>T (predictive of Asn2Ile) segregated with the type I and type IIb PC deficiency phenotypes respectively, but co-segregated in the siblings with severe thrombosis. Soluble thrombomodulin (sTM)-mediated inhibition of plasma thrombin generation from an individual with PC-Asn2Ile was lower (endogenous thrombin potential (ETP) 56 +/- 1% that of ETP determined without sTM) than control plasma (ETP 15 +/- 2%) indicating reduced PC anticoagulant activity. Recombinant APC-Asn2Ile exhibited normal amidolytic activity but impaired anticoagulant activity. Protein S (PS)-dependent anticoagulant activity of recombinant APC-Asn2Ile and binding of recombinant APC-Asn2Ile to endothelial protein C receptor (EPCR) were reduced compared to recombinant wild-type APC. Asn2 lies within the omega-loop of the PC/APC Gla domain and this region is critical for calcium-induced folding and subsequent interactions with anionic phospholipids, EPCR and PS. The disruption of these interactions in this naturally-occurring PC variant highlights their collective importance in mediating APC anticoagulant activity in vivo.
Asunto(s)
Sustitución de Aminoácidos , Coagulación Sanguínea/genética , Deficiencia de Proteína C/genética , Proteína C/genética , Adolescente , Adulto , Anciano , Autoantígenos/sangre , Pruebas de Coagulación Sanguínea , Niño , Femenino , Genotipo , Humanos , Masculino , Linaje , Fenotipo , Proteína C/inmunología , Proteína C/metabolismo , Deficiencia de Proteína C/complicaciones , Deficiencia de Proteína C/metabolismo , Púrpura Fulminante/genética , Trombina/biosíntesis , Trombosis/etiología , Trombosis/genéticaAsunto(s)
Anticoagulantes/uso terapéutico , Puente de Arteria Coronaria Off-Pump , Heparina/uso terapéutico , Precalicreína/deficiencia , Anciano , Trastornos de la Coagulación Sanguínea/diagnóstico , Pérdida de Sangre Quirúrgica/prevención & control , Inhibidores del Factor Xa , Humanos , Masculino , Monitoreo Intraoperatorio , Tiempo de Tromboplastina Parcial , Tiempo de Coagulación de la Sangre TotalRESUMEN
The gene encoding vitamin K epoxide reductase complex subunit 1 (VKORC1), a component of the enzyme that is the therapeutic target site for warfarin, has recently been identified. In order to investigate the relationship betweenVKORC1 and warfarin dose response, we studied the VKORC1 gene (VKORC1) in patients with warfarin resistance. From a study group of 820 patients, we identified 4 individuals who required more than 25 mg of warfarin daily for therapeutic anticoagulation. Three of these had serum warfarin concentrations within the therapeutic range of 0.7-2.3 mg/l and showed wild-type VKORC1 sequence. The fourth warfarin resistant individual had consistently high (> or =5.7 mg/l) serum warfarin concentrations, yet had no clinically discernible cause for warfarin resistance. VKORC1 showed a heterozygous 196G-->A transition that predicted aVal66Met substitution in the VKORC1 polypeptide. This transition was also identified in 2 asymptomatic family members who had never received warfarin. These individuals had normal vitamin-K dependent coagulation factor activities and undetectable serum PIVKAII and vitamin K1 2,3 epoxide suggesting that their basal vitamin K epoxide reductase activity was not adversely affected by the VKORC1 Val66Met substitution. The association between a nucleotide transition in VKORC1 and pharmacodynamic warfarin resistance supports the hypothesis that VKORC1 is the site of action of warfarin and indicates thatVKORC1 sequence is an important determinant of the warfarin dose response.
