RESUMEN
Inherited thrombocytopenias (ITs) encompass a group of rare disorders characterized by diminished platelet count. Recent advancements have unveiled various forms of IT, with inherited thrombocytopenia 2 (THC2) emerging as a prevalent subtype associated with germline variants in the critical 5' untranslated region of the ANKRD26 gene. This region is crucial in regulating the gene expression of ANKRD26, particularly in megakaryocytes. THC2 is an autosomal dominant disorder presenting as mild-to-moderate thrombocytopenia with minimal symptoms, with an increased risk of myeloproliferative malignancies. In our study of a family with suspected IT, three affected individuals harbored the c.-118C>T ANKRD26 variant, while four healthy members carried the c.-140C>G ANKRD26 variant. We performed a functional analysis by studying platelet-specific ANKRD26 gene expression levels using quantitative real-time polymerase-chain reaction. Functional analysis of the c.-118C>T variant showed a significant increase in ANKRD26 expression in affected individuals, supporting its pathogenicity. On the contrary, carriers of the c.-140C>G variant exhibited normal platelet counts and no significant elevation in the ANKRD26 expression, indicating the likely benign nature of this variant. Our findings provide evidence confirming the pathogenicity of the c.-118C>T ANKRD26 variant in THC2 and suggest the likely benign nature of the c.-140C>G variant.
What is the context?Inherited thrombocytopenias (ITs) are rare conditions characterized by low platelet counts. Inherited thrombocytopenia 2 (THC2) is caused by ANKRD26 gene changes leading to increased ANKRD26 expression as the main reason for subsequent thrombocytopenia. THC2 results in a mild-to-moderate decrease in platelet count and increases blood cancer risk. We focused on understanding two ANKRD26 variants in a family with a history of thrombocytopenia.What is new?We conducted functional analysis to understand the effect of variants on platelet function and gene expression. We identified three thrombocytopenic family members as carriers of ANKRD26 variant c.-118C>T. This variant is linked to increased expression of the ANKRD26 gene and confirmed as the likely cause of THC2. Another variant, c.-140C>G, was present in four healthy family members. Although it was considered causal for THC2 in the past, our study suggests that the c.-140C>G variant does not elevate ANKRD26 expression and does not cause thrombocytopenia.What is the impact?Understanding the genetic and functional implications of ANKRD26 gene variants is crucial for THC2 diagnosis and management. Our study emphasizes the necessity of conducting functional analyses to precisely evaluate the clinical significance of variants linked to inherited blood disorders. Carriers of the c.-118C>T variant should undergo vigilant monitoring for THC2 and potential cancer development. Conversely, the c.-140C>G variant does not pose a risk of THC2 or heightened cancer susceptibility.
Asunto(s)
Regiones no Traducidas 5' , Linaje , Trombocitopenia , Humanos , Trombocitopenia/genética , Femenino , Masculino , Adulto , Persona de Mediana Edad , Predisposición Genética a la Enfermedad , Péptidos y Proteínas de Señalización IntercelularRESUMEN
Bernard-Soulier syndrome (BSS) is a rare inherited disorder characterized by unusually large platelets, low platelet count, and prolonged bleeding time. BSS is usually inherited in an autosomal recessive (AR) mode of inheritance due to a deficiency of the GPIb-IX-V complex also known as the von Willebrand factor (VWF) receptor. We investigated a family with macrothrombocytopenia, a mild bleeding tendency, slightly lowered platelet aggregation tests, and suspected autosomal dominant (AD) inheritance. We have detected a heterozygous GP1BA likely pathogenic variant, causing monoallelic BSS. A germline GP1BA gene variant (NM_000173:c.98G > A:p.C33Y), segregating with the macrothrombocytopenia, was detected by whole-exome sequencing. In silico analysis of the protein structure of the novel GPIbα variant revealed a potential structural defect, which could impact proper protein folding and subsequent binding to VWF. Flow cytometry, immunoblot, and electron microscopy demonstrated further differences between p.C33Y GP1BA carriers and healthy controls. Here, we provide a detailed insight into its clinical presentation and phenotype. Moreover, the here described case first presents an mBSS patient with two previous ischemic strokes.
Asunto(s)
Alelos , Síndrome de Bernard-Soulier/diagnóstico , Síndrome de Bernard-Soulier/genética , Predisposición Genética a la Enfermedad , Variación Genética , Fenotipo , Complejo GPIb-IX de Glicoproteína Plaquetaria/genética , Síndrome de Bernard-Soulier/sangre , Plaquetas/metabolismo , Plaquetas/ultraestructura , República Checa , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Humanos , Inmunofenotipificación , Masculino , Linaje , Recuento de Plaquetas , Complejo GPIb-IX de Glicoproteína Plaquetaria/metabolismo , Trombocitopenia/sangre , Trombocitopenia/diagnósticoRESUMEN
Heparin-induced thrombocytopenia (HIT) is an immunologically-mediated complication, which usually follows heparin exposition, less frequently exposition to other drugs or even occurs spontaneously. The type of heparin, its dose and mode of application as well as the exposition time, major trauma or operation, and obesity represent the main risk factors for HIT. The probability of HIT correlates with so-called 4T-score. A confirmatory laboratory diagnostic should be exclusively reserved for patients with a medium to a high probability of HIT development (more than 3 points in 4T-score). The screening method is based on serological detection of antibodies against heparin-platelet factor-4 complexes; confirmation tests aim to identify the activation of platelets. The treatment of HIT requires an immediate interruption of heparin application and rigorous antithrombotic treatment with an alternative agent. Herein authors describe a clinical case of HIT manifested as an extreme urticarial reaction in the location of nadroparin application as well as thrombosis of deep subcutaneous veins in a polymorbid obese patient with an extensive and infected burn. Due to timely diagnosis and fondaparinux treatment, no more severe thrombotic events occurred in this patient.
Asunto(s)
Trombocitopenia , Trombosis , Anticoagulantes/efectos adversos , Fondaparinux , Heparina/efectos adversos , Humanos , Trombocitopenia/inducido químicamente , Trombocitopenia/diagnósticoRESUMEN
Well-managed warfarin therapy remains an important method of anticoagulation in the 21st century, despite the introduction of new antithrombotics into the clinical practice. The main advantages of warfarin are decades of treatment experience, the possibility to monitor its anticoagulant effect using the INR and the last, but not least, the low cost. Currently, approximately 75 % of anticoagulated patients in the Czech Republic are treated with warfarin and warfarin remains the only option for oral anticoagulant therapy in certain clinical conditions (particularly in patients with valvular atrial fibrillation or mechanical heart valves). For physicians across specialties it is still indispensable to master the basics of safe and effective warfarin therapy, including the management of treatment complications.Key words: anticoagulant therapy - INR - thrombosis - warfarin.