1,721,155 research outputs found
Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists.
No full textKnowledge in the field of inherited thrombocytopenias (ITs) has considerably improved over the recent years. In the last 5 years, nine new genes whose mutations are responsible for thrombocytopenia have been identified, and this also led to the recognition of several novel nosographic entities, such as thrombocytopenias deriving from mutations in CYCS, TUBB1, FLNA, ITGA2B/ITGB3, ANKRD26 and ACTN1. The identification of novel molecular alterations causing thrombocytopenia together with improvement of methodologies to study megakaryopoiesis led to considerable advances in understanding pathophysiology of ITs, thus providing the background for proposing new treatments. Thrombopoietin-receptor agonists (TPO-RAs) represent an appealing therapeutic hypothesis for ITs and have been tested in a limited number of patients. In this review, we provide an updated description of pathogenetic mechanisms of thrombocytopenia in the different forms of ITs and recapitulate the current management of these disorders. Moreover, we report the available clinical and preclinical data about the role of TPO-RAs in ITs and discuss the rationale for the use of these molecules in view of pathogenesis of the different forms of thrombocytopenia of genetic origin
Diagnosis and treatment of inherited thrombocytopenias
No full textKnowledge in the field of inherited thrombocytopenias (ITs) has greatly improved over the last 15years. Several new genes responsible for thrombocytopenia have been identified leading to the definition of novel nosographic entities and to a much better characterization of the phenotypes of these diseases. To date, ITs encompass 22 disorders caused by mutations in 24 genes and characterized by different degrees of complexity and great variability in prognosis. Making a definite diagnosis is important for setting an appropriate follow-up, choosing the best treatments and providing proper counseling. Despite the abovementioned progress, diagnosis of ITs remains difficult and these disorders are still underdiagnosed. The purpose of this review is to provide an updated guide to the diagnosis of ITs based on simple procedures. Moreover, the currently available therapeutic options for these conditions are recapitulated and discussed. © 2016 John Wiley & Sons A/S
Desmopressin and super platelets.
No full textn this issue of Blood, Colucci et al provide experimental data supporting the hypothesis that desmopressin (DDAVP) favors the hemostatic process not only by inducing the release of von Willebrand factor (VWF) from endothelial cells, but also by enhancing the procoagulant activity of platelets.1 © 2014 by The American Society of Hematology
Hereditary thrombocytopenias: A growing list of disorders
Full text linkThe introduction of high throughput sequencing (HTS) techniques greatly improved the knowledge of inherited thrombocytopenias (ITs) over the last few years. A total of 33 different forms caused by molecular defects affecting at least 32 genes have been identified; along with the discovery of new disease-causing genes, pathogenetic mechanisms of thrombocytopenia have been better elucidated. Although the clinical picture of ITs is heterogeneous, bleeding has been long considered the major clinical problem for patients with IT. Conversely, the current scenario indicates that patients with some of the most common ITs are at risk of developing additional disorders more dangerous than thrombocytopenia itself during life. In particular, MYH9 mutations result in congenital macrothrombocytopenia and predispose to kidney failure, hearing loss, and cataracts, MPL and MECOM mutations cause congenital thrombocytopenia evolving into bone marrow failure, whereas thrombocytopenias caused by RUNX1, ANKRD26, and ETV6 mutations are characterized by predisposition to hematological malignancies. Making a definite diagnosis of these forms is crucial to provide patients with the most appropriate treatment, follow-up, and counseling. In this review, the ITs known to date are discussed, with specific attention focused on clinical presentations and diagnostic criteria for ITs predisposing to additional illnesses. The currently available therapeutic options for the different forms of IT are illustrated
Lessons in platelet production from inherited thrombocytopenias.
No full textOur knowledge of the cellular and molecular mechanisms of platelet production has greatly expanded in recent years due to the opportunity to culture in vitro megakaryocytes and to create transgenic animals with specific genetic defects that interfere with platelet biogenesis. However, in vitro models do not reproduce the complexity of the bone marrow microenvironment where megakaryopoiesis takes place, and experience shows that what is seen in animals does not always happen in humans. So, these experimental models tell us what might happen in humans, but does not assure us that these events really occur. In contrast, inherited thrombocytopenias offer the unique opportunity to verify in humans the actual effects of abnormalities in specific molecules on platelet production. There are currently 20 genes whose defects are known to result in thrombocytopenia and, on this basis, this review tries to outline a model of megakaryopoiesis based on firm evidence. Inherited thrombocytopenias have not yet yielded all the information they can provide, because nearly half of patients have forms that do not fit with any known disorder. So, further investigation of inherited thrombocytopenias will advance not only the knowledge of human illnesses, but also our understanding of human platelet production
A therapy-related myelodysplastic syndrome with unusual features in a patient treated for acute promyelocytic leukemia.
No full textMYH9-Related Disorders.
No full textClinical characteristics.
MYH9-related disorders (MYH9RD) are characterized by large platelets (i.e., >40% of platelets >3.9 μm in diameter) and thrombocytopenia (platelet count <150 x 109/L), both of which are present from birth. MYH9RD is variably associated with young-adult onset of progressive sensorineural hearing loss, presenile cataract, elevation of liver enzymes, and renal disease manifesting initially as glomerular nephropathy. Before identification of the gene in which mutation is causative, MYH9, individuals with MYH9RD were diagnosed as having Epstein syndrome, Fechtner syndrome, May-Hegglin anomaly, or Sebastian syndrome based on the combination of different clinical findings at the time of diagnosis. However, the realization that they all are due to heterozygous pathogenic variants in MYH9 and that the clinical findings often worsen throughout life as a result of late onset of non-hematologic manifestations has led the four conditions to be regarded as one disorder, now known as MYH9RD.
Diagnosis/testing.
The diagnosis is established by the finding of typical MYH9 protein aggregates in neutrophils detected through immunofluorescence analysis of a peripheral blood smear and/or by the identification of a heterozygous pathogenic variant in MYH9. Absence of MYH9 protein aggregates in neutrophils excludes the diagnosis of MYH9RD.
Management.
Treatment of manifestations: For active hemorrhage, application of local measures, desmopressin (DDAVP), and antifibrinolytic agents are used; platelet transfusion is necessary for: hemorrhages not controlled by the above treatments, life-threatening bleeding, or hemorrhages at critical sites. Hearing loss, renal complications, and cataract are managed in a standard fashion; individuals with severe/profound deafness benefit from cochlear implantation.
Prevention of primary manifestations: Platelet transfusion, desmopressin, antifibrinolytic drugs, or eltrombopag can be used to reduce the risk of bleeding prior to surgery or invasive procedures; oral contraceptives may be effective in preventing or treating menorrhagia; regular dental care to prevent gingival bleeding.
Surveillance: In those with bleeding episodes, blood count at least every six months to identify anemia. In all affected individuals, annual urinalysis (including 24-hour protein or protein [albumin]/creatinine ratio on a spot urine sample) and measurement of serum concentration of creatinine prior to onset of renal disease; serum liver enzyme measurements and audiometric and ophthalmologic evaluations every three years.
Agents/circumstances to avoid: Drugs that inhibit platelet function or blood coagulation; ototoxic, nephrotoxic, and hepatotoxic drugs should be used only after careful assessment of risk versus benefit; hazardous noise and activities with high risk of injury should be avoided.
Evaluation of relatives at risk: Screen at-risk newborns with molecular genetic testing if the family-specific pathogenic variant is identified; otherwise assess platelet count and size.
Pregnancy management: Deliveries should be managed as they are in women with other forms of thrombocytopenia; a platelet count of ≥50 x 109/L is generally recommended for safe delivery.
Genetic counseling.
MYH9RD is inherited in an autosomal dominant manner. Approximately 35% of affected individuals represent simplex cases, half of whom have a documented de novo pathogenic variant. Each offspring of an individual with MYH9RD has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known
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