ABSTRACT
Inherited thrombocytopenias are rare, heterogenous and probably under-diagnosed because often classified as autoimmune thrombocytopenia. About 20 genes were described responsible for these thrombocytopenias. Precise diagnosis is necessary because the prognosis is different and some of them can evolve into hemopathies. First of all, it is important to gather a body of evidence to orientate towards an inherited cause: presence of the thrombocytopenia since childhood and of other family cases is a strong argument. Secondly, it is difficult to target the genetic investigations that settle the precise diagnosis. Genetic variants responsible for inherited thrombocytopenias affect different stage during megakaryocytopoiesis and cause thrombocytopenias with distinct characteristics. Presence of extra-hematological features, platelets' size measurement and evaluation of bone marrow megakaryocyte morphology when it is possible allow a primary orientation. We propose a diagnostic approach considering extra-hematological features, mode of inheritance, morphology, molecular and functional platelets' studies and bone marrow megakaryocyte morphology in order to better target genetic study. Nevertheless, despite this approach, some inherited thrombocytopenias remain still unexplained and could benefit from new methods of new generation sequencing in the future.
Subject(s)
Thrombocytopenia/diagnosis , Thrombocytopenia/genetics , Algorithms , HumansABSTRACT
Reactive thrombocytosis (secondary thrombocytosis) is frequent and typically moderate. We report a case of extreme thrombocytosis and leukocytosis secondary to an iron deficiency anemia. A 21-year-old woman is admitted in emergency department for acute headache. Biological assessment reveals a severe microcytic anaemia (5.4 g/dL) with thrombocytosis (2500 giga/L) and leukocytosis (35 giga/L) leading to multiple diagnosis hypotheses. Finally, biological evaluation concludes to a diagnosis of iron deficiency anaemia related to insufficient oral intake and menorrhagia. Reactive hyperleukocytosis and thrombocytosis rapidly resolved with iron supplementation. This case is a reminder that iron deficiency-related thrombocytosis can sometimes be severe. However, the associated reactive leukocytosis is quite exceptional.
Subject(s)
Anemia, Iron-Deficiency/complications , Leukocytosis/etiology , Thrombocytosis/etiology , Adult , Female , Humans , Severity of Illness IndexABSTRACT
PURPOSE: Gaucher disease is the most frequent lysosomal storage disease, and corresponds to an inherited deficiency of glucocerebrosidase. Due to excessive accumulation of glucocerebroside in bone marrow, cytopenia and bone lesions occur. KEY POINTS: The clinical signs at diagnosis include frequently anaemia, thrombopenia and splenomegaly. The hematologist is often in first line of the diagnosis, but it must avoid certain diagnostic traps (pseudo-Gaucher cells or even pseudo-pseudo-Gaucher cells in certain crystal storage diseases). The treatment of substitution when adequately carried out generally makes it possible to quickly improve the hematologic parameters. Another hematologic aspect must be evoked in Gaucher disease, i.e. the incidence of associated malignant pathologies and more particularly of multiple myeloma. Many cases of association between multiple myeloma and Gaucher disease have been reported in the literature. Recently two important series demonstrated the nonfortuitous character of this association. PROJECTS: The physiopathological links which could connect myeloma and Gaucher disease are not known to date. Immune network imbalance could be an interesting hypothesis that should require further investigations.
Subject(s)
Gaucher Disease/complications , Hematologic Diseases/etiology , Multiple Myeloma/complications , Anemia/etiology , Diagnosis, Differential , Gaucher Disease/diagnosis , Gaucher Disease/drug therapy , Gaucher Disease/physiopathology , Glucosylceramidase/therapeutic use , Humans , Immunohistochemistry , Multiple Myeloma/diagnosis , Recombinant Proteins/therapeutic use , Splenomegaly/etiology , Thrombocytopenia/etiologyABSTRACT
The cyclin-dependent kinase inhibitor p21(Waf-1/Cip-1) is expressed at high level during megakaryocyte differentiation, but its precise function remains unknown. In this study, it is confirmed that p21 was expressed at a high level in hypoploid (2N and 4N) and polyploid (at least 8N) human megakaryocytes derived from CD34(+) cells. A high expression of p27(Kip1), p16, cyclin E, and cyclin D3 was also found in both populations associated with a hypophosphorylated form of retinoblastoma protein, suggesting that the majority of hypoploid and polyploid megakaryocytes are G(1)-arrested cells. As human megakaryocytes grown in vitro present a defect in their polyploidization, the study switched to the murine model. The modal ploidy of megakaryocytes derived from lineage-negative cells was 32N, and an elevated expression of p21 was found in high-ploidy megakaryocytes. In addition, p21 and p27 were coexpressed in the majority of mature polyploid megakaryocytes. The p21 was detected by immunofluorescence in megakaryocytes derived from p53(-/-) mice, demonstrating a p53-independent regulation during megakaryocyte differentiation. Megakaryocytopoiesis of p21(-/-) mice was subsequently studied. No marked abnormality in the ploidy of primary or cultured megakaryocytes was detected. Overexpression of p21 in p21(-/-) or normal murine megakaryocytes and in human megakaryocytes showed in all these cases a marked inhibition in megakaryocyte polyploidization. In conclusion, while a reciprocal relation is observed between p21 levels in megakaryocytes and the cycling state of the cells, p21 is not essential for the determination of the ploidy profile in normal megakaryocytes in vivo. However, high levels of its expression in cultured megakaryocytes arrest the endomitotic cell cycle.
