A novel genetic variant in <scp><i>PTGS1</i></scp> affects N‐glycosylation of cyclooxygenase‐1 causing a dominant‐negative effect on platelet function and bleeding diathesis

Src-related thrombocytopenia (SRC-RT) is a rare autosomal dominant inherited platelet disorder due to the p.E527K heterozygous germline gain-of-function variant of Src. To date, genetic diagnosis of the disease has only been reported in seven patients from three unrelated families. The clinical features ranged from isolated thrombocytopenia to complex syndromic manifestations characterized by thrombocytopenia, bleeding, myelofibrosis, splenomegaly, and bone disease. We report a new three-generation kindred with the Src p.E527K variant. Patients presented with rather variable platelet counts (38 - 139 x 109/L), mildly impaired platelet function, >15% immature platelet fraction, and with a significant proportion of large-giant platelets. Four adults from the family were diagnosed with immune thrombocytopenia (ITP) and underwent splenectomy, achieving sustained platelet counts above 75 x 109/L for several years; increases in platelet counts were also observed after corticosteroid therapy. Four of seven Src p.E527K variant carriers showed immune defects and recurrent infections. In addition, a range of neurological symptoms, from specific language impairment to epilepsy was seen in some family members. Patient platelets exhibited constitutive Src, BTK, and PLC2 activation, and after stimulating CD19 cells by crosslinking surface IgM, phosphorylated ERK was significantly increased in B cells from individuals carrying the Src p.E527K substitution. In summary, in addition to causing impaired platelet production, SRC-RT may associate immune dysregulation, and increased platelet consumption. In families in whom several members are responsive to ITP directed therapies, an underlying Src p.E527K variant should be excluded.

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Src-related thrombocytopenia: a fine line between a megakaryocyte dysfunction and an immune-mediated disease

Palma-Baqueros

Revilla

Zaninetti³

et al. 2022

Blood Advances

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Inherited Platelet Disorders: An Updated Overview

Palma-Barqueros

Revilla

Sánchez

et al. 2021

IJMS

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Platelets play a major role in hemostasis as ppwell as in many other physiological and pathological processes. Accordingly, production of about 1011 platelet per day as well as appropriate survival and functions are life essential events. Inherited platelet disorders (IPDs), affecting either platelet count or platelet functions, comprise a heterogenous group of about sixty rare diseases caused by molecular anomalies in many culprit genes. Their clinical relevance is highly variable according to the specific disease and even within the same type, ranging from almost negligible to life-threatening. Mucocutaneous bleeding diathesis (epistaxis, gum bleeding, purpura, menorrhagia), but also multisystemic disorders and/or malignancy comprise the clinical spectrum of IPDs. The early and accurate diagnosis of IPDs and a close patient medical follow-up is of great importance. A genotype–phenotype relationship in many IPDs makes a molecular diagnosis especially relevant to proper clinical management. Genetic diagnosis of IPDs has been greatly facilitated by the introduction of high throughput sequencing (HTS) techniques into mainstream investigation practice in these diseases. However, there are still unsolved ethical concerns on general genetic investigations. Patients should be informed and comprehend the potential implications of their genetic analysis. Unlike the progress in diagnosis, there have been no major advances in the clinical management of IPDs. Educational and preventive measures, few hemostatic drugs, platelet transfusions, thrombopoietin receptor agonists, and in life-threatening IPDs, allogeneic hematopoietic stem cell transplantation are therapeutic possibilities. Gene therapy may be a future option. Regular follow-up by a specialized hematology service with multidisciplinary support especially for syndromic IPDs is mandatory.

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A novel genetic variant in PTGS1 affects N‐glycosylation of cyclooxygenase‐1 causing a dominant‐negative effect on platelet function and bleeding diathesis

Cited by 2 publications

References 15 publications

Src-related thrombocytopenia: a fine line between a megakaryocyte dysfunction and an immune-mediated disease

Src-related thrombocytopenia: a fine line between a megakaryocyte dysfunction and an immune-mediated disease

Inherited Platelet Disorders: An Updated Overview

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