Abstract Number: OC 31.2
Meeting: ISTH 2021 Congress
Background: The heterozygous gain-of-function c.1579G>A [p.E527K] in SRC has been associated with a rare autosomal dominant inherited thrombocytopenia, namely SRC-RT, in three unrelated families. Reported clinical features ranged from isolated thrombocytopenia to a complex syndrome with bleeding, myelofibrosis, splenomegaly and bone pathologies.
Aims: To expand the clinical and biological knowledge of SRC-RT.
Methods: Two siblings with lifelong thrombocytopenia, enrolled the Spanish Project of Inherited Platelet Disorders. Clinical assessment, extensive platelet phenotyping and DNA analysis were performed in these patients and relatives.
Results: The sibling´s mother and brother had undergone splenectomy due to a misdiagnosis of immune thrombocytopenia. DNA analysis using high throughput sequencing gene panel identified the SRC variant c.1579G>A. Sanger sequencing recognized five additional carriers in the pedigree. Clinical and platelet phenotyping data are summarized in Figure & Table . p.E527K carriers showed mild to severe thrombocytopenia and normal MPV values, but platelet anisocytosis was observed in May‐Grünwald‐Giemsa-stained blood smear (BS) with about 20% large platelets. BS Immunofluorescence with specific antibodies showed impaired α-granule markers (thrombospondin, vWF, P-selectin). Flow cytometry revealed increased platelet size, normal expression of glycoproteins Ib/IX and Ia, slightly increased IIb/IIIa and reduced GPVI levels in p.E527K carriers. Agonist-induced fibrinogen binding and α- and δ–granule secretion (CD62P and CD63 expression, respectively) were impaired in p.E527K carriers´ platelets. Aggregometry in three available p.E527K carriers showed impaired platelet aggregation with collagen and CRP, but minimally or variably affected aggregation with ristocetin, PAR-1 and ADP. Clinical investigation revealed that most p.E527K carriers have a severe syndromic phenotype, which includes recurrent infections, immuno-allergic disorders, bone disease, neurological manifestations, prothrombotic tendency, and mild bleeding complications (Table).
|ID||Platelet (x109/L)||MPV (fL)||WBC (x109/L)||RBC (x1012/L)
|Skeletal compaint||Teeth abnormalities||Neurological manifestations||Immuno-allergic defects||Thrombosis|
|Chronic pain||No||No||LRI (bronchitis in childhood) Psoriasis||No|
|No||Periodontal disease||No||LRI (recurrent bronchitis, >2-3 episodes/yr||No|
|No||Chronic maxillary pain||Epilepsy, depression, significant memory loss and cognitive impairment||URI (one a year), Epididymo-orchitis
|Portal cavernomatosis post-splenectomy, PE|
|Chronic pain||No||No||LRI (recurrent bronchitis, 4-5 episodes/yr
|No||Delay in teeth eruption||Speech and language impairment||LRI (recurrent bronchitis, <3episodes/yr)||No|
|Chronic pain||No||Anxiety and behavoir abnormalities||LRI (brinchitis in childhood)||DVT|
|Chronic pain||No||No||LRI (recurrent bronchitis)||No|
|Abbreviations: ID, number in family pedigree (Figure 1); †Dead; #: Splenectomized before 30ys old; nd: not determined; nd*: not determined, but thrombocytopenia referred by the family; nr: not reported; SUDEP: sudden unexpected death in epilepsy; URI: upper respiratory tract infection; LRI: lower respiratory tract infection; PE: pulmonary embolism; DVT: deep vein thrombosis.|
Conclusions: This new large family with thrombocytopenia associated to the SRC p.E527K variant consolidates the knowledge about SRC-RT, highlights its clinical and biological heterogeneity and argues toward a multidisciplinary approach for its diagnosis and management.
To cite this abstract in AMA style:Revilla N, Palma-Barqueros V, Galera A, Zaninetti C, Bohdan N, Rodriguez-Alén A, Sánchez-Fuentes A, Marin-Quilez A, Zamora-Canovas A, Vicente V, Greinacher A, Lozano ML, Bastida JM, Rivera J. Clinical and Biological Assessment of the Largest Family with SRC-RT due to p.E527K Gain-of-Function Variant [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/clinical-and-biological-assessment-of-the-largest-family-with-src-rt-due-to-p-e527k-gain-of-function-variant/. Accessed November 29, 2023.
« Back to ISTH 2021 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/clinical-and-biological-assessment-of-the-largest-family-with-src-rt-due-to-p-e527k-gain-of-function-variant/