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Clinical and Biological Assessment of the Largest Family with SRC-RT due to p.E527K Gain-of-Function Variant

N. Revilla1, V. Palma-Barqueros2, A. Galera3, C. Zaninetti4, N. Bohdan2, A. Rodriguez-Alén5, A. Sánchez-Fuentes2, A. Marin-Quilez6, A. Zamora-Canovas2, V. Vicente2, A. Greinacher4, M.L. Lozano2, J.M. Bastida6,7, J. Rivera2,7

1Hospital Universitario Ramón y Cajal, Madrid, Spain, 2Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CIBERER-U765, Murcia, Spain, 3Hospital Universitario Virgen de la Arrixaca, Murcia, Spain, 4Institut für Immunologie und Transfusionsmedizin, Universitätsmedizin Greifswald Hospital, Greifswald, Germany, 5Hospital Virgen de la Salud, Complejo Hospitalario de Toledo, Toledo, Spain, 6Department of Hematology, Complejo Asistencial Universitario de Salamanca (CAUSA), Instituto de Investigación Biomédica de Salamanca (IBSAL), Universidad de Salamanca (USAL), Salamanca, Spain, 7Grupo Español de Alteraciones Plaquetarias Congénitas (GEAPC), Murcia-Salamanca, Spain

Abstract Number: OC 31.2

Meeting: ISTH 2021 Congress

Theme: Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies » Inherited Thrombocytopenias

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).

Novel pedigree with SRC-RT due to c.1579G>A [p.E527K] gain-of-function mutation in SRC and main platelet features

ID Platelet (x109/L) MPV (fL) WBC (x109/L) RBC (x1012/L)
Hb (g/L)
Skeletal compaint Teeth abnormalities Neurological manifestations Immuno-allergic defects Thrombosis
2†,# Nd* nd nd Nd/nd nr nr Epilepsy. SUDEP nr nr
3# 90 9.7 9.1 4.6
145
Chronic pain No No LRI (bronchitis in childhood) Psoriasis No
6# 122 10.4 12.3 4.1
125
No Periodontal disease No LRI (recurrent bronchitis, >2-3 episodes/yr No
7# 140 8.0 6.9 3.7
104
No Chronic maxillary pain Epilepsy, depression, significant memory loss and cognitive impairment URI (one a year), Epididymo-orchitis
Psoriasis
Portal cavernomatosis post-splenectomy, PE
9 23 10.3 6.1 5.7
107
Chronic pain No No LRI (recurrent bronchitis, 4-5 episodes/yr
Severe allergy
No
11 46 NR 5.7 5.0
139
No Delay in teeth eruption Speech and language impairment LRI (recurrent bronchitis, <3episodes/yr) No
12 76 NR 5.6 4.8
111
Chronic pain No Anxiety and behavoir abnormalities LRI (brinchitis in childhood) DVT
13 102 13.3 7.6 4.5
129
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.

General and clinical features of p.E527 carriers of the novel large family with SRC-RT 

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.

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