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.« 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/