RASopathies and hemostatic abnormalities: key role of platelet dysfunction

Orphanet Journal of Rare Diseases

Gerardo Magliacane¹  Maria Anna Siano²  Giovanni Boccia²  Stefano Pagano³  Antonia Assunto³  Valeria Marchetti³  Pietro Strisciuglio³  Carmen Rosano³  Francesca Di Candia³  Daniela Melis³  Marco Tartaglia⁴  Alessandro De Luca⁵  Valentina Pinna⁵  Mariateresa Falco⁶  Giovanni Di Minno⁷  Ferdinando Cirillo⁷  Alessandro Di Minno⁷ 

[1] Clinic Pathology, San Giovanni di Dio e Ruggi d’Aragona University Hospital;Department of Medicine, Surgery and Dentistry, University of Salerno;Dipartimento di Scienze Mediche Traslazionali, Università degli studi di Napoli Federico II;Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS;Medical Genetics Division, Fondazione IRCCS Casa Sollievo della Sofferenza;Pediatric Unit, San Giovanni di Dio e Ruggi d’Aragona University Hospital;Regional Reference Centre for Coagulation Disorders, Department of Clinical and Experimental Medicine, Federico II University of Naples;

关键词: RASopathies;    Noonan syndrome;    Bleeding disorders;    Laboratory test abnormalities;    Screening surgical procedures;    Abnormal platelet function;   

DOI  :  10.1186/s13023-021-02122-7

来源: DOAJ

【 摘 要 】

Abstract Background Bleeding anomalies have been reported in patients affected by Noonan syndrome. No study has been performed in patients with molecularly confirmed RASopathy. We aimed to characterize the frequency and types of bleeding disorders in patients with RASopathies and evaluate any significant association with laboratory findings. Patients and methods Forty-nine individuals (PTPN11, n = 27; SOS1, n = 7; RIT1, n = 3; SPRED1, n = 1; LZTR1, N = 3; RAF1, n = 2; BRAF, n = 4; MEK1, n = 1; MEK2, n = 1), and 49 age- and sex-matched controls were enrolled. The “Paediatric Bleeding Questionnaire Scoring Key” was administered to patients and families. Laboratory screening tests including clotting factors dosing, platelet count, Prothrombin Time and Partial Thromboplastin Time, were employed both in patients and controls to characterize the bleeding diathesis. A subgroup of 29/49 patients and 29/49 controls was also tested for platelet function. Results Regardless of the gene involved, pathological paediatric bleeding scores were recorded in 14/49 (28.5%) patients. Indeed, 7 were mutated in PTPN11, 3 in SOS1, 2 in RIT1, 1 in BRAF, and 1 in MEK1. Compared to patients with normal bleeding scores, those with pathologic bleeding score showed higher prevalence of splenomegaly (p = 0.006), prolonged aPTT (p = 0.04), lower levels of coagulation factor V (FV, p = 0.001), FVII (p = 0.003), FX (p = 0.0008) and FXIII (p = 0.002), higher vWAg (p = 0.04), and lower platelet sensitivity to Ristocetin (p = 0.001), arachidonic acid (AA) (p = 0.009) and collagen (p = 0.01). The presence of hematomas inversely correlated with factor V (p = 0.002), factor VII (p = 0.003), factor X (p = 0.002) and factor XIII (p = 0.004) levels, and directly correlated with platelet response to collagen (p = 0.02) and AA (p = 0.01). The presence of splenomegaly directly correlated with the presence of hematoma (p = 0.006), platelet response to Ristocetin (p = 0.04) and AA (p = 0.04), and inversely correlated with factor V levels (p = 0.03). Conclusions Patients with RASopathies and a bleeding tendency exhibit multiple laboratory abnormalities, including platelet-related disorders. Splenomegaly is frequently detected and might be a suggestive sign for qualitative platelet dysfunction. A comprehensive clinical assessment should be carried out at diagnosis, during the follow-up and before any surgical procedures. Since there is currently no consensus on management of bleeding complications, it is important that physicians closely monitor these patients.

【 授权许可】

Unknown