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. 2021 Dec 2;16(1):499.
doi: 10.1186/s13023-021-02122-7.

RASopathies and hemostatic abnormalities: key role of platelet dysfunction

Francesca Di Candia  1 , Valeria Marchetti  1 , Ferdinando Cirillo  2 , Alessandro Di Minno  2 , Carmen Rosano  1 , Stefano Pagano  1 , Maria Anna Siano  3   4 , Mariateresa Falco  4 , Antonia Assunto  1 , Giovanni Boccia  3 , Gerardo Magliacane  5 , Valentina Pinna  6 , Alessandro De Luca  6 , Marco Tartaglia  7 , Giovanni Di Minno  2 , Pietro Strisciuglio  1 , Daniela Melis  8   9   10
Affiliations

RASopathies and hemostatic abnormalities: key role of platelet dysfunction

Francesca Di Candia et al. Orphanet J Rare Dis. .

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.

Keywords: Abnormal platelet function; Bleeding disorders; Laboratory test abnormalities; Noonan syndrome; Platelet optical aggregometry; RASopathies; Screening surgical procedures.

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Conflict of interest statement

The authors declare that they have no competing interests.

References

    1. Tajan M, Paccoud R, Branka S, Edouard T, Yart A. The RASopathy family: consequences of germline activation of the RAS/MAPK pathway. Endocr Rev. 2018;39(5):676–700. doi: 10.1210/er.2017-00232. - DOI - PubMed
    1. Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab. 2011;25(1):161–179. doi: 10.1016/j.beem.2010.09.002. - DOI - PMC - PubMed
    1. Tartaglia M, Zampino G, Gelb BD. Noonan syndrome: clinical aspects and molecular pathogenesis. Mol Syndromol. 2010;1(1):2–26. doi: 10.1159/000276766. - DOI - PMC - PubMed
    1. Keren B, Hadchouel A, Saba S, Sznajer Y, Bonneau D, Leheup B, et al. PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience. J Med Genet. 2004;41(11):e117. doi: 10.1136/jmg.2004.021451. - DOI - PMC - PubMed
    1. Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001;29(4):465–468. doi: 10.1038/ng772. - DOI - PubMed

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