RASopathies and hemostatic abnormalities: key role of platelet dysfunction.

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

Journal

Orphanet journal of rare diseases
ISSN: 1750-1172
Titre abrégé: Orphanet J Rare Dis
Pays: England
ID NLM: 101266602

Informations de publication

Date de publication:
02 12 2021
Historique:
received: 19 04 2021
accepted: 06 11 2021
entrez: 3 12 2021
pubmed: 4 12 2021
medline: 12 3 2022
Statut: epublish

Résumé

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. 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. 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). 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.

Sections du résumé

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.

Identifiants

pubmed: 34857025
doi: 10.1186/s13023-021-02122-7
pii: 10.1186/s13023-021-02122-7
pmc: PMC8638204
doi:

Substances chimiques

Hemostatics 0
LZTR1 protein, human 0
Transcription Factors 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

499

Informations de copyright

© 2021. The Author(s).

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Auteurs

Francesca Di Candia (F)

Dipartimento di Scienze Mediche Traslazionali, Università degli studi di Napoli Federico II, Naples, Italy.

Valeria Marchetti (V)

Dipartimento di Scienze Mediche Traslazionali, Università degli studi di Napoli Federico II, Naples, Italy.

Ferdinando Cirillo (F)

Regional Reference Centre for Coagulation Disorders, Department of Clinical and Experimental Medicine, Federico II University of Naples, Naples, Italy.

Alessandro Di Minno (A)

Regional Reference Centre for Coagulation Disorders, Department of Clinical and Experimental Medicine, Federico II University of Naples, Naples, Italy.

Carmen Rosano (C)

Dipartimento di Scienze Mediche Traslazionali, Università degli studi di Napoli Federico II, Naples, Italy.

Stefano Pagano (S)

Dipartimento di Scienze Mediche Traslazionali, Università degli studi di Napoli Federico II, Naples, Italy.

Maria Anna Siano (MA)

Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Salerno, Italy.
Pediatric Unit, San Giovanni di Dio e Ruggi d'Aragona University Hospital, Salerno, Italy.

Mariateresa Falco (M)

Pediatric Unit, San Giovanni di Dio e Ruggi d'Aragona University Hospital, Salerno, Italy.

Antonia Assunto (A)

Dipartimento di Scienze Mediche Traslazionali, Università degli studi di Napoli Federico II, Naples, Italy.

Giovanni Boccia (G)

Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Salerno, Italy.

Gerardo Magliacane (G)

Clinic Pathology, San Giovanni di Dio e Ruggi d'Aragona University Hospital, Salerno, Italy.

Valentina Pinna (V)

Medical Genetics Division, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.

Alessandro De Luca (A)

Medical Genetics Division, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy.

Marco Tartaglia (M)

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.

Giovanni Di Minno (G)

Regional Reference Centre for Coagulation Disorders, Department of Clinical and Experimental Medicine, Federico II University of Naples, Naples, Italy.

Pietro Strisciuglio (P)

Dipartimento di Scienze Mediche Traslazionali, Università degli studi di Napoli Federico II, Naples, Italy.

Daniela Melis (D)

Dipartimento di Scienze Mediche Traslazionali, Università degli studi di Napoli Federico II, Naples, Italy. melisdaniela2418@gmail.com.
Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Salerno, Italy. melisdaniela2418@gmail.com.
Pediatric Unit, San Giovanni di Dio e Ruggi d'Aragona University Hospital, Salerno, Italy. melisdaniela2418@gmail.com.

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