Dipartimento di Scienze Mediche Traslazionali, Università degli studi di Napoli Federico II, Naples, Italy.
Regional Reference Centre for Coagulation Disorders, Department of Clinical and Experimental Medicine, Federico II University of Naples, Naples, Italy.
Orphanet J Rare Dis. 2021 Dec 2;16(1):499. doi: 10.1186/s13023-021-02122-7.
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.
已有研究报道，患有努南综合征的患者会出现出血异常。然而，目前尚未对分子确诊的 RAS 病患者进行相关研究。本研究旨在描述 RAS 病患者出血障碍的频率和类型，并评估其与实验室检查结果的显著相关性。
本研究纳入了 49 名患者（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）和 49 名年龄和性别相匹配的对照者。我们采用“儿科出血问卷评分关键”对患者及其家属进行评估。所有患者和对照者均接受了凝血因子剂量、血小板计数、凝血酶原时间和部分凝血活酶时间等实验室筛查检测，以评估出血倾向。此外，还对 29/49 名患者和 29/49 名对照者进行了血小板功能检测。
无论基因如何，有 14/49（28.5%）例患者的儿科出血评分异常。其中，7 例患者 PTPN11 突变，3 例 SOS1 突变，2 例 RIT1 突变，1 例 BRAF 突变，1 例 MEK1 突变。与出血评分正常的患者相比，出血评分异常的患者更易出现脾肿大（p=0.006）、延长的部分凝血活酶时间（p=0.04）、更低的凝血因子 V（FV，p=0.001）、VII（p=0.003）、X（p=0.0008）和 XIII（p=0.002）水平，更高的血管性血友病因子（vWAg，p=0.04），以及对瑞斯托霉素（p=0.001）、花生四烯酸（AA，p=0.009）和胶原（p=0.01）的血小板敏感性降低。存在血肿与 FV（p=0.002）、VII（p=0.003）、X（p=0.002）和 XIII（p=0.004）水平呈负相关，与胶原（p=0.02）和 AA（p=0.01）的血小板反应呈正相关。脾肿大与血肿的存在（p=0.006）、瑞斯托霉素（p=0.04）和 AA（p=0.04）的血小板反应呈正相关，与 FV 水平呈负相关（p=0.03）。
患有 RAS 病且存在出血倾向的患者表现出多种实验室异常，包括血小板相关疾病。脾肿大很常见，可能是血小板功能障碍的提示性体征。在诊断时、随访期间和任何手术前都应进行全面的临床评估。由于目前尚无关于出血并发症管理的共识，因此密切监测这些患者非常重要。
