Background: Noonan Syndrome (NS) is a rare genetic disorder characterized by several morphological anomalies, and bleeding diathesis for which causes remain unclear.  

Aims: We aimed to characterize the bleeding phenotype of patients with NS using coagulation and platelet functions assays.

Methods: In our center, 26 patients with NS, irrespective of their genotype, were screened for bleeding risk. Bleeding phenotype was scored using the ISTH Bleeding assessment tool. Prothrombin time, activated partial thromboplastin time, as well as coagulation factors including factor II, V, VII, X, VIII, IX, XI, and von Willebrand factor were measured. Platelet count, morphology, and function were extensively assessed.  Light-transmission on blood smear, and transmission electron microscopy (TEM) on whole mount and ultrathin section of platelets, were performed. Platelet activation in response to various platelets agonists was studied using light-transmission aggregometry (LTA). In addition, platelet surface glycoprotein, CD62P, PAC1, and fibrinogen binding expressions were measured using flow cytometry analysis (FCM).

Results: Maximum platelet aggregation after platelet activation by various agonists using LTA in patients with NS compared to normal values. *p<0.05 ; the numbers above bars represent the number of patients studied; NS : Noonan syndrome ; PTPN11 : patients with NS having a PTPN11 mutation, SOS1 : patients with NS having a SOS1 mutation, RIT1 : patients with NS having a RIT1 mutation, RAF1 : patients with NS having a RAF1 mutation.8/26 (31%) patients had significant hemorrhagic diathesis, with cutaneous and/or mucosal bleedings. 6/26 (23%) patients had up to 3 factor levels below the normal laboratory values, but above the corresponding hemostatic threshold. Platelet count, blood smear, glycoprotein expression, and whole-mount TEM were normal for all patients. However, TEM studying ultrathin section of platelets showed elongated platelets with reduced alphatocrite in 11/26 (65%) patients. All patients with NS presented a lower maximum aggregation intensity compared to normal values (Figure 1), and a lower CD62P, PAC1 and fibrinogen binding expressions, irrespective of the agonist used for platelet activation. The most frequent and the more pronounced defects were observed after TRAP, and ADP-induced platelet activation.  

Conclusions: Platelet function defects were the most frequent disorders observed in patients with NS. Therefore, we recommend platelet functions to be screened systematically in such patients to adapt the best therapeutic strategy for preventing bleeds during surgical procedures.  

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/noonan-syndrome-bleeding-diathesis-coagulation-factor-deficiencies-and-or-platelet-function-disorders/