Background: Noonan Syndrome (NS) is an autosomal dominant genetic disorder with multiple anomalies, including bleeding diathesis. Although the bleeding phenotype is mild, surgical management is often required including procedures with high bleeding risk. CBC, PT, aPTT and F XI are recommended at diagnosis, however platelet function abnormalities were rarely reported in these patients.

Aims: To charachterize hemostatic and platelet function abnormalities in NS patients.

Methods: PT, aPTT were determined with IL Werfen automated coagulation analyzer. ISTH-BAT was administered to patients. Platelet function was investigated using light transmission aggregometry (LTA) and PRP stimulated by ADP, collagen, epinephrine, PAR1 activating peptide (AP). Maximal aggregation (MA, %) for all agonist and lag phase (LP, seconds) for collagen were measured. Platelet secretion was investigated by flow cytometry using MoAbs directed against CD63 and CD62p on ADP and PAR1-AP stimulated platelets. Mean fluorescence intensity (MFI) was measured.

Results: A-F: Maximal aggregation (MA %) to ADP 2 µM, ADP 4 µM, collagen 2 µg/ml, epinephrine 5 µM, PAR1-AP 10 µM in patients with Noonan syndrome and controls. G-H: Flow cytometry analysis for of platelet secretion markers (CD63 and CD62p) after stimulation with ADP 10 µM and PAR1-AP 10 µM. A-E: One-Way ANOVA, followed by Bonferroni’s test, was used to determinate significant differences. F-H: A two-tailed t-test was used to determinate significant differences. **** P< 0.0001; *** p< 0.001; ** p< 0.01; * p< 0.05.General characteristics of the study population, ISTH-BAT bleeding score, coagulation tests and genetic testing.The study population included 24 patients and 14 controls. Platelet count, PT and fibriongen were not significantly different in the 2 groups, 30% of NS had aPTT prolongation (Table 1). Noonan patients had significant reduction of platelet aggregation with ADP 2 µM (91,6% with MA <60%), ADP 4 µM (79,1 % with MA<60%), collagen 2 µg/ml (41,6 % with MA<75%, 87% with LP>50 sec), epinephrine 5 µM (87% with MA< 60% at 180 sec, 62.5% with MA <70% at 300 sec), PAR1-AP (45.8% with MA<75%). A significant reduced expression of activation-dependent markers CD63 and CD62p was found after PAR1-AP stimulation, and of CD62p after ADP stimulation. (Fig.1).

Conclusions: In the present cohort, large majority (>90%) of Noonan pts showed platelet dysfunction, whereas their platelet count was normal and only 30% of NS had aPTT prolongation. Platelet secretion defect is suggested by activation-dependent CD63 and CD62p marker exposure.  Platelet dysfunction is the most frequent hemostasis abnormality in NS.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/platelet-dysfunction-in-noonan-syndrome/