PB0237 - Bleeding assesment in children with Noonan syndrome

Background: Noonan syndrome (NS) is an autosomal dominant disease involving multisystem clinical aspects including a bleeding tendency. The exact nature of the hemostatic impairment in NS has not been elucidated. Various hematological abnormalities have reported including impairment of platelet number and function as well as clotting factor deficiencies and von Willebrand disease. Hemostatic evaluation by global coagulation assays has not been reported.

Aims: To assess clinical aspects and laboratory parameters of hemostasis in a cohort of children diagnosed with NS, including application of thromin generation (TG) assays.

Methods: Clinical bleeding tendency was evaluated by the ISTH bleeding assessment tool (BAT). Hemostatic assessment included platelets number, Platelets function by light transmission aggregometry (LTA). PT, aPTT, Fibrinogen, Von Willebrand factor antigen, Ristocetin Cofactor, FVIII levels and TG parameters (peak height and endogenous thrombin potential- ETP in platelet rich plasma (PRP) .

Results: Twenty patients (10 males) whose median age at evaluation was 6.5 years IQR (3-13) years composed our NS cohort. The most common pathogenic genetic variants were in PTPN11 and KRAS. Four patients (20%) had an elevated BAT score. Platelet number, PT and aPTT were within normal range for the entire cohort. Five patients had lower than normal Fibrinogen levels. Reduced levels of VWF antigen and activity were detected in three patients, two of which had pulmonic stenosis. Platelet aggregation studies as evaluated by LTA were impaired in half of the cohort mostly in response to Epinephirine. Median peak height 136 nM IQR (108-153) and median ETP 1657 (nM × min) IQR (1511-2026) levels were lower as compared to healthy controls.

Conclusion(s): Impaired hemostasis may commonly be encountered among individuals with NS. The most common abnormality is impaired platelet aggregation. NS patients especially, those with pulmonic stenosis, should be evaluated for VWD. The clinical association of TG with patients' bleeding phenotype should be further investigated.