Bleeding diathesis in Noonan syndrome: is acquired von Willebrand syndrome the clue?

Introduction: Noonan syndrome (NS) is characterized by dysmorphic facies, short stature and congenital heart defects. Various haemostatic disorders have been described in NS patients, but not all were related to bleeding, which itself is present in up to 65%. Several subgroups of NS - especially those with PTPN11 mutation - are associated with pulmonary stenosis. As it is known that some heart defects are prone to a shear stress related destruction of the von Willebrand factor as an important haemostatic component, we aimed to find out, whether the pulmonary stenosis could be responsible for such a mechanism in NS patients.

Patients, methods and results: We investigated the haemostatic system in 15 children with genetically proven NS (14 with PTPN11, one with SOS1 mutation). Platelet count, basic coagulation parameters, fibrinogen and antithrombin were normal in all patients, none had a relevant reduction of coagulation factor activities. Five patients had pulmonary valve stenosis with systolic gradients>60 mmHg. In three of them a deficiency of the high molecular weight multimers and a pathologic collagen-binding capacity were detected, suggesting acquired von Willebrand syndrome. Nine of our patients indicated a relevant bleeding diathesis and complained of easy bruising, three reported spontaneous gum bleeding.

In conclusion: the destruction of the von Willebrand factor could explain the bleeding in some of the NS patients with pulmonary valve stenosis. Our finding is of clinical relevance since most of these patients require either interventional cardiac catheterization or open heart surgery which may be complicated by the haemorrhagic tendency.