Idiopathic pulmonary arterial hypertension – a unrecognized cause of high‐shear high‐flow haemostatic defects (otherwise referred to as acquired von Willebrand syndrome) in children

Abstract

Acquired von Willebrand syndrome (AVWS) is reported in high-flow high-shear congenital cardiac disorders. We hypothesized that the narrowed pulmonary vasculature in idiopathic pulmonary arterial hypertension (IPAH) may induce AVWS. We conducted a cross-sectional evaluation of children with IPAH. Patients with bleeding symptoms and/or laboratory abnormalities (thrombocytopenia, anomalies in coagulation screening tests) were tested in-depth for haemostatic defects. Fourteen children were followed with IPAH of which 8 were eligible. Four children exhibited abnormal bleeding scores (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool: 3-5). All 8 patients showed very prolonged platelet function analyser (PFA)-100 closure times. Six children demonstrated either mild thrombocytopenia or low-normal von Willebrand factor (VWF) antigen (VWF:Ag) or VWF activity [mean (range), in iu/dl: VWF:Ag: 70 (61-91); VWF activity: 57 (34-70)]. Average VWF collagen binding capacity (VWF:CB) was 64 iu/dl (range: 53-123 iu/dl), with low-normal VWF activity/VWF:Ag or VWF:CB/VWF:Ag ratios occurring in five patients. All children had normal multimers distribution patterns. One patient underwent a lung transplantation, with normalization of haemostatic abnormalities post-surgery. Overall, 8 out of 14 children with IPAH had mild to moderate bleeding symptoms and/or laboratory abnormalities in keeping with AVWS. Normalization of the haemostatic defects following lung transplantation and lack of family history of bleeding attests to the acquired nature of their defects.

Coagulation Profiles of Pulmonary Arterial Hypertension Patients, Assessed by Non-Conventional Hemostatic Tests and Markers of Platelet Activation and Endothelial Dysfunction

“…Lastly, we evaluated VWF:Ag and VWF:Acin our study population, which were found to be decreased in PAH patients compared to controls, along with the VWF Ac/Ag ratio. Some studies in the field have linked PAH with acquired von Willebrand syndrome [ 27 , 28 ]. VWF multimers are particularly large in size, making them vulnerable to biophysical forces, including shear stress [ 29 ].…”

“…PAH is a chronic and progressive disorder, where endothelial dysfunction plays a central role in its development and evolution [ 27 ]. The chronic injury to the pulmonary endothelium could result in chronic platelet and coagulation cascade activation, extended platelet degranulation and, subsequently, in platelet function abnormalities [ 31 ].…”

Platelets, extracellular vesicles and coagulation in pulmonary arterial hypertension

“… 52 Subsequent studies have shown low and low–normal levels of vWF antigen and activity in PAH. 53 , 54 These results were attributed to an acquired von Willebrand syndrome in the context of a ‘high-shear high-flow’ circulation.…”

Treatment of pulmonary arterial hypertension in children

“…Anticoagulation with warfarin or phenprocoumon was once not recommended on a routine basis in children with idiopathic pulmonary arterial hypertension (6). Chronic anticoagulation can be useful in patients with progressive IPAH/HPAH (empirical goal INR 2.0 to 2.5), patients with CTEPH, patients with low cardiac output, and those with hypercoagulable states (7).…”

“…must be weighed against potential benefits in patients with low cardiac output. Often right heart failure will be associated with bleeding symptoms and/or anomalies in coagulation screening tests (6).…”