Shear-stress induced acquired von Willebrand syndrome in children with congenital heart disease

Florian Loeffelbein 1 3 4 Dominika Funk 3 4 Lea Nakamura 2 4 Barbara Zieger 2 4 Jochen Grohmann 3 4 Matthias Siepe 0 4 Johannes Kroll 0 4 Brigitte Stiller 3 4 0 Department of Cardiovascular Surgery, University Heart Center Freiburg - Bad Krozingen , Freiburg , Germany 1 Pediatric Cardiology, Heart Center, University Hospital , Leipzig , Germany 2 Department of Pediatrics and Adolescent Medicine, University Medical Centre Freiburg , Freiburg , Germany 3 Department of Congenital Heart Disease and Pediatric Cardiology, University Heart Center Freiburg - Bad Krozingen , Freiburg , Germany 4 Authors: Ugur Kucuk, Zafer Isilak, Omer Uz and Sevket Balta Department of Cardiology, Gulhane Military Medical Academy , Istanbul , Turkey doi : 10.1093/icvts/ivu401 The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved OBJECTIVES: To determine the frequency and severity of acquired von Willebrand syndrome (AVWS) in children with stenotic congenital heart disease (CHD) before and after intervention. METHODS: In this single-centre prospective observational case-control study, 50 children [median age: 26 (range, 0-175) months, bodyweight: 9.5 (2.2-7.5) kg] underwent catheter interventions or cardiac surgery. A total of 26 children with high stenosis [mean gradient: 80 (range, 52-130) mmHg] represented the stenosis group and 24 without relevant stenosis (<20 mmHg) served as the control group. von Willebrand factor (VWF) was analysed with respect to quantity and function before and after corrective or palliative intervention. RESULTS: Demographic data were comparable. The stenosis group had more surgical and the control group more interventional procedures (P = 0.025). Before intervention, 13 patients from the stenosis group (50%) showed a significant reduction in VWF-multimers compared with no patients in the control group (P <0.001). Collagen binding capacity (VWF:CB) was lower in the stenosis group [0.5 (0.2-2.6) U/ml vs 0.8 (0.4-2.1) U/ml, P <0.05), as was the collagen binding capacity to antigen ratio (VWF:CB/Ag) [0.8 (0.4-1.4) U/ml vs 1 (0.4-1.7) U/ml, P <0.001). After intervention, VWF parameters normalized rapidly within the first 24 h after the procedure and showed no group differences. {VWF:CB [1.7 (0.6-3.7) vs 1.7 (0.6-4.2) U/ml, P = n.s.], VWF:CB/Ag [1.1 (0.5-2.9) vs 1.2 (0.7-2.2), P = n.s} Time in the intensive care unit, respirator time, duration of stay and bleeding before and after intervention were not significantly different. CONCLUSIONS: AVWS is detected in half of the children with high intra- or extracardiac stenoses and resolves completely after surgical or interventional repair. Even when undergoing surgery on cardiopulmonary bypass, excessive surgical site bleeding was not detected in our study patients. - With a supposed prevalence of between 0.8 and 1.3%, von Willebrand disease or syndrome (VWS) is one of the most common inherited coagulation disorders [1]. The underlying cause is a defect of the von Willebrand factor (VWF), a protein that is usually found as covalently bound multimers in plasma [2]. During activation, the globally structured VWF-multimer is stretched due to high shear stress [3] and exposes binding sites for platelets [4], collagen [5] and integrins [6]. These binding sites mediate the formation of a stable net with the corresponding structures of the extracellular matrix and platelets and, thus, initiate haemostasis to form a stable thrombus [7]. If this interaction is disturbed, bleeding occurs and blood loss can be life-threatening, especially in gastrointestinal or surgical bleeding [8]. The acquired von Willebrand syndrome (AVWS) is a well-characterized condition in neoplastic and immunological disorders with receptors on neoplastic cells or antibodies inactivating VWF-multimers [1]. Ten years ago, the first patient with AVWS with aortic stenosis was described [9, 10]. Later, AVWS was identified in patients after mitral valve prolapse/regurgitation [11] and mitral valve replacement [12], hypertrophic cardiomyopathy [13] and in adults mechanically supported with ventricular assist devices and extracorporeal life support [1416]. In all these patients, the stenosis (valvular, muscular or mechanical) induces high shear stress, with the result of stretching and rupturing of the VWF-multimers if the stenosis exceeds a certain threshold [16]. The ruptured VWF loses its function and is assigned for proteolysis by ADAMTS13 [1719] (a disintergrin and metalloproteinase with a thrombospondin type 1 motif, member 13), a metalloprotease enzyme that cleaves large VWF-multimers. The aim of this study was to analyse the impact of stenosis and/or gradient-related shear stress on VWF in children with congenital heart disease (CHD), the frequency of AVWS and the risk of bleeding during surgery. Furthermore, we asked whether an AVWS resolves after reduction or relief of the stenosis or the gradient. In this single-centre prospective, observational, case-controlled study, 50 children underwent either cardiac catheter intervention or cardiac surgery. The study protocol was approved by the local ethics committee. Written consent was obtained from the parents. The stenosis group was represented by 26 children with CHD and high-gradient stenosis (echocardiographic systolic instantaneous peak gradient >50 mmHg), determined by Doppler echocardiography (Vivid7, GE Medical, Munich, Germany) by the modified Bernoulli equation. Twenty-four children without rele vant stenosis (<20 mmHg, if determinable) undergoing surgical or interventional procedures served as the control group. Blood tests to check for coagulation disorders were performed before, 4 h, optionally 24 and 48 h after surgical or catheter intervention, if a central line was still present. In accordance with the study protocol, we did not take blood samples from young children without a central line, especially in patients undergoing catheter intervention. All sample analyses were performed in our laboratory with commercially available kits: total blood count (automated counter Sysmex SE 9000, Sysmex, Norderstedt, Germany), partial thomboplastin time, prothrombin time, international normalized ratio, antithrombin III [enzyme-linked immunosorbent assay (ELISA), Dade Behring, Eschborn, Germany], Protein C (ELISA, Dade Behring, Eschborn, Germany), Protein S (LIA Chromogenix, Milano, Italy), D-Dimers (ELISA, Dade Behring, Eschborn, Germany), APC-resistance (Kit Pentapharm, Basel, Switzerland), lipoprotein A, VWF:Ag (ELISA, Dako-Cytomation, Hamburg, Germany). VWF collagen binding capacity (VWF:CB) is proportional to intact multimers and was measured using collagencoated plates and a commercially available antibody (ELISA, Dako-Cytomation, Hamburg, Germany). VWF:CB/Ag represents collagen binding capacity to antigen ratio. Cut-off values are as follows: VWF:Ag, 0.61.5 U/ml, VWF:CB, 0.61.5 U/ml and VWF:CB/ Ag, 0.81.5. VWF-m (...truncated)