Lea Nakamura

Acquired von Willebrand syndrome in patients with extracorporeal life support (ECLS)

PurposeExtracorporeal life support (ECLS) is used for patients with refractory heart failure with or without respiratory failure. This temporary support is provided by blood pumps which are connected to large vessels. Bleeding episodes are a typical complication in patients with ECLS. Recently, several studies illustrated that acquired von Willebrand syndrome (AVWS) can contribute to bleeding tendencies in patients with long-term ventricular assist devices (VAD). AVWS is characterized by loss of the high molecular weight (HMW) multimers of von Willebrand factor (VWF) as a result of high shear stress and leads to impaired binding of VWF to platelets and to subendothelial matrix. Since ECLS and VAD share several features, we investigated patients with ECLS for AVWS.MethodsWe analyzed 32 patients with ECLS and 19 of them without support. To diagnose AVWS, ratios of ristocetin cofactor activity (VWF:RCo) and collagen binding capacity (VWF:CB) to VWF antigen (VWF:Ag) were employed in conjunction with multimeric analysis.ResultsReduced VWF:RCo/VWF:Ag ratios were identified in 28 ECLS patients. Furthermore, VWF:CB/VWF:Ag ratios were decreased in 31 patients. HMW multimers of VWF were missing in the same 31 patients. Thus, 31 of 32 ECLS patients presented with AVWS. Twenty-two of the 32 patients suffered from bleeding complications. Without support, AVWS was not detectable in any analyzed patient.ConclusionOur data indicate that AVWS is a typical disorder in patients with ECLS. We hypothesize that AVWS could contribute to aggravation of bleeding tendencies in ECLS patients.

Acquired von Willebrand syndrome in patients with ventricular assist device or total artificial heart.

Unexplained bleeding episodes are associated with ventricular assist devices (VAD) and can occur in part due to acquired von Willebrand syndrome (AVWS). AVWS is characterised by loss of high molecular weight (HMW) multimers of von Willebrand factor (VWF) and decreased ratios of collagen binding capacity and ristocetin cofactor activity to VWF antigen. Loss of multimers can occur as VWF is subjected to increased shear stress, which occurs in presence of VADs. We studied 12 patients who required mechanical support of their native heart for terminal cardiac insufficiency. Nine patients underwent placement of a VAD, while three underwent placement of a total artificial heart (TAH), which is connected directly to heart and large cardiac vessels without cannulas. Within one day of VAD implantation, four of five patients evaluated demonstrated loss of HMW multimers and impaired VWF function. AVWS was present within two weeks of implantation in eight of nine patients, and in all seven tested patients after >/=3 months. Patients with different VAD types developed varying severities of AVWS. After VAD explantation, HMW multimers were detectable and VWF function normalised in all patients. AVWS was not observed in the TAH patients studied. Our findings demonstrate that patients with an implanted VAD experience a rapid onset of AVWS that is quickly and completely reversed after device explantation. In addition, TAH patients do not develop AVWS. These results suggest that shear stress associated with exposure of blood to VAD cannulas and tubes may contribute to the development of AVWS.

Acquired Von Willebrand syndrome is an early-onset problem in ventricular assist device patients,

OBJECTIVE Acquired Von Willebrand syndrome (AVWS) can contribute to bleeding complications in patients with ventricular assist devices (VADs). AVWS results from shear stress, which causes unfolding of the high-molecular-weight (HMW) multimers of Von Willebrand factor (VWF) with subsequent cleavage. Loss of the HMW multimers of VWF is the leading finding in AVWS. In consequence, binding of VWF to collagen and to platelets is impaired. The onset of AVWS after VAD implantation is not yet determined. We examined VAD patients for presence of an AVWS in the early, intermediate, and late phase after VAD implantation. METHODS Patients with a biventricular Thoratec-PVAD(®) (BVAD, n = 6) or a left-ventricular HeartMateII(®) (HMII, n = 11) were analyzed prior to VAD implantation and after 1, 3, 14, 30, and 60 days. Diagnosis of AVWS based on VWF:ristocetin cofactor activity/VWF:VWF antigen (VWF:RCo/VWF:Ag), collagen-binding capacity:VWF antigen (VWF:CB/VWF:Ag), and multimeric analysis. In addition, we analyzed the number of bleeding episodes, which required surgical intervention. RESULTS No patient had an AVWS prior to VAD implantation. An AVWS was identified already in the very early postoperative period, that is, in almost all patients on the first day and in all patients on the third day. The AVWS was also detected in the majority of patients in the further course. Nine of all 17 patients suffered bleeding complications and required a total of 25 interventions due to hemorrhages. Forty percent of re-interventions were carried out within the first 10 days after implantation; five of these were necessary within the first 24h. CONCLUSION The AVWS is present already in the early postoperative phase after VAD implantation. Therefore, reduced shear stress has to be an important feature of newly developed assist devices in the future.

Platelet secretion defect in patients with familial hemophagocytic lymphohistiocytosis type 5 (FHL-5).

To the editor: Familial hemophagocytic lymphohistiocytosis (FHL) is a genetic disorder of lymphocyte cytotoxicity caused by mutations in the gene encoding perforin (FHL-2) or in genes encoding proteins important for intracellular trafficking and exocytosis of perforin-containing lytic granules.[1][

Early Diagnosis of Acquired von Willebrand Syndrome (AVWS) is Elementary for Clinical Practice in Patients Treated with ECMO Therapy

AIMS Acquired Von Willebrand syndrome (AVWS) is an acquired bleeding disorder that has been reported to aggravate bleeding complications in patients with ventricular assist devices or aortic stenosis. AVWS is characterized by the loss of the high-molecular-weight (HMW) multimers of Von Willebrand factor (VWF) with consequent impaired VWF binding to platelets and collagen. The aim of this study was to investigate the development of AVWS in patients treated with veno-venous ECMO (extracorporeal membrane oxygenation) support. METHODS We examined the presence of AVWS in adult patients receiving ECMO support (n=18) and control subjects treated without ECMO support (n=18). The diagnosis of AVWS was made based on the ratio of collagen-binding capacity to VWF-antigen (VWF:CB/VWF:Ag) and a VWF multimeric analysis. In addition, bleeding episodes were monitored. RESULTS All patients supported with ECMO developed AVWS. AVWS was identified in the early period after ECMO implantation, i.e. within 24 hours after ECMO implantation. In 17 patients, the VWF:CB/VWF:Ag ratio was significantly reduced and HMW multimers were severely missing, and 17 of the 18 patients developed bleeding complications and required transfusions of blood, FFP and/or platelet concentrates.In addition, nine patients without an ECMO device were investigated (prior to ECMO implantation: n=2, after ECMO explantation: n=7). CONCLUSIONS In this study, all patients treated with ECMO support developed AVWS, and AVWS was detectable within 24 hours after ECMO implantation. However, the AVWS was reversible after ECMO explantation. Making an early diagnosis of AVWS and providing appropriate treatment may reduce the incidence of life-threatening bleeding.

Platelet dysfunction and acquired von Willebrand syndrome in patients with left ventricular assist devices

OBJECTIVES Unexplained bleeding events are a severe complication in patients with left ventricular assist devices (LVADs). Platelet dysfunction and acquired von Willebrand syndrome (AVWS) may contribute to bleeding tendencies. Yet, comprehensive data with respect to platelet function and AVWS in LVAD patients in terms of bleeding events are scarce. METHODS Thirty-nine HeartMate II patients were included in this study. Data of at least two time points were available for each patient. Platelet function was analysed via light transmission aggregometry in 19 patients without LVAD, 28 in early (≤14 days) and 30 in late postimplantation states (≥30 days). Von Willebrand factor (VWF) antigen, VWF collagen binding capacity and VWF multimeric analyses were performed in 26 patients without LVAD, 39 in early and 33 in late postimplantation states to diagnose AVWS. Bleeding complications were recorded for 39 patients in the early and 33 in the late postoperative period. RESULTS Platelet dysfunction was detectable in 18 of 19 without LVAD and in all patients following LVAD implantation. Platelet aggregation values did not change over time (without-early, P = 0.27, n = 14; early-late, P = 0.17, n = 21). AVWS was not diagnosed in patients without LVAD, except for one. On LVAD, 33 of 39 patients had AVWS in the early and all in the late period (n = 33). Bleeding events occurred in 44% of patients in the early and in 64% of patients in the late period. CONCLUSIONS According to our data, platelet aggregation is often impaired in LVAD patients even without an implanted LVAD. Additionally, appearance of AVWS seems to be closely linked to LVAD implantation.

Comparison of Von Willebrand factor (VWF) activity VWF:Ac with VWF ristocetin cofactor activity VWF:RCo

INTRODUCTION Ristocetin cofactor activity of Von Willebrand factor (VWF:RCo) and the ratio VWF:RCo to its antigen VWF:Ag are used as routine screening to estimate VWF function and to detect types of Von Willebrand disease (VWD) caused by loss of high molecular weight multimers. However, the VWF:RCo test is prone to analytic imprecisions due to various reasons. We compared an assay for VWF activity (VWF:Ac) with VWF:RCo putting emphasis on the ratios to VWF:Ag. MATERIALS AND METHODS We evaluated 942 samples from 432 patients and evaluated three groups in detail: normal patients (normal multimers, VWF:Ag and VWF:RCo >0.5 U/ml, VWD type 1 excluded; n=258), VWD type 1 (n=76) and acquired Von Willebrand syndrome (AVWS, n=326). In addition, 30 healthy subjects were analysed. RESULTS VWF:Ac and VWF:RCo correlated well (Pearson´s r=0.96, p<0.01), so did their ratios to VWF:Ag (Pearson´s r=0.82, p<0.01). We calculated the normal range of VWF:Ac/VWF:Ag for healthy subjects as 0.8-1.16. In comparison, the reference range (mean±2std) derived from normal patient samples was 0.73-1.14. The corresponding ranges for VWF:RCo/VWF:Ag came to 0.74-1.23 (healthy) and 0.62-1.25 (normal patients). The ratios showed similar results regarding VWD type 1. The sensitivity for AVWS was higher with VWF:Ac/VWF:Ag than with VWF:RCo/VWF:Ag (97.5% versus 84.7%). CONCLUSIONS The data suggest that the results obtained with the VWF:Ac assay are comparable to that of the VWF:RCo assay. An AVWS was more reliably detected by VWF:Ac/VWF:Ag. We assume that the VWF:Ac assay could replace VWF:RCo for routine screening for AVWS, especially when prompt evaluation is required.

First characterization of platelet secretion defect in patients with familial hemophagocytic lymphohistiocytosis type 3 (FHL-3)

To the editor: Familial hemophagocytic lymphohistiocytosis (FHL), a rare autosomal recessive disorder of lymphocyte cytotoxicity, is caused by mutations in genes encoding perforin (FHL-2) or proteins important for intracellular trafficking/exocytosis of perforin-containing lytic granules: Munc13-4

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

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.