Acquired Von Willebrand Syndrome In Patients Research Articles

Acquired von willebrand syndrome in patients with philadelphia-negative myeloproliferative neoplasm.

Acquired von Willebrand syndrome (AVWS) has not been investigated in Korean patients with Philadelphia chromosome-negative myeloproliferative neoplasm. This study analyzed the prevalence at diagnosis and clinical features of AVWS in patients with essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic/early primary myelofibrosis (pre-PMF), or overt PMF (PMF) diagnosed between January 2019 and December 2021 at Chungam National University Hospital, Daejeon, Korea. AVWS was defined as below the lower reference limit (56%) of ristocetin cofactor activity (VWF:RCo). Sixty-four consecutive patients (36 with ET, 17 with PV, 6 with pre-PMF, and 5 with PMF; 30 men and 34 women) with a median age of 67 years (range, 18‒87 yr) were followed for a median of 25.1 months (range, 2.6‒46.4 mo). AVWS was detected in 20 (31.3%) patients at diagnosis and was most frequent in ET patients (41.4%), followed by patients with pre-PMF (33.3%) and PV (17.6%) patients. VWF:RCo was negatively correlated with the platelet count (r=0.937; P=0.002). Only one episode of minor bleeding occurred in a patient with ET and AVWS. Younger age (<50 yr) [odds ratio (OR), 7.08; 95% confidence interval (CI), 1.27‒39.48; P=0.026] and thrombocytosis (>600×109/L) (OR, 13.70; 95% CI, 1.35‒138.17; P=0.026) were independent risk factors for developing AVWS. AVWS based on VWF:RCo was common in patients with ET and pre-PMF, but less common in patients with PV in the Korean population. Clinically significant bleeding is rare in these patients.

Diagnosis and Management of Acquired von Willebrand Disease in Heart Disease: A Review of the Literature.

The incidence of acquired von Willebrand syndrome (AvWS) in patients with heart disease is commonly perceived as rare. However, its occurrence is underestimated and underdiagnosed, potentially leading to inadequate treatment resulting in increased morbidity and mortality.In patients with cardiac disease, AvWS frequently occurs in patients with structural heart disease and in those undergoing mechanical circulatory support (MCS).The clinical manifestation of an AvWS is usually characterized by apparent or occult gastrointestinal (GI) or mucocutaneous hemorrhage frequently accompanied by signs of anemia and/or increased bleeding during surgical procedures. The primary change is loss of high-molecular weight von Willebrand factor multimers (HMWM). Whereas the loss of HMWM in patients with structural heart disease is caused by increased HMWM cleavage by von Willebrand factor (vWF)-cleaving protease, ADAMTS13, AvWS in MCS patients is predominantly a result of a high shear stress coupled with mechanical destruction of vWF itself.This manuscript provides a comprehensive review of the evidence regarding both diagnosis and contemporary management of AVWS in patients with heart disease.

Prevalence of acquired von Willebrand syndrome during essential thrombocythemia: a retrospective analysis of 170 consecutive patients.

The identification of patients with essential thrombocythemia (ET) who are at increased risk of acquired von Willebrand syndrome (AVWS) would likely facilitate individualization of treatment and improve its outcomes. The aim of the study was to determine the prevalence of AVWS in patients with ET and to verify whether individuals with and without this bleeding disorder differ in terms of their baseline clinical parameters. The study included 170 consecutive patients with ET. AVWS was diagnosed on the basis of reduced levels of von Willebrand factor and abnormal results of other routine tests. Patients with and without concomitant AVWS were compared in terms of their demographic characteristics, past and current medical histories, and laboratory parameters. Concomitant AVWS was found in 34 patients (20%). Individuals with AVWS were diagnosed with ET at a significantly younger age than those without the syndrome. In addition, these patients significantly less often were in remission at the time of testing, had significantly higher erythrocyte and platelet counts, and showed abnormalities of the coagulation profile corresponding to defects of primary hemostasis as well as abnormal values of most parameters used i n the routine diagnosis of AVWS. Even every fifth patient with ET may develop AVWS. Young age at diagnosis of ET and the lack of response to its previous treatment are potential risk factors for AVWS that should be considered during the management of the primary condition. All patients with ET and signs of a bleeding disorder, irrespective of the platelet count, should be tested for the presence of AVWS.

Early diagnosis of acquired von Willebrand Syndrome (AVWS) is elementary for clinical practice in patients treated with ECMO therapy.

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. 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. 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). 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.

Predictors of Acquired Von Willebrand Syndrome in Patients with Aortic Stenosis,

Abstract 3318▪▪This icon denotes a clinically relevant abstract Background:Acquired von Willebrand syndrome (AVWS) due to loss of high molecular weight multimers (HMWM), is a frequent cause of bleeding in aortic stenosis (AS), and is reversed by valve replacement. The goal of this study was to explore predictors of AVWS in patients with AS. Methods:A total of 91 patients (59 men, median age 79 years) with AS (n=64) or heart valve replacement (n=27) were included. We recorded peripheral blood count, vital signs, mean gradient (MG), peak velocity (peak vel), aortic valve time velocity integral (AV-TVI), aortic valve area (AVA) and valve area index (AVAi), time velocity integral ratio (TVI ratio), VWF antigen (VWF:Ag), VWF activity by latex immunoturbidity assay (VWF:Lx), VWF multimer analysis, closure times of platelet function analyzer ADP and epinephrine cartridges (PFA-CADP and –CEPI). HMWM losses were graded as normal, mild or severe when compared to HMWM analyses of pooled plasma samples from normal donors. Potential predictors of HMWM loss were explored using logistic regression analysis. Results:Of the 91 patients, 42 (46%) had loss of HMWM (23 mild and 19 severe). In single variable logistic regression analysis, AVWS was associated with a low AVA (<1.0 cm2; OR=5.08, P<0.001), and low AVAi (<0.60 cm2/m2; OR=5.54, P<0.001), low TVI ratio (<0.25; OR=10.80, P<0.001), prolonged PFA-CADP (≥121 sec; OR=6.76, P<0.001), and low VWF:Lx/Ag (≤0.8; OR=8.06, P=0.008). Moderate peak vel (3–4 m/sec) and high peak vel (>4 m/sec) were associated with loss of HMWM (OR[vs. <3 m/sec]=5.80 and 37.70 respectively, P<0.001) as were moderate MG (25–40 mmHg) and high MG (>40 mmHg), (OR [vs. <25mmHg]=4.50 and 32.50 respectively, P<0.001). In exploratory multivariable analysis, mean gradient remained one of the strongest predictor of loss of HMWM. The estimated sensitivity of MG (≥25mmHg) in diagnosing AVWS was 83% (35/42, 95% CI: 69%-93%) and estimated specificity was 71% (35/49, 95% CI: 57%-83%). Considering the very strong correlation with mean gradient, we also considered the diagnostic utility of peak vel. Peak vel≥ 3 m/sec had a sensitivity of 89% (38/42, 95% CI: 77%-97%) and a specificity of 59% (29/49, 95% CI: 44%-73%) in detecting loss of HMWM. Conclusion:Our data suggest that mean gradient (>25 mmHg) and peak vel (≥ 3 m/sec), both derived from the Doppler aortic valve velocity envelope, are accurate predictors for AS-AVWS, and should be incorporated into algorithmic approaches to laboratory screening for AVWS.Table:Predictors of AS-AVWS (N=91)Single variable analysisMultivariable analysis1VariableOR (95% CI)p-valueOR (95% CI)p-valueGender (male)0.79 (0.33–1.87)0.590.61 (0.20–1.82)0.37Age (years)1.20 (0.84–1.78)0.340.96 (0.62–1.54)0.86Patient type (AS vs. valve replacement)12.48 (3.86–56.47)<0.0013.03 (0.65–16.69)0.17Aortic stenosis symptoms1.58 (0.67–3.73)0.300.27 (0.05–1.01)0.076Current use of coumadin0.14 (0.04–0.39)<0.0010.23 (0.06–0.83)0.031Current use of aspirin1.35 (0.58–3.19)0.491.29 (0.44–3.88)0.64GFR (60 vs. <60)1.96 (0.80–5.05)0.152.25 (0.71–7.73)0.18Atrial fibrillation0.56 (0.22–1.36)0.210.86 (0.27–2.73)0.80Left ventricular hypertrophy2.02 (0.80–5.21)0.141.17 (0.34–3.89)0.80Heart rate (10 bpm increase)1.30 (0.92–1.90)0.151.15 (0.75–1.77)0.52Systolic blood pressure ≥(140 mmHg2.41 (0.99–6.04)0.0523.41 (1.06–12.39)0.047Platelet (100 unit increase)2.12 (1.02–4.77)0.0533.83 (1.53–10.85)0.006Hemoglobin (1 unit increase)0.95 (0.72–1.24)0.691.08 (0.76–1.55)0.67Mean Gradient<0.001<0.001<25 mmHg1.00 (reference)1.00 (reference)25–40 mmHg4.50 (1.36–15.77)4.50 (1.36–15.77)>40 mmHg32.50 (9.47–140.35)32.50 (9.47–140.35)Peak velocity(m/sec)<0.001NA<3 m/sec1.00 (reference)3–4 m/sec5.80 (1.70–23.70)>4 m/sec37.70 (10.15–179.37)Aortic valve area <1.0 cm 25.08 (2.09–13.06)<0.001NAAortic TVI (10 cm increase)1.73 (1.41–2.21)<0.001NATVI Ratio<0.25210.80 (4.08–31.91<0.001NAAortic valve area index<0.60 cm25.54 (2.30–14.09)<0.001NAvWF: Lx/Ag = 0.8) 28.06 (1.99–54.58)0.009NAPFA collagen ADP closure time ≥ 121 sec6.76 (2.72–18.04)<0.001NA- Odds ratios (ORs), 95% confidence intervals (CIs), and corresponding p-values result from logistic regression analysis.2Variable was not included in multivariable analyses due to strong collinearity with mean gradient.1Multivariable models are adjusted for mean gradient. Disclosures:No relevant conflicts of interest to declare.

Acquired von Willebrand syndrome in multiple myeloma

Acquired von Willebrand syndrome (AvWS) is an uncommon complication of multiple myeloma (MM), and it is believed to be connected with paraprotein. The aim of this study was to determine the incidence of AvWS in patients with MM, and estimate the role of paraprotein in its occurrence. The study included 40 patients with MM. The plasma level of paraprotein, platelet adhesion on glass pearls, plasma von Willebrand factor antigen concentration, and ristocetin-induced platelet aggregation (RIPA) were measured initially. Absence of RIPA was found in six patients with MM (15%); however, all six of them had normal levels of von Willebrand factor antigen. Paraprotein was isolated from the serum of these patients. Platelet aggregation was measured in six healthy donors before and after addition of the isolated paraprotein. RIPA was significantly decreased in healthy donors in the presence of paraprotein (P<0·001). The same test was repeated with added human immunoglobulins for intravenous use without any change in RIPA. A significant negative correlation between plasma paraprotein level and RIPA was found (P<0·001). These investigations have shown that paraprotein is associated with AvWS in patients with MM.

Investigations on the Importance and Prevalence of the Acquired von Willebrand Syndrome in Patients with Myeloproliferative Disease.

The acquired von Willebrand syndrome (AVWS) is a bleeding disorder, which is amongst others associated with myeloproliferative diseases. Its prevalence varies from 0,04–0,13% in literature. Typical laboratory findings such as a low VWF:RCo/VWF:Ag- Ratio, a prolonged aPTT, PFA and bleeding time, a decrease of VWF:RCo, FactorVIII:, VWF:Ag, typical VWF multimeric structure and the absence of a family history of bleeding are the basis for the diagnosis of AVWS. Bleeding episodes are typical for AVWS and are mostly of the mucocutaneous type (epistaxis, heavy menstrual bleeding, gingival and postoperative bleedings). Myeloproliferative diseases, particularily essential thrombocythemia, are with 15–18% the third most frequent observed comorbidity of patients with AVWS, but the prevalence of AVWS in patients with MPS is -at our knowledge- still unknown. We investigated 54 patients with the diagnosis of myeloproliferative disease (44 ET, 9 PV, 1 IMF), which was established according to the WHO-criteria over a period of 6 years (2000–2006). By analysing the typical laboratory parameters for AVWS, the VWF multimeric structure and the own and family history of bleeding we detected that 67% (36/45) of these patients had an AVWS: 27/44 ET (61%), 8/9 PV (89%), 1/1 IMF. The two most sensitive parameters in this context were VWF:RC/vWF:Ag- Ratio and VWF:RCo. It is well known that AVWS can disappear by treating the MPD. We could also show that treating the MPD with Hydroxycarbamid platelets, VWF multimeric structure, VWF:RCo/VWF:Ag-Ratio and VWF:RCo and the bleeding tendency were normalized. The JAK2-V617F mutation is frequently found in myeloproliferative disorders (MPD): Up to 97% patients with polycythemia vera (PV) and about 50% of patients with essential thrombocythemia (ET) carry this mutation. A further goal in this investigation was to find out a correlation between JAK2-V617F mutation, MPD and AVWS. JAK2-V617F diagnosis was performed in 27 of the 54 patients with MPD. 10 of these 27 patients carried a mutated JAK2-allele. However we observed no significant difference between mutated and unmutated patients in correlation to AVWS. In our investigation the high prevalence of 67% AVWS in patients with MPD confirm the hypothesis that until now AVWS is an underdiagnosed disease. Because of this high prevalence, the possibility of regression by treating MPD and the importance of early diagnosis for prevention of unexpected, sometimes letal bleeding complications, it would be benefical to introduce the AVWS- diagnosis-procedure as a routine step for patients with MPD.