Von Willebrand Syndrome Research Articles

Misleading antigenic von Willebrand factor levels in acquired von Willebrand syndrome secondary to monoclonal gammopathy of undetermined significance.

In the diagnosis and treatment of acquired von Willebrand syndrome (AVWS), von Willebrand factor (VWF) antigen levels (VWF:Ag) are helpful for quantifying blood VWF-protein levels. Most clinical laboratories measure VWF:Ag by latex immunoassay (LIA), but underlying diseases of AVWS may influence LIA results. A 60year-old AVWS patient with immunoglobulin G (IgG) kappa-type monoclonal gammopathy of undetermined significance (MGUS) showed reduced VWF activity but normal levels of VWF:Ag. His VWF multimers were broadly decreased, which represented a large discrepancy with VWF:Ag. To investigate the mechanism of this discrepancy, we measured the patient's plasma VWF:Ag by in-house enzyme-linked immunosorbent assay (ELISA) and LIA. We also purified the IgG fraction from the patient's serum and measured VWF:Ag in VWF-deficient plasma supplemented with this fraction. VWF:Ag measured by in-house ELISA (VWF:AgELISA) was much lower than that measured by LIA (VWF:AgLIA), which indicated reduced VWF-protein volume in blood. Indeed, VWF:Ag was detected by LIA in VWF-deficient plasma spiked with a patient-derived IgG fraction. These results suggest that LIA detected a non-specific immunoreaction and overestimated the patient's VWF:AgLIA. Clinicians should be aware that underlying diseases of AVWS could influence the LIA system, and interpret VWF:Ag cautiously.

Efficacy and safety of a recombinant von Willebrand factor treatment in acquired von Willebrand syndrome in case of bleeding and surgical procedures.

Acquired von Willebrand syndrome (AVWS) is a rare haemorrhagic disorder. The prophylaxis and treatment of bleeding before surgery are complex. Since 2018, a new recombinant VWF (rVWF) concentrate that contains no factor VIII (FVIII) but a high amount of high molecular weight VWF multimers has been available in France. To describe the real-world experience of using rVWF in non-surgical bleeding and surgical procedures in patients with AVWS. Fifteen bleeding episodes in seven patients and 16 surgeries in 10 patients were retrospectively analysed in t French haemostasis centres. During bleeding, the median number of infusions was only 1 (range 1-27) with a median loading dose of 58IU/kg (range 17-116) rVWF and a total median dose of 65IU/kg (range 35-1488) rVWF. Bleeding control was rated markedly effective in 73% (11/15) of the cases and ineffective in 27% (4/15). During surgeries, the median number of infusions was 3 (range 1-8) with a preoperative loading dose of 60IU/kg (range 23-118) rVWF and a total median dose of 123IU/kg (range 31-542). The overall clinical efficacy was qualified as excellent, good and poor (ISTH criteria) in respectively 7 (43%), 6 (38%) and 3 (19%) procedures. There was no accumulation of VWF or FVIII during postoperative monitoring. No thromboembolic events nor adverse events were reported. This French 'real-world' experience shows that rVWF could be of interest in the treatment and prophylaxis of bleeding in patients with AVWS, with no clinically significant safety concern.

Risk of bleeding in patients with essential thrombocythemia and extreme thrombocytosis

AbstractApproximately 25% of patients with essential thrombocythemia (ET) present with extreme thrombocytosis (ExT), defined as having a platelet count ≥1000 × 109/L. ExT patients may have an increased bleeding risk associated with acquired von Willebrand syndrome. We retrospectively analyzed the risk of bleeding and thrombosis in ExT vs non-ExT patients with ET at Dana-Farber Cancer Institute and Massachusetts General Hospital from 2014 to 2022 to inform treatment decisions. We abstracted the first major bleed, clinically relevant nonmajor bleed (CRNMB), and thrombotic events from medical records. We identified 128 ExT patients (28%) and 323 non-ExT patients (72%). Cumulative incidence of bleeding was not different in ExT vs non-ExT patients (21% vs 13% [P = .28] for major bleed; 16% vs 15% [P = .50] for CRNMB). Very low and low thrombotic risk ExT patients were more likely to be cytoreduced than very low- and low-risk non-ExT patients (69% vs 50% [P = .060] for very low risk; 83% vs 53% [P = .0059] for low risk). However, we found no differences in bleeding between ExT and non-ExT patients when restricting the risk of bleed from diagnosis to cytoreduction start date (28% vs 19% [P = .29] for major bleed; 24% vs 22% [P = .75] for CRNMB). Cumulative incidence of thrombosis was also not different between ExT and non-ExT patients (28% vs 25%; P = .98). This suggests that cytoreduction may not be necessary to reduce bleeding risk based only on a platelet count of 1 million. We identified novel risk factors for bleeding in patients with ET including diabetes mellitus and the DNMT3A mutation.

Acquired von Willebrand syndrome: case report and literature review

Acquired von Willebrand syndrome: case report and literature review

The clinical impact of acquired von Willebrand syndrome secondary to Waldenström macroglobulinemia: an underrecognized source of major bleeding events.

The clinical impact of acquired von Willebrand syndrome secondary to Waldenström macroglobulinemia: an underrecognized source of major bleeding events.

Successful treatment of acquired von Willebrand syndrome secondary to low-grade CLL with rituximab and venetoclax

Successful treatment of acquired von Willebrand syndrome secondary to low-grade CLL with rituximab and venetoclax

Critical hematological parameters in bleeding during extracorporeal membrane oxygenation support.

Bleeding complications are frequently observed in patients undergoing extracorporeal membrane oxygenation and are associated with increased mortality. Due to the complex mechanisms, managing bleeding during ECMO remains a challenge. Acquired von Willebrand syndrome (AVWS) in ECMO highlights a potentially reduced affinity of von Willebrand factor (vWF) for binding to platelets and collagen in response to vascular damage, thus contributing to increased bleeding in ECMO patients. Conventional coagulation parameters are incomplete predictors for bleeding in ECMO patients, whereas AVWS is often overlooked due to the absence of vWF evaluation in the coagulation profile. Therefore, clinical physicians should evaluate AVWS in patients experiencing bleeding complications during ECMO support.

Investigation of von Willebrand factor multimer abnormalities before and after aortic valve replacement using the Hydragel-5 assay

BackgroundSevere aortic stenosis (sAS) is associated with acquired von Willebrand syndrome (AVWS) by loss of high-molecular-weight multimers (HMWM) of von Willebrand factor (VWF), potentially resulting in perioperative bleeding. Analysis of VWF multimers remains challenging. Recently, the new, rapid Hydragel 5 assay has been developed, using electrophoretic protein separation for dividing VWF-multimers into low (LMWM), intermediate (IMWM), and HMWM, the hemostatically active part of VWF. Here, we evaluated its impact on predicting blood loss in presence of AVWS after surgical aortic valve replacement (SAVR). MethodsWe prospectively examined 52 patients (age: 68 ± 7 years; 54 % male) admitted to SAVR. They were divided in two groups (A: normal VWF, n = 28; B: abnormal VWF, n = 24, defined as VWF-activity/antigen (VWF:Ac/Ag)-ratio < 0.7 and/or HMWM loss). Blood samples and echocardiographic data were collected before, seven days and three months after SAVR. Blood loss and transfusions were recorded. ResultsBaseline characteristics and clinical data were similar in both groups. HMWM loss was present in 38.5 % of all patients. HMWM, the VWF:Ac/Ag- and HMWM/(IMWM+LMWM)-ratios were significantly decreased preoperatively in group B but normalized after SAVR. Bleeding, re-thoracotomy and transfusion rates were comparable. HMWM loss was inversely correlated with the peak aortic gradient (Pmax) and positively with the aortic valve area (AVA), while HMWM/(IMWM+LMWM)-ratio negatively correlated with the mean aortic gradient (Pmean). ConclusionHMWM and HMWM/(IMWM+LMWM)-ratio inversely correlate with severity of AS and normalize after SAVR. The Hydragel-5 assay's might be valuable for routine diagnostics to assess bleeding risk and postoperative normalization of AS and VWF abnormalities in SAVR patients.

Impact of extracorporeal membrane oxygenation treatments on acquired von Willebrand syndrome in patients with out-of-hospital cardiac arrest: a retrospective observational study

BackgroundVon Willebrand factor (vWF) plays a crucial role in hemostasis, acting as a key factor for platelet adhesion/aggregation and as a transport protein for coagulation factor VIII. vWF is secreted as a giant multimer, and it undergoes shear stress-dependent cleavage by a specific metalloproteinase in plasma. Among vWF multimers, high-molecular-weight (large) multimers are essential for hemostasis. Acquired von Willebrand syndrome, linked to various conditions, is a hemostatic disorder due to reduced vWF activity. Extracorporeal membrane oxygenation (ECMO), utilized recently for out-of-hospital cardiac arrest patients, generates high shear stress inside the pump. This stress may induce a conformational change in vWF, enhancing cleavage by a specific metalloproteinase and thereby reducing vWF activity. However, no study has investigated the effects of ECMO on vWF-related factors in patients receiving or not receiving ECMO. This study aimed to elucidate the relationship between ECMO treatment and acquired von Willebrand syndrome-related factors in patients with out-of-hospital cardiac arrest.MethodsThis study included patients with cardiogenic out-of-hospital cardiac arrest admitted to our hospital. The patients were categorized into two groups (ECMO and non-ECMO) based on the presence or absence of ECMO treatment. Plasma samples were collected from patients admitted to the emergency department (days 0–4). The vWF antigen (vWF: Ag), vWF ristocetin cofactor activity (vWF: RCo), and factor VIII activity were measured. Additionally, a large multimer of vWF was evaluated through vWF multimer analysis, utilizing western blotting to probe vWF under non-reducing conditions.ResultsThe ECMO and non-ECMO groups included 10 and 22 patients, respectively. The median ECMO treatment in the ECMO group was 64.6 h. No differences in vWF: Ag or factor VIII activity were observed between the two groups during the observation period. However, the ECMO group exhibited a decrease in large vWF multimers and vWF: RCo during ECMO. Strong correlations were observed between vWF: RCo and vWF: Ag in both groups, although the relationships were significantly different between the two groups.ConclusionsECMO treatment in patients with out-of-hospital cardiac arrest resulted in the loss of large vWF multimers and decreased vWF activity. Hence, decreased vWF activity should be considered as a cause of bleeding during ECMO management.

Mitral regurgitation is associated with similar loss of von Willebrand factor large multimers but lower frequency of anemia compared with aortic stenosis

BackgroundVarious cardiovascular diseases cause acquired von Willebrand syndrome (AVWS), which is characterized by a decrease in high-molecular-weight (large) von Willebrand factor (VWF) multimers. Mitral regurgitation (MR) has been reported as a cause of AVWS. However, much remains unclear about AVWS associated with MR. ObjectivesTo evaluate VWF multimers in MR patients and examine their impact on clinical characteristics. MethodsModerate or severe MR patients (n = 84) were enrolled. VWF parameters such as the VWF large multimer index (VWF-LMI), a quantitative value that represents the amount of VWF large multimers, and clinical data were prospectively analyzed. ResultsAt baseline, the mean hemoglobin level was 12.9 ± 1.9 g/dL and 58 patients (69.0%) showed loss of VWF large multimers defined as VWF-LMI < 80%. VWF-LMI in patients with degenerative MR was lower than in those with functional MR. VWF-LMI appeared to be restored the day after mitral valve intervention, and the improvement was maintained 1 month after the intervention. Seven patients (8.3%) had a history of bleeding, 6 (7.1%) of whom had gastrointestinal bleeding. Gastrointestinal endoscopy was performed in 23 patients (27.4%) to investigate overt gastrointestinal bleeding, anemia, etc. Angiodysplasia was detected in 2 of the 23 patients (8.7%). ConclusionModerate or severe MR is frequently associated with loss of VWF large multimers, and degenerative MR may cause more severe loss compared with functional MR. Mitral valve intervention corrects the loss of VWF large multimers. Gastrointestinal bleeding may be relatively less frequent and hemoglobin level remains stable in MR patients.

Management of multiple cerebral embolisms due to polycythemia vera with acquired von Willebrand syndrome

AbstractPolycythemia vera (PV) is a rare blood disorder associated with thrombosis or acquired von Willebrand syndrome (AvWS); however, their coexistence is unusual. Here, we report about a 59‐year‐old man with PV who developed both ischemic stroke (IS) and AvWS. Although the patient had no history of thrombosis, he had refractory epistaxis 2 years prior. Brain magnetic resonance imaging and angiography (MRI and MRA) revealed new IS and mural thrombi at the left distal carotid artery. Laboratory investigations showed elevated hemoglobin and hematocrit levels with mild leukocytosis and thrombocytosis, corresponding to PV. Additionally, suppressed platelet aggregation and activity despite normal antigen of von Willebrand factor indicated AvWS. Appropriate repeated phlebotomies successfully resolved the MRA abnormalities and prevented IS recurrence, although the patient refused the recommended treatment with hydroxyurea. This case highlights the need for careful management to prevent recurrent IS and major bleeding in patients with PV who develop IS accompanying AvWS.

Sustained good response to rituximab in acquired von Willebrand syndrome.

Sustained good response to rituximab in acquired von Willebrand syndrome.

(565) - Role of Acquired Von Willebrand Syndrome in the Development of Bleeding Complications in Patients Treated Using Right Ventricular Microaxial Flow Pump Devices: A Retrospective Cohort Study

(565) - Role of Acquired Von Willebrand Syndrome in the Development of Bleeding Complications in Patients Treated Using Right Ventricular Microaxial Flow Pump Devices: A Retrospective Cohort Study

Use of Vonicog Alpha and Acquired von Willebrand Syndrome, a New Approach: A Case Report.

Therapeutic management of acquired von Willebrand syndrome (AVWS) can be challenging, particularly in cases of AVWS associated with monoclonal IgM such as Waldenström macroglobulinemia (WM) where several therapeutic options may be ineffective. Here, we describe the case of an 88-year-old patient who developed AVWS during follow-up for WM. The presence of a severe bleeding symptomatology not controlled by several therapies (plasma-derived von Willebrand factor, plasmapheresis) led us to introduce a supplementation with recombinant von Willebrand factor, vonicog α (Veyvondi, Takeda, Japan), starting at a dose of 50 IU/kg/d. This supplementation allowed clinical (no further bleeding) and biological (hemoglobin level, von Willebrand factor parameters) improvements. Because of the persistence of bleeding risk factors, the treatment was maintained at a prophylactic dose (20 UI/kg three times a week), without recurrence of bleeding events for a period of 9 months.

A Review About the Assessment of the Bleeding and Thrombosis Risk for Patients With Myeloproliferative Neoplasms Scheduled for Surgery.

Myeloproliferative neoplasms (MPNs) present a unique challenge in surgical management due to their inherent predisposition to both bleeding and thrombosis. MPNs are a heterogenous group of acquired clonal conditions. The three classic MPNs are essential thrombocythemia (ET), myelofibrosis (PMF), and polycythemia vera (PV). All subtypes of MPN are associated with both thrombotic and bleeding complications. There are four risk categories for thrombosis in MPN patients: age, thrombosis history, and JAK-2 mutation. They are further classified as very low, low, intermediate, and high risk. The genetic landscape of MPN is fascinating and complex like all myeloid disorders. Bleeding risk can be assessed through leukocytosis, thrombocytosis, acquired von Willebrand syndrome (AVWS), and a previous history of bleeding in a patient.Risk assessment and perioperative management are important aspects of improving the quality of life and preventing complications in surgeries. Preoperative management includes a risk assessment of venous thromboembolism, use of appropriate pharmacological treatment, platelet count control, and correction and cardiovascular risk factors. This review summarizes the assessment of bleeding and thrombosis risk for patients with MPNs scheduled for surgery. Furthermore, this review discusses various tools that can be used to identify MPN patients at risk of thrombosis prior to surgery.

Acquired von Willebrand syndrome and post-operative drainage: a comparison of patients with aortic stenosis versus coronary artery disease.

Degenerative aortic stenosis and coronary artery disease are considered to be the most prevalent cardiovascular diseases in industrialized countries. This study aims to determine the change over time in von Willebrand factor antigen, von Willebrand factor activity, and factor VIII and where there is a correlation with total post-operative drainage. The single-center retrospective study included 203 consecutive patients (64.5% male), undergoing coronary artery bypass surgery between March 1, 2019 and June 30, 2020 at the University Clinical Center of Serbia in the Clinic for Cardiac Surgery in Belgrade, Serbia. All patients 18years or older who presented with isolated, hemodynamically significant aortic stenosis were included. The control group consisted of patients who presented with only coronary artery disease. Between patients with only coronary artery disease and patients with coronary artery diseases and aortic stenosis, there was a statistically significant difference between pre-op and 1-month post-op fibrinogen, factor VIII, von Willebrand factor antigen, and von Willebrand factor (p < 0.001), post-op drainage, with overall lower drainage in coronary artery disease patients, and consistent increase in von Willebrand factor antigen, von Willebrand factor activity, and Factor VIII post-operatively in patients with coronary artery diseases and aortic stenosis. This study has shown that there is a correlation between von Willebrand factor antigen, von Willebrand factor activity and total drainage to the level of statistical significance in aortic stenosis patients and in the overall study population.

Digestive Bleeding Revealing Aortic Valve Stenosis: Heyde’s Syndrome

Heyde’s syndrome is an under reported systemic disease of gastrointestinal and cardiac manifestation in older adults. It is characterized by a triad of aortic stenosis, angiodysplasia with bleeding and acquired von Willebrand syndrome. Heyde’s syndrome is a treatable condition in most cases, especially in the current era of evolution in interventional cardiology and gastroenterology. Newer endoscopic technologies may prove beneficial. Aortic valve replacement is claimed to minimize or even stop the bleeding in such patients. The aim of our review article is to summarize the basic pathophysiology, diagnostics and management of Heyde’s syndrome.

Management of a Young Patient With High-risk Multiple Myeloma Complicated by Acquired von Willebrand Syndrome: A Diagnostic and Therapeutic Emergency

Multiple myeloma associated with bleeding events secondary to von Willebrand syndrome is underdiagnosed. The management of this entity is highly complex, and aims to control the hemorrhagic syndrome and reduce plasma viscosity with plasmapheresis and multiple myeloma-specific treatment. The authors report the rare case of a young patient with high-risk multiple myeloma complicated by hyperviscosity syndrome and presenting an acquired von Willebrand syndrome with hemorrhagic manifestations, requiring urgent therapeutic management to save the patient's life.

Does a preoperative coagulation sheet change the postoperative bleeding rate after adenoidectomy?

Adenoidectomy (AT) represents one of the first and most common surgeries in childhood. A joint statement of the German Society for Anesthesiology & Intensive Care Medicine as well as Pediatric & Adolescent Medicine and Otolaryngology, Head and Neck Surgery was published in 2006 to prevent of a possibly life-threatening postoperative bleeding after AT in Child age. Routine blood sampling should be avoided during preoperative preparations and instead a standardized coagulation questionnaire (GB) should be performed to clarify a coagulation disorder (GS). If the GB is abnormal, there is an indication for coagulation diagnostics (GD). This unicenter, nonrandomized, retrospective study compared the rate of bleeding after AT and Re-AT without (2011 to early 2014) and with (early 2014 to 2018) the use of a GB. 2633 children aged one to six years, were included in the statistical analysis to assess whether the introduction of GB in early 2014 was able to reduce the rate of bleeding after AT and Re-AT. Of the 2633 children, 1451 had GB and 1182 did not. Without GB, there was a bleeding rate of 0.83% and 2,08% with GB. 174 GB were abnormal and 169 GD were performed, 164 of these were unremarkable, 2 resulted in a confirmed mild type 1 von Willebrand syndrome as well as 2 suspected vWS and 1 suspected factor VII deficiency. The sensitivity of the GB was 16% and the specificity was 87.5%. The positive predictive value was 2.8% and the negative predictive value was 98%. The GB is a tool for detecting possible GS, but is not useful for reducing the rate of postoperative bleeding.

Optimal design of infusion tests for the identification of physiological models of acquired von Willebrand syndrome

Acquired von Willebrand syndrome (AVWS) is a bleeding disorder resembling inherited Von Willebrand disease (VWD) characterised by a qualitative and/or quantitative deficiency of von Willebrand factor (VWF) that occurs in patients with no personal or family history of bleeding as a result of underlying pathological conditions. To treat AVWS patients, desmopressin (DDAVP) and plasma-derived VWF concentrates are the primary therapies for spontaneous acute bleeding episodes and for preventing bleeding during invasive or surgical procedures. Pharmacokinetic (PK) models have been recently developed and applied to characterize VWD and AVWS, but these models cannot be calibrated from infusion tests data, and their calibration requires stressful 24-hours long tests to be carried out on subjects to achieve a satisfactory estimation of the individual haemostatic parameters. The objectives of this paper are: i) to present a new physiological model of VWD including exogenous infusion of plasma-derived VWF concentrates, suitable to describe AVWS; ii) to validate the newly proposed model from clinical data; iii) to quantify the information that can be obtained from clinical tests using different VWF concentrates by applying model-based design of experiments (MBDoE) techniques. Results show that the newly developed model calibrated from infusion data allows to estimate precisely the full set of haemostatic parameters for a subject affected by AVWS preserving the same level of information obtained from conventional tests. Most importantly, results demonstrate that the overall duration of infusion tests for the identification of key haemostatic parameters can significantly be reduced from 24 h to 2.5 h.