Acquired Von Willebrand Syndrome Research Articles

Retrospectively diagnosed autoimmune VWF deficiency in a patient with repeated hemorrhagic events after two common colds.

Autoimmune von Willebrand factor (VWF) deficiency (AiVWFD) caused by anti-VWF autoantibodies is a rare bleeding disorder, whereas "non-immune" acquired von Willebrand syndrome (AVWS) caused by other etiologies is more common. Therefore, only 40 patients with AiVWFD have been identified in Japan through an ongoing nationwide survey on autoimmune coagulation factor deficiencies. This may be due to the inability to efficiently detect anti-VWF antibodies, as anti-VWF antibody testing is not routine. An 80-year-old Japanese woman developed AVWS and experienced bleeding after two separate common colds. She took the same cold medicine each time and recovered spontaneously after discontinuation of the medicine. Severe VWF deficiency normalized each time. Initial immunological tests did not detect anti-VWF autoantibodies, and thus a diagnosis of "non-immune" AVWS of unknown origin was made. However, after 6years, new ELISA assays using purified VWF proteins detected free anti-VWF autoantibodies, which led to a retrospective diagnosis of AiVWFD. It is probable that the cold medicine (and/or cold virus infection) induced the autoantibodies, as the recurrence and normalization of the same coagulation abnormality and the clinical course (including drug administration and discontinuation) were completely synchronized. If AiVWFD is suspected, highly sensitive autoantibody tests should be performed.

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.

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.

Von Willebrand factor Ristocetin co-factor activity to von Willebrand factor antigen level ratio for diagnosis of acquired von Willebrand syndrome caused by aortic stenosis

BackgroundSevere aortic stenosis (AS) causes acquired von Willebrand syndrome by the excessive shear stress–dependent cleavage of high molecular weight multimers of von Willebrand factor (VWF). While the current standard diagnostic method is so-called VWF multimer analysis that is western blotting under nonreducing conditions, it remains unclear whether a ratio of VWF Ristocetin co-factor activity (VWF:RCo) to VWF antigen levels (VWF:Ag) of <0.7, which can be measured with an automated coagulation analyzer in clinical laboratories and is used for the diagnosis of hereditary von Willebrand disease. ObjectivesTo evaluated whether the VWF:RCo/VWF:Ag is useful for the diagnosis of AS-induced acquired von Willebrand syndrome. MethodsVWF:RCo and VWF:Ag were evaluated with the VWF large multimer index as a reference, which represents the percentage of a patient’s VWF high molecular weight multimer ratio to that of standard plasma in the VWF multimer analysis. ResultsWe analyzed 382 patients with AS having transaortic valve maximal pressure gradients of >30 mmHg, 27 patients with peripheral artery disease, and 46 control patients free of cardiovascular disease with osteoarthritis, diabetes, and so on. We assumed a large multimer index of <80% as loss of VWF large multimers since 59.0% of patients with severe AS had the indices of <80%, while no control patients or patients with peripheral artery disease, except for 2 patients, exhibited the indices of <80%. The VWF:RCo/VWF:Ag ratios, measured using an automated blood coagulation analyzer, were correlated with the indices (rs = 0.470, P < .001). When the ratio of <0.7 was used as a cut-off point, the sensitivity and specificity to VWF large multimer indices of <80% were 0.437 and 0.826, respectively. ConclusionVWF:RCo/VWF:Ag ratios of <0.7 may indicate loss of VWF large multimers with high specificity, but low sensitivity. VWF:RCo/VWF:Ag ratios in patients with AS having a ratio of <0.7 may be useful for monitoring the loss of VWF large multimers during their clinical courses.

Acquired Von Willebrand Syndrome, Epidemiology, Laboratory Findings and Molecular Alterations on Classic Myeloproliferative Neoplasms in Mexican Population

Introduction: Acquired von Willebrand syndrome (AvWS) has been associated with Philadelphia-negative chronic myeloproliferative neoplasms (MPN) since 1984. However, the epidemiology of these disorders is not precise and has been underestimated worldwide but prevalence of 10-20% has been described in other series. Determinations of the antigenic von Willebrand factor (VWF:Ag) and its activity (VWF:RCo) are only performed when patients present thrombocytosis over 1,000 x10 3/µL. Essential Thrombocythemia (ET) is the most commonly associated MPN, found in 5-30%. Some cases have been described in patients with polycythemia vera (PV) and primary myelofibrosis (PMF) who develop AvWS even with platelet counts below 1,000 x10 3/µL. The epidemiology of AvWS in MPN and its association between laboratory and molecular parameters among the Mexican population have not been described. Objectives - Describe the clinical, biochemical and molecular characteristics of patients who develop AvWS with the aim of establishing the difference between cut-off scores of platelets to suspect AvWS in Mexican patients. - Establish the association between mutations in JAK2, CALR and MPL, and the appearance of AvWS. Material and methods: Retrospective, descriptive, observational, and single-center analysis. Patients over 18 years of age with a diagnosis of MPN from the INCMNSZ were recruited. The mutational analysis in peripheral blood (PB) for JAK2, CALR and MPL was assessed, with at least one follow-up between 2012 and 2022, excluded whose medical record were incomplete. Information was consecutively collected from 184 patients with MPN diagnosis between 01/01/2000 to 05/31/2022. Thirty patients were identified as having AvWS with a VWF:RCo/VWF:Ag diagnostic ratio of &amp;lt; 0.7. The epidemiology, clinical, laboratory and mutational alterations of the patients who developed AvWS by was analyzed using descriptive statistics with SPSS. This study was approved by the institutional bioethics committee. Results: AvWS developed in 16.4% (n = 30) of patients with MPN with an annual incidence of 2.4 cases per year was identified. Most patients were women in 66% (n = 20), with a median age of 57 years (IQR 20-72 years). Of the thirty cases with AvWS, 46.7% (n =14) corresponded to PMF, 40% (n =12) to PV, and 13.3% to ET (n = 4). The most frequently found mutation was JAK2 exon 14 with 76.7%, followed by CALR in 13.3% and triple negatives in 10%, no patient presented MPL mutations. The global median of VWF:RCo/VWF:Ag was 0.47 [PV 0.47 (IQR 0.31-0.64), ET 0.53 (IQR 0.5-0.64) and PMF 0.48 (0.29-0.65)] (Figure 1) and the median of the VWF:Ag 118 U/dL with FVW:RCo of 44.6 UI/dL (Table 1). The median platelet count for patients with the JAK2 mutation was 987.9 x103/µL (IQR 218 - 2307 x10 3/µL), while those with CALR and triple negatives were 1,033 x10 3/µL (IQR 713 - 1339 x10 3/µL), and 1,325 x10 3/µL (IQR 760 - 2059 x10 3/µL), respectively. Regarding hemoglobin (Hb) and hematocrit (Hto) levels, patients with PV and JAK2 mutation with AvWS presented medians of 17.45 g/d and 54.4% respectively, highlighting that AvWS was generated in some patients with platelet counts below 1,000 x10 3/µL. At diagnosis, bleeding episodes occurred in 13.3%. Lastly, 96.7% of the patients were treated with hydroxyurea, which corrected cellular alterations and laboratory abnormalities found in AvWS. Conclusions: AvWS can be found in patients with platelet counts below 1,000 x10 3/µL, especially among those with PV with elevated Hb and Hct levels. This may deem it necessary to carry out diagnostic tests in patients with MPN and any degree of thrombocytosis. To our knowledge, this is the most comprehensive study among latin american patients that describes the coexistence of PMF and AvWS; even though the mechanism by which some PMF patients develop AvWS is not perfectly understood. In our study, patients with PMF presented AvWS more frequently; this is a contrasting result from other international reports where ET was most attributed. We attribute this finding to changes made to the WHO criteria between 2008 and 2016.

Efficacy of aortic valve replacement on Heyde syndrome-related acquired von Willebrand syndrome and gastrointestinal bleeding: a systematic review and meta-analysis

Abstract Background Heyde syndrome is the co-occurrence of aortic stenosis, acquired von Willebrand syndrome, and gastrointestinal bleeding. Aortic valve replacement has been shown to resolve all three associated disorders. Purpose To assess the efficacy of aortic valve replacement (both surgical aortic valve replacement and transcatheter aortic valve implantation) on acquired von Willebrand syndrome recovery and gastrointestinal bleeding cessation. Methods A systematic review and meta-analysis using MEDLINE, Embase, and the Cochrane Library was performed to identify articles on Heyde syndrome and aortic valve replacement. Primary outcomes were the proportion of patients with recovery of acquired von Willebrand syndrome within 24 hours (T1), 24 to 72 hours (T2), 3 to 21 days (T3), and 4 weeks to 2 years (T4) after aortic valve replacement, and the proportion of patients with cessation of gastrointestinal bleeding. Pooled proportions and risk ratios (RR) were calculated using random-effects models. Results We identified 33 studies (32 observational studies and one randomized controlled trial) on acquired von Willebrand syndrome (n = 1,054), and 11 observational studies on gastrointestinal bleeding (n = 300). One study reported on both associated disorders (n = 6). The pooled proportion of Heyde patients with acquired von Willebrand syndrome recovery was 86% (95% CI, 79-91%) at T1, 90% (74-96%) at T2, 92% (84-96%) at T3, and 87% (67-96%) at T4. The pooled proportion of Heyde patients with cessation of gastrointestinal bleeding was 73% (62-81%). Residual aortic valve disease was associated with lower recovery rates of both acquired von Willebrand syndrome (RR 0.20; 0.05-0.72; p = 0.014) and gastrointestinal bleeding (RR 0.57; 0.40-0.81; p = 0.002). Conclusion Aortic valve replacement is associated with a rapid recovery of the bleeding diathesis in Heyde syndrome and cessation of gastrointestinal bleeding. Residual aortic valve disease negatively impacts clinical benefits of aortic valve replacement.Graphical Abstract

Abstract 13671: A Case of Diffuse Alveolar Hemorrhage While on Systemic Anticoagulation for Impella

A 57 year old male with PMH of non-ischemic cardiomyopathy (EF 30%), atrial fibrillation, and VT s/p ICD was admitted to the cardiac intensive care unit for cardiogenic shock. His condition deteriorated necessitating Impella 5.5 implantation as bridge to cardiac transplant. Systemic heparin was started per Impella protocol with a lower anti-Xa goal of 0.2 - 0.3 given post-op bleeding at the R axillary Impella site. Five days post Impella placement he developed bloody secretions from the endotracheal tube requiring multiple blood transfusions and discontinuation of systemic heparin, while maintaining heparin purge. Labs were notable for anti-Xa 0.22, hemoglobin 9.7, and platelets 221. CT Chest demonstrated parenchymal opacities concerning for diffuse alveolar hemorrhage (DAH) which was confirmed via bronchoalveolar lavage; he had no known history of lung disease. High-dose corticosteroids were administered as a high ANA titer (1:128) and low C3 suggested capillaritis. However, decreasing ANA (1: 320) and a negative autoimmune workup decreased the likelihood of a rheumatologic cause for DAH and steroids were discontinued. DAH secondary to acquired von Willebrand syndrome (aVWS) was considered, but factor VIII and vWF activity levels were normal. The bloody secretions improved with inhaled thromboxane and systemic heparin was restarted. Orthotopic heart and kidney transplant was performed with subsequent Impella removal 104 days after Impella placement. Discussion: We present the first documented case of DAH with isolated Impella 5.5 support. Previously reported cases of DAH post-Impella were observed in patients with concurrent ECMO or RVAD. As autoimmune and coagulopathic causes of DAH were excluded, bland DAH secondary to systemic anticoagulation is most likely in this case. This raises a question about how to balance the risk of bleeding with the risk of device thrombosis, stroke and embolic events and when to switch from heparin to sodium bicarbonate purge.

Allopurinol-induced acquired von Willebrand syndrome

Acquired von Willebrand syndrome (AVWS) is a relatively infrequent but often overlooked finding when testing for von Willebrand factor (VWF) levels in a patient with mucocutaneous bleeding. Known causes include cardiovascular disorders, hematologic and solid tumors, autoimmune disorders, hypothyroidism, and drugs. An incoercible oral bleeding after a two-teeth removal in a patient with a mechanical aortic valve eventually raised suspicion about an AVWS that was confirmed through laboratory testing. Substitution therapy with an exogenous VWF factor was required to control the bleeding. Known causes of AVWS, including Heyde’s syndrome, were ruled out. VWF levels finally normalized two days after suspension of allopurinol, which the patient received for symptomatic hyperuricemia, leading to his complete recovery and early discharge without any other complications. AVWS is an underdiagnosed entity due to a lack of testing. Allopurinol has never been postured before as a possible etiology and should be evaluated when reaching a diagnosis.

PB0085 Pitfalls of Complications due to Coagulopathy in Patients with Severe COVID-19 during ECMO: Beware of Bleeding Caused by Acquired von Willebrand Syndrome

PB0085 Pitfalls of Complications due to Coagulopathy in Patients with Severe COVID-19 during ECMO: Beware of Bleeding Caused by Acquired von Willebrand Syndrome

PB1234 Prevalence of Studies with Acquired von Willebrand Syndrome Laboratory Profile at the Hospital Italiano de Buenos Aires (HIBA)

PB1234 Prevalence of Studies with Acquired von Willebrand Syndrome Laboratory Profile at the Hospital Italiano de Buenos Aires (HIBA)

OC 06.4 Therapeutic Efficacy of aNovel Humanized anti-ADAMTS13 Antibody to Treat Left Ventricular Assist Device-Induced Acquired Von Willebrand Syndrome

OC 06.4 Therapeutic Efficacy of aNovel Humanized anti-ADAMTS13 Antibody to Treat Left Ventricular Assist Device-Induced Acquired Von Willebrand Syndrome

PB0260 Immune Complex-Mediated Acquired von Willebrand Syndrome in a 5-year-old Boy after Allogeneic Hematopoietic Stem Cell Transplantation

PB0260 Immune Complex-Mediated Acquired von Willebrand Syndrome in a 5-year-old Boy after Allogeneic Hematopoietic Stem Cell Transplantation

Influence of Aortic Valve Stenosis and Wall Shear Stress on Platelets Function.

Aortic valve stenosis (AS) is a common heart valve disease in the elderly population, and its pathogenesis remains an interesting area of research. The degeneration of the aortic valve leaflets gradually progresses to valve sclerosis. The advanced phase is marked by the presence of extracellular fibrosis and calcification. Turbulent, accelerated blood flow generated by the stenotic valve causes excessive damage to the aortic wall. Elevated shear stress due to AS leads to the degradation of high-molecular weight multimers of von Willebrand factor, which may involve bleeding in the mucosal tissues. Conversely, elevated shear stress has been associated with the release of thrombin and the activation of platelets, even in individuals with acquired von Willebrand syndrome. Moreover, turbulent blood flow in the aorta may activate the endothelium and promote platelet adhesion and activation on the aortic valve surface. Platelets release a wide range of mediators, including lysophosphatidic acid, which have pro-osteogenic effects in AS. All of these interactions result in blood coagulation, fibrinolysis, and the hemostatic process. This review summarizes the current knowledge on high shear stress-induced hemostatic disorders, the influence of AS on platelets and antiplatelet therapy.