Minor Procedures in Patients with Congenital Bleeding Disorders - One Centre Experience

Introduction: Patients with congenital bleeding disorders (CBD) have an increased bleeding tendency, which varies according to the factor deficiency and severity. In most cases, prolonged bleeding is observed after trauma, surgery and/or invasive procedures. Haemostatic treatment is needed to prevent bleeding complications and allow a good clinical outcome. Our aim is to evaluate the management of patients with CBD in minor procedures. Method(s): Retrospective study of patients with CBD who performed minor procedures over a 7-year period, through review of clinical files. Result(s): Between January 2015 and December 2021, 249 minor procedures were performed in 113 patients with CBD: 42 had diagnosis of Haemophilia A (HA) (15 severe without inhibitors;3 severe with inhibitors;4 moderate and 20 mild);12 had Haemophilia B (HB) (7 severe without inhibitors;2 moderate and 3 mild);5 were carriers of HA and 2 of HB. 35 had von Willebrand disease (VWD);15 had rare bleeding disorders (8 FVII deficiency;6 FXI deficiency;1 FX deficiency) and 2 had diagnosis of inherited platelet glycoprotein deficiencies (1 Glanzmann thrombasthenia and 1 Bernard Soulier syndrome). Most procedures were dental treatments (189);synoviorthesis/ infiltration/mesotherapy (17);endoscopies and colonoscopies (15);skin lesions excision (8);COVID-19 vaccination (5);sebaceous cyst excision (4);cardiac catheterization (3);ureteral stent removal (3);bone marrow biopsy (2);cystoscopy (2) and breast fibroadenoma excision (1). Prophylactic treatment was performed in 237 (95%) of the procedures, respectively FVIII concentrate factor (59);FIX concentrate factor (27);DDAVP (66);von Willebrand factor/factor VIII concentrates (44);bypassing agents (24);platelet (6);inactivated human plasma (9);tranexamic acid (47) and epsilon-aminocaproic acid (161). No side effects were reported. Discussion/Conclusion: Most patients that underwent minor procedures had Haemophilia and VDW(83%). The most common procedure was dental treatment (76%). Patients with CBD require attention and special care in dental practice. The haemostatic prophylactic treatment varies according to the specific haemostatic defect, severity and type of procedure. The treatment performed has been demonstrated safe and effective, with low incidences of haemorrhagic and treatment-related complications. These patients' treatment requires multidisciplinary teams and reference centres.

Heyde Syndrome Complicated by Essential Thrombocythemia: A Case Report.

Heyde syndrome is a multisystem disorder characterized by the triad of aortic stenosis (AS), gastrointestinal bleeding, and acquired von Willebrand syndrome. Age-related degeneration is the most common cause of aortic stenosis and is frequently encountered in today's aging society. Approximately 20% of patients with severe aortic stenosis have Heyde syndrome. We encountered an older patient with primary thrombocytosis who was brought to a rural community hospital with bloody stools and was diagnosed with bleeding from an intestinal arteriovenous malformation. A final diagnosis of Heyde syndrome was made based on the presence of severe aortic stenosis and the presence of schistocytes in peripheral blood smears. Valvular diseases can complicate chronic hematological diseases. When the rapid progression of anemia and segmented red blood cells in the peripheral blood are observed in patients with severe aortic stenosis, Heyde syndrome should be considered based on peripheral blood smears and clinical course.

Treatment of Acquired von Willebrand Disease due to Extracorporeal Membrane Oxygenation in a Pediatric COVID-19 Patient with Vonicog Alfa: A Case Report and Literature Review.

Acquired von Willebrand disease (aVWD) is frequently observed in patients with the need for extracorporeal membrane oxygenation (ECMO). aVWD can be treated by plasma-derived concentrates containing factor VIII (FVIII) and/or von Willebrand factor (VWF) and recombinant VWF concentrate as well as adjuvant therapies such as tranexamic acid and desmopressin. However, all of these therapeutic options possibly cause thromboembolism. Therefore, the optimal treatment remains uncertain. This report presents a case of a 16-year-old patient suffering from severe acute respiratory distress syndrome due to coronavirus disease 2019 with the need of ECMO support. Our patient developed aVWD under ECMO therapy characterized by loss of high-molecular-weight multimers (HMWM) and severe bleeding symptoms following endoscopic papillotomy due to sclerosing cholangitis. At the same time standard laboratory parameters showed hypercoagulability with increased fibrinogen level and platelet count. The patient was successfully treated with recombinant VWF concentrate (rVWF; vonicog alfa; Veyvondi) combined with topic tranexamic acid application and cortisone therapy. rVWF concentrate vonicog alfa is characterized by ultra-large multimers and absence of FVIII. Patient could be successfully weaned from ECMO support after 72 days. Multimer analysis 1 week after ECMO decannulation showed an adequate reappearance of HMWM.

Patients with von Willebrand disease in China: Results of an online survey.

INTRODUCTION: Little is known about the clinical characteristics of von Willebrand disease (VWD) patients in China, the impact of Covid-19 on them and their genetic mutation. AIM: To describe the clinical characteristics of a group of VWD patients in China, the impact of Covid-19 on them and their genetic mutation. METHODS: An online survey using a self-designed questionnaire was conducted among patients within a WeChat group of VWD patients in China. Data were analysed using t-test, the Chi-square test, Fisher's exact test and rank sum test. RESULTS: Data from a total of 96 patients were collected. Several important findings are yielded. Above all, type 3 patients accounted for over half of the surveyed patients. Secondly, a surprising rate (>40%) of patients had experience of being misdiagnosed. Thirdly, treatment regimens were dominated by cryoprecipitate, blood-derived FVIII and plasma, and only a small percentage of patients received prophylaxis. Fourthly, we identified 17 new von Willebrand factor (VWF) mutant genes which merit further investigation. Additionally, Covid-19 was found to pose some challenges for the patients. CONCLUSION: In China, the high rates of type 3 patients and misdiagnosis suggest that most of the VWD patients may never be diagnosed in China. When it comes to diagnosis and treatment, there is a large gap between developing countries like China and developed countries.

Prognostic value of von Willebrand factor in clinical practice

The von Willebrand factor (vWF) is a multimeric plasma glycoprotein, which quantification has important prognostic value. The current literature review demonstrates a relationship between the disease severity and vWF level. For example, von Willebrand disease is characterized by a quantitative/qualitative genetic vWF deficiency resulting in potentially developed massive bleeding, which knowledge can prevent development of formidable complications. We should also not forget about an opportunity of developing acquired Willebrand syndrome most often occurring in response to autoimmune diseases. A marked vWF increase during pregnancy may evidence about developing preeclampsia, whereas in newborns exposed to additional risk factors, it can lead to thrombosis. In cancer patients, a substantially elevated vWF level correlates with low survival, especially in those with ovarian cancer, glioblastomas, esophageal and lung cancer. The emergence of a novel coronavirus infection COVID-19 allowed us to take a fresh look at prognostic value of vWF, because numerous studies show that increased blood plasma vWF:Ag is associated with more adverse outcome in patients with COVID-19. Here, we demonstrate an importance of determining vWF level, because early diagnostics and treatment can improve the outcomes of all such patients. Copyright © 2022 Obstetrics, Gynecology and Reproduction. All rights reserved.

A COVID Constellation: A Case of Transverse Myelitis and Acquired von Willebrand Syndrome.

The coronavirus disease 2019 (COVID-19) pandemic revealed a myriad of postinfectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequelae, many of which remain poorly understood. We describe a rare presentation of a patient developing 2 simultaneous COVID-19 sequelae: transverse myelitis and acquired von Willebrand syndrome (AVWS). There have been numerous published case reports of patients developing transverse myelitis after a diagnosis of COVID-19. However, none have described AVWS as an observed complication from SARS-CoV-2 infection. To our knowledge, this case report is the first to describe AVWS as a result of COVID-19 infection, suggesting that patients with a prior diagnosis of COVID-19 are susceptible to developing this rare bleeding disorder.

von Willebrand disease and von Willebrand factor.

Progress in both basic and translational research into the molecular mechanisms of VWD can be seen in multiple fields. GENETICS OF VWD: In the past several decades, knowledge of the underlying pathogenesis of von Willebrand disease (VWD) has increased tremendously, thanks in no small part to detailed genetic mapping of the von Willebrand Factor (VWF) gene and advances in genetic and bioinformatic technology. However, these advances do not always easily translate into improved management for patients with VWD and low-VWF levels. VWD AND PREGNANCY: For example, the treatment of pregnant women with VWD both pre- and postpartum can be complicated. While knowledge of the VWF genotype at some amino acid positions can aid in knowledge of who may be at increased risk of thrombocytopenia or insufficient increase in VWF levels during pregnancy, in many cases, VWF levels and bleeding severity is highly heterogeneous, making monitoring recommended during pregnancy to optimize treatment strategies. VWF AND COVID-19: New challenges related to the consequences of dysregulation of hemostasis continue to be discovered. The ongoing COVID-19 pandemic has highlighted that VWF has additional biological roles in the regulation of inflammatory disorders and angiogenesis, disruption of which may contribute to COVID-19 induced vasculopathy. Increased endothelial cell activation and Weibel-Palade body exocytosis in severe COVID-19 lead to markedly increased plasma VWF levels. Coupled with impairment of normal ADAMTS13 multimer regulation, these data suggest a role for VWF in the pathogenesis underlying pulmonary microvascular angiopathy in severe COVID-19. CONCLUSION: With the increased affordability and availability of next-generation sequencing techniques, as well as a push towards a multi-omic approach and personalized medicine in human genetics, there is hope that translational research will improve VWD patient outcomes.

The von willebrand disease aging and bleeding correlation (VWD ABC) study

Introduction It is well established that von Willebrand factor (VWF) levels increase with age among healthy adults. Recently, there is emerging research demonstrating this may also occur in patients with von Willebrand disease (VWD), particularly type 1 VWD, and may be related to comorbidities. Despite increasing VWF levels, it remains unclear as to whether or not this alters bleeding phenotype. It is also unclear why this occurs most commonly in patients with type 1 VWD, but VWF mutation status may play a role. Older patients commonly undergo invasive procedures, and all VWD patients require periprocedural VWD-specific therapy to ensure appropriate hemostasis. If older type 1 VWD patients have experienced normalization of VWF levels, and no longer have an increased risk of bleeding, VWD-specific therapy may increase thrombosis risk, especially among patients with underlying cardiovascular disease or related risk factors, subject the patient to other adverse reactions such as hyponatremia, and is unnecessarily costly. For these reasons, investigation into the effect of age on VWF levels and bleeding risk in type 1 VWD patients is sorely needed. Methods This is an NHLBI-funded K23 multicenter, cross-sectional study to determine the effect of age on VWF levels and bleeding risk in patients with type 1 VWD, and to determine if pathogenic VWF mutations alter this effect.Individuals with a new or historical diagnosis of type 1 VWD (defined as clinical symptoms consistent with VWD and VWF antigen level or ristocetin cofactor activity <0.50 IU/mL) and age 18 or older are enrolled during routine clinic visits at participating Hemophilia Treatment Centers (HTCs). Following enrollment, pertinent medical history is obtained;the condensed MCMDM-1 VWD Bleeding Assessment Tool is administered, with bleeding history based on bleeding symptoms during the past 5 years;and blood samples are collected for the following: VWF antigen (VWF:Ag) level, VWF ristocetin cofactor activity, factor VIII activity, blood type, and VWF gene sequencing. We hypothesize age is associated with increased VWF:Ag levels and lower condensed MCMDM-1 VWD bleeding scores in patients with type 1 VWD, and this association is weaker among those with a pathogenic VWF mutation. In addition, we hypothesize multimorbidity partially explains the association between age and VWF:Ag levels, and VWF:Ag levels partially explain the association between age and condensed MCMDM-1 VWD bleeding scores in patients with type 1 VWD. A sample size of 250 participants provides 90% power to detect an effect size of Beta=±0.032 points per year of age, which is much smaller than the observed effect size, Beta=-0.080, from preliminary data. The primary analyses will be based on multivariable linear regression models with adjustment for blood type O, exogenous estrogen therapy, multimorbidity (defined as 2 or more of the core set of 20 chronic conditions, i.e., cancer, hypertension, stroke, etc., as selected by the United States Department of Health and Human Services), and medications (aspirin, nonsteroidal antiinflammatory drugs, and anticoagulants). In the regression models, two-sided t-tests will be used with an alpha=0.05. Results This multicenter, cross-sectional study consists of seven HTCs: Hemophilia Center of Western Pennsylvania, Children's Hospital of Pennsylvania, Mary M. Gooley Hemophilia Center, Ohio State University, Bleeding & Clotting Disorders Institute, Mayo Clinic, and University of California, San Diego. During the first year of the study, site initiation visits were conducted, regulatory approval obtained, and contracts executed. Delays in these activities occurred in large part due to the COVID-19 pandemic. As the first year of the study concludes, all sites are now active and enrolling participants. Thus far, 43 participants have been enrolled (Table 1). No barriers to enrollment have been encountered and very few patients have declined study participation. Discussion In conclusion, this ongoing multicenter, cross-section study seeks to determine the effect ge has on VWF levels and bleeding risk in patients with type 1 VWD while exploring the role of VWF mutations and multimorbidity in this process. The results will be used to justify a longitudinal study, which is the ideal approach to research the effects of aging in this population.

A VERY COMPLICATED COURSE after VAGINAL DELIVERY in TYPE 3 von WILLEBRAND DISEASE with ALLOANTIBODIES to von WILLEBRAND FACTOR and FACTOR VIII

Introduction: Delivery in type 3 VWD with alloantibodies, a rare clinical entity with few treatment options, is a very high-risk situation. Methods: Case report Results: A 28 yo patient with type 3 VWD and alloantibodies to VWF and FVIII became pregnant after extensive preconceptional counselling. Previous ITI was unsuccessful and complicated by anaphylaxis. The pregnancy was complicated by a mild COVID-19 infection in the 2nd trimester, but otherwise uncomplicated. Delivery was induced at 38 4/7 weeks with prostaglandin and rFVIIa (NovoSeven®) started when in active labor. After a rapid vaginal delivery and afterbirth, manual placental removal was performed and a Bakri balloon inserted for ongoing bleeding despite rFVIIa 90μg/kg every 2h. As bleeding still continued, plasma-derived VWF was infused with initial excellent recovery and successful embolization of the aa uterinae was performed. Another infusion of VWF to prevent rebleeding resulted in minimal recovery and an allergic reaction despite prednisolone and clemastine. Rebleeding did not occur and patient was discharged at day 8. At day 12 she was readmitted because of endometritis followed by vaginal bleeding unresponsive to rFVIIa. Re-embolization was performed and off label emicizumab started to prevent rebleeding. A loading dose of 6mg/kg on day 1 and 3mg/kg on day 2 was given, followed by 3mg/kg EOW from the 2nd week onwards. As the infection was uncontrolled by broadspectrum antibiotics, hysterectomy was performed at dag 29, again complicated by diffuse bleeding requiring direct intra-abdominal packing and rFVIIa 90μg/kg every 2 hours in addition to emicizumab. A week after unpacking, asymptomatic pulmonary embolisms and thrombosis of the left v iliaca were discovered on CT. rFVIIa was stopped, prophylactic LMWH started and a third embolization performed when bleeding reoccurred. Two months after delivery she was discharged with low dose LMWH, emicizumab and antibiotics because of an intra-abdominal abcess. Discussion/Conclusion: Delivery in patients with severe bleeding disorders in the presence of alloantibodies is a high-risk situation. Emicizumab was partially helpful in maintaining hemostatic control. Besides bleeding, postpartum patients receiving intensive correction of coagulation and especially with additional risk factors like surgery and infection, are also at risk for thrombotic events.

Depression and Anxiety in Persons with Von Willebrand Disease

[Formula presented] Background: Depression and anxiety are associated with poor health-related quality of life (HRQoL), lower functioning and decreased treatment adherence. In 2019, 7% adults in the US had moderate/severe symptoms of depression, while <5% had anxiety. Impacts of depression and anxiety in persons with von Willebrand disease (VWD) are unclear and less studied. Objective: We assessed sociodemographic and clinical characteristics associated with depression and anxiety in a geographically diverse cohort of individuals with VWD obtaining care at seven US Hemophilia Treatment Centers (HTCs). Methods: The study enrolled and collected data on individuals age ≥12 with VWD Type 1 (VWF:Ag/RCo: ≤30%), low VWF(VWF:Ag/RCo: 30-50%), Type 2, and type 3 between September 2018-June 2021. Participants completed a survey at enrollment to collect sociodemographic and clinical characteristics, self-reported pain, joint problems and HRQoL measured by the EQ-5D-3L. A quarterly survey administered one year post-enrollment collected similar data. The patient health questionnaire (PHQ-8) and the generalized anxiety disorder (GAD-7) were administered with the last follow-up survey after August 2019. Chart reviews ed VWD type information. The association of sociodemographic and clinical characteristics with depression or anxiety was assessed using Chi-square tests for categorical variables, as well as logistic regression models with stepwise selection. Results: We analyzed data from 77 participants who completed both baseline and last follow-up surveys. Mean age was 34.2 (standard deviation (SD)=18.8) years, 74.0% were adults ≥18 years, 79.2% were female, 60.8% had Type 1/low VWF, and 3.9% had Type 3 VWD. Mean age at VWD diagnosis was 13.9 (SD=13.2) years. Overall reported depression rate was 63.4%, and 58.3% for anxiety (values ≥10 on either PHQ-8 or GAD-7). Proportion of those with depression (75% vs. 62%) or anxiety (58% vs. 58%) prior to and during the COVID-19 pandemic were not significantly different. Persons with low VWF had higher rates of depression (86.7%) or anxiety (69.2%) as compared to those with type 1 VWD (55.3% for depression, 52.8% for anxiety) or types 2 and 3 (62.5%, 60.9%, p=0.10, not significant (NS) for depression and p=0.56, NS for anxiety, respectively). Females reported a higher rate of anxiety (61.4%) than males (46.7%, p=0.30, NS). When compared to individuals who rated their general health as the same or better than 3-months ago, those who rated their health as worse had significantly higher rates of depression (92.3% vs. 57.8%, p=0.02) and anxiety (83.3% vs. 53.3%, p=0.05). Participants with chronic pain reported a significantly higher depression rate (81.6% vs. 36.8%, p=0.0003). Those who reported having joint problems also reported depression at a significantly higher rate (82.4% vs. 48.8%, p=0.002) or anxiety (74.1% vs. 46.3%, p=0.02) than those without joint problems. Logistic regression analyses demonstrated that among adults or parents of pediatric patients, being single or not with a partner was the most important variable associated with depression (odds ratio (OR)=7.0, confidence interval (CI): 1.7-29.0), followed by having joint problems (OR=6.3, CI=2.0-20.1). The most important variable associated with anxiety was being a youth aged 12-18 years old (OR=6.7, CI=1.6-26.9), followed by being single or not with a partner (OR=10.8, CI=2.5-47.5), or having worse health compared to 3-months prior (OR=12.3, CI=1.3-116.2). Mean covariates adjusted EQ index scores were lower among persons with depression (0.75±standard error (SE) 0.03 vs. 0.83±0.04, p=0.06 NS) or anxiety (0.75±0.03 vs. 0.82±0.04, p=0.7 NS) than among those without depression or anxiety. As compared to individuals without depression or anxiety, mean covariates adjusted EQ VAS was significantly lower in persons with depression (68.7±3.1 vs. 77.6±4.2, p=0.03), but not among those with anxiety (69.3±3.7 vs. 71.3±4.3, p=0.66 NS). Conclusions: Our study revealed higher rates of major depression and anxiety in thi VWD sample than the general US population. Depression had a significant negative impact on HRQoL. Mental health screening is imperative for persons with VWD, especially those with low VWF, chronic pain or joint problems. Special attention should be paid to women and youth. This study underscores the need for a multidisciplinary approach in the comprehensive care of patients seen at HTCs. Disclosures: Roberts: Genentech, Novo Nordisk, Octapharma, Pfizer, Sanofi, Takeda, uniQure: Consultancy;Takeda;Speakers Bureau: Novo Nordisk, Octapharma, Sanofi, Takeda.: Research Funding. Kulkarni: Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees;CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees;Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees;Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees;Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees;Sanofi Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees;Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees;Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sidonio: Bayer: Consultancy;Catalyst: Consultancy;Genentech: Consultancy, Research Funding;Novo Nordisk: Consultancy;Guardian Therapeutics: Consultancy;Octapharma: Consultancy, Research Funding;Biomarin: Consultancy;Pfizer: Consultancy;Takeda: Consultancy, Research Funding. Carpenter: Genentech: Honoraria;Novo Nordisk: Honoraria;Kedrion Pharmaceuticals: Honoraria;Hemophilia and Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees. Konkle: Pfizer, Sangamo, Sanofi, Sigilon, Spark, Takeda and Uniqure: Research Funding;BioMarin, Pfizer and Sigilon: Consultancy. Wu: Baxalta US Inc., Bannockburn, IL (a Takeda Company), CSL Behring L.L.C., Octapharma USA, Inc., Genentech Inc.: Research Funding. Curtis: Pfizer, Bayer, and Novo Nordisk: Consultancy;University of Southern California: Consultancy. Nichol: Pfizer, Genentech Inc., Baxalta US Inc., Bannockburn, IL (a Takeda Company), Octapharma, CSL Behring, Global Blood Therapeutics, and Novo Nordisk: Research Funding.

Registry of patients with congenital bleeding disorders and COVID-19 in Madrid.

INTRODUCTION: We present the first registry of patients with congenital bleeding disorders and COVID-19. The study has been carried out in the Community of Madrid, which has the highest number of cases in Spain. The objective is to understand the incidence of COVID-19, the course of the disease if it occurs and the psychosocial and occupational impact on this population. METHODS: We included 345 patients (246 of haemophilia, 69 of von Willebrand Disease, two rare bleeding disorders and 28 carriers of haemophilia). A telephone survey was used to collect the data. RESULTS: Forty-two patients presented symptoms suggestive of infection by COVID-19, and in six cases, the disease was confirmed by RT-PCR. The cumulative incidence of our series was 1.73%. It is worth noting the complexity of the management of COVID-19 in two patients on prophylaxis with non-factor replacement therapy. Adherence to the prescribed treatment was maintained by 95.5% of patients. Although 94% were independent for daily living activities, 42.4% had a recognized disability and 58% required assistance, provided by the Madrid Haemophilia Association (Ashemadrid) in 75% of cases. Only 4.4% of consultations were held in person. CONCLUSIONS: Patients with congenital bleeding disorders infected with SARS-CoV-2 presented a mild course of the disease that did not require admission. Their identification and treatment by a specialist team from a Haemophilia Treatment Center are essential to make a correct assessment of the risk of haemorrhage/thrombosis. COVID-19 had a major impact on the psychosocial aspects of these patients which must be remedied with recovery plans.