Podcast appearances and mentions of von willebrand

Join The Bad Girl, The Playa, and our new co-host Tiffany Star, as we complete the POS Peterson Trilogy and examine the controversial case of renowned author Michael Peterson. Michael Iver Peterson (born October 23, 1943) is an American novelist who was convicted in 2003 of murdering his second wife, Kathleen Peterson, on December 9, 2001. After eight years, Peterson was granted a new trial after the judge ruled a critical prosecution witness gave misleading testimony. In 2017, Peterson submitted an Alford plea to the reduced charge of manslaughter. He was sentenced to time already served and freed. Elizabeth Ratliff, a friend of the Petersons, who died in Germany in 1985, had also been found dead at the foot of her staircase with injuries to the head. Her death had been investigated by both the German police and U.S. military police. An autopsy at the time of her death concluded Ratliff died from an intra-cerebral hemorrhage secondary to the blood coagulation disorder Von Willebrand's disease, based on blood in her cerebrospinal fluid and reports that she had been suffering severe, persistent headaches in the weeks leading up to her death. The coroner determined that the hemorrhage resulted in immediate death, followed by Ratliff falling down the stairs after collapsing. The Petersons had dinner with Ratliff and her daughters, and Peterson had stayed and helped Ratliff put the children to bed before going home. The children's nanny, Barbara, discovered the body when she arrived the next morning. Peterson was the last known person to see her alive. Did Peterson get off too easy? T.I.F.O.! (Tune In Find Out) #truecrime #michaelpeterson #staircase #thestaircasemurders

In this Review Series episode on Basic/Translational Science of Factor VIII, Factor IX, and von Willebrand Factor introduced by Dr. Thomas Ortel, we'll hear from contributing authors Drs. Ben Samuelson Jones, Mac Monroe and Peter Lenting as they discuss how the functional roles of these 3 proteins are interconnected. Click here to view the complete Review Series featured in Volume 144 Issue 21 of Blood.

This conversation kicks off a new series that takes a deep dive into anything blood-related. During this episode, Dr. Andrew Jenzer revisits the podcast alongside Dr. Maxwell Lloyd to demystify some of the key ideas underpinning hemostasis, coagulation, and PTT levels. Join us as we discuss helpful tools to navigate detection, monitoring, testing, and all the factors that may affect results. From PTT and D-Dimer testing to mixed testing options and thrombal elastography, we cover it all. Next, we get into abnormalities and all the elements to consider before going about an invasive surgery of this nation. We get into detail about Von Willebrand's disease and what testing can tell you, after considering why clinical history is specifically important for the treatment of bleeding issues. Lastly, we discuss OMS-specific hemostatic agents, and the impact of CRASH 1, 2, and 3 trials on how we implement TXA. Join us today to hear all this and more. Key Points From This Episode:Introducing Drs. Andrew Jenzer and Maxwell Lloyd.Dr. Jenzer's upcoming mock boards course for residents.The topic of this episode which kicks off a new series: blood and anything blood related.Differentiating between primary and secondary hemostasis. Understanding intrinsic and extrinsic pathways. Why all coagulation factors are ultimately made in the liver.The importance of interpreting the lab values.Using the WETT acronym in the context of anti-coagulation.Monitoring through PTT. D-Dimer testing and why it is so often misunderstood. What is essential to do when mixing tests together. Another test option: thrombal elastography.Thinking about the risks and benefits of stopping anticoagulation. Developing a schema to think about abnormalities. Understanding how to address Haemophilia A and B. Why clinical history is particularly important for bleeding issues.Demystifying Von Willebrand's disease and what testing can tell you. OMS-specific hemostatic agents, which ones work best, and more. CRASH 1, 2 and 3 trials and TXA. Links Mentioned in Today's Episode:Dr. Maxwell Lloyd on Google Scholar — https://scholar.google.com/citations?user=D0agka0AAAAJ Dr. Andrew Jenzer Email — andrew.jenzer@gmail.com Dr. Andrew Jenzer — https://surgery.duke.edu/profile/andrew-clark-jenzer CRASH-1 — https://pmc.ncbi.nlm.nih.gov/articles/PMC33506/ CRASH-2 — https://pmc.ncbi.nlm.nih.gov/articles/PMC4576020/ CRASH-3 — https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)32233-0/fulltext Everyday Oral Surgery Website — https://www.everydayoralsurgery.com/ Everyday Oral Surgery on Instagram — https://www.instagram.com/everydayoralsurgery/ Everyday Oral Surgery on Facebook — https://www.facebook.com/EverydayOralSurgery/ Dr. Grant Stucki Email — grantstucki@gmail.com Dr. Grant Stucki Phone — 720-441-6059

La enfermedad de Von Willebrand es un trastorno de sangrado de por vida en el cual la sangre no coagula adecuadamente.

Darshan H. Brahmbhatt, Podcast Editor of JACC: Advances, discusses a recently published original research paper on Von Willebrand factor activity association with outcomes after transcatheter edge-to-edge mitral valve repair.

Picture this: you're on the admit shift on a Tuesday morning, and your next patient is a 6-month-old Doberman for routine neutering. Is there anything you'd be particularly worried about before surgery? Is there anything you'd discuss with the client or any tests you'd speak to your vet about? Dobermans are a classic breed affected by von Willebrand's disease, which is a disease that sits somewhere between thrombocytopenia and coagulopathy. If they have it, bleeding is a very real risk. Thankfully, if we know beforehand, we can implement strategies to manage the patient's disease and prevent severe haemorrhage. That starts with understanding von Willebrand's disease and how it works, which is exactly what we're covering in this episode of the Medical Nursing Podcast. ---

In this week's episode we'll discuss the findings from a study assessing the utility of free light chain mass spectrometry in AL amyloidosis, learn more about distinct single-cell RNA-sequencing signatures of bone marrow T cells of AML patients in remission after an allogeneic stem cell transplant, and discuss why von Willebrand factor clearance is critical for the protective effect of ADAMTS13 in mice with sickle cell anemia.Articles featured in this episode: Clearance of VWF by hepatic macrophages is critical for the protective effect of ADAMTS13 in sickle cell anemia mice Complete responses in AL amyloidosis are unequal: the impact of free light chain mass spectrometry in AL amyloidosisThe remission status of patients with AML post-alloSCT is associated with a distinct single-cell bone marrow T-cell signature 

Thank you for joining us for our 2nd Cabral HouseCall of the weekend! I'm looking forward to sharing with you some of our community's questions that have come in over the past few weeks…   Laura: Hi Dr. Cabral, I'm an IHP2 OG, and loving how it expanded my practice to support others. Thank you for making that possible. I have a client who gets severe dizziness, brain fog and fatigue the day after she eats any sugar, starchy veggies, sugar, almonds to name a just a few. She can't even have the DNS. We did OAT, PCP extensive blood work, hormones and HTMA. No gut based issues on OAT and she does not experience any gut based symptoms. Her Insulin was 2.3 which was on the lower end and she has VERY high ferritin (250). Since working together she is starting to feel good in other areas, but this is one that lingers. I realize we do not treat, cure or diagnose - but I thought possible reactive hypoglycemia? I could not find any root causes for this and wanted to know your thoughts.   Laura: Hi Dr Cabral! I know you have shared your thoughts on fecal transplants before, but I could not find anything on Postbiotic Supplement. I realize you can't say the name, so basically the freeze dried feces supplement. I have a client who had another practitioner recommend this to her (She does not even experience any digestive destress). If someone had severe gut based issues, or auto immune like Ulcerative colitis or crohns and they still suffer after trying many things, do you think there is a time and place for this? Thank you!   Anonymous: Hi Dr. Cabral, my wife has lived with Type 1 Von Willebrands her whole life and has been given the traditional western medicine approach to manage it. I am curious if you have ever encountered this and what recommendations you would have, especially when it comes to pregnancy/child birth. That is not too far down the road for us and would like to have some basic knowledge from a functional medicine standpoint. Thank you!   Ria: Delta-8 and Delta-9 THC infused drinks are popping up everywhere. Are they safe? I worry about the unknowns of how these products are manufactured, plus the reported health issues and reactions. Thanks for all you do!   Kelsi: hi dr. cabral! my cycle the last 6 months has been longer than usual (about 35-40 days) before it restarts. i only bleed for 3-4 days which is normal for me but days 25-35, i'm holding a lot of water, sweating at night, etc. i'm waiting to purchase the stress mood & metabolism test until im done with the CBO protocol -there anything i can do about this in the meantime? Thank you for tuning into this weekend's Cabral HouseCalls and be sure to check back tomorrow for our Mindset & Motivation Monday show to get your week started off right! - - - Show Notes and Resources: StephenCabral.com/2886 - - - Get a FREE Copy of Dr. Cabral's Book: The Rain Barrel Effect - - - Join the Community & Get Your Questions Answered: CabralSupportGroup.com - - - Dr. Cabral's Most Popular At-Home Lab Tests: > Complete Minerals & Metals Test (Test for mineral imbalances & heavy metal toxicity) - - - > Complete Candida, Metabolic & Vitamins Test (Test for 75 biomarkers including yeast & bacterial gut overgrowth, as well as vitamin levels) - - - > Complete Stress, Mood & Metabolism Test (Discover your complete thyroid, adrenal, hormone, vitamin D & insulin levels) - - - > Complete Food Sensitivity Test (Find out your hidden food sensitivities) - - - > Complete Omega-3 & Inflammation Test (Discover your levels of inflammation related to your omega-6 to omega-3 levels) - - - Get Your Question Answered On An Upcoming HouseCall: StephenCabral.com/askcabral - - - Would You Take 30 Seconds To Rate & Review The Cabral Concept? The best way to help me spread our mission of true natural health is to pass on the good word, and I read and appreciate every review!  

In this weeks episode, we'll learn more about the role of IL-7 receptor signaling in the differentiation and expansion of human B-cell progenitors, discuss the use of fixed-duration venetoclax plus obinutuzumab in older patients with chronic lymphocytic leukemia, and learn how low-density lipoprotein promotes microvascular thrombosis by enhancing von Willebrand Factor self-association 

It is well known that menstrual cycles can be stressful and painful – especially when a young person first starts their period. Most people learn from their family members about what to expect and how to be as comfortable as possible during menstrual cycles.   But what if your family's “normal” isn't normal at all? Margo D'Agostino had excessively heavy menstrual bleeding for years – including some symptoms, that in hindsight, were quite alarming. But her mom had the same experience, so they together decided it must be normal. Spoiler, it wasn't normal – Margo has a bleeding disorder called Von Willebrand's disease, that other members of her family likely have too.   On the podcast today, Margo and Dr. Maria Carter Febres, a pediatric hematologist, join us to talk about bleeding disorders and Margo's journey to find answers about her health. We talk about typical menstruation experiences, the importance of normalizing conversations about monthly cycles and what to do if something doesn't seem quite right with your own or your child's health.

In this episode, Director of Community Engagement, Luke Pembroke, and Director of Research, Kate Khair spoke with community advocates Sunny Maini and Hannah Yarnalll. Sunny and Hannah share their experiences of living with von Willebrand Disorder (VWD), their journey in to the world of advocacy and tell us about their latest venture establishing the VWD working group through The Haemophilia Society UK. For more information about the VWD working group and their upcoming event in Sheffield on 26th August, you can contact Sunny via email: sunny@haemophilia.org.uk

Michéle nahm lange an, dass die Schuhe zu eng sind oder weil sie zu ausgiebig mit dem Kind gerangelt hat? Das ist doch nicht normal. Extrem starke Menstruationsblutungen und starke Nachblutungen nach einer OP sind auch nicht normal. Schlechte bis gar nicht heilende Wunden sind ebenfalls nicht typisch. Jede Situation für sich genommen lassen in aller Regel selten aufhorchen, aber in Summe bilden sie ein Muster, das unbedingt analysiert werden muss, in diesem Fall von Ärzten auf dem Fachgebiet der Gerinnungsstörung. Was ist also los, wenn das Blut einfach nicht gerinnen will? Wenn Wunden bluten und die natürliche Blutgerinnung wie bei Michéle nicht einsetzt? Bei Michéle, Patientin der MediosApotheke, vergingen viele Jahre, bis eine lebensbedrohliche Situation zum Auslöser wurde, dass endlich aus dem erwähnten Muster eine Diagnose gestellt werden konnte. Über frühe Warnzeichen und Hinweise auf das Von-Willebrand-Syndrom, welches sowohl angeboren oder erworben (also im Laufe des Lebens auftretend) vorkommen kann, sprechen wir mit Michéle Zerfass. Sie ist eine Patientin mit dem Von-Willebrand-Syndrom, Typ 3, welches Michéle von Geburt an hat und eine genetisch bedingte Gerinnungsstörung ist. In Ihrem Blut fehlt ein bestimmtes Eiweiß, welches normalerweise für die Blutgerinnung zuständig ist, der sogenannte Von-Willebrand-Faktor. Um in der Öffentlichkeit eine größere Sensibilität für diese seltene Erkrankung zu schaffen, erzählt uns Michéle ihre ganz persönliche Geschichte und klärt über die frühen Anzeichen und die entsprechenden Symptome aus ihrer Perspektive auf. Falls du Fragen zu dem Von-Willebrand-Syndrom hast, melde dich jederzeit bei uns in der MediosApotheke.

With Natalie Philbert, Manager of Women's Programs and Services at Hemophilia Ontario, and Dr. Meghan Pike, pediatrician and clinical fellow in Pediatric-Hematology Oncology at Dalhousie University/IWK Health Centre.   We don't always have the language to speak about our periods – let alone menstrual bleeding disorders. What are the signs and symptoms? What are the gaps in care and diagnosis? And how does it connect with gendered inequities?   May 28 was International Day of Action for Women's Health, so for the next few episodes, we're focusing on gender and health matters we may know bits and pieces of but probably need to learn more about. Today, we focus on menstrual bleeding disorders.  Natalie Philbert is a PhD candidate focusing on delay in diagnosis for menstruators with bleeding disorders. Natalie brings a professional and personal passion to the bleeding disorder community given her own diagnosis of Von Willebrand disease Type 1. She co-created a website called heroixx.ca, specifically designed for menstruators with bleeding disorders.    Dr. Meghan Pike launched the WeThrive App that can identify adolescents with heavy menstrual bleeding.  She is an advocate for free access to menstrual products. Her research interests include patient-reported outcome measures, impacts of cancer treatment on reproductive and menstrual health, and advocacy for menstruators.  Relevant links: heroixx.ca, WeThrive App (Apple App Store | Google Play)  Please listen, subscribe, rate, and review this podcast and share it with others. If you appreciate this content, if you want to get in on the efforts to build a gender equal Canada, please donate at ⁠⁠⁠⁠⁠canadianwomen.org⁠⁠⁠⁠⁠ and consider becoming a monthly donor.   Episode ⁠⁠⁠⁠⁠Transcripts⁠⁠⁠⁠⁠   Facebook: ⁠⁠⁠⁠⁠Canadian Women's Foundation⁠⁠⁠⁠⁠   Twitter: ⁠⁠⁠⁠⁠@cdnwomenfdn ⁠⁠⁠⁠⁠   LinkedIn: ⁠⁠⁠⁠⁠The Canadian Women's Foundation ⁠⁠⁠⁠⁠   Instagram: ⁠⁠⁠⁠⁠@canadianwomensfoundation⁠⁠

Um in der Öffentlichkeit eine größere Sensibilität für die seltene Erkrankungen Hämophilie und Von-Willebrand-Syndrom zu schaffen, erzählt uns Michele Zerfass, selber Von-Willebrand Patientin, ihre ganz persönliche Geschichte und erklärt, warum sie ein Notfallarmband trägt. Um in einer Notfallsituation ihre Krankendaten Ärzt*innen, Sanitäter*innen, aber vor allem auch Ersthelfenden zur Verfügung stellen, trägt Michele ein Notfallarmband. Dieses Armband verweist zunächst erstmal auf die Information, dass die Trägerin eine spezielle Behandlung benötigt und Notfalldaten von ihr zur Verfügung gestellt werden. Auf der Rückseite des Armbands ist ein 12-stelligen Code eingedruckt, der mit dem Smartphone von Michele verbunden ist und Zugang zu ihren Patientinnendaten gewährt. Alternativ kann der Code auch in der App Notfall-ID Notfallpass oder auf der Website https://notfallpass-id.de auf die Patientinnendaten von Michele weiterleiten.. Warum ist diese Notfallarmband für Michele wo wichtig, bzw. unter Umständen sogar lebensrettend? Michele ist eine Patientin mit dem Von-Willebrand-Syndrom, Typ 3, was bedeutet, dass Michele von Geburt an eine genetische Gerinnungsstörung hat. Ihrem Blut fehlt ein bestimmtes Eiweiß, welches normalerweise für die Blutgerinnung zuständig ist. Das fehlende Eiweiß im Blut bezeichnet den sogenannten Von-Willebrand-Faktor. Bei Michele schließen sich Wunden von daher nicht ohne Verabreichung von speziellen Medikamenten. Das von Sanitäter*innen und/oder Ärzt*innen erstmal gespritzte blutverdünnende Mittel würde bei Michele von daher absolut kontraproduktiv wirken. Michele ist die Aufklärung und Verbreitung über die Diagnosestellung, die Versorgung und der alltägliche Umgang mit der seltenen Erkrankung eine Herzensangelegenheit, weshalb wir mehr als glücklich sind, dass wir Michele in unser YouTube Studio einladen und sie interviewen durften. Ihre ganz persönliche Geschichte hat sie uns bereits in diesem Video erzählt: https://www.youtube.com/watch?v=KlIraI9Av50&t=627s

Was aber ist los, wenn das Blut einfach nicht gerinnen will? Wenn Wunden bluten und die natürliche Blutgerinnung nicht einsetzt? Über das Thema sprechen wir mit Michele Zerfass. Sie ist eine Patientin mit dem Von-Willebrand-Syndrom, Typ 3, was bedeutet, dass Michele von Geburt an eine genetische Gerinnungsstörung hat. Ihrem Blut fehlt ein bestimmtes Eiweiß, welches normalerweise für die Blutgerinnung zuständig ist. Das fehlende Eiweiß im Blut bezeichnet den sogenannten Von-Willebrand-Faktor. Große Wunden, OPs, Geburten oder schon die monatliche Menstruation stellen Michele vor eine sehr große Herausforderung, weshalb sie nach ihrer Diagnose in dem Gerinnungszentrum Hochtaunus lernen musste, sich im Alltag ihre Medikation selber zu spritzen, damit ihre Organe weiterhin gut durchblutet und versorgt bleiben. Mit Ruhe, Geduld, einem gut strukturierten Alltag und vielen helfenden Händen hat Michele gelernt, die Krankheit zu akzeptieren, den häufig wellenförmigen Verlauf der Krankheit anzunehmen, um damit ihre Lebensqualität zu sichern. Unterkriegen und Aufgeben ist für Michele absolut keine Option. Um in der Öffentlichkeit eine größere Sensibilität für diese seltene Erkrankungen zu schaffen, erzählt uns Michele ihre ganz persönliche Geschichte und erklärt zum anderen in unserem nächsten Video, warum sie Tag und Nacht ein Notfallarmband trägt und so in einer Notsituation ihre Krankendaten zur Verfügung stellen kann. Wichtige und weiterführende Links für dich: Paul Ehrlich Institut: https://www.pei.de/DE/regulation/melden/dhr/dhr-node.html Netzwerk von-Willebrand-Syndrom: https://www.netzwerk-von-willebrand.de/selbsttest Allgemeine und weiterführende Informationen zur Ersten Hilfe: https://gesund.bund.de/erste-hilfe Interessengemeinschaft Hämophiler e.V.: https://www.igh.info/notfall Deutsche Hämophiliegesellschaft: https://www.dhg.de/nachrichten-und-publikationen/publikationen.html Bundeszentrale für gesundheitliche Aufklärung: https://www.bzga.de/was-wir-tun/schutzimpfungen-und-persoenlicher-infektionsschutz/

This week's episode will be focusing on a bleeding disorder, Von Willebrand disease (VWD). We will go over all the important details on the diagnosis, types of VWD (& ways to remember them!) as well as treatment options.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.25.513669v1?rss=1 Authors: Swinkels, M., Hordijk, S., Bürgisser, P. E., Slotman, J. A., Carter, T., Leebeek, F. W. G., Jansen, A. J. G., Voorberg, J., Bierings, R. Abstract: Background: Platelet alpha-granules contain Von Willebrand factor (VWF), which is stored in eccentric alpha-granule nanodomains, and VWF propeptide (VWFpp). Differential release of VWF and VWFpp has been reported from endothelial cells. It is unclear if this also occurs during platelet alpha-granule exocytosis. We have recently developed a 3D super-resolution imaging workflow for quantification of platelet alpha-granule content based on Structured Illumination Microscopy (SIM). With this we can study alpha-granule cargo release following platelet activation in hundreds of platelets simultaneously. Aims: To study release of VWF and VWFpp from alpha-granules using quantitative super-resolution microscopy. Methods: Platelets were activated with PAR-1 activating peptide (PAR-1 ap) or collagen-related peptide (CRP-XL). Alpha-tubulin, VWF, VWFpp, SPARC and fibrinogen were imaged using 3D-SIM, followed by semi-automated analysis in FIJI. Uptake of anti-VWF nanobody during degranulation was used to identify alpha-granules that partially released content. Results: VWF+ and VWFpp+ structures overlapped nearly completely (~90%) in resting platelets, implying they are stored in similar eccentric alpha-granule nanodomains. A subset of VWF+/VWFpp+-structures was released completely at 0.6 M PAR-1-ap, but at higher concentration (20 M) significantly more VWFpp (85.3{+/-}1.6%) was released than VWF (37.6{+/-}1.4%). Release of other cargo was intermediate at 20 M (SPARC: 62.2{+/-}1.4% ; fibrinogen: 51.9{+/-}2.9%), providing further evidence for differential cargo release. Similar results were obtained using CRP-XL. Anti-VWF nanobody was taken up by VWF+/VWFpp- structures and increased with stimulus strength, demonstrating these were post-exocytotic structures. Conclusions: VWF and VWFpp are differentially released from alpha-granules. This may affect how platelet-derived VWF and VWFpp contribute to formation and stabilization of hemostatic clots. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Von Willebrand disease (VWD) is a hereditary quantitative deficiency or functional abnormality of von Willebrand factor (VWF), which causes platelet dysfunction. Bleeding tendency is usually mild in the most common types, but it can be severe and present with factor VIII deficiency as well as platelet dysfunction in the rarer subtypes. It is diagnosed based on testing von willebrand factor antigen levels which is low in most subtypes, VWF activity which is low in most subtypes and VWF multimer distribution which is abnormal in a small number of the subtypes.  Treatment depends on the degree of bleeding. Mild mucosal bleeding can often be managed with tranexamic acid alone to help stabilise the clots that are present. Desmopressin might be used in more significant bleeding or perioperatively. Occasionally von willebrand factor concentrates might need to be given. Follow us on Instagram @yourekiddingrightdoctors Our email is yourekiddingrightpod@gmail.com Make sure you hit SUBSCRIBE/FOLLOW so you don't miss any episodes and RATE to help other people find us! (This isn't individual medical advice, please use your own clinical judgement and local guidelines when caring for your patients)

This week, please join authors Paul Ridker and Eric Van Belle, editorialist Robert Harrington, and Guest Editor Allan Jaffe as they discuss the original research articles "Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy" and “Cerebral Microbleeds During Transcatheter Aortic Valve Replacement: A Prospective Magnetic Resonance Imaging Cohort” and the editorial "Trials and Tribulations of Randomized Clinical Trials." Dr. Carolyn Lam:             Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore. Dr. Greg Hundley:           And I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam:             It's double feature time Greg. We've got two totally unique and interesting papers that we'll be discussing. The first, a biomarker substudy from the REDUCE-IT trial, that is looking at the effects of randomized treatment with icosapent ethyl, versus a mineral oil comparator, on inflammatory biomarkers. Now, don't use roll your eyes at me, because I'm telling you, this has results that you may not expect, and very, very important clinical implications, and implications for clinical trials. The second paper, very much up your alley, Greg, is a prospective MRI study of cerebral microbleeds during TAVR. But okay, enough now to whet your appetite, let's now just first grab coffees, and discuss the other papers and the issue, shall we? Dr. Greg Hundley:           You bet, Carolyn. And how about if I go first? Dr. Carolyn Lam:             Please. Dr. Greg Hundley:           So, Carolyn, my first paper comes from a group of investigators led by Dr. Araz Rawshani from the Institute of Medicine, and it included 715,143 patients with diabetes, registered in the Swedish National Diabetes Register, and compared them with over two million match controls, randomly selected from the general population, to determine the role of diabetes in the development of valvular heart disease, and particularly, the relation with risk factor control. Dr. Carolyn Lam:             Huh? Interesting, diabetes and valve disease. All right. What did they find, Greg? Dr. Greg Hundley:           Right, Carolyn. So they found, that individuals with type one and two diabetes, have greater risk for stenotic lesions. Whereas, risk for valvular regurgitation was lower in type two diabetes. Patients with well controlled cardiovascular risk factors, continued to display higher risk for valvular stenosis, without a clear stepwise decrease in risk between various degrees of risk factor control. So Carolyn, diabetes and a link with valvular heart disease. Dr. Carolyn Lam:             Wow. Really interesting, Greg. Thanks. Well, the next paper is a preclinical study with really interesting clinical implications. Now, we know the human heart has limited capacity to regenerate new cardiomyocytes, and that this capacity declines with age. Now, because loss of cardiomyocytes may contribute to heart failure, it is important to explore how stimulating endogenous cardiac regeneration, to favorably shift the balance between loss of cardiomyocytes and birth of new cardiomyocytes, occurs in the aged heart. Now, these authors, Doctors Rosenzweig, from Massachusetts General Hospital, and Dr. Lee from Harvard University and colleagues, previously showed that cardiomyogenesis can be activated by, guess what? Exercise in the young adult mouse heart. However, whether exercise also induces cardiomyogenesis in aged hearts, however, is not yet known. So in today's paper, the authors aim to investigate the effect of exercise on generation of new cardiomyocytes in the aged heart. And here, we're talking about 20 month old mice, who were subjected to an eight week voluntary running protocol, and age matched sedentary animals who served as controls. Dr. Greg Hundley:           Wow, Carolyn. Really interesting evaluation of exercise on cardiomyogenesis. So what did they find? Dr. Carolyn Lam:             Endogenous cardiomyogenesis can be stimulated by exercise in aged hearts. Comparative global transcriptional analysis further revealed, that exercise and age specific changes occurred in gene programs. The regulator of calcineurin RCAN1.4 was specifically found to be induced with exercise in aged hearts, and was accompanied by reduced calcineurin activity. So what's a take-home message? Exercise induced cardiomyogenesis may counter the increased cardiomyocyte loss and reduced cardio myogenic capacity in elderly patients. Dr. Greg Hundley:           Great, Carolyn. Well from the mail bag, there's an exchange of letters to the editor from Professor Zhou and Veith regarding a prior letter to the editor from Professor Jin and associates, pertaining to the previously published article “SPARC, A Novel Regulator of Vascular Cell Function in Pulmonary Hypertension.” And also, there's a Perspective piece, from Professor Mentz entitled, “Catastrophic Disruptions in Clinical Trials.” Dr. Carolyn Lam:             There's also a Research Letter by Dr. Kumar on [entitled] “von Willebrand Factor Is Produced Exclusively by Endothelium, Not Neointima, in Occlusive Vascular Lesions in Both Pulmonary Hypertension and Atherosclerosis.” There's also this beautiful tour of Cardiology News from the literature, from Tracy Hampton, which ranges from a study linking COVID-19 to higher long term cardiovascular risks, which was published in Nature Med, to uncovering alternative metabolic pathways involving cell fate transitions, published in Nature, to designing an autonomous biohybrid fish, from human stem cell derived cardiac muscle cells, that was published in Science. Wow. Isn't that amazing, Greg? Well, let's get on now though, to our two feature papers. Shall we? Dr. Greg Hundley:           You bet. Welcome listeners, to these two feature discussions on this particular day. And our first feature today, we have with us Dr. Paul Ridker, from Brigham and Women's Hospital in Boston, Massachusetts. Dr. Bob Harrington, from Stanford University in California. And also, Dr. Allan Jaffe, from Rochester, Minnesota. Welcome to you all. And Paul, we're going to start for you. Can you describe for us, the background information that really went into the construct of your study, and what was the hypothesis that you wanted to address? Dr. Paul Ridker: Sure, Greg. So first of all, my thanks to the AHA and the Circulation for publishing this paper, we always want to support the AHA, and we're delighted to be here today for these podcasts. The field of omega-3 fatty acids has been a complicated one for a long time. Epidemiology suggested that, fish consumption would lower cardiovascular risk, and there was a number of trials done. And my friend and colleague here at the Brigham, Deepak Bhatt, was the lead of a very big trial, called REDUCE-IT. Some 8,000 plus patients who received EPA alone, and they got a terrific result. A 25% reduction in their primary endpoint. And this was a New England Journal paper, back in 2019 or so. But another friend of mine, Steve Nicholls, ran another large trial of a combination of eicosapentaenoic acid, or EPA, plus docosahexaenoic acid that's DHA called STRENGTH. And that one showed, really, no benefit. And so, there's been some controversy out there. In any event, when Deepak and his colleagues published their original paper, they said it's interesting, because they got this big risk reduction, but it wasn't apparently due to the triglyceride lowering of the drug. And so, my interest, as many people know, has largely been in inflammation biology. And so we said, well maybe we should just do a test. Well, we said, we'll measure a number of biomarkers that we know were associated with atherosclerosis, some inflammatory, some with coagulation. And so, that was the core hypothesis, was simply to look at some other markers, and see what we might learn. And sometimes, you learn things that you didn't expect. And I think, that goes to the heart of what complicated clinical trials are all about. And I'd also say perhaps, what the roles of surrogate endpoints are, as compared to hard clinical endpoints, and things that make this whole field kind of interesting. Dr. Greg Hundley:           Right. Very nice, Paul. So you mentioned REDUCE-IT, so describe a little bit more for your study. What was the study population, and what was your study design? Dr. Paul Ridker: We were fortunate enough to work with REDUCE-IT investigators, to use their biobank. They had put together, again, it's 8,000 plus patients. I think, it was two thirds secondary prevention, one third primary prevention. And when they received the combination of EPA and DHA, as I said earlier, they had about a 25% reduction in the risk of their primary endpoint, which was cardiovascular death, nonfatal AMI, nonfatal stroke, coronary revascularization, and the like. What we did is, we basically said, "Okay, since the mechanism was uncertain, why don't we go ahead and measure a series of biomarkers?" Things that a lot of us are interested in, homocysteine, LPLa, oxidized LDL, my own interest in inflammation. We measured, IL-1β, we measured, IL-6, we measured CRP. We measured another molecule, Lp-PLA2, that people have been interested in. And the hypothesis, of course, was to see what the drug did, as compared to the comparator did. And the findings were interesting to us, in that, to simplify them, the actual icosapent ethyl arm didn't do much to most of those biomarkers, very little change. But the mineral oil comparator arm had some small to modest effects on all those biomarkers, all of which went up again. Now, some of these effects are pretty small, two to 3% for things homocystine, LPLa. Others were moderate, 10 to 20% increases in oxidized LDL, Lp-PLA2. And the inflammatory markers went up about 25%, sometimes, even a little more. So it's complicated. It's important to point out, that these changes on an absolute scale are relatively small. On a percent scale, they're different. The REDUCE-IT investigators themselves, to their credit, had earlier published that, they saw some increase in LDL cholesterol as well, about 10, 11% in those who had received the mineral oil comparator. So it's not exactly what we thought we were going to find, I guess, is the simplest way to express it. Dr. Greg Hundley:           Very nice. And so, describe for us just a little bit more, any differences in men and women, and what about age? Or for example, premenopausal, postmenopausal women. Dr. Paul Ridker: No, the effects were quite consistent across all various subgroups. It's a very large study. There were, again, 8,000 patients, lots of blood samples been drawn. And I should again, commend the REDUCE-IT investigators, for allowing us to do this work with them. And again, as I point out, sometimes you find things out that weren't what you expected. And the hard part, I was glad this got tossed over with Dr. Harrington, is sort to figure out well, what's it really mean? Because again, as a clinical trial list, I will say, my instincts are to trust the primary endpoint of the trial. That's what they did. They're going to go out and lower heart attacks and strokes. And then, here we are a couple years later, trying to figure out what the mechanism might be, and just came across some puzzling results. Dr. Greg Hundley:           Very nice. Well, next listeners, we're going to turn to the editor that actually processed this manuscript, Dr. Allan Jaffe. Allan, what drew you to this particular article? Dr. Allan Jaffe:   Well, I was asked to be a guest editor this week, by the Journal, because of some conflicts that were intrinsic to the editorial board. And since I have an interest in biomarkers, and had for a long time, it made perfect sense for me to become involved. I was particularly interested in this particular area, because I was aware that there were these two trials that had found different endpoints, and that there were some controversy as to what the mechanisms might be by which these effects could occur. And so I was pleased to get involved. And I think it's a compliment to the REDUCE-IT investigators, and to Dr. Ridker, that they were willing to put the data out there so that everybody could see it. And we could then begin to look. So it was of interest to me. I thought it was important to the field, to get really good reviewers who would be, make sure that the data that would eventually be published was clear, so that readers would understand it. And so that, at the end, we'd be able to at least, come to some conclusions that we could end up having an expert in clinical trials. And I thought about Bob Harrington, right from the beginning, might be able to comment on. Dr. Greg Hundley:           Very nice. Well, Bob he's setting you up here nicely, both Paul and Allan, to really help us put these results in perspective with other studies that have been performed in this space. What are your thoughts? Dr. Robert Harrington:   So first off, Greg, thanks for having me. And Allan, thanks for inviting me to review and comment on the paper. As both Allan and Paul have indicated, that I've spent the last 30 plus years doing clinical trials of all sizes. Very small, where we try to understand mechanisms, and very large, where what we're trying to understand is clinical outcomes. And I've been intrigued in this field, because of the inconsistency of the data across the field. Where in some trials, Paul had indicated this STRENGTH, there seemed to be no effect of omega-3 fatty acids, and in REDUCE-IT, there was quite a pronounced effect of the test agent. And so, when one sees discordance in a field, one tries to understand, well, why might that be? And so in the editorial, I took the position that, well, what are we trying to do in clinical trials? And in outcomes trials, we're trying to figure out what matters to patients. Do they live longer? Do they feel better? Do they avoid bad stuff happening to them? Like having to undergo revascularization procedure. So you're trying to do things that are really clinically meaningful, but that doesn't say that you're also not trying to understand mechanism. And as Allan said, there have been some questions raised. And so, trying to understand mechanism in the edit in trials can be quite useful, not just to understand that trial results, but to really form hypothesis for a field going forward. And so, I took the approach of, we learn things from different trials, and sometimes we learn things in the same trial. Meaning that, there's mechanistic work embedded in the large trial. One of the most famous examples of this, in the GUSTO trial 30 years ago, we learned through the mechanistic substudy, that it was rapid reprofusion TIMI-3 establishment of TIMI-3 flow, that really explained the difference between TPA and streptokinase. So I was very intrigued by how we might use these data to explore the results. And I find the findings fascinating, as Paul said. It is complicated, but it raises a really fundamental issue in clinical trials. There's an assumption in a placebo control trial, that because randomization is allowing you to balance everything, except for the randomized treatment groups, and therefore, that comparison has causal information in it. There's an underlying assumption that's really important. And that is, that the placebo is inert. That it has no biological effect of its own. Well, that assumption was violated here. The placebo is not inert in this clinical trial. Now, the investigators, I think to their credit, have said, "Well, this is small, probably doesn't matter." And that might be right, but it also may be wrong. And you can't just say, well, it doesn't matter, these are small effects. As Paul said, some of the effects are small, some are medium, some are large. So what explains it? And I made a point in the editorial, you could model all of this. If you get 5% of this, and 10% of this, and 20% of this, you could make some assumptions and say, well, the magnitude of the benefit was so great that it couldn't have been overcome by this. But that's just modeling, and there's uncertainty. So for me, as a trialist, and somebody who really believes in using evidence to guide practice and to guide public policy, I think there's uncertainty here. It's likely that the treatment effect is not as large as was observed, but how large is it? And how large is important? And how large might we want to consider to put into our practice guidelines? I think all of those open questions, particularly in a field where there is inconsistency across trials, in terms of the observation of the outcome. So my conclusion is, we need more work. We need another trial, if we really want to understand this. And we need to use an inert placebo, to really understand what the contribution was. I'd like nothing better to see that it didn't matter. But I can't say that it doesn't matter because I don't know. Dr. Greg Hundley:           Well, listeners, boy, we've got kind of some interest here in that an unexpected result. So Paul, it's nice doing an interview like this listeners, because each speaker sets up the next one. Paul, Bob is saying, well, what should we do next to clarify the results here? So maybe we'll go through each of you, and start with Paul. Just describe for us, what do you think is the next study that we need to perform? Dr. Paul Ridker: Well, Greg, it's a really interesting issue. We saw it, as authors, to write as neutral a paper as we could possibly write, and sort of do our academic job and say, here are the data. And I think we did it that way because, we don't really know what the interpretation should be. On the one hand, you have a very big beneficial result, which is great for patients. And there's a prior clinical trial called JELIS, which was open label, the same drug, and also got a large benefit. And we were trying to figure out mechanism. That being said, as Bob pointed out, I think what we stumbled into is some level of uncertainty. And the question is, how uncertain would it be, and does it matter in the big picture? Allan was interesting, because the Journal asked us to use the word comparator, rather than placebo. Now this was designed as a placebo controlled trial, but our paper uses the word comparator, because of the possibility, that as Bob Harrington points out, it may not be totally inert. So the writing of this was quite carefully done. I think, at the end of the day, my REDUCE-IT colleagues, who I have great respect for, and really worked terribly hard to do the main trial, understandably feel, that the trial would've showed, and I have a lot of sympathy for that, because it's the hard endpoints we should go with. On the other hand, I have sympathy with the idea that it never hurts to have more data. And if there could be a way to have a second trial, and I might change the population a little bit, maybe I'd do it in true primary prevention. This was one third primary prevention. My colleague, Joanne Manson had done her, she had a trial where they showed some potential benefit in the black populations. Maybe you might over sample some minority groups. But just the pragmatic issues here, make it tough to have a second trial. And so, uncertainty is just part of what we, as physicians, have to learn to live with. Dr. Greg Hundley:           Allan, turning to you. What do you think is a next study to perform in this space? Dr. Allan Jaffe:   Well, I think what Paul has said is correct. That it would be very hard to generate enthusiasm funding for a large trial. But it might not be nearly as difficult to begin to explore the effects of the mineral oil comparator, versus the active agent, versus perhaps, another potential placebo, and see over time what happens in primary prevention patients, as a way of beginning to put some context around what these results might mean. So for example, it could turn out that, the active agent actually kept the values from rising as they normally would've, and mineral oil had no effect at all. Alternatively, mineral oil may well have been a negative. It had a negative effect. And I think, those are the sorts of questions that could be explored reasonably in the short term, without doing another multimillion dollar randomized trial. Dr. Greg Hundley:           And Bob, your thoughts. Dr. Robert Harrington:   Well, and I mentioned this in the editorial, Greg. I didn't make my recommendation lightly. I know that these trials are expensive. I know these trials take a great deal of time, a great deal of energy. And I know that the REDUCE-IT investigators worked enormously hard over the years to get this done. So I don't say tritely, "Oh, just do another trial." But if you think about the magnitude of the public health issue here, there are millions of people to who this kind of therapy might apply globally. And so, shouldn't we be more certain than less certain, if we want to include it, for example, in ACC/AHA guidelines? I would say, the answer to that is yes. And so, I think of it as, okay, let's make some assumptions. Let's assume, that the effect that was observed in JELIS and REDUCE-IT, is the true effect. That's ground truth. Well, there are different study designs one might think about, from an analytic perspective, using Bayesian statistics, as opposed to frequency statistics. One might think about an intense interim analysis plan, to understand where the data are going, and be able to pull in the prior data for evaluation. I would advise getting a smart group of people together, who spend their lives thinking about trials in the atherosclerotic space, and the REDUCE-IT team is pretty darn good, and say, "How could we do this efficiently?" I do think, there's enough uncertainty that it would be ethical, from an equipoise perspective, to include high risk patients in a second evaluation, because we do have uncertainty. And if we really want to nail this down, I think we could look at high risk patients with hypertriglyceridemia, and try to use some interesting design issues, and some interesting analytical issues, to try to reduce the sample size, lot of attention in interim analyses, to try to answer the question. I'd like, as I said, nothing better to say, "Oh look, REDUCE-IT was the truth." This next trial is consistent. That'd be, to me, a terrific outcome of this. On the other hand, if you said to me, "Well, the effect's not 25%, it's more in the 15% range." Well, maybe then we think about how we apply it to our patients a little differently, maybe a little more cautiously. So I don't make the recommendation lightly, as I said, but I do think that there are some conversations that could be had, being respectful of the effort and the expense that goes into these kind of things. To try to answer the question efficiently. Dr. Greg Hundley:           Very nice. Well listeners, we want thank Dr. Paul Ridker, from Brigham and Women's Hospital, Dr. Bob Harrington from Stanford University, Dr. Allan Jaffe, from the Mayo Clinic, for bringing us the results of a substudy of the REDUCE-IT trial, that assessed a variety of serum biomarkers, pertaining to systemic inflammation, and highlighting uncertainty around the mechanism regarding the efficacy of icosapent ethyl, that's been used previously for primary or secondary prevention of cardiovascular events. And next listeners, we are going to move to our second feature discussion and review some data pertaining to microbleeds in the central nervous system, during and after TAVR procedures. Welcome listeners, to our second feature discussion on this August 2nd. And we are going to explore some of the world of TAVR and its potential complications. And we have with us today, Dr. Eric Van Belle, from Lille, France. And also, Dr. Manos Brilakis, from Minneapolis, Minnesota. Welcome gentlemen. And Eric, we'll start with you. Can you describe for us a little, the background information that you use to assemble and construct your study, and describe, or list for us, the hypothesis that you wanted to address? Dr. Eric Van Belle:           Yes. Thanks a lot for the question. So we knew for many years, that some of the complication of the TAVR procedure relate to the brain. And it has been described by many others, that there were some complication in the brain of patient undergoing TAVR. And there was no previous investigation on potential bleeding or microbleeding in this population. And on the other side, there are previous publication on, of course, initially chronic microbleeding, in patient with some of, let's say, disease in the brain, but also, a possibility of acute microbleeding. And especially, in some interesting population relating to the TAVR feed, that is patient with valve disease, patient with endocarditis, or patient with assist device. In this population, microbleedings, acute microbleeding, have been described. And what is interesting, if you look at all these populations, these are population in which the Von Willebrand factor has been impacted and modified, and could be one of the reason of the microbleeding. And one of the similar feature of the patient with aortic stenosis that undergo TAVI, or TAVR, that are patient with indeed also, this kind of Von Willebrand disease. So if we put everything together that is previously, we only looked at antibody complication in those population, and that Von Willebrand disease, which is present in patient with aortic valve stenosis, could promote a bleeding, in particular, bleeding in the brain. We decided to look at the potential appearance of microbleeding, in patient undergoing TAVR procedure. Dr. Greg Hundley:           Very nice. And Eric, can you describe for us, your study design, and who was your study population? Dr. Eric Van Belle:           Yes. So basically, the study population is a basic population of patient undergoing TAVI. Just to make sure that one of the difficulty of this study, was to conduct and perform an MRI, a brain MRI, before the procedure, and as short as possible after the procedure, within three days, which is logistically challenging. And also, to make sure that we keep most of the population to undergo the MRI, we had to exclude patient with a high risk of pacemaker, or patient with pacemaker that could not undergo the MRI. But basically, without this, it's just a regular population. And if we indeed, compare to some of the previous work I was mentioning, about describing the acute MRI, it was important for us to make sure, or to be as sure as we could get, that indeed, this microbleeding, if we observe them, could be related to the procedure. And it means that, the MRI, after the procedure, should be done as short as possible. And also, that an MRI, a baseline MRI, should be performed. Because we know, that in this population, you could have some microbleedings also observed before starting the procedure. Dr. Greg Hundley:           So a cohort study design where MRIs are performed before, and then very soon after, TAVR procedures. So Eric, what did you find? Dr. Eric Van Belle:           So what we observed, the first thing that we confirmed was indeed, that in this population of that age, that is patient around 80 years old, when we do the baseline MRI, you find in about one out of four patients already, some microbleedings. And this was expected, and it is very similar to what is expected in this kind of population. But what was indeed more striking, that when we repeated the MRI after three days, we observed another 23% of patient with a new microbleedings that were observed. This is indeed the most important observation. What was also important that, the patient with microbleedings, and the location of the microbleedings, were not related to the cerebellum brain, because indeed we could observe some cerebellum arise in this population, as it is expected. And there was no relation between the two. So it's also, an important observation, suggesting that this microbleeding are not hemorrhagic transformation of cerebellum brain, for instance. And we also observed that, the risk of microbleeding, or the chance to observe the microbleeding, was increased when the procedure was longer. And also, when the total duration of anticoagulation was longer, we also observed that, when the procedure was, when we used protamine at the end of the procedure, the risk of microbleeding was less. And also, importantly, the status of the Von Willebrand factor, and indeed, an alteration of the multimer of Von Willebrand factor, was also associated with the risk of microbleeding in this population. Dr. Greg Hundley:           Very nice. So in this cohort of 84 individuals, average age around 80, undergoing TAVR procedure, and about 50/50 men and women, you had several factors. Prior history of bleeding, amount of heparin, absence of protamine, all indicating a higher risk of these microbleeds. So very practical information. Well, Manos, you have many papers come across your desk. What attracted you to this particular paper? And then secondly, how do we put these results really, in the context of maybe other complications that can occur during or after TAVR procedures? Dr. Emmanouil Brilakis: Yes, thanks so much, Greg. And also, congratulations Eric, for a wonderful paper, and thanks for sending it to circulation. I think, with increasing the number of targets, as you know, TAVR now is becoming the dominant mode for treating severe aortic stenosis. Safety is of paramount importance. And even though there's been a lot of progress, we still have issues with the safety of the procedure. So understanding how can make it safer is very important. And I think, what was unique in this paper, again, congratulations for creating this study, is that it opens a new frontier. We worry about stroke. We're all very worried about the stroke, and having the patient have a permanent neurologic damage during the procedure. But there may be more to it than the classic embolic stroke. And I think, this study opens actually, a new frontier with the micro cerebral bleeds. Now we don't completely understand, despite the study, we don't understand the functional significance from this. And I think, that's one of the areas that will need further research. But I think, trying to understand what causes them, and preventing those microbleeds, would have a very important role in the future, for making TAVR even safer than it is. Dr. Greg Hundley:           Very nice. Well, Manos, you really lead us into the kind of the next question. So Eric, what do you see as the next study to be performed in this sphere of research? Dr. Eric Van Belle:           Again, to me, and to follow with the comment of Manos, we need to include, I would say, to solve two questions. We have to solve the question of, what could really impact these microbleedings. And what would be the impact of this microbleeding on the long term outcome of this patient? So it's means that we have to set, as part of the studies that we will design, potentially studies on aortic immolation. Or let's say for instance, we could investigate the role of protamine. It has been suggested that protamine could be something interesting, so it could be tested as part of a randomized study. But this means that, as part of such randomized study on the use of protamine, for instance, you would include a last cohort of patients with MRI after the procedure. And also, a long term follow of the neurological complication, which indeed, is the missing part of our current study. We would need to have a much larger cohort of patients, to be able to reconnect the neurological outcome to the MRI outcome, and also to include this. So let's say, for me, one of the studies we would be interested to perform, is to conduct a study on the use of protamine, which is very simple, randomized, yes or no, and includes brain MRI in this population, as a systematic investigation, which is difficult to conduct. You have to know that it's difficult to do, but it will be very important. And then, to look at the long term neurological outcome. Dr. Greg Hundley:           And I see, Eric, you mentioned the long term, because really in the short term, so within six months, you really didn't see any changes in neurological functional outcome or quality of life. So Manos, just coming back to you. What do you see is the next study that should be performed in this space? Dr. Emmanouil Brilakis: Yeah, I agree actually, with Eric. The next step is, this was an 80 patient study. Right? It's a very small preliminary data, all that opens a new system for evaluation, we're still a very small number of patients. So having a larger number of patients, I think for me, the key thing is to understand the connection. Does this actually cause neurologic symptoms? What does it mean having a microbleed? I think right now, we're still confused on the study. There was not really much impact on the neurologic status of the patient. So for me, the number one thing is, to understand how it impacts the patient's quality of life, the neurologic status. Perhaps more sensitive studies, neurocognitive studies, to understand exactly how it impacts. And then after doing that, I agree with Eric, if this is a bad, something really bad, then we can find different ways to prevent them from happening. Protamine is one of them during the procedure time, and not be a very feasible one. Or it could be interesting to see if different valves, for example, have different propensity for causing those microbleeds. Dr. Greg Hundley: Very nice. Well listeners, we want to thank Dr. Eric Van Belle, from Lille, France, and also, our own associate editor, Dr. Manos Brilakis, from Minneapolis, Minnesota for bringing this very important study, highlighting that one out of four patients undergoing TAVR has cerebral microbleeds before the procedure. And then, after the procedure, one in four patients develop new cerebral microbleeds. And then, procedural and antithrombotic management, and persistence of acquired Von Willebrand factor defects, were associated with the occurrence of these new cerebral microbleeds. Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week On the Run. Dr. Greg Hundley:           This program is copyright of the American Heart Association 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.

Get a free nursing lab values cheat sheet at NURSING.com/63labs   What is the Lab Name for Activated Partial Thromboplastin Time Lab Values? Activated Partial Thromboplastin Time   What is the Lab Abbreviation for Activated Partial Thromboplastin Time? APTT   What is Activated Partial Thromboplastin Time in terms of Nursing Labs? APPT is a test that measures the amount of time it takes for a fibrin clot to form after reagents have been added to the specimen. It is useful in diagnosis clotting disorders. In conjunction with PT it can be used to differentiate the specific factor that may be missing.   What is the Normal Range for Activated Partial Thromboplastin Time? 25-39 seconds   What are the Indications for Activated Partial Thromboplastin Time? Identifying Congenital deficiencies in clotting Monitoring Effects of liver disease Protein deficiency Fat malabsorption on clotting   What would cause Increased Levels of Activated Partial Thromboplastin Time? Vitamin K deficiency DIC Patients on hemodialysis Afibrinogenemia Polycythemia Liver disease Von Willebrand disease   What would cause Decreased Levels of Activated Partial Thromboplastin Time? N/A

Charlene’s son, Luke, was diagnosed with Vascular Ehlers-Danlos Syndrome (VEDS) at the age of 4, after persistent issues with bruising and bleeding led to a hematologist and a diagnosis of Von Willebrand’s at 2 years old, and then later, a rheumatologist who sent him to a genetic counselor who recognized VEDS at 4 years old. … Continue reading Charlene Terrell-Newman and Luke

Hur kommer det sig att en flicka med Von Willebrands typ 1 kunde ha mens konstant i fem år – utan att få hjälp av vården? Trots att medvetenheten har blivit bättre, är okunskapen om sjukdomen fortfarande stor. Det kan inte minst många kvinnor vittna om. I det här avsnittet får vi möta Anna Tollwé, patient och sammankallande i kvinnokommittén FBIS. Hon har under hela sitt liv fått kämpa för att få den vård hon behöver för sin von Willebrands typ 2. Med i samtalet är också Anna Ågren, överläkare på koagulationsmottagningen på Karolinska sjukhuset. Dessutom - nya internationella riktlinjer för von Willebrand har tagits fram. Hur kommer de att påverka behandlingen framöver?

Ms Wajiha Javaid has been working with the Haemophilia Foundation – Pakistan (HFP) since she was 16. She is currently Executive member of HFP and coordinator of the National Women’s group, which was officially formed in 2017. She shares her experience as a woman living with Von Willebrand disease and part of the core team at HFP which worked on developing the National Women’s group to provide a safe place for women to meet, exchange and learn from each other. She is proud to have seen a lot of girls empowered to blossom over the years.

This episode covers nosebleeds.Written notes can be found at https://zerotofinals.com/surgery/ent/nosebleeds/ or in the ear, nose and throat section of the Zero to Finals surgery book.The audio in the episode was expertly edited by Harry Watchman.

La gravidanza, il travaglio ed il parto comportano degli adattamenti materni cardiovascolari ed emocoagulativi, questi adattamenti hanno significative implicazioni anestesiologiche.La prima parte del video parla della riduzione delle resistenze vascolari sistemiche e dell'aumento del volume di plasma e dei globuli rossi, della diminuzione della pressione arteriosa sistemica e dell'aumento della gittata cardiaca in gravidanza.Si descrive la sindrome ipotensiva supina e come evitarla in corso di anestesia grazie al decubito laterale sinistro e al dislocamento manuale dell'utero. La seconda parte del video è una panoramica sulla coagulazione in gravidanza, dai principali esami emocoagulativi, come PT e aPTT, ai fattori della via intrinseca ed estrinseca che aumentano, come il fattore VII, il fattore X, il fattore XII, il fattore VIII, la protrombina. In questo video si possono inoltre trovare descritti i concetti di anemia fisiologica in gravidanza, la definizione di anemia in gravidanza secondo la WHO, la trombocitopenia e le recenti raccomandazioni 2021 per le tecniche di anestesia neuroassiale in gravidanza in corso di trombocitopenia. Il video si conclude con i livelli di fibrinogeno, antitrombina, fattore di Von Willebrand, proteina S trimestre per trimestre.

El Dr. Mauricio Jaramillo Restrepo, médico internista y hematólogo, adscrito a "Integral I.P.S" en Medellín, Colombia, de acuerdo con su experiencia nos comenta sobre la situación de la enfermedad de von Willebrand en Colombia. El Dr. Jaramillo considera importante la creación de unas guías de práctica clínica para el país, ya que hoy en día la oportunidad de desarrollar guías en enfermedades huérfanas es limitada, dado que la evidencia sólida es escaza. De los principales retos en el diagnóstico de la enfermedad de von Willebrand en Colombia es que el diagnóstico no se hace en etapas tempranas del paciente y no se hace una valoración adecuada de la sintomatología, haciendo pasar diversos casos como desapercibidos. Otros retos son la alimentación y la disponibilidad de las pruebas en los laboratorios en el país, es recomendable que cada población tenga estandarizados los valores normales de von Willebrand - comenta el Dr. Jaramillo. Una manera de optimizar la sospecha diagnóstica de la enfermedad de von Willebrand en médicos de atención primaria y otras especialidades es con educación a todo el equipo multidisciplinario encargado de dar el diagnóstico. Gracias al apoyo educativo de CSL Behring Colombia

Colorectal cancer screening update, COVID-19 vaccine update, and abnormal uterine bleeding basics.Today is May 24, 2021.Colorectal cancer screening update Written by Hector Arreaza, MD. Participation: Ikenna Nwosu, MD, and Daniela Viamontes, MD.Today is May 24, 2021.On august 29, 2020, we were in the midst of a pandemic and we woke up with the sad news about the death of Chadwick Aaron Boseman (also known as Black Panther). An interesting fact: The tweet in which his family announced his death on Twitter became the most-liked tweet in history. But why are we talking about Chadwick’s death? Because he died of colon cancer. I do not know if this recommendation came because of Chadwick, but it’s a good way to open this episode: remembering Black Panther.We heard the rumors, but now it’s official. On May 18, 2021, the USPSTF released their final recommendation statement about colorectal cancer screening. The age to start screening has been changed from 50 to 45 years old. This is a grade B recommendation. Grade B means that this recommendation has moderate to substantial net benefit, so offer this service to your patients. Screening adults between 76 and 85 years old who have been previously screened has a small net benefit (grade C recommendation). So, select patients may be screened for colorectal cancer in this age group (76-85), especially those who have never been screened.Do you remember this recommendation from medical school for high risk patients? Start screening at age 40 or 10 years before a patient’s direct-relative was diagnosed with colon cancer. This was a recommendation given by the US Multi-Society Task Force (which includes the American College of Gastroenterology, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy). This same organization already recommended in 2017 to start screening at age 45 in African American patients, and the American Cancer Society recommended screening all patients at age 45 in 2018. The ACS does not have a guideline to screen high risk patients for colon cancer. Most organizations agreed on not screening after age 85.Strategies for screening:High-sensitivity guaiac fecal occult blood test (HSgFOBT) or fecal immunochemical test (FIT) every yearDani: Stool DNA-FIT every 1 to 3 years (Cologuard®)  CT colonography every 5 years Flexible sigmoidoscopy every 5 years OR Flexible sigmoidoscopy every 10 years + annual FIT Colonoscopy screening every 10 yearsDiscuss different options with your patients, choose your favorite and do it!  Introduction: Update on COVID 19 vaccines  By Hector Arreaza, MD, and Lillian Petersen, RN. COVID-19 vaccines now can be co-administered with other vaccines according to the ACIP. COVID-19 vaccines and other vaccines may now be administered without regard to timing. They can be given on the same day or within the 14 days previously recommended between vaccines.  It is not known if reactogenicity of COVID-19 vaccine is increased with co-administration with other reactogenic vaccines (such as vaccines with live attenuated viruses).  How do you decide if you want to co-administer a vaccine? 1. Consider whether the patient is behind or at risk of becoming behind on recommended vaccines.2. Consider their risk of vaccine-preventable disease.3. Consider the reactogenicity profile of the vaccines. If multiple vaccines are administered at a single visit, administer each injection in a different injection site, at least one inch apart or in different limbs. Current or previous SARS-CoV-2 infection: Everyone should be offered COVID-19 vaccination regardless of their history of COVID-19 infection. Viral testing or serologic test is not recommended for the purposes of vaccine decision-making. People with current SARS-CoV-2 infection should be deferred until the person has recovered from the acute illness (if the person had symptoms) and they have met criteria to discontinue isolation. This applies to patients who got the disease before receiving any vaccine or after receiving the first dose.  A minimum interval between infection and vaccination has not been established, but evidence suggests that the risk of reinfection is low in the months after initial infection but may increase with time due to waning immunity. People with a history of multisystem inflammatory syndrome in children (MIS-C) or adults (MIS-A):It is unclear if people with a history of MIS-C or MIS-A are at risk of recurrence of the same dysregulated immune response following reinfection with SARS-CoV-2 or in response to vaccination. People with a history of MIS-C or MIS-A may choose to be vaccinated but they should consider delaying vaccination until they have recovered from their illness and for 90 days after the date of diagnosis. Find more information at the CDC.gov website. This is Rio Bravo qWeek, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California. Our program is affiliated with UCLA, and it’s sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home. ___________________________Abnormal Uterine Bleeding. By Sherika Adams, MS3, P. Eresha Perera, MS3, and Hector Arreaza, MD.  Definition. AUB is a symptom, not a diagnosis. It is equivalent to say: “This patient’s periods are abnormal.” Anything that falls out of what is considered “normal periods” is classified as abnormal uterine bleeding.These 4 elements are assessed when determining if a patient has AUB: Regularity, frequency, duration, and volume.  What is considered normal? Frequency = Every 24-38 days, regularity +/- 2-20 days over 12 months, duration = 4.5 to 8 days, volume = 5-80 mL. 10-30% of women of reproductive age may have AUB. According to the American College of Obstetricians and Gynecologists (ACOG), abnormal uterine bleeding is characterized by bleeding or spotting following sexual intercourse or menopause, between menstrual cycles, menstrual cycles lasting more than 38 days or shorter than 24 days, heavy bleeding during menstruation, and “irregular” menstrual cycles that have 7-9 days of variation.Terms no longer used: menorrhagia, metrorrhagia, and dysfunctional uterine bleeding (DUB). Not all symptoms reported as “vaginal bleeding” are coming from the vagina. For example, bleeding from anus, urethra, bladder, and perineum should be ruled out before establishing the diagnosis of AUB. Classification of Abnormal Uterine Bleeding (AUB). Abnormal uterine bleeding (AUB) in nonpregnant premenopausal women can be classified by the acronym PALM-COEIN, which was established by the International Federation of Gynecology and Obstetrics (FIGO) in 2011.  PALM-COEIN: Palm: Structural etiologies, Coein: Non-structural etiologies P is for polyps: Polyps are epithelial tumors in the endometrium or cervix and can be identified by hysterosonography or hysteroscopic imaging. A is for adenomyosis: Adenomyosis is endometrial stroma and glands in the myometrium and can be identified by histopathology, and now MRI and transvaginal ultrasound. L is for leiomyomas: Leiomyomas also known as uterine fibroids are benign smooth muscle tumors that are diagnosed by pelvic examination and pelvic imaging such as ultrasound with contrast or MRI. M is for malignancy and hyperplasia: Malignancy and hyperplasia are often abnormal epithelial tissue that is benign or cancerous that can be seen with transcervical endometrial sampling. C is for coagulopathy: Coagulopathy is bleeding disorders such as Von Willebrand disease is identified by laboratory testing. O is ovulatory dysfunctions: Ovulatory dysfunction occurs when there is a variation of more than seven days of the menstrual cycle in the past 12 months and ovulation is dysfunctional. In a woman without ovulation, there is no corpus luteum, and there is no progesterone, so estrogen goes unopposed, causing a buildup of endometrium and irregular bleeding.   E is endometrial causes: Endometrial causes can occur when there is normal ovulation, no other identifiable cause of AUB, and there is heavy menstrual bleeding, which includes intermenstrual bleeding. Primary disorders of endometrial hemostasis are likely due to vasoconstriction disorders, inflammation, or infection. Endometrial dysfunction is poorly understood; there are no reliable diagnostic methods, and it should be considered only after other causes are excluded. I is for iatrogenic cause: Iatrogenic causes include gonadal steroids (estrogen, androgens), anticoagulants, intrauterine devices, antipsychotics, antidepressants, and anti-hypertensives. N is for not otherwise classified: Example of an etiology under not otherwise classified might be AV malformations. This classification does not include pregnancy. Postmenopausal bleeding: Abnormal uterine bleeding can also occur in post-menopausal women and is an indication of potentially lethal endometrial cancer. Post-menopausal women should be worked up for cancer when they present with bleeding. However, most common cause of bleeding in this population is atrophy of the vaginal mucosa or endometrium. If younger than 45 patients but history of unopposed estrogen exposure (PCOS, obesity, estrogen therapy) should also undergo endometrial biopsy to rule out possibility of endometrial cancer.  Management of AUB. Management of the AUB can be initiated only after the etiology of the bleeding has been established. Firs of all, rule out pregnancy related bleeding by performing a pregnancy test. Also, rule out other sources of bleeding. The first question to answer would be: Does this patient need an emergent treatment for her AUB or can she be treated as outpatient? Determine that by checking the history, vitals, orthostatic vitals, physical exam, and labs.  If patient requires admission, the options for treatment include: uterine tamponade, intravenous estrogen, dilation and curettage, and uterine artery embolization. In case of severe bleeding without hemodynamic instability, patients can be treated initially with oral estrogen, high-dose estrogen-progestin oral contraceptives, oral progestins, or intravenous tranexamic acid.For chronic AUB, once etiology has been established, the goal is to treat the underlying condition. The goal of treatment is to control the bleeding since AUB can persists until menopause.  Initial outpatient treatment is usually pharmacological. For those not wanting to conceive soon, consider IUD placement. “Among medical therapies, the 20-mcg-per-day formulation of the levonorgestrel-releasing intrauterine system (Mirena) is most effective for decreasing heavy menstrual bleeding (71% to 95% reduction in blood loss) and performs similarly to hysterectomy when quality-adjusted life years are considered.”[8] Other long-term medical treatment options include estrogen-progestin oral contraceptives, oral progestins, oral tranexamic acid, NSAIDs (nonsteroidal anti-inflammatory drugs), and depot medroxyprogesterone. Surgical treatment is often considered for patients on long term medical therapy with no response, or for severe cases of bleeding with recurrent need for emergent treatment. Some surgical options are endometrial ablation, which performs as well as the levonorgestrel-releasing intrauterine system. Some structural lesions can be resected via hysteroscopy (polyps). Myomectomy and uterine artery embolization are options for patients with severe AUB who want to preserve fertility. Uterine leiomyomas or adenomyosis can be medically managed with OCPs but can also be treated with surgery as well, depending on the physician-patient discussion of options. Hysterectomy is the definitive treatment of severe AUB. Remember, PALM COEIN stands for: Polyps, Adenomyosis, Leiomyomas, Malignancy and hyperplasia, Coagulopathy, Ovulatory dysfunction, Endometrial causes, Iatrogenic cause, Not otherwise classified. ____________________________Conclusion. Written by Hector Arreaza, MDNow we conclude our episode number 53 “Abnormal Uterine Bleeding”. Eresha and Sherika did a great job explaining the Palm-Coein classification, and gave us a good overview of the management of AUB. Remember to start screening for colorectal cancer at age 45 now, what strategy for screening will you use? And for those patients who were hesitant about getting the COVID-19 vaccine with other vaccines, well, the ACIP said we can co-administer it with other vaccines. Even without trying, every night you go to bed being a little wiser.Thanks for listening to Rio Bravo qWeek. If you have any feedback about this podcast, contact us by email RBresidency@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. This podcast was created with educational purposes only. Visit your primary care physician for additional medical advice. This week we thank Hector Arreaza, Daniela Viamontes, Ikenna Nwosu, Lillian Petersen, Sherika Adams, and P. Eresha Perera. Audio edition: Suraj Amrutia. See you next week! _____________________References:U.S. National Library of Medicine, Clinical Trials.Gov, https://clinicaltrials.gov/ct2/show/study/NCT02026869. Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the United States, Centers for Disease Control and Prevention, https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-considerations.html#Coadministration, accessed on May 20, 2021.  Colorectal Cancer: Screening, Final Recommendation Statement, U.S. Preventive Services Task Force, May 18, 2021, https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/colorectal-cancer-screening. Abnormal Uterine Bleeding FAQ, The American College of Obstetricians and Gynecologists (ACOG), https://www.acog.org/womens-health/faqs/abnormal-uterine-bleeding, accessed on May 17, 2021.  Fraser, Ian, et al. Abnormal uterine bleeding in reproductive-age women: Terminology and PALM-COEIN etiology classification, Up to Date, last updated: Dec 16, 2019. https://www.uptodate.com/contents/abnormal-uterine-bleeding-in-reproductive-age-women-terminology-and-palm-coein-etiology-classification?search=palm%20coein&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1. Goodman Annekathryn, et al, Postmenopausal uterine bleeding, Up to Date, last updated: Feb 02, 2021. https://www.uptodate.com/contents/postmenopausal-uterine-bleeding?search=abnormal%20uterine%20bleeding%20postmenopausal&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1 Kaunitz, Andre M, Abnormal uterine bleeding: Management in premenopausal patients, Up to Date, last updated: Aug 25, 2020. https://www.uptodate.com/contents/abnormal-uterine-bleeding-management-in-premenopausal-patients?search=abnormal%20uterine%20bleeding%20management&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1 Wouk N, Helton M. Abnormal Uterine Bleeding in Premenopausal Women. Am Fam Physician. 2019 Apr 1;99(7):435-443. PMID: 30932448. https://pubmed.ncbi.nlm.nih.gov/30932448/ 

Commentary by Dr. Douglas Mann

Today’s episode is about an important topic that hasn’t yet been addressed on the podcast: bleeding disorders. Find out how bleeding disorders affect women, and why they often go undiagnosed. You won’t want to miss my interview with Dr. Fiona Bethea and Jhon Velasco. Dr. Fiona Bethea is a Health Scientist on the Bleeding Disorders Team in the Epidemiology and Surveillance Branch of the Division of Blood Disorders (DBD), Centers for Disease Control and Prevention (CDC). She joined DBD in 2009 and served as the project coordinator and technical advisor for a study of hemophilia inhibitors, a serious treatment complication. Since 2016, she has worked with community partners to develop evidence-based health promotion and education programs to reduce and prevent complications of bleeding disorders. She also collaborates in the monitoring and evaluation of the Community Counts bleeding disorders surveillance program. Dr. Bethea has been privileged to serve this community and contribute to the scientific evidence base to help prevent and reduce complications of bleeding disorders. She received her PhD in Epidemiology at Georgia State University. She also has a BS in Neuroscience and Behavioral Biology and an MPH in Global Health, Community Health and Development from Emory University. Jhon Velasco is the Manager of Education and Training at National Hemophilia foundation, where he focuses on women with bleeding disorders, the Spanish speaking community and mental health. He earned his Masters in Health Education from Columbia University, where he focused on health education focusing on marginalized communities. A consistent theme in his career has been the development, implementation and analysis of new and existing public health projects for a variety of international communities, specifically undeserved populations. A common theme among these projects is his commitment to working with individuals and groups to improve their lives through education, mentorship and empowerment. Jhon is also a certified yoga and meditation instructor, having practiced throughout the Americas, Europe and South East Asia. Today’s episode is sponsored by the Fertility Awareness Mastery LIVE 8 week group coaching program!  We start on May 4th! Will you be joining us? Click here to register now!   Topics discussed in today's episode: Dr. Bethea's background and what drew her to the study of bleeding disorders Jhon’s background and what drew him to the study of bleeding disorders What are bleeding disorders How a woman would detect she had a blood disorder in terms of her menstrual cycle Signs or symptoms of bleeding disorders Signs that a woman has a bleeding disorder over other health related causes Types of screenings that would take place to rule out bleeding disorders Importance of tracking your menstrual cycle in determining if you have a bleeding disorder Steps to follow if you are trying to differentiate a bleeding disorder versus a heavy menstrual cycle What is Von Willebrand disease, the different types and how it can affect the menstrual cycle What is Hemophilia and the most common symptoms What is a joint bleed The most common bleeding disorders Treatment for women after being diagnosed with a bleeding disorder Bleeding disorders are heriditary  Connect with Dr. Bethea & Jhon: You can connect with Dr. Bethea on LinkedIn and John on LinkedIn. Resources mentioned: https://betteryouknow.org Fertility Awareness Mastery Mentorship (FAMM) Class of 2021 The Fifth Vital Sign: Master Your Cycles & Optimize Your Fertility (Book) | Lisa Hendrickson-Jack Fertility Awareness Mastery Charting Workbook Fertility Awareness Mastery Online Self-Study Program Related podcasts & blog posts: FFP 246 | Heavy Flow | Managing the Complexities of Menstruation | Amanda Laird FFP 230 | Essure Problems | The Bleeding Edge | Angie Firmalino and Amanda Rusmisell FFP 127 | What Does a Normal Period Look Like? | How Much Am I Supposed To Bleed During My Period? | Lisa | Fertility Friday Join the community! Find us in the Fertility Friday Facebook Group. Subscribe to the Fertility Friday Podcast in Apple Podcasts! Music Credit: Intro/Outro music Produced by J-Gantic A Special Thank You to Our Show Sponsors: Fertility Friday | Fertility Awareness Programs This episode is sponsored by my Fertility Awareness Programs! Master Fertility Awareness and take a deep dive into your cycles and how they relate to your overall health! Click here to apply now! The Fertility Awareness Charting Workbook This episode is sponsored by my new book the Fertility Awareness Mastery Charting. Click here to buy now.

In this episode we take a deep dive into a rare bleeding disorder- Von Willebrand Disease! We discuss the importance of VW factor, the different types of VWD, common symptoms, pertinent investigations and an approach to management. Check out our associated infographic at www.theinternatwork.com.  

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.09.290304v1?rss=1 Authors: Webb, E., Kania, S., Oztekin, A., Cheng, X., Zhang, X. F. Abstract: Extensional flow-induced transitions from a compact to an unfolded conformation are explored for the human glycoprotein von Willebrand factor (vWF). Multimer unfolding is a crucial step in the process of blood clotting and protein size maintenance. Previous studies have shown that flow-induced conformational transitions are initiated by a thermally nucleated polymeric protrusion. Below a certain strain rate, such a transition is a rare event that cannot be studied using standard stochastic dynamic simulation. In the present study, we have employed Weighted Ensemble Brownian dynamic (WEBD) simulations to study rare events of conformation transition in extensional flow. Results are presented for the transition rate of VWF multimer unfolding, with concomitant analysis of the likelihood of pathological unfolding as a function of strain rate. Relative to the typical half-life of vWF proteins in the human body, results here indicate that pathological unfolding would not manifest for strain rate less than 2000/s. Copy rights belong to original authors. Visit the link for more info

Does von Willebrand factor have something to do with COVID? What’s NHF’s virtual BDC all about? And are Natalie and Patrick pregnant?! (Spoiler: YES!) All this plus we welcome Amy Board and interview Nikole Scappe! Presenting Sponsor: Takeda NHF’s Virtual Bleeding Disorders Conference: Interactive Program COVID-19 & Von Willebrand Factor: Article SOBO 4 Save One Life: William Addision’ Appalachian Trail Fundraiser!  SUBSCRIBE to BloodStream on Apple Podcasts! LIKE BloodStream on Facebook! WATCH BloodStream on YouTube!

A sip of Von-Willebrand disease --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app --- Send in a voice message: https://anchor.fm/snapmd/message

Ines hat sich mit Thorben über Gerinnung und vor allem über das von-Willebrand-Syndrom unterhalten.Das Ergebnis kann sich wirklich sehen und auch hören lassen! Der Beitrag „titriert“ Von-Willebrand-Syndrom erschien zuerst auf pin-up-docs - don't panic.

CCP Virus Update- Young People are Dying of Strokes, John Stossel- Coronavirus Overreach and My Brother's Life-saving Discovery.John Stossel- Coronavirus Overreach and My Brother's Life-saving DiscoveryCCP Virus Update- Young people are dying of strokesAddiction: You Will Be Freed Coronavirus OverreachJohn StosselGovernments pass ever more restrictive rules in the name of saving us. How many of these rules are helpful? ---- Don't miss a single video from Stossel TV. Sign up here: https://johnstossel.activehosted.com/f/1 ---- In Encinitas, California, police gave $1000 tickets to people inside cars-- watching the sunset. Surfers were arrested, despite being far from anyone. Such excessive restrictions may even do harm, by preventing people from getting exercise. Michigan's governor condescended to allow big stores to stay open, but told them they must not sell "carpet, flooring, furniture, garden centers, plant nurseries, or paint.” The stores had to rope off those aisles. These rules are arbitrary, and excessive. Sweden took the opposite approach, reasoning that isolating people blocks the creation of “herd immunity,” the long term solution to new contagious diseases like Covid-19. In Europe, many countries are relaxing rules and starting to r  My Brother's Life-saving Discoveryhttps://www.youtube.com/watch?v=tsNp_4tBPvMJohn StosselCumbersome FDA regulations delay new drugs. It generally takes at least 10 YEARS to bring a new drug to market. The pandemic got regulators to say they'll speed things up -- but their process still holds up promising treatments. I know about this first hand, because now I’m trying to help get a new treatment approved. ---- Don't miss a single video from Stossel TV. Sign up here: https://johnstossel.activehosted.com/f/1 —— Years ago, my older brother Tom, a medical researcher, discovered a protein called gelsolin that may save some people with diseases like Covid-19, pneumonia, & sepsis. It's being worked on by Tom's old company, BioAegis: https://www.bioaegistherapeutics.com/ Gelsolin reduces excess inflammation. That should help Covid-19 patients, because many die NOT from the virus itself, but because their body’s own immune response causes too much inflammation. That destroys organs. Despite gelsolin's promise, even very sick patients can't get access to it because it’s still winding its way through the FDA's regulations. Gelsolin got through animal studies, and also passed some human safety tests. But it can’t be given to patients until it passes all FDA’s tests. That usually takes years. My brother died last year, so I’m now trying to help BioAegis raise funds to cover the FDA’s tests. The video above explains more about Tom, gelsolin, and BioAegis' efforts to get it into further FDA-required trials.  Coronavirus Pandemic Update 61: Blood Clots & Strokes in COVID-19; ACE-2 Receptor; Oxidative Stresshttps://youtu.be/22Bn8jsGI54MedCram - Medical Lectures Explained CLEARLYCOVID-19 Update 61 with critical care specialist Roger Seheult, MD of https://www.MedCram.com Thrombosis (blood clots), strokes, and myocardial infarctions are mysterious complications for some patients with COVID-19. Dr. Seheult discusses a recent case study involving a 72-year-old with elevated d-dimer and plasma Von Willebrand factor, and goes on to illustrate a hypothesis for how downregulation of ACE-2 may result in oxidative stress. This process may put patients with underlying elevated levels of oxidative stress (cardiovascular diseases, diabetes, obesity, etc.) at the greatest risk for severe COVID-19 infection. To share ideas, questions, and evidence-based information, please visit our MedCram Communities. We will be reviewing these regularly for questions and topic ideas to address in future videos. You will need a free MedCram.com profile to join the discussion: COVID-19 Community: https://www.medcram.com/communities/Q... MedCram Community: https://www.medcram.com/communities/Q... Links referenced in this video: Johns Hopkins - https://coronavirus.jhu.edu/map.html Worldometer - https://www.worldometers.info/coronav... Thrombosis Research - https://www.ncbi.nlm.nih.gov/pmc/arti... PubMed - https://www.ncbi.nlm.nih.gov/pubmed/1... Washington Post - https://www.washingtonpost.com/health... Clotting Cascade - https://fpnotebook.com/hemeonc/Exam/C... WebMD - https://www.webmd.com/lung/news/20200... JAMA - https://jamanetwork.com/journals/jama... Some previous videos from this series (visit MedCram.com for the full series): - Coronavirus Pandemic Update 60: Hydroxychloroquine Update; NYC Data; How Widespread is COVID-19? https://youtu.be/fn2yk5SbGiw - Coronavirus Pandemic Update 59: Dr. Seheult's Daily Regimen (Vitamin D, C, Zinc, Quercetin, NAC) https://youtu.be/NM2A2xNLWR4 - Coronavirus Pandemic Update 58: Testing; Causes of Hypoxemia in COVID-19 (V/Q vs Shunt vs Diffusion) https://youtu.be/nO4xgcIaPeA - Coronavirus Pandemic Update 57: Remdesivir Treatment Update and Can Far-UVC Disinfect Public Spaces? https://youtu.be/2U4DAQ3kjRs - Coronavirus Pandemic Update 56: What is “Forest Bathing” & Can It Boost Immunity Against Viruses? https://youtu.be/PgDjVEpEOdQ - Coronavirus Pandemic Update 55: How COVID-19 Infection Attacks The Immune System & Differs From HIV: https://youtu.be/8NffZAGELGg - Coronavirus Pandemic Update 54: COVID-19 Antibody vs. PCR Testing; When to Relax Social Distancing?: https://youtu.be/kgzFAdYwYLM - Coronavirus Pandemic Update 53: Anticoagulation; Can Mechanical Ventilation Make COVID 19 Worse?: https://youtu.be/o8aG63yigjA - Coronavirus Pandemic Update 52: Ivermectin Treatment; Does COVID-19 Attack Hemoglobin?: https://youtu.be/qc6VV7ue4cE - Coronavirus Pandemic Update 51: State by State Projections; Ultrasound to Diagnose COVID19 Pneumonia: https://youtu.be/E7MufS6dnJw - Coronavirus Pandemic Update 50: Dip in Daily New Deaths; Research on Natural Killer Cells & COVID-19: https://youtu.be/fya6Zwxch88 - Coronavirus Pandemic Update 49: New Data on COVID-19 vs Other Viral Infections (Ventilator Outcomes): https://youtu.be/uaIzj3s3p4A - Coronavirus Pandemic Update 48: Curve Flattening in California, PPE in the ICU, Medication Trials: https://youtu.be/JN-8bGB1cLM - Coronavirus Pandemic Update 47: Searching for Immunity Boosters & Possible Lessons From Spanish Flu: https://youtu.be/H1LHgyfPPQ8 -Coronavirus Pandemic Update 46: Can Hot/Cold Therapy Boost Immunity? More on Hydroxychloroquine https://youtu.be/EFRwnhfWXxo - How Coronavirus Kills: Acute Respiratory Distress Syndrome (ARDS) & Treatment: https://youtu.be/okg7uq_HrhQ Many other videos on COVID-19 (coronavirus outbreak, coronavirus symptoms, influenza, coronavirus epidemic, corona virus updates, coronavirus vaccine, boosting the immune system, vitamin D, vitamin C, Zinc, Quercetin, NAC, n-acetyl cysteine, Insomnia, PPE, hydroxychloroquine, ultrasound to diagnose COVID-19, coronavirus New York) and other medical topics (ECG Interpretation, strokes, thrombosis, pulmonary embolism, myocardial infarction, hypercoagulation, hypertension, anticoagulation, DKA, acute kidney injury, influenza, measles, mechanical ventilation, etc.) at MedCam.com Speaker: Roger Seheult, MD Board Certified in Internal Medicine, Pulmonary Disease, Critical Care, and Sleep Medicine. MedCram provides videos to a variety of medical schools, education programs, and institutions (please contact us at customers@medcram.com if you are interested) Media Contact: customers@medcram.com Media contact info: https://www.medcram.com/pages/media-c... MedCram medical videos are for medical education and exam preparation, and NOT intended to replace recommendations from your doctor. #COVID19 #SARSCoV2 #Coronavirus Article mentioned- Young and middle-aged people, barely sick with covid-19, are dying of strokeshttps://www.washingtonpost.com/health/2020/04/24/strokes-coronavirus-young-patients/  Addiction: You Will Be Freedhttps://youtu.be/ry8-YIwnEcUThe Church of Jesus Christ of Latter-day SaintsThrough the Atonement of Jesus Christ, all can be transformed, cleansed, and freed from addiction. Read the entire address from Elder M. Russell Ballard: http://bit.ly/hN5Svf The Church of Jesus Christ of Latter-day Saints --------------------------------------------------------------------  HELP ACU SPREAD THE WORD! Ways to subscribe to the American Conservative University PodcastClick here to subscribe via iTunesClick here to subscribe via RSSYou can also subscribe via StitcherIf you like this episode head on over to iTunes and kindly leave us a rating, a review and subscribe! People find us through our good reviews. FEEDBACK + PROMOTIONYou can ask your questions, make comments, submit ideas for shows and lots more. Let your voice be heard.Email us at americanconservativeuniversity@americanconservativeuniversity.comNote- ACU Students and Alumni are asked to commit to donating Platelets and Plasma.  Make an Appointment Today! Call Your local Hospital or The Red Cross at 1-800-733-2767

I det här avsnittet fokuserar vi på von Willebrands sjukdom och diskuterar rätt så komplicerade saker med några riktiga proffs på ämnet. Forskaren och överläkaren på koagulationsmottagningen i Skåne, Erik Berntorp, berättar om skillnaderna mellan von Willebrand och hemofili och varför det på grund av centralisering och kunskapsbrist fortfarande kan vara svårt att få en diagnos. Vi har även fått tag på 2019 års Aroseniusstipendiat Iva Pruner som med sin forskning ämnar se förbi koagulationsprocessen för att ta reda på andra orsaker till von Willebrands sjukdom. En forskning som förhoppningsvis på sikt kan förbättra både behandlingar och diagnostik

Contributor: Charleen Melton, PharmD Educational Pearls: Desmopressin (DDAVP) is an analogue of anti-diuretic hormone (ADH) that has been used for the treatment of intracranial hemorrhage. It works by increasing the release of Von Willebrand factor, helping to stabilize clots.  The use of DDAVP for intracranial hemorrhage in patients on antiplatelet agents (mainly Aspirin and Plavix) was recently reviewed In this retrospective review, they found an 88% decreased likelihood of hemorrhage expansion, in those who received DDAVP, compared to those who did not. Furthermore, they found no significant increase in adverse effects like hyponatremia or thrombosis  However, no difference in mortality or neurological status was found DDAVP for intracranial hemorrhage in the setting of antiplatelet agents may be safe and reduce the expansion of intracranial bleeds but not change important patient outcomes References Feldman EA et al. Retrospective assessment of desmopressin effectiveness and safety in patients with antiplatelet-associated intracranial hemorrhage. Crit Care Med 2019 Sep 24; [e-pub] Summarized by Will Dewispelaere, MS4 | Edited by Erik Verzemnieks, MD

  This month on the Discover CircRes podcast, host Cindy St. Hilaire highlights three featured articles from recent issues of Circulation Research and talks with Denisa Wagner and Nicoletta Sorvillo about their article on how PAD4 in blood promotes VWF strings and thrombosis. Article highlights: Goodyer et al: ScRNA-seq of the Cardiac Conduction System   Xiong et al: Chemotaxis Mediated Second Heart Field Deployment   Ranchoux et al: Pulmonary Hypertension and Metabolic Syndrome   Rühl et al. Thrombin/APC Response in FVL and FII 20210G>A   Mahmoud et al. LncRNA SMILR’s Mechanism and Therapeutic Potential   Transcript   Cindy St. H:                         Hi, welcome to Discover CircRes, the monthly podcast of the American Heart Association's Journal, Circulation Research. I'm your host, Cindy St. Hilaire, and I'm an assistant professor at the University of Pittsburgh. My goal as host of this podcast is to share with you some highlights from the recent articles published in the August 2nd and August 16th issues of Circulation Research. Cindy St. H:                         After I discuss some highlights, we'll also have an in-depth conversation with Drs. Denisa Wagner and Nicoletta Sorvillo, from Boston Children's Hospital and Harvard Medical School, who are the lead authors of one of the exciting discoveries from the August 16th issue. Cindy St. H:                         The first article I want to share with you today is titled Transcriptomic Profiling of the Developing Cardiac Conduction System at Single-Cell Resolution. The first author is William R. Goodyer, and the corresponding author is Sean Wu. They are both located at the Cardiovascular Institute and the Department of Pediatrics at Stanford University. Cindy St. H:                         Have you ever wondered how your heart beats, and why there's always this glub-glub pattern, and where did it come from? How is the heart able to initiate that pattern, from cells that don't contract to cells that contract? Well, the beating of the heart is regulated by what's called the cardiac conduction system, and this is an area in the heart of specialized cells, and these cells establish the rhythmic beating by coordinating the contraction of the chambers of the heart. Cindy St. H:                         There's several components to the CSS. The sinoatrial node acts as the pacemaker in the right atrium. The arterial ventricle node is the electrical relay that slows down the pulse from the SA node. A His bundle helps to transmit those impulses, and the Purkinjie fibers are the terminus of the electrical signal. Between all of these different components are a heterogeneous population of what are called transitional cells. There are several studies that have linked these somewhat amorphous or heterogeneous transitional cells to different arrhythmic disorders. Cindy St. H:                         For the normal function of the heart, all of these parts must come together, and when they don't, there's severe clinical manifestations such as arrhythmias, like I said, but also you can get decreased cardiac output and even sudden cardiac death. While important, the cells of the CSS are rather elusive, and that's because they're in a relatively small number compared to the rest of the cells in the heart, and there also aren't very clear markers to identify the cells in the CSS. Cindy St. H:                         To address this, Goodyer and colleagues harvested cells from embryonic mouse hearts and performed single-cell RNA sequencing on 22,000 individually barcoded cells. What they were looking for is learning what type of cells they are, but more importantly, they had the goal of identifying what these elusive transitional cells are, and can we find a marker for these cells to study them? And in some, yes. Together, the sequencing and spatial data provided gene expression atlas of the mouse CSS. Hopefully, this atlas will guide future studies into the essential electrical system that regulates the heartbeat. Cindy St. H:                         The next article I'd like to highlight is titled Single-Cell Transcriptomics Reveals Chemotaxis-Mediated Intra-Organ Crosstalk During Cardiogenesis. We're really going to hit you over the head with some single-cell transcriptomics in this month's podcast. The first authors of this article are Halqing Xiong, Yingjie Lou, Yanzhu Yue, Jiejie Zhang and the corresponding author is Aibin He and they're all from the Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and the Peking-Tsinghua Center for Life Sciences, all at Peking University in Beijing, China. Cindy St. H:                         During development, the mammalian heart originates from two distinct areas in the early embryo and they're called the first heart field and the second heart field. Progenitor cells from these regions give rise to very different structures. From the first heart field comes the atria and the left ventricle, and the second heart field forms the right ventricle and the outflow tract. While we know the outcomes of these different developmental layers, a full understanding of how the first and second heart fields are regulated and how they actually interact with one another is actually lacking a lot of detail and we're not exactly sure how those structures can influence one another. Cindy St. H:                         So to learn more, Xiong and colleagues utilized two different murine models that were engineered to label cells coming from either the first or second heart fields red, and by labeling these cells red, it allows for their very pure isolation and then downstream studying at the single-cell level. So from each of these two models, they collected about 600 red-labeled cells and they collected these cells at four different time points, that were essentially at 12 hour intervals, and they did this starting at embryonic day 7.5, and that's because that's the time point in the mouse where these second and first heart fields are starting to develop. Cindy St. H:                         What they found, by using single-cell RNA sequencing, is that the first heart field cells differentiated into cardiomyocytes, in what they called a gradual, wave-like manner, while the second heart field cells differentiated in what they referred to as a more stepwise, defined pattern. The team also found high expression of migration factor MIF in first heart field cells and they found MIF's receptor CXCR2 in the second heart field progenitor cells. This suggests that perhaps the first heart field cells could regulate the migration of the second heart field cells. Sure enough, blocking MIF- CXCR2 interaction in cultured mouse embryos prevented second heart field cell migration and also prevented normal development of the right ventricular outflow tract structures. So together these results provide insight into both normal heart development and also suggest what might go awry in certain congenital heart malformations. Cindy St. H:                         The next paper I want to highlight is titled Metabolic Syndrome Exacerbates Pulmonary Hypertension due to Left Heart Disease. The first author is Benoit Ranchoux and the corresponding author is Francois Potus, and they are from the Pulmonary Hypertension Research Group at Laval University in Quebec City in Quebec, Canada. The disease pulmonary hypertension can arise from a number of causes, but one of the main drivers of what's called group two pulmonary hypertension is left heart disease. Left heart disease itself is caused by several conditions, such as diastolic dysfunction, aortic stenosis, which is a disease that I study, or mitral valve disease. All of these pathologies result in the left heart not beating efficiently or exerting too much energy. Cindy St. H:                         More than half of all group 2 PH patients also have metabolic syndrome, and metabolic syndrome is a condition that is ever increasing in the modern age, especially in America, and it's characterized by obesity coupled with pathology such as dyslipidemia, type 2 diabetes and high blood pressure. Metabolic syndrome is also marked by elevated levels of the inflammatory cytokine IL6. Rat studies have shown that IL6 can induce proliferation of the pulmonary artery smooth muscle cells and consequently, pulmonary hypertension. Cindy St. H:                         In this study Ranchoux and colleagues pulled together all these different pieces in a rat model and essentially want to test left heart disease coupled with metabolic syndrome coupled with does pulmonary hypertension happen or get worse? What they found was really interesting. Left heart disease was induced in a rat model using super coronary aortic banding and then metabolic syndrome was induced with a high fat diet feeding, or with treatment with Olanzapine, which is a second generation anti-psychotic agent, and it's known to induce metabolic syndrome not only in rats, but also in humans. The data from this paper show that inducing metabolic syndrome in rats coupled with left heart disease resulted in elevated IL6 levels and also greatly exacerbated pulmonary hypertension. Cindy St. H:                         Digging into this mechanism, they found that inhibition of IL6, using either an anti-IL6 antibody or by reducing IL6 secretion from macrophages, using the diabetes drug Metformin, ameliorated the pulmonary hypertension in the rats. They then went on and looked at human samples and they found that IL6 was higher in the lungs of pulmonary hypertension patients and that this IL6 could induce proliferation of human pulmonary artery smooth muscle cells. So together these data suggest that the observation in rats holds true for humans, but further goes on to suggest that perhaps Metformin, which is a well-known, well-used diabetic drug, could perhaps be used for the potential treatment of Group 2 pulmonary hypertension patients.   Cindy St. H:                           In the August 16th issue, we have an article titled Increased Activated Protein C Response Rates Reduce the Thrombotic Risk of Factor V Leiden Carriers but not of Prothrombin 20210G>A Carriers. That is some title. The first authors are Heiko Rühl, and Christina Berens, and Dr Rühl is also the corresponding author, and they are at the Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, in Bonn, Germany. Genetic studies have found two mutations that convey particularly increased risk for venous thrombo-embolism, and VTE is also more commonly referred to as deep vein thrombosis. These mutations are called factor five Leiden mutations, or FVL, and the prothrombin 20210G>A mutation we're just going to call F2. Interestingly, the penetrance of these mutations, or how likely they are to exhibit a phenotype, is variable. Some individuals with mutations never experience deep vein thrombosis, while others experience multiple episodes. Cindy St. H:                         As a group, the FVL carriers produce a higher than normal level of an anticoagulation factor called APC, or activated protein c. They also produce high levels of the pro-coagulation factor thrombin, and the authors of this study wondered if it was the balance, or rather perhaps an imbalance, of these factors that could explain the phenotypic variations in the patients that harbor the same mutation. To test this, they collected 58 patients. 30 were FVL and 28 were F2 carriers, and they injected these patients with clotting factors and examined their response rates. In both of the groups, about half of the individuals had no history of deep vein thrombosis, while the other half had had at least one episode. Cindy St. H:                         The team found that while both types of mutations were associated with increased APC and thrombin levels after coagulant injection compared with a control group, in the FVL group lower APC levels correlated with a much higher risk of deep vein thrombosis. In other words, the FVL carriers who had never experienced deep vein thrombosis produced higher levels of APC. Translating this to the clinic, perhaps APC testing could help identify individuals who are carriers of the FVL mutation and determine which of them are at higher risk due to lower levels of APC. Cindy St. H:                         The last paper we're going to highlight before switching to our interview is titled The Human- and Smooth Muscle Cell Enriched lncRNA, SMILR, Promotes Proliferation by Regulating Mitotic CENPF mRNA and Drives Cell Cycle Progression Which Can Be Targeted to Limit Vascular Remodeling. Now that is a crazy title! We’ve got to limit these names here this is difficult. The first authors are Amira Mahmoud and Margaret Ballantyne and the corresponding author is Andrew Baker, and they're all from Queens Medical Research Institute, BHF Center for Cardiovascular Sciences at University of Edinburgh in Edinburgh, UK. Cindy St. H:                         Before we dive into this article, I think it's important that we give a quick explanation of what is a lncRNA? lncRNA, or L-N-C RNA, stands for long non-coding RNA, and these are described as being transcripts which are made into RNA that are in lengths exceeding 200 nucleotides. So that differs them from micro RNAs or peewee RNAs or snRNAs, and they are classically or, I guess originally, considered not to be translated into protein. However, I think now more and more studies are finding that perhaps they are made into peptide sequences. However it's not fully clear what the function of those sequences are. Similar to micro RNAs, they also harbor regulatory functions that can control cellular functions by helping to fine tune the regulation of gene transcription and translation. Cindy St. H:                         Largely speaking, vascular smooth muscle cells are quiescent, but they can be stimulated to proliferate and migrate following injury to the vessel wall. While such activation of smooth muscle cells is essential for wound healing, these same processes are operative in vascular disease or after a cardiovascular procedure. Often what happens is an excess of proliferation of the smooth muscle cell wall can lead to dangerous occlusion of the blood vessel. The long non-coding RNA, SMILR, was recently identified as a promoter of smooth muscle cell proliferation and now in this article, Mahmoud and colleagues have defined its mechanism of action. Through transcriptome analysis of human smooth muscle cells, in which the levels of SMILR were either modulated to be increased or suppressed, the team found that lncRNA regulated expression of several genes involved in mitosis, or cell division. Furthermore, RNA interaction experiments revealed that the messenger RNA encoding the mitotic centromere protein, CENPF, was a direct interaction partner of SMILR. So just like the suppression of SMILR, the inhibition of CENPF resulted in reduced mitosis of the smooth muscle cells. Cindy St. H:                         The team then went on to show the inhibition of SMILR via RNA interference could block the smooth muscle cell proliferation ex-vivo, and they did this using intact sections of human saphenous vein. These results suggest that targeting this lncRNA could be a potential clinical treatment in situations where vessel occlusion is at risk. Cindy St. H:                       Okay, so now we're going to switch and have our interview with Drs Denisa Wagner and Nicoletta Sorvillo, and we're going to discuss their paper entitled Plasma Peptidylarginine Deiminase IV Promotes VWF-Platelet String Formation and Accelerates Thrombosis after Vessel Injury. Thank you Drs. Wagner and Sorvillo for joining us today. I think a funny thing is that between Nicoletta in Switzerland, me and you on the East coast and my producer on the West coast, I think we're spanning about nine hours of time zones here. Thank you all for taking the time, whatever time of day it is, wherever you are. Dr Wagner:                         Thank you. Cindy St. H:                         I was wondering, Denisa, if you could please introduce yourself and tell us a little bit about your background. Dr Wagner:                         I am a vascular biologist. I was always interested in platelets, endothelial cells, and leukocyte. I started with a background of von Willebrand factor research. Von Willebrand factor is the most important adhesion molecule for platelets and it is stored in endothelial cells as we have found very early on, in an organelle called Weibel-Palade bodies. So my work on this paper is actually related to the first observation I ever made scientifically of showing that von Willebrand factor is released from endothelium. Cindy St. H:                         Wow, that's wonderful. And Nicoletta, could you please introduce yourself and tell us a little bit about your background? Nicoletta:                            I'm Italian, I studied in Italy and I did my PhD in the Netherlands, and I've always worked on inflammation and thrombosis during my PhD. One of the major proteins I was working on is ADAMTS13. That is again a protagonist of our paper. Then I moved to Boston, where I had the pleasure to be able to work in Denisa Wagner's lab, and there I continued working on inflammation and ADAMTS13 and now currently I moved here to Bern and I'm bringing my expertise here, but I moved a little bit towards ischemia and reperfusion injury and transplantation. Cindy St. H:                         Interesting. Wow. Denisa, I want to circle back to this factor being one of the first findings that you worked on. How does it feel to still be working on it? Is it still exciting? Dr Wagner:                         It is nice and it's refreshing to come back to it. I did a lot of stuff in between. We did a lot of adhesion molecule work, leukocyte rolling. We made the early knockouts like b-selectin, p-selectin, and von Willebrand factor knockout as well. So it's fun. And by the way, since Nicoletta said that she was Italian, I am originally Czech, from Prague. Cindy St. H:                         Interesting. I did not know that. And actually, Denisa, I don't know if you remember, but when I was a graduate student in Katya Ravid’s lab, we collaborated with you to use some of this intravital imaging on one of our JCI papers. Dr Wagner:                         Oh right, right. I was wondering where I knew your name from. That's funny. Cindy St. H:                         Yes. Yeah, yeah. So it's wonderful to speak to you again. Really I wanted to interview you because I loved this paper, not only because it was a really interesting mechanism that actually I wasn't very well aware of, this citrullination and also because of the beautiful intravital imaging you could do and then link it to patient disease states. Maybe you can start by telling me what's the clinical unmet need or the question that your paper was trying to address? Nicoletta:                            So Denisa Wagner's lab always has worked on neutrophils and NETs and it has been shown that these NETs are involved in thrombosis. So we were curious what happens when even the enzyme that is important to make these NETs, this extracellular DNA, does when it's in the circulation. And this enzyme is of course PAD4 and it is known that it can modify our [inaudible] residues on protein through this process of citrullination. So we went to see if it could modify plasma proteins and as Denisa already said, an important molecule that initiates thrombotic processes is vWF that can be released during inflammation or when there's a damage to the endothelium .  So we went to see what happens if the enzyme that is involved in removing this vWF that is ADAMTS13 happens if it gets modified by this enzyme path. So our question was more like what happens if you have the release of an enzyme that is normally intracellular? What would happen if it gets outside of the cell? Cindy St. H:                         Interesting. So before we get too deep in the weeds, what is citrullinization and why is it important? What do these modifications do? Nicoletta:                            It changes the charge of a protein. It goes and modifies arginine, and it transforms it into citrulline. It changes the charge of a protein and therefore you can imagine if you change a charge of protein it can change even the structure of a protein and if you change the structure then you can change the function. So this is what this modification can do. Cindy St. H:                         And that's what it's doing on the ADAMTS13? It's essentially altering or inhibiting its function? Nicoletta:                            Yes. What we saw is that we can find these citrullinated residues on ADAMTS13 and we identify them by mass spectrometry and then we saw that if it is modified by citrullination, it loses its activity so it doesn't function anymore. Cindy St. H:                         Interesting. Very neat. Could you talk a little bit about the process of where this is happening naturally and where it goes wrong in a diseased state such as either sepsis or aging or just general clotting? Dr Wagner:                         These neutrophil extracellular traps are generated often more during a disease state when there is either an infection or exacerbated inflammation that would be like in sepsis or for example, in a metabolic disorder like diabetes. So there is a lot more of them being generated. Also, for example, in diabetes, PAD4 is elevated inside the neutrophil four-fold. If it's released from diabetic neutrophils , then there would be really a lot more of it. And in aging also, then a NETosis becomes much more prominent. We have done this only with mice, but I believe that it will be also, unfortunately, the case with humans that old mice make a lot more NETs than young mice. Therefore this is relevant to look. Since thrombosis increases both with aging, the incidence of thrombosis, thrombosis increases with a disease like diabetes or in sepsis, you will have micro thrombosis. We thought it would be interesting to study those processes as well, then. Cindy St. H:                         That's really neat. One of the techniques that you utilize heavily in this paper and several of your papers that I'm familiar with is this intravital imaging or intravital microscopy. Just so people can get a sense of what it is you're actually doing, could you maybe describe what that experiment is? Maybe Nicoletta, you could describe that for us? Nicoletta:                            During intravital microscopy, we are able to image in vivo, a vessel in a live mouse. And in this case we use mice and we can label leukocytes and platelets and then look at them in the vessel in vivo and you can then look for a thrombus forming or you can look at the [inaudible 00:23:43] already had leukocyte rolling and you can see what is happening inside the vessel during a proper blood flow and you can damage the vessel in some cases. In our case, in our paper, we do a ferric chloride injury where we damaged the vessel with ferric chloride and therefor you initiate a thrombus development and you can visualize it in vivo and real time. Cindy St. H:                         Excellent. Yes. And hopefully our listeners will look and see the beautiful pictures because those are some serious clots you get forming in the vessels. Yeah. Yeah. And so the other thing that you did was confirming the modification on ADAMTS13, you use mass spectrometry. How difficult was it to confirm that what you thought was happening was happening using that technique? Nicoletta:                            It was very difficult and challenging, I have to say. Dr Wagner:                         See, I would love to hear more about it because you often read, Oh, then we did mass spec and we got this beautiful whatever. Could you tell us a little bit about the struggles? Nicoletta:                            It was quite a struggle. I mean I think trying to identify such a modification that is very, first of all, novel and it changes the math only of one thousandth it's very difficult. To identify you can confuse it with a deiminasion again because of the increase of mass is the same. And another problem was that ADAMTS13, our plasma protein, is low abundance in plasma compared to other plasma proteins like Fibrinogen, that is very, very much abundant. It was a challenge for this reason. So trying to pinpoint out a small, tiny modification already in a protein that is not so abundant in plasma and therefore we have to use this probe, this Biosyn PG program. And we did this in collaboration with Paul Thompson's lab and we were able to then fish out what was modified by the citrullination, but it was very challenging. We tried several different types of techniques that were different types of approaches before being able to show that in vivo. So in human samples we can find this modification. Dr Wagner:                         Nicoletta grew a lot of gray hair during that period. (laughs) Dr Wagner:                         It took us about a year to figure out how we could detect it in vivo because also some antibodies to ADAMTS13 don't work so well. It's a minor protein, but she figured it out. Cindy St. H:                         Wow. That's amazing. Well, congratulations on that. That's excellent. I guess what I'm wondering now is what are the next steps and what might your findings mean in terms of future potential therapeutic options or treatment strategies for different detrimental thrombotic events? Dr Wagner:                         I think what we have really verified that the PAD4 remains active when it circulates in circulation, when the release, and there are several diseases in which PAD4 levels were found to be elevated, like rheumatoid arthritis and what it means in general. That is PAD4 is actually causing havoc. It is citrullinating probably quite indiscriminately. Several proteins may be finding the exposed parts. Maybe it could have some binding sites, but I think it just affects proteins in general and for some of them like, ADAMTS13, this had a very detrimental effect. So in diseases where there is a lot of PAD4, one has to worry about the consequences of citrullinating things and perhaps spot for inhibitors should be used. What do you think, Nicolleta? Nicoletta:                            I totally agree with you. Yes, I totally agree. I mean PAD4 outside the cell could be dangerous, of course. However, we never know if there's something good that it can do that protects by citrullinating proteins so there's so much more to discover about extracellular PAD4 and its effect on the environment. Dr Wagner:                         However, Nicoletta when she wrote a paper at the end she decided to talk about ADAMTS13 as a therapeutic because both she and I, we are convinced that ADAMTS13 it's a possible future therapeutic and it's already given to patients who are lucky in ADAMTS13 and may be given to patients who have thrombotic events in the future, like stroke or myocardial infarction. And these situations are highly pro-inflammatory. Therefore, we would anticipate that in these situations, NETs, and we know NETs are released and therefore, what Nicolleta suggests at the end, is that introducing together with ADAMTS13 an inhibitor of citrullination would be a good thing so that the protein, the ADAMTS13, remains active in circulation. Cindy St. H:                         Wow. So a two-hit strategy. I mean I can think of a handful of potential diseases this would be good for. You know, patients with sickle cell, there's a lot of NETs released then thrombotic events or even stroke. I mean, do you see that this is a potential mechanism that's common to all thrombotic disease or just kind of specific subsets? Nicoletta:                            All is a big word I think, but I think that there are many disorders where together with a thrombotic event, you can find also low levels or low activity of ADAMTS13 and in many of these disorders, nobody knew really why you have a reduction of ADAMTS13 activity, what is happening? Why do you lose this ADAMTS13? What we believe, but of course further studies are needed, is that maybe in these disorders, what is causing the loss of ADAMTS13 is this release of PAD4 because in stroke or in some DIC sepsis, you can find patients or many patients who do have low levels of ADAMTS13 activity and we believe that it's due to maybe citrullination by PAD4. So in that case, I agree with you maybe then that this therapy can be used in different thrombotic events as you suggested. Cindy St. H:                         So what does PAD4 normally do when it's intracellular? What is its, I guess healthy role, in a cell, if it has one? Nicoletta:                            So what is known now is that it really regulates transcription. So that's very important because it citrullinates transcription factors to facilitate transcription. And what Denisa Wagner's lab has identified is that it's extremely important to form these NETs because it citrullinates histone and allows the unraveling of the chromatin and then the NET release. However, it's extremely interesting. We are very interested to understand what else does it do within the cell. Cindy St. H:                         Interesting. That is so neat. I love this story. Dr Sorvillo and Dr Wagner, thank you so much for joining us and congratulations again on a wonderful paper. Dr Wagner:                         Thank you. Nicoletta:                            Thank you for having us and inviting us. Thank you. Cindy St. H:                         So that's it for the highlights from our August issues of Circulation Research. Thank you for listening. This podcast is produced by Rebecca McTavish and edited by Melissa Stoner and supported by the editorial team of Circulation Research. Copy text for the highlighted articles is provided by Ruth Williams. I'm your host, Cindy St Hilaire and this is Discover CircRes, your source for the most up-to-date and exciting discoveries in basic cardiovascular research.  

This episode reviews the management of an outpatient with a bleeding phenotype. How does one grade severity and what tools might we use? What are signs on physical exam that should be assessed? Consider both inherited and acquired bleeding disorders when assessing your patients. Lastly, we discuss the initial management and some evidence behind these management strategies in our medicine minute!Podcast written by: Dr. Ying LingReviewed by: Dr. Michelle Shozlberg and Dr. Jonathan AilonAs always, we have associated resources and infographics at www.theinternatwork.com.

This week I'm talking to Jenna Lovell, founder of My Missing Factor, about her experience with Von Willebrand disease, how it affects her menstrual and overall health, and the gender disparity in bleeding disorder treatment. This episode of Heavy Flow is supported by Diva Cup, a sustainable, easy-to-use, cost-effective and eco-friendly menstrual cup. What we discussed:  How Jenna's horrific early periods led to her to be diagnosed with Von Willebrand disease (VWD) The common symptoms of VWD How VWD affects your menstrual health without being a reproductive disorder or disease The gender disparity in bleeding disorder treatment Why the birth control pill is often prescribed to women with bleeding disorders, despite factor therapy being the gold standard of treatment The blood taboo How fertility awareness helped Jenna better understand and manage her bleeding disorder Sex and sexuality with a bleeding disorder Connect with Jenna: Website Facebook Instagram Resources mentioned in this episode: Heavy Flow Episode 6 with Jessica Murnane Women Who Bleed "What is Normal?" Part One, WWB Period Video Logs Subscribe & leave a review:  If you're into Heavy Flow, please subscribe in iTunes and write a review - that's the best way to support the show and help others find this podcast! Music Credit: Julia and Bradley of Home Studios Graphic Design: Rachel Laird

These are most important in trauma patients!!! Platelet Disorders Symptoms of SUPERFICIAL bleeding Mucosal bleeding GI bleeding Recurrent epistaxis Thrombocytopenia When the platelets ARE LOW Refer to THIS episode Von-Willebrand disease When the platelets CAN'T BIND Treatment Desmopressin (DDAVP) Causes increase in amount of von-willebrand factor (vWF) available Also causes free water retention Treatment of […]

Von Willebrands sjukdom är den vanligaste ärftliga blödningsrubbningen. I det åttonde avsnittet av Blödigt värre åker vi till Åland för att finna sjukdomens rötter. Vi träffar samtidigt Anders Ingves, pappa till blödarsjuke elitidrottaren Wilhelm som vi mötte i avsnitt 6 av podcasten. Men varför Åland? Jo, sjukdomen har nämligen fått sitt namn av den finländske läkaren Erik von Willebrand, som på 1920-talet beskrev en blödningssjukdom som han inte tyckte liknade hemofili och som uppträdde i ovanligt hög utsträckning i en stor släkt på Åland. Medverkar gör också Dag Nyman, som arbetat kliniskt med blödarsjuka och blodproppar, samt forskat specifikt om trombocytfunktion och von Willebrands sjukdom.

On the Health Slot this week we spoke to Clinical Haematologist, Dr Andrew McDonald about Von Willebrand disease which is a common hereditary bleeding disorder, more common and usually milder than haemophilia...

Platelet function testing has traditionally been used to diagnose inherited qualitative and quantitative defects in platelet function, such as Von Willebrand disease, but with the increased use of anti-platelet agents to prevent arterial thrombosis and the interest in identifying patients at risk for thrombosis despite anti-platelet therapy, the use of platelet function testing to monitory response to anti-platelet therapy, for example, aspirin, has become a hot topic.

Thu, 5 Dec 2013 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/16536/ https://edoc.ub.uni-muenchen.de/16536/1/Kapfhammer_Elisabeth.pdf Kapfhammer, Elisabeth

Dr Evan Sadler talks to ecancer at the 18th EHA Congress to discuss diseases associated with Von Willebrand Factor and ADAMTS13, a protein circulating in the blood that prevents bleeding by collecting platelets.

Interview of Dr. Evan Sadler, President of ASH, Prof of Medicine, Chief of Hematology at the Washington University Medical School, St. Luis. conducted by Shaun McCann, Chair of EHATol Unit, Member of EHA Education Committee on the question 'Is von Willebrand factor always associated with bleeding?'.

Interview of Dr. Evan Sadler, President of ASH, Prof of Medicine, Chief of Hematology at the Washington University Medical School, St. Luis. conducted by Shaun McCann, Chair of EHATol Unit, Member of EHA Education Committee on the question 'Is von Willebrand factor always associated with bleeding?'.

On episode #93 of the podcast This Week in Virology, Vincent, Alan, and Rich answer listener questions about lab procedures, prokaryotes, endogenous retroviruses, the iPad and teaching, prions, mimivirus, splitting water with viruses, and the polio outbreak in Tajikistan. Host links Vincent Racaniello, Alan Dove, and Rich Condit Links for this episode: Biomedical Advanced Research and Development Authority (BARDA) SIGA responds to BARDA request for smallpox antiviral BARDA contract for filovirus vaccine What is a Ph.D? (pdf) HHMI resources for early career scientists Pace article on abandoning prokaryote (Nature) Three domains of life (Forterre article) Mechanoenzymatic cleavage of Von Willebrand's factor (Science) Splitting water with viruses WHO coverage on Tajikstan polio outbreak Wild type polio infection in immunized Indian children (JID) Letters read on TWiV 93 Weekly science picks: Alan - Southern Fried Science Rich - Tree of Life web project Vincent - Dickson Despommier at Big Think

Jesus San Miguel - Discussing Myeloma. Prof Ian Peake - Discussing recent advances in the diagnosis and management of Von Willebrand's disease. Michael Andreef - Discussing drug resistance and the bone marrow microenvironment. John Goldman - Discussing the progress that has been made in the management of chronic myeloid leukaemia in the last decade.

Background: Growing evidence indicates that ambient air pollution is associated with exacerbation of chronic diseases like chronic pulmonary disease. A prospective panel study was conducted to investigate short-term changes of blood markers of inflammation and coagulation in response to daily changes in air pollution in Erfurt, Germany. 12 clinical visits were scheduled and blood parameters were measured in 38 male patients with chronic pulmonary disease during winter 2001/2002. Additive mixed models with random patient intercept were applied, adjusting for trend, weekday, and meteorological parameters. Hourly data on ultrafine particles (UFP, 0.01-0.1 mu m), accumulation mode particles (ACP, 0.1-1.0 mu m), PM(10) (particulate matter

Orthotopic liver transplantation is frequently associated with a complex coagulation disorder, influencing the outcome of the procedure. In this respect, disseminated intravascular coagulation (DIC) had been suggested to be of causative importance for bleeding complications after reperfusion of the liver graft. In 10 consecutive patients undergoing orthotopic liver transplantations, we studied the occurrence of two phagocyte proteinases of different origin in the graft liver perfus-ate and in systemic blood during the operation, as well as their effects on hemostasis. As compared with plasma samples taken at the end of the anhepatic phase, highly significant increases of cathepsin B and thrombin-anti-thrombin III complexes (TAT), as well as highly significant decreases in antithrombin III, protein C, and C1-inhibitor were observed in graft liver perfusate. Von Willebrand factor and fibrinogen were slightly decreased, whereas the elastase-alpha1 proteinase inhibitor complexes (EPI) were elevated. In plasma the activity of cathepsin B remained unchanged during the prereperfusion phases, but immediately after revascularization of the graft this cysteine proteinase increased. The EPI showed a gradual increase in plasma during the preanhepatic and anhepatic phases but a more pronounced increase in the reperfusion phase. In parallel with the rise in these two proteinases TAT increased and the activities of antithrombin III and C1-inhibitor in plasma decreased after reperfusion. At 12 hr after revascularization plasma levels of TAT, antithrombin III, and C1-inhibitor had returned to the prereperfusion ranges, whereas cathepsin B and EPI were significantly above the baseline levels. These observations are consistent with the hypothesis that extracellularly released lysosomal proteinases may play a role in the development of a DIC-like constellation, including thrombin formation after revascularization of the liver graft. For the first time we could prove the occurrence of phagocyte proteinases in graft liver perfusate and evaluate the importance of these proteinases for the understanding of the pathophysiology leading to bleeding complications in patients undergoing orthotopic liver transplantation.