Podcasts about vwf

 N-acetyl cysteine (NAC) shows promise for heart attack preventionHeart attacks and strokes are a leading cause of death in developed countries - accounting for ~20% of all deaths in the U.S. Frequently, heart attacks and strokes are caused by blood clots (blood platelets that form when they are not needed, causing a narrowing/blockage of blood vessels) formed through arterial thrombosis. Current antiplatelet agents (e.g., aspirin) are effective but can increase major bleeding risk. As such, there is a growing need to prevent arterial thrombosis different from antiplatelet agents.A recent study published in Arteriosclerosis, Thrombosis, and Vascular Biology investigated the potential of NAC as an agent to prevent arterial thrombosis. Utilizing both [cell-based] human blood models and mouse (in vitro) models, the research demonstrated that NAC significantly delayed and even prevented thrombus formation dose-dependently without increasing bleeding risks.Findings:*NAC treatment extended clot formation times by up to 3.7 times compared to controls in the human blood [cell] model.*NAC entirely inhibited platelet aggregation and occlusive clot formation at higher doses than the above point in the cell model.*A 400 mg/kg (via injection in rodents) dose of NAC in mice effectively prevented arterial occlusion post-injury.*Lower doses (200 mg/kg - via injection in rodents) of NAC reduced clot stability, suggesting working as both an acute and preventative clotting therapy.The study showed that NAC interferes with von Willebrand factor (a large protein crucial for blood clotting) activity. NAC acts against VWF rather than platelets to prevent clot formation. Thus, providing a safer alternative to traditional antiplatelet drugs that carry higher bleeding risks. Support the Show.

In this week's podcast we'll discuss another step forward in stamping out high-risk myeloma. Then we'll hear about the plasmin-cleaved von Willebrand factor, or VWF, in microthrombosis. Finally we'll hear about new insights into the origins of sickle cell pain. Featured Articles:Daratumumab, carfilzomib, lenalidomide, and dexamethasone with tandem transplant for high-risk newlydiagnosed myelomaPlasmin-cleaved von Willebrand factor as a biomarker for microvascular thrombosisSickle cell disease iPSC-derived sensory neurons exhibit increased excitability and sensitization to patientplasma

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 

Shri Dattatreya is one of the most revered sages who incarnated on earth. And he gave teachings which are in the form of Tripura Rahasya. In the Jnana Khanda which is a section on wisdom, the commentator narrates a story of the Jivatma, its sense of bondage and liberation. It is Sri Dattatreya Jayanti on 26th December 2023 and we hear his teaching today. Avadhuta Gita - https://podcasters.spotify.com/pod/show/the-river-of-wisdom/episodes/113-Avadhuta-Gita---Learning-from-24-masters-1-of-3-ekisp9 New course on Svadharma starting 14th January 2024 - Discovering and living our life purpose - https://www.hua.edu/courses/svadharma-discovering-and-living-our-life-purpose/ Our December 2023 newsletter of Aarsha Vidya Bharati - Looking back l Gita Jayanti l Vishnu Krpa l VWF l The Lie of Objectivity l Vedanta camp l Narmada Parikrama and more ! - https://mailchi.mp/90bb015c61ff/aarsha-vidya-bharati-dec2023 Our monthly newsletter will bring you more happiness, more wisdom and more freedom. To subscribe to Aarsha Vidya Bharati - https://mailchi.mp/cea95b9ad987/aarsha-vidya-bharati Vedanta - the river of wisdom is a weekly podcast by Swamini B (Brahmaprajnananda), a Vedanta teacher, writer and Hindu monk. Please follow, learn and enjoy Youtube - https://www.youtube.com/@DiscoverAtma Instagram - https://www.instagram.com/discoveratma Twitter - https://twitter.com/discoveratma To connect and learn Vedanta - www.discoveratma.com --- Send in a voice message: https://podcasters.spotify.com/pod/show/the-river-of-wisdom/message

This year was a happy year! We did a lot of karma. We upheld Dharma by practising universal values. Dharma made us happy. Do you know which values mentioned in the Bhagavad Gita, you effortlessly embodied? The podcast transcript - https://discoveratma.com/257-your-tree-of-karma-how-did-it-grow-this-year/ Our December 2023 newsletter of Aarsha Vidya Bharati - Looking back l Gita Jayanti l Vishnu Krpa l VWF l The Lie of Objectivity l Vedanta camp l Narmada Parikrama and more ! - https://mailchi.mp/90bb015c61ff/aarsha-vidya-bharati-dec2023 Our monthly newsletter will bring you more happiness, more wisdom and more freedom. To subscribe to Aarsha Vidya Bharati - https://mailchi.mp/cea95b9ad987/aarsha-vidya-bharati Vedanta - the river of wisdom is a weekly podcast by Swamini B (Brahmaprajnananda), a Vedanta teacher, writer and Hindu monk. Please follow, learn and enjoy Youtube - https://www.youtube.com/@DiscoverAtma Instagram - https://www.instagram.com/discoveratma Twitter - https://twitter.com/discoveratma To connect and learn Vedanta - www.discoveratma.com --- Send in a voice message: https://podcasters.spotify.com/pod/show/the-river-of-wisdom/message

All of us have used Vedanta to avoid or bypass uncomfortable emotions or the challenges of daily living, at some time of the other. If allowed to continue, spiritual bypassing prevents us from enjoying the fruits of this knowledge. And so we look at ourselves clearly and gain the right perspective to our emotions in the light of Vedanta. The podcast transcript - https://discoveratma.com/category/podcast/ Our December 2023 newsletter of Aarsha Vidya Bharati - Looking back l Gita Jayanti l Vishnu Krpa l VWF l The Lie of Objectivity l Vedanta camp l Narmada Parikrama and more ! - https://mailchi.mp/90bb015c61ff/aarsha-vidya-bharati-dec2023 Our monthly newsletter will bring you more happiness, more wisdom and more freedom. To subscribe to Aarsha Vidya Bharati - https://mailchi.mp/cea95b9ad987/aarsha-vidya-bharati Vedanta - the river of wisdom is a weekly podcast by Swamini B (Brahmaprajnananda), a Vedanta teacher, writer and Hindu monk. Please follow, learn and enjoy Youtube - https://www.youtube.com/@DiscoverAtma Instagram - https://www.instagram.com/discoveratma Twitter - https://twitter.com/discoveratma To connect and learn Vedanta - www.discoveratma.com --- Send in a voice message: https://podcasters.spotify.com/pod/show/the-river-of-wisdom/message

Here is a lovely story from Sri Swami Rama Tirtha, a teacher of Vedanta who lived before Swami Vivekananda. Guess what the person finds when he looks for God? The podcast transcript - https://discoveratma.com/255-the-one-who-looked-for-god-story/ Our December 2023 newsletter of Aarsha Vidya Bharati - Looking back l Gita Jayanti l Vishnu Krpa l VWF l The Lie of Objectivity l Vedanta camp l Narmada Parikrama and more ! - https://mailchi.mp/90bb015c61ff/aarsha-vidya-bharati-dec2023 Our monthly newsletter will bring you more happiness, more wisdom and more freedom. To subscribe to Aarsha Vidya Bharati - https://mailchi.mp/cea95b9ad987/aarsha-vidya-bharati Vedanta - the river of wisdom is a weekly podcast by Swamini B (Brahmaprajnananda), a Vedanta teacher, writer and Hindu monk. Please follow, learn and enjoy Youtube - https://www.youtube.com/@DiscoverAtma Instagram - https://www.instagram.com/discoveratma Twitter - https://twitter.com/discoveratma To connect and learn Vedanta - www.discoveratma.com --- Send in a voice message: https://podcasters.spotify.com/pod/show/the-river-of-wisdom/message

*Paster Kevin Lea: RSR hosts Fred Williams & Doug McBurney welcome Pastor Kevin Lea of Calvary Church Port Orchard WA for a deep dive into his presentation, (along with faithful co-laborers) of Hydroplate Theory to the headquarters staff at the Institute for Creation Research. *Attend! The First Creationist Hydroplate Conference: September 21-23, 2023. Join Fred, Doug and an “A-List” of RSR favorites for the first conference on Creation and Hydroplate Theory Science! Attend virtually by registering today at: Hydroplate.org. *Not the Hydroplate Theory: But it was great to see John Knox and our fellow workers at the Babylon Bee's “straight” news site Not the Bee cite Walt Brown in a story about unrelated water possibly trapped within the earth's mantle. While those waters, (if they exist) are not necessarily related to Walt Brown's Hydroplate Theory we welcome the boys at the Bee to link to Walt as often as they can! *Can I Get a Witness? Since none of us were there at the time of the flood, (except Jesus Christ), we must turn to His Word first in analyzing flood models, and everything else in life!

Listen to Part II of the interview HERE! *Paster Kevin Lea: RSR hosts Fred Williams & Doug McBurney welcome Pastor Kevin Lea of Calvary Church Port Orchard WA for a deep dive into his presentation, (along with faithful co-laborers) of Hydroplate Theory to the headquarters staff at the Institute for Creation Research. *Attend! The First Creationist Hydroplate Conference: September 21-23, 2023. Join Fred, Doug and an “A-List” of RSR favorites for the first conference on Creation and Hydroplate Theory Science! Attend virtually by registering today at: Hydroplate.org. *Not the Hydroplate Theory: But it was great to see John Knox and our fellow workers at the Babylon Bee's “straight” news site Not the Bee cite Walt Brown in a story about unrelated water possibly trapped within the earth's mantle. While those waters, (if they exist) are not necessarily related to Walt Brown's Hydroplate Theory we welcome the boys at the Bee to link to Walt as often as they can! *Can I Get a Witness? Since none of us were there at the time of the flood, (except Jesus Christ), we must turn to His Word first in analyzing flood models, and everything else in life!

In this week's episode, we'll discuss involvement of IL-13 and IL-4 signaling in fibrotic progression of myelofibrosis; next, we review results on a novel agent using vWF-dependent mechanisms to lyse pathological thrombi in acute ischemic stroke. Finally, we'll shed new light on findings that implicate the GARP-TGF-beta-1 pathway in the loss of natural killer cell cytotoxicity in relapsed AML.

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)

Emergencies happen in hematology and oncology. This is a fact. But how do we manage these emergencies? Look no further. In this episode, we talk all about our fourth hematologic emergency: thrombotic thrombocytopenic purpura (TTP). Thrombotic thrombocytopenic purpura (TTP):- Be sure to check out episode 009 on thrombocytopenia for a general approach and differential!- New anemia and thrombocytopenia should raise concerns for TTP! Workup: - Peripheral smear - concern for schistocytes. Look at this first! Example of these cells from ASH image bank here- ADAMTS13 level - always draw ASAP before any intervention- Repeat CBC- Reticulocyte count - will have elevated retic count- Citrated platelet count - CMP- PT, PTT, INR- Fibrinogen- Haptoglobin - LDH- Viral serologies Clinical manifestations: - Fever, Anemia, Thrombocytopenia, Renal (AKI), Altered Mental Status- If you see this - the patient is in bad shapeMechanism:- Tiny blood clots form in the body, causing platelet shearing- Loss of ADAMTS13 - This protein normally is responsible for chopping up von Willebrand's factor (vWF)- In the absence of ADAMTS13, vWF multimers are extra long, therefore interacting with platelets/collagen more and causing activation of platelets and clotting system- This causes red blood cell shearing due to small vessel microthrombi (brain, kidneys, heart)- Cytokine release causes fevers Management:- Do not reflexively transfuse platelets; can make situation worse - PLASMIC Score: helps to stratify likelihood of TTP; MDCalc link (https://www.mdcalc.com/plasmic-score-ttp)Treatment: - Plasma exchange: replacing ADATMS13-deficient plasma with ADAMTS13-rich plasma- This is different than plasmapheresis, where we replace plasma with albumin- Steroids: 1mg/kg prednisone daily to stop auto-antibody (against ADAMTS13) production- Confirm with ADAMTS13 levels; if

Vascular Ehlers Danlos Syndrome (Vascular EDS/VEDS) is just one of 13 sub-types of a group of connective tissue disorders called Ehlers Danlos. Due to a deficiency in collagen the walls of blood vessels are prone to dissection, rupture or aneurysm with potentially fatal consequences. However considering the serious complications of vascular EDS its presentation can be subtle and hard to spot. Clare, Jared and Dr Paddy Coughlin explain how patients with vascular EDS may present and what challenges they face. Trigger warning - descriptions of vascular events and bleeding.And here endeth Season 2! Join us in September for the next Season! LinksAccompanying blog with images about vascular EDS. Annabelle's Challenge aims to promote awareness and medical research into the rare, life-threatening and incurable genetic condition Vascular Ehlers-Danlos Syndrome (Vascular EDS). It was founded in 2013 by Jared and Sarah Griffin, after their daughter Annabelle was diagnosed with Vascular EDS at the age of 3.Please watch this short video where you can see Jared and Sarah talk about Annabelle's diagnosis. As well as hear other families share their stories.Ehlers Danlos Support UK (EDS UK) was set up in 1987 to support, advise and inform those living with the Ehlers-Danlos syndromes.  The charity represents and supports people with all types of EDS.Ehlers Danlos GP Toolkit Orphanet's description of Vascular Ehlers DanlosLoeys-Dietz is another connective tissue disorder that Paddy mentioned. Loyes-Dietz also causes aneurysms as well as other features. Von Willebrand Disorder (VWD) is a common misdiagnosis given to people with vascular EDS. VWD is a clotting disorder unlike vascular EDS which is a connective tissue disorder.  People with VWD have low levels of a protein involved in blood clotting, von Willebrand Factor (VWF) in their blood, or their VWF is dysfunctional, so it takes longer for the clotting process to work and for bleeding to stop.Sponsorship NoticeThis podcast is brought to you by Medics4RareDiseases. M4RD receives sponsorship from commercial companies. In 2022 this includes:Alexion Therapeutics, Amicus Therapeutics UK Ltd, BioMarin, Bionical Emas, Healx, Kyowa Kirin, Orchard Therapeutics and SOBI.These companies have no editorial control over this or any other M4RD content. Sponsorship does not equate to endorsement of companies or products. Views expressed during this podcast are personal and don't reflect those of M4RD sponsors.Go here to find out more about how M4RD works with sponsors. Companies have no editorial control over any of M4RD's activities or content of this podcast.

In this episode, Ara Metjian, MD; Paul Coppo, MD, PhD; and Marshal Mazepa, MD, answer questions from an audience of healthcare professionals on topics related to the management of acquired thrombotic thrombocytopenic purpura (aTTP), including:  Rationale of the CAPLAVIE regimen of caplacizumab with corticosteroids and rituximab in aTTP in the acute phaseData for caplacizumab in pediatric patients with aTTPInitiating rituximab after completion of plasma exchangeInternational Society on Thrombosis and Haemostasis guideline recommendations against using aspirinTriggers of aTTP episodes aside from infectionEffect of COVID-19 vaccines and COVID-19 infections on aTTP onset or relapsePresenters:Ara Metjian, MDAssociate ProfessorDivision of HematologyDepartment of MedicineUniversity of Colorado, Anschutz Medical CampusAurora, ColoradoPaul Coppo, MD, PhDProfessor of HematologyHematology Department, AP-HPSorbonne UniversityParis, FranceMarshall Mazepa, MD Assistant Professor of MedicineDivision of Hematology, Oncology,  and TransplantationUniversity of MinnesotaMinneapolis, MinnesotaLink to the complete program, including downloadable slidesets, an expert commentary, an on-demand webcast, and healthcare professional resource guide:https://bit.ly/3J1fcad 

Merhabalar… Sevdiğim çömezimin isteği üzerine bu yazımızda sizlere The Journal of Emergency Medicine' da Eylül 2021 yayınlanan derleme aracılığıyla Acil Serviste Trombotik Trombositopenik Purpuranın Değerlendirilmesi ve Yönetimi'nden bahsedeceğim. Derleme'nin tamamına buradan ulaşabilirsiniz. Trombotik trombositopenik purpura (TTP), acil serviste teşhis edilmesi güç lakin yüksek mortalite ve morbitidesi olmasından ötürü erken teşhisin elzem olduğu bir hastalıktır. TTP; mikroanjiyopatik hemolitik anemi, şiddetli trombositopeni ve multiorgan iskemik hasarı ile seyreden bir hastalıktır .Edinilmiş veya kalıtsal olabilir. Spesifik bir metalloproteaz olan ADAMTS-13 ile ilişkilendirilmiştir. TTP'de beklediğimiz klinik ateş, nörolojik anormallikler, purpuralı trombositopeni, mikroanjiyopatik hemolitik anemi ve akut böbrek hasarından oluşmaktadır. Ancak sadece

The 100th episode of The Litigation Psychology Podcast features trial attorneys Paul Motz from Segal McCambridge Singer & Mahoney and Brad Hughes from Clark Hill. Bill Kanasky, Jr., Ph.D. and Steve Wood, Ph.D. talk to Paul and Brad about the challenges of connecting with jurors during trials where masks are required and ideas on what to do. The group discuss their thoughts on counter-anchoring damages, why the insurance adjuster playbook doesn't work, and steps that need to be taken to diffuse a nuclear verdict before getting to trial. Paul and Brad offer their suggestions on how younger attorneys who lack experience can be provided opportunities to learn and talk about the difficult conversations that attorneys must have with their clients and their insurance companies about the investments that are necessary to avoid the ever-increasing nuclear verdicts and settlements. Watch the video of this episode: https://www.courtroomsciences.com/r/VWF

Coagulation Factor Disorders von Willebrand Disease A spectrum of low production to production of poorly functioning von Willebrand's Factor. von Willebrand's factor (vWF) has two major functions. vWF helps platelets to stick together in the subendothelial collagen vWF binds to and maintains Factor VIII in circulation. Factor VIII breaks down very quickly in the bloodstream […] The post S2 E081 Coagulation Disorders appeared first on Physician Assistant Exam Review.

Earlier this year, clinical practice guidelines for the diagnosis and management of von Willebrand disease (VWD) were published in Blood Advances. The guidelines (https://bit.ly/2OIfKLE) are a collaborative effort from the American Society of Hematology, the International Society on Thrombosis and Haemostasis, the National Hemophilia Foundation, and the World Federation of Hemophilia. Guideline author Paula James, MD, of Queens University, Kingston, Ont., reviews some of the recommendations in these guidelines with host David H. Henry, MD, in this episode. Case discussion A patient presents with the complaint of heavy menstrual bleeding, which could indicate a bleeding disorder such as VWD. How does one diagnose or rule out VWD? Tests to order include CBC, prothrombin time (PT), and partial thromboplastin time (PTT). Results of CBC, PT, and PTT could be normal, which would necessitate special testing to specifically look at factor VIII and von Willebrand factor (VWF). A patient’s family history may be helpful, as most types of VWD are autosomal dominant, though two subtypes are recessive. Diagnostic evaluation of VWD VWF is the chaperone protein for factor VIII in the intrinsic pathway, which is measured by the PTT. In more severe forms of VWD, the PTT is prolonged because of factor VIII. VWF is measured separately because it is not reflected in the PT or PTT. The recommendation is to measure VWF antigen and employ a functional assay to see how well VWF binds platelets. The recommendation in the new guidelines is to use the GPIbM assay rather than the ristocetin cofactor assay. Many labs in the United States are still using the ristocetin cofactor assay. However, in Canada, Europe, and other parts of the world, many labs have moved to a newer assay that is automated. It has a much lower coefficient of variation and fewer issues with measurement of VWF in Black populations, which is a major issue with the cofactor assay. Types of VWD Type 1 VWD is characterized by a decreased amount of VWF. Type 1 patients have low VWF antigen and low platelet-dependent VWF function to a similar degree, with low or normal factor VIII. Type 2 VWD is characterized by aberrant VWF. The functional assay is a lot lower than VWF antigen. The platelet-dependent function to VWF antigen ratio cutoff is 0.7. Further testing is warranted to determine subtypes (2A, 2B, 2N, or 2M), including VWF multimers. Genetic testing can be helpful to further delineate subtypes. Type 3 VWD is characterized by the absence of VWF. The patient will have a VWF antigen level of 0, platelet-dependent VWF function of 0, and a reduced factor VIII level (usually less than 10%). Pregnant patients with VWD There is a protective adaptation in pregnancy, in which factors normalize in the third trimester, which works to prevent hemorrhage at delivery. This protective effect is because of the hormonal changes of pregnancy, and it is seen in patients with milder forms of VWD. WVF levels peak within 8-24 hours after delivery and then slowly return to baseline. There is a risk of delayed postpartum hemorrhage once VWF levels return to baseline, which tends to happen 7-14 days postpartum. Procedural planning: Desmopressin challenge test Desmopressin causes the release of VWF from the Weibel-Palade bodies of the endothelium, and it can be used as prophylaxis or treatment of bleeding in type 1 VWD. The desmopressin challenge test is used to check how the patient responds to desmopressin when well, to predict the patient’s response after an anticipated procedure. The test involves measuring VWF levels before desmopressin is given and at 1 hour, 2 hours, and 4 hours after desmopressin administration. The idea is to measure the magnitude of increase in VWF levels and observe how sustained that increase is to predict the patient’s response to desmopressin after future procedures. There is a subset of patients with type 1 VWD who have increased clearance of VWF that causes their decreased VWF levels. They may not have a sustained plateau in the VWF level after desmopressin, which emphasizes why testing as far as 4 hours after desmopressin administration is important. The dose of desmopressin given in this test is typically 0.3-0.4 mcg/kg. Recommendations for preprocedure prophylaxis for type 1 VWD Minor procedures (e.g., wisdom tooth extraction) The patient should receive an antifibrinolytic agent, such as tranexamic acid or aminocaproic acid, 2 hours before the procedure, followed by desmopressin 30-60 minutes prior to the procedure. After the procedure, the patient should continue to receive the antifibrinolytic agent for 3-4 days. Major procedures/surgeries (e.g., gallbladder removal) The guidelines do not recommend desmopressin for major procedures because patients need to be fluid-restricted for approximately 24 hours after administration because of the risk of hyponatremia. Desmopressin is a synthetic analog of vasopressin, which results in the accumulation of free water similarly to vasopressin. The guidelines do recommend giving VWF-containing concentrate to increase VWF and factor VIII to greater than 50% from baseline for at least 3 days. VWF concentrates can be given every 12 hours or as continuous intravenous infusions. Tranexamic acid should be given as an adjuvant both prior to the procedure and in the days following. Cryoprecipitate is not recommended because it can’t be virally inactivated.  Preprocedure prophylaxis in type 2 or 3 VWD Desmopressin does not work for most patients with type 2 or 3 VWD. So even for minor procedures, these patients will need to receive VWF concentrate coupled with antifibrinolytics. Show notes written by Sheila DeYoung, DO, a resident at Pennsylvania Hospital, Philadelphia. Disclosures Dr. Henry has no relevant disclosures. Dr. James disclosed relationships with Baxter/Baxalta/Shire, CSL Behring, Bayer, and Octapharma. *  *  * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd

  Bleeding Disorders, also known as Hemophilia, von Willebrand Disease, Coagulation Disorders, Blood Clotting Disorders, Clotting Factor Deficiencies ​Bleeding disorders are rare disorders affecting the way the body controls blood clotting. If your blood does not clot normally, you may experience problems with bleeding too much after an injury or surgery. This health topic will focus on bleeding disorders that are caused by problems with clotting factors, including hemophilia and von Willebrand disease. Clotting factors, also called coagulation factors, are proteins in the blood that work with small cells, called platelets, to form blood clots. Any problem that affects the function or number of clotting factors or platelets can lead to a bleeding disorder. A bleeding disorder can be inherited, meaning that you are born with the disorder, or it can be acquired, meaning it develops during your life. Signs and symptoms can include easy bruising, heavy menstrual periods, and nosebleeds that happen often. Your doctor will review your symptoms, risk factors, medical history, and blood test results to diagnose a bleeding disorder. Your doctor may recommend medicines or clotting factor replacement therapy to treat the bleeding disorder. Some bleeding disorders are lifelong conditions, and some can lead to complications. Even if you do not need medicine to treat the bleeding disorder, your doctor may recommend taking precautions before a medical procedure or during a pregnancy to prevent bleeding problems in the future. (credits to NIH)   TRANSCRIPT Lita T  00:07  Hello and welcome to another episode of PodcastDX. The show that brings you interviews with people just like you whose lives were forever changed by a medical diagnosis. I'm Lita. Ron  00:18  I'm Ron Jean  00:19  and I'm moving to Hawaii. Lita T  00:21 No, she's not Jean  00:22   it snowed again last night. Lita T  00:23  I know but Ron  00:24  and today Jean  00:25  and today Lita T  00:26  still not moving to Hawaii. Jean  00:27  ohhh moving to Hawaii Lita T  00:28  Remember when you said you cannot shovel lava? Jean  00:30  Lava  Lita T  00:31  Okay, Jean  00:31  this is true. Lita T  00:32  We're staying here. Jean  00:33  Okay. Lita T  00:33  Collectively we're the host of podcast dx. March is bleeding disorders Awareness Month, although bleeding disorders may be acquired. On today's show, we're going to be talking about the most common inherited bleeding disorder, von Willebrand disease, Jean  00:53  someone with (unitelligable) the blah...blah Lita T  00:55  What? Jean  00:56   Someone living with a bleeding disorder has blood, which does not clot properly. Ron  01:02  When someone is injured and bleeding, a blood clot forms to hopefully...to hopefully stop that person from losing too much blood. This process requires both blood platelets and clotting factors which clump together to form something like a dam to stop the bleeding. Lita T  01:20  Right?  I remember watching Grey's Anatomy. Ron  01:22  (Chuckle) Lita T  01:23  Okay, we need more platelets, right? Jean  01:26  I don't watch Grey's Anatomy...but sure I could see them saying that. Lita T  01:28  Yeah, cuz you know, somebody is bleeding. They need more platelets! Jean  01:31  Right Ron  01:31  That's not scripted. Lita T  01:33  No, it's not. Jean  01:33  No. Lita T  01:35  Someone with a bleeding disorder may notice that they bruise easily bleed; excessively during medical or dental procedures or when cut; have unexplained nosebleeds and bleeding gums and internal bleeding. And when I was on blood thinners...no Jean  01:54  Here we go... Lita T  01:54  Right? Wait was I am blood thinners or aspirin? I was either on blood thinners or a baby aspirin at one time. And I was outside gardening. And I grabbed a thorn bush.  Right? I was clipping and the thorn punctured something on my wrist. And I'm watching it and it's going: squirt, squirt, squirt, and I'm just watching it. I like Isn't that interesting? As it squirting like a squirt gun every you know it would like with my pulse. Squirt, squirt, squirt. And then finally I said: "Okay, better stop this." So, I put pressure on it to stop it. But um, yeah. Jean  02:24  We're all surprised she's still here. (Chuckle) Lita T  02:36  (Boisturious laughter) Ron  02:36  But you definitely painted a picture. Lita T  02:38  Yeah. Right. So that's what it would be like, if you have a bleeding disorder. Jean  02:41  I don't know if that's exactly what it would be like, that sounds like an arterial spray that squirting in very, very dangerous. Lita T  02:47  Okay, that's a bleeding disorder. Jean  02:49  Bleeding problem. Ron  02:50  So Lita T  02:51  yeah. Ron  02:52  In addition to obtaining a complete medical history, your healthcare provider may order a complete blood count, a bleeding time test and or a platelet aggregation test to help diagnose your condition. Jean  03:07  And have you guys ever had a bleeding time test? Ron  03:10  Me personally? No. Jean  03:11  Oh, they like cut your, nick, your ear and then stand there and wait to see when it stops bleeding. Lita T  03:18  (chuckling) Jean  03:19  That's what I remember. Lita T  03:19  like watching. paint dry? Ron  03:20  I don't like your doctor's. Jean  03:21  Yeah, well, that wasn't my doctor. That was my mom. Oh, no, just kidding. Okay. Um, treatment for bleeding disorders will likely depend on the severity and cause of the specific bleeding disorder an individual has. Lita T  03:33  Right. And although I had never heard of it before, today, the most commonly inherited bleeding disorder is von Willebrand disease. Ron  03:45  Well I can say that approximately 1% of the population here in the US are affected by von Villa brain disease. And it's characterized by an insufficient amount of a protein. Ironically, the von Willebrand factor or VFW Jean  04:03  VWF Lita T  04:04  The VFW hopefully doesn't. It's causing you to bleed you're going to the wrong  VWF Ron  04:11  Did I say I do glasses. I'm sorry, the von Willebrand factor or v w F, which aids in the clotting, Lita T  04:18  right? There are three forms of von Willebrand disease. Jean  04:24  We're gonna say it differently every time you say Lita T  04:26  Yes, okay. Individuals with type one have less VWF than average and may have associated bleeding issues. Jean  04:37  Were and those living with type two von Willebrand disease have enough v wF in their system, but their Vidya wF does not function correctly or is incorrectly formed. And Ron  04:49  type three, v w.f Jean  04:52  Vwd  willen brand disease Oh, tight as opposed to von Willebrand factor. Oh, Okay, Lita T  05:00  okay. So type three v WD. Ron  05:03  Okay? So type three v WD is very serious individuals with this form of von Willebrand disease, do not make v w f at all. Oh, yeah, right. And their platelets cannot clot and this is very This is a very serious condition which makes bleeding difficult to control. Lita T  05:23  That sounds terrible. Individuals with von Willebrand disease should typically avoid taking medications which may increase their risk of bleeding such as aspirin, or non steroidal anti inflammatories. Jean  05:37  And if you have a bleeding disorder, it is vital that you inform your health care providers, including your doctors and dentists. And I would suggest if you know if it's a very serious form, that you have an ID bracelet that states that Lita T  05:50  Oh, yeah, for sure. And carry a lot of gauze. Jean  05:54  I don't get a tourniquet. I don't think you should be able to carry a tourniquet, no band aids. I think people that carry Okay, tourniquets are very serious, Lita T  06:02  right. Okay. If you would like to know more about bleeding disorder awareness, check out the link to the national hemophilia foundation Foundation's website which will be on our web page, or you may want to donate to a red tie fundraiser. Jean  06:21  And I think Haemophilia is what we've all associated with writing disorders. That's what I've heard, right? But it's very, very rare. It just gets a lot of publicity, because you hear about, you know, like Royals hat being haemophiliac and or being haemophiliacs because, Lita T  06:34  you know, that's, that's where it came from. Jean  06:37  No, it's just inbreeding, and the those, you know, because then you're passing the factor on and you're increasing the chance, or likelihood that two people with the same factor will pass it on. But Ron  06:47  that's the most common, right. No, Jean  06:49  no, no, it's not. It's very rare. von Willebrand disease is the most common. Isn't that weird? And we've never heard of that. Yeah, right. That's Yeah, it's very counterintuitive. It is very counterintuitive. But that's what the internet says, and we believe everything on the internet. Lita T  07:07  And gene would like you to know about a blood parfait recipe in case you wanted to share this with your friends. Jean  07:17  Well, the National hemophilia foundation does try to utilize different techniques to help people understand more about their blood and clotting. And to help illustrate that, they suggest that you could try to make a blood purvey, you could use a cream colored substance like vanilla ice cream, or maybe a yogurt as your base use Cheerios. And that will represent your platelets, although they're nice and round, which I don't understand. And you kind of want something like awkwardly shaped but red m&ms or red Hots, and those could be the red blood cells, white chocolate chips, or mini marshmallows. And these can be the white blood cells, pretzels. And these can be the fibrin which is the kind of the stuff that joins with platelets to form that your clot, okay. Gummy worms in the eye can actually represent the V WD. And to top it off, put on some rainbow sprinkles, and that'll represent the 13 other blood factors. Lita T  08:14  Yeah, we'll be doing that. Ron  08:18  I gotta tell you, I learned quite a bit on this. This morning.  Lita  08:21  Oh well, that's Jean  08:22  that's good. Lita T  08:23  Yeah, I'm glad somebody did. Yeah, I Jean  08:24  learned we're not moving to Hawaii. Lita T  08:26  No, we're not moving to Hawaii. Ron  08:28  Well, for our listeners, if you have any questions or comments related to today's show, you can drop us a line at podcast dx@yahoo.com through our website, podcast, dx comm on Facebook pitter pitter pitter patter pitter patter on Jean  08:47  his own app. Wow. Have you heard from somebody on Twitter? I hear they have a lot of patter. Ron  08:54  Let's try this again. Okay, through our website, podcast, dx.com on Facebook, Twitter, Pinterest, or Instagram, Jean  09:02  I can appear as a combination of Twitter and Pinterest. I like it. Lita T  09:05  Yeah. Okay. And if you have a moment to spare, please give us a review wherever you get your podcast. As always, please keep in mind that this podcast is not intended to be a substitute for professional medical advice, diagnosis or treatment. Always seek the advice of a physician or other qualified health care provider with any questions you may have regarding a medical condition or treatment and before undertaking a new health care regime. Never disregard professional medical advice or delay of seeking it because of something you have heard on this podcast till next week.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.07.356311v1?rss=1 Authors: Shen, S., Wang, Y., Xia, R., Zeng, F., Cao, J., Liu, X., Zhang, Y., Wang, Z., Tao, T. Abstract: The cell type-specific molecular pathology of post-stroke cognitive impairment (PSCI) in the hippocampus has not been thoroughly elucidated. We analyzed 27,069 cells by using single-cell RNA sequencing, and four oligodendrocyte precursor cell (OPC) subtypes were identified, Vcan+ OPCs, which were determined to be the primary cluster among them. Additionally, we examined the features of endothelial cells (ECs) and found that Lcn2+ ECs might play neuroprotective roles via Vwf after stroke. These results may facilitate further studies attempting to identify new avenues of research and novel targets for PSCI treatment. Copy rights belong to original authors. Visit the link for more info

On today's episode we discuss: —Epidemiology: Public health experts affiliated with Indiana University estimated the infection fatality ratios (IFR) of SARS-CoV2 based on antibody tests in a random sample of residents aged 12+ in Indiana. The average age of decedents was 76.9 (SD 13.1). 1099 COVID-19 deaths were recorded and the average IFR was 0.26%, but stratified IFR varied by age: >60yo IFR 1.71%,

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

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.09.196220v1?rss=1 Authors: Gogate, N., Lyman, D., Crandall, K. A., Kahsay, R., Natale, D. A., Sen, S., Mazumder, R. Abstract: Scientists, medical researchers, and health care workers have mobilized worldwide in response to the outbreak of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; SCoV2). Preliminary data have captured a wide range of host responses, symptoms, and lingering problems post-recovery within the human population. These variable clinical manifestations suggest differences in influential factors, such as innate and adaptive host immunity, existing or underlying health conditions, co-morbidities, genetics, and other factors. As COVID-19-related data continue to accumulate from disparate groups, the heterogeneous nature of these datasets poses challenges for efficient extrapolation of meaningful observations, hindering translation of information into clinical applications. Attempts to utilize, analyze, or combine biomarker datasets from multiple sources have shown to be inefficient and complicated, without a unifying resource. As such, there is an urgent need within the research community for the rapid development of an integrated and harmonized COVID-19 Biomarker Knowledgebase. By leveraging data collection and integration methods, backed by a robust data model developed to capture cancer biomarker data we have rapidly crowdsourced the collection and harmonization of COVID-19 biomarkers. Our resource currently has 138 unique biomarkers. We found multiple instances of the same biomarker substance being suggested as multiple biomarker types during our extensive cross-validation and manual curation. As a result, our Knowledgebase currently has 265 biomarker type combinations. Every biomarker entry is made comprehensive by bringing in together ancillary data from multiple sources such as biomarker accessions (canonical UniProtKB accession, PubChem Compound ID, Cell Ontology ID, Protein Ontology ID, NCI Thesaurus Code, and Disease Ontology ID), BEST biomarker category, and specimen type (Uberon Anatomy Ontology) unified with ontology standards. Our preliminary observations show distinct trends in the collated biomarkers. Most biomarkers are related to the immune system (SAA, TNF-, and IP-10) or coagulopathies (D-dimer, antithrombin, and VWF) and a few have already been established as cancer biomarkers (ACE2, IL-6, IL-4, and IL-2). These trends align with the proposed hypotheses of clinical manifestations compounding the complexity of COVID-19 pathobiology. We explore these trends as we put forth a COVID-19 biomarker resource that will help researchers and diagnosticians alike. All biomarker data are freely available from https://data.oncomx.org/covid19. Copy rights belong to original authors. Visit the link for more info

  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.  

Clinical Presentation Incidental finding on routing CBC Petechiae/purpura Mucosal bleeding Epistaxis Gingival bleeding Hematuria Vaginal bleeding 5 Major Causes of Thrombocytopenia Thrombotic Thrombocytopenic Purpura (TTP) Clinical presentation (pentad) Thrombocytopenia Fever Microangiopathic hemolytic anemia “schistocytes” Neurologic abnormalities Renal dysfunction Physiology Low ADAMTS13 results in impaired vWF breakdown Widespread “platelet plugs” Treatment Plasma exchange Hemolytic Uremic Syndrome […]

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 […]

★★ • Réalisé par Nicolas Benamou, Philippe Lacheau, Avec Christian Clavier, Alice David, Tarek Boudali, Vincent Desagnat, Julien Arruti, Charlotte Gabris, Élodie Fontan, Joséphine Drai, Jérôme Commandeur • Franck, Sonia, Sam, Ernest, Alex et Estelle s’envolent pour le Brésil. Ils se rendent en vacances à l’hôtel d’Alain, le père de Sonia. Franck va profiter de ce voyage entre amis pour la demander en mariage. A l’hôtel, ils sont accueillis par Alain et Yolande, la grand-mère acariâtre de Sonia. Les garçons organisent une excursion dans la jungle avec un guide chevronné. Alain leur confie Yolande de peur qu’elle ne trouble le processus de remise du « label éco VWF ». Le soir, les garçons ne sont pas revenus. Ils ont disparu avec la grand-mère et le guide. Le lendemain matin, la caméra GoPro avec laquelle ils étaient partis est retrouvée…

Join host Flint Engleman for a special show to honor our military veterans!  Tune into WCHV Sunday at 8PM Eastern or listen online. Featured Guests: Bob Hull of the Vietnam War Foundation.  Mr. Hull returns to the show to talk about the Vietnam War Foundation.  We'll also talk about the VWF's Memorial Weekend Open House with new exhibits and re-enactors.  http://www.vietnamwarfoundation.org/ Susan Wilkinson of the "For the Wounded 5K".  We'll talk with Susan about the great work of the UVA Foundation to sponsor the annual road race.  All to benefit the Wounded Warriors Project.  She'll provide details about how to register as a runner or how to make a contribution.  For more info, http://www.4thewounded5k.com/  Connect with The American Maverick!  Check out our acclaimed blog www.TheAmericanMaverick.com and follow us on Twitter @AmericanMav. The American Maverick Show is a production of Maverick Media.  We are a proud national affiliate of Red State Talk Radio Network.  Our show originates from the studios of News Talk 107.5 FM WCHV in Charlottesville, Virginia.

The end of January means many things, but in the whisky world, it means a trip to the Victoria Whisky Festival in British Columbia. The VWF is one of the world's best whisky festivals, and this week's episode features some of the highlights from this weekend's event. We'll get the latest on new whiskies from Cooley, Glenfarclas, Glenmorangie, and many more distillers, along with the results of the Canadian Whisky Awards and the newest chapter of the Scotch Malt Whisky Society.

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

Atheromatöse Plaques sind vulnerabel, und deren Ruptur kann die Bildung gefäßverschließender plättchen- und fibrinreicher Thromben induzieren, welche akute Myokardinfarkte und ischämische Schlaganfälle verursachen können. Bisher geht man davon aus, dass der Plaque-„tissue factor“ als Aktivator der extrinsischen Blutgerinnung und Stimulator der Thrombin-vermittelten Plättchenaktivierung und Aggregation die bedeutendste prothrombogene Substanz atheromatöser Läsionen darstellt. Zu Beginn dieser Arbeit war nicht geklärt, ob und wie das lipidreiche atherosklerotische Plaquematerial auch direkt mit den Thrombozyten im Blut interagieren und auf diese Weise die Bildung eines gefäßverschließenden Plättchenthrombus induzieren kann. Die atheromatösen Läsionen von mehr als 60 verschiedenen Patienten mit Karotisstenose wurden mittels Endarterektomie isoliert und Kollagen Typ I- und Kollagen Typ III-positive, morphologisch äußerst heterogene Strukturen in den Plaques identifiziert, welche direkt die Adhäsion, Sekretion und Aggregation von Plättchen in Puffer, Plasma und Blut stimulierten. Darüber hinaus lösten die Plaques auch die Bildung von Thrombozyten-Monozyten-Aggregaten sowie eine plättchenbeschleunigte Fibrinbildung und Gerinnung aus. Unter arteriellen Flussbedingungen induzierten die kollagenpositiven Komponenten des Plaquematerials die Adhäsion, das Ausbreiten und die Aggregatbildung der Thrombozyten. Die Plaque-stimulierte Plättchenaggregatbildung erfolgte sehr rasch (< 5 min) und wurde in Hirudin-antikoaguliertem Blut beobachtet, was darauf schließen lässt, dass diese direkt und unabhängig von der Plaque-„tissue factor“-vermittelten Koagulation erfolgte und sehr wahrscheinlich für die initiale und schnelle Thrombusbildung nach einer Plaqueruptur in vivo von Bedeutung ist. Sowohl die Ergebnisse mit humanen, als auch mit murinen Blutplättchen wiesen auf eine essentielle Rolle morphologisch diverser Kollagen Typ I- und Kollagen Typ III-positiver Plaquestrukturen und des thrombozytären Kollagenrezeptors GPVI bei der durch atheromatöse Läsionen stimulierten Plättchenformveränderung, Adhäsion, Ausbreitung, Sekretion und Aggregation im statischen System und unter arteriellen Flussbedingungen hin. Der zweite bedeutende thrombozytäre Kollagenrezeptor, das Integrin α2β1, schien hingegen nicht an der durch die atheromatösen Läsionen hervorgerufenen Plättchenadhäsion und Aggregation im statischen System und unter Fluss beteiligt zu sein. Diese Beobachtungen führten zur Annahme, dass die Verabreichung von z. B. spezifischen anti-GPVI-Antikörpern oder löslichem GPVI-Protein, welche die Interaktion des thrombozytären GPVI-Rezeptors mit dessen Liganden im Plaquegewebe (Kollagen Typ I/Typ III) inhibieren, viel versprechende neue und effektive antithrombotische Strategien zur frühen Prävention kardio- und cerebrovaskulärer Gefäßverschlüsse darstellen könnten. Der thrombozytäre VWF-Rezeptor GPIbα war weder im gerührten System, noch unter Fluss mit niedrigeren Scherraten von 500 s-1 von Bedeutung für die durch atheromatöse Plaques induzierte Plättchenaggregation im Blut. Unter arteriellen Flussbedingungen mit höheren Scherraten von 1500 s-1 allerdings resultierte die Blockade von GPIbα in einer starken Reduktion (77±5%) der Plaque-stimulierten Thrombozytenadhäsion und Aggregatbildung. Dies lässt darauf schließen, dass unter diesen Strömungebedingungen auch die Interaktion des VWF mit dem Plättchen-GPIbα-Rezeptor eine wichtige Rolle für die Thrombusbildung nach Plaqueruptur spielt. Sowohl die ADP-Rezeptor-Antagonisten MRS2179 (P2Y1-Antagonist) und AR-C69931MX (P2Y12-Antagonist), als auch Aspirin® konnten die Plaque-vermittelte Thrombozytenaggregation in gerührtem PRP und Blut signifikant verringern, wobei die Kombination aller drei Plättchenhemmer am effektivsten wirkte und die Plaque-induzierte Aggregation vollständig inhibierte. Unter arteriellem Fluss (Scherraten: 1500 s-1) wirkten MRS1279, AR-C69931MX sowie deren Kombination allerdings deutlich weniger effizient als im statischen System und reduzierten die Plaque-stimulierte Plättchenaggregatbildung nur um 35±14%, 32±13% und 58±12%. Überraschender Weise führte die Zugabe von Aspirin® unter Fluss zu keiner signifikanten Reduktion der Plaque-induzierten Thrombozytenaggregatbildung. Diese Ergebnisse lassen vermuten, dass ADP-Rezeptor-Antagonisten sowie Aspirin® die Bildung eines gefäßverschließenden Thrombus nach Plaqueruptur eher ineffizient hemmen dürften. Die atheromatösen Plaquehomogenate verschiedener Patienten wiesen unterschiedliche thrombozytenaktivierende Eigenschaften auf, welche weder auf deren variierenden Gehalt an löslichem Kollagen, noch auf die unterschiedliche Morphologie der Kollagen Typ I- und Kollagen Typ III-positiven Plaquekomponenten zurückgeführt werden konnte. Weiterhin verhielt sich sowohl fibrilläres als auch lösliches Kollagen Typ I und Kollagen Typ III anders als das Plaquematerial bezüglich der Plättchenaggregation im PRP. Die Bindung des thrombozytären GPVI-Rezeptors an das Plaquematerial stellte die Voraussetzung für die Plättchenaktivierung der Plaques dar, wobei jedoch keine eindeutige positive Korrelation zwischen der GPVI-Bindung und der Aktivität der atheromatösen Läsionen verschiedener Patienten hergestellt werden konnte. Der Grund für die unterschiedliche Thrombozytenaktivierung induziert durch das Plaquematerial verschiedener Patienten bleibt letztlich also unklar. Die weitere Erforschung möglicher Ursachen für die unterschiedlichen plättchenaktivierenden Eigenschaften der lipidreichen atheromatösen Läsionen verschiedener Patienten stellt eine interessante und vor allem klinisch relevante zukünftige Fragestellung dar.

It is unclear how angiogenesis and restoration of perfusion determine graft function after free parathyroid autotransplantation.We provide a new animal model allowing simultaneous and repetitive in vivo assessment of angiogenesis and endocrine function of parathyroid transplants. Methods:Fresh human parathyroid tissue from patients with secondary hyperparathyroidism was grafted into dorsal skinfold chamber preparations of athymic nude mi(CD1-nu BR; n=8). Equivalent pieces of the same human donor specimens were heat-inactivated and served as control grafts (n=7).Results:In all animals receiving parathyroid transplants human parathyroid hormone levels were detectable by species-specific ELISA analysis of plasma samples on day 5 after transplantationand increased by 2.5 fold over the observation (19 days) in contrst to controls (day 19: 82.5+/-29.3 vs. 0.0+/-0.0 pg/ml; p

Trotz des kleinen Läsionsvolumens lakunärer Schlaganfälle ist die Progression neurologischer Defizite bei diesem durch Mikroangiopathie verursachten Schlaganfall-Subtyp ein häufiges Problem in der klinischen Praxis. Ziel dieser prospektiven klinischen Studie war, die Häufigkeit, den zeitlichen Verlauf, mögliche zugrunde liegende Pathomechanismen sowie die Prognose der klinisch-neurologischen Verschlechterung bei lakunären Schlaganfällen zu untersuchen. Es wurden 46 Patienten mit akutem lakunärem Syndrom innerhalb von 12 Stunden nach Beginn der Schlaganfallsymptome in die Studie eingeschlossen. Die Beurteilung des Schweregrads der neurologischen Ausfälle erfolgte anhand der National Institutes of Health Stroke Skala (NIHSS) täglich an den ersten drei Tagen nach Beginn der Symptomatik sowie bei Entlassung. Für die Evaluation der Prognose wurde der Barthel Index bei Entlassung und telefonisch nach 90 Tagen erhoben. Die Progression der neurologischen Symptomatik wurde als Verschlechterung um ≥ 1 Punkt im NIHSS im Bereich der motorischen Funktionen definiert. Die Patienten mit progredienten und nicht-progredienten lakunären Schlaganfällen wurden hinsichtlich demographischer Daten, Vorerkrankungen, Vormedikation, der Häufigkeit der lakunären Syndrome, der Lokalisation der lakunären Läsionen, des zeitlichen Verlaufs der klinischen Progression, des NIHSS und Barthel Index sowie hinsichtlich Entzündungsparametern (Leukozyten, Körpertemperatur, C-reaktives Protein, Fibrinogen), Gerinnungsparametern (D-Dimer, von Willebrand Faktor, PTT), der Glutamatplasmakonzentration, des Blutzuckers und Blutdrucks miteinander verglichen. Diese prospektive klinische Studie zeigte, dass ungefähr ein Viertel (23,9%) der Patienten mit lakunärem Schlaganfall eine frühe klinische Verschlechterung innerhalb der ersten 72 Stunden, 81,8% davon sogar innerhalb der ersten 24 Stunden nach Beginn der Symptomatik erfahren. Bei Aufnahme bestand kein signifikanter Unterschied im Schweregrad der neurologischen Ausfälle –quantitativ erfasst durch den NIHSS- zwischen den Patienten mit progredientem und nicht-progredientem Verlauf. 24 Stunden nach Beginn des Schlaganfalls bis hin zur Entlassung war der NIHSS-Score bei den Patienten mit progredienten lakunären Schlaganfällen signifikant höher als bei den Patienten mit stabilem Verlauf. Die Patienten mit progredientem Verlauf hatten eine deutlich schlechtere Langzeitprognose als die Patienten, die sich in der Frühphase stabilisierten oder sogar verbesserten. Lakunäre Schlaganfälle mit progredientem Verlauf waren signifikant häufiger im Bereich der Capsula interna lokalisiert. Die frühe Progression war signifikant mit einer höheren Leukozytenzahl, einer höheren Körpertemperatur und einer höheren Fibrinogenplasmakonzentration bei Aufnahme assoziiert. Diese Ergebnisse sprechen für eine Rolle der Akuten-Phase-Reaktion bei der Progression des lakunären Schlaganfalls. Die Parameter der Akuten-Phase-Reaktion, die reaktiv auf die cerebrale Ischämie erhöht sind, können über komplexe Pathomechanismen den ischämischen Schaden verstärken und somit zur klinischen Progression führen. Die Ergebnisse lassen die Leukozytenzahl, die Körpertemperatur und die Fibrinogenplasmakonzentration bei Aufnahme als Prädiktoren für eine frühe klinische Verschlechterung beim lakunären Schlaganfall vermuten. Für den Blutzucker fanden sich erst am Tag 3 nach Beginn des Schlaganfalls signifikant höhere Werte bei den Patienten mit progredientem Verlauf im Vergleich zu den Patienten mit nicht-progredienten lakunären Schlaganfällen, so dass dies eher als Folge der klinischen Verschlechterung zu interpretieren ist. Bezüglich der demographischen Faktoren, der Häufigkeit der lakunären Syndrome, der Gerinnungsparameter (D-Dimer, vWF, PTT), der Glutamatplasmakonzentration und des Blutdrucks wurden keine signifikanten Unterschiede zwischen Patienten mit progredienten und nicht-progredienten lakunären Schlaganfällen gefunden. Die Aussagekraft dieser Analyse ist durch die kleine Fallzahl mit 46 Patienten eingeschränkt. Weiterführende statistische Berechnungen des positiv prädiktiven Werts der signifikanten Faktoren, insbesondere eine Regressionsanalyse konnten daher nicht durchgeführt werden. Die Ergebnisse sind somit zur Hypothesengenerierung geeignet, um weitere klinische Studien mit größeren Patientenzahlen anzustoßen, die die Rolle der Akuten-Phase-Reaktion bei der Progression des lakunären Schlaganfalls bestätigen und zur Entwicklung therapeutischer, z.B. antiinflammatorischer Strategien zur Verhinderung der frühen Progression beim lakunären Schlaganfall beitragen sollen.