Introduction to Hemostasis Webinar

Welcome Ladies and champion to the lecture et d'action to host a ses i will be your press enter in my name is dr Andreas Rechner. English lecture, Julia the following learning Objektivs. First you will learn about the different stages of calculation, then we will look into the clinical conditions and indications rich lite hämostase assessment and final i you will learn about d most commonly ordert assets in hämostase is testing. Who has me start? Would definition be what is emphasis? What is Word comes from the War of Hemo Sannikov Blood and thesis for the Station? So the has me in the house thesis is the Ation of Bleeding and in the LO open or to Kurt Koagulation Because The Blood kouakou Lights F Dead Process Cookie in Andre Finition is hemostase this is the meccanismo. When shoes net blood in the Integ circulatory system remains fluid. Wat cooles spontaneous Lee in response to injury injuries the Key Word what triggers hemostasis symbol? And consists of three stages of the Prime Hermes Phases, the NGO Curse, Antihaft, Blazor, thrombo side Switch over the key players in the process double bed here @the site of injury. Ein will Form ekat und formal First Claude Witt, Seals to Bund. If so, the Second Degré Hemostasis is in Bols is the calculation Factors and Formation of Fibra in Wichita. Sry der Menschen und merschwitz Holz, Stäbe, leases the Cloth initially forms by the Playlist. He calls VF the Cross Linking of the File Remix even more stable and in and after. The club is never Danny More Because lives is, held Sandy will Hefter Process of Hype Release Riester Dissolution of the Clot. Known process of in vivo Hermes is relatively complex Battery to guide you through what happens in the beginning stapled injury, which is risk Rector, since the duck silie longer in Side ressel is removed and the the blood, including itself is comes into contact with sub in many tissue, which is correct reist du first contain collagen Barroso tissue factor, which is an. An Important pro Team with Viruses counter later, but first the main part is about the college because the collision is aber tobi and large molecule in the circulation call by Bille Brown Factor Annette von Willy Brandt Factor knows beant ander.eu countries high school condition as fast Blood Flow to the Colin and will an Role and Can Dan recruit and Beat The Blood Lipids and Latex got activities Dr Come into contact with collision again so. The song of the Process of blood Activation and Aggregation. So, and this will not deactivate here with Shape Change and then they der the blacklist stato plot together using other fibrinogen or von Willy Brandt Faktor, so der d Form Frieder Menschen, El Clot mit can close or cover the injury. Forsed, porn, activation, which even GP Tobias A receptor and Surface of the Blitz got it activity can be and while being activated. This 2 Central proteins. And. Can you plot? Closing habited and you see here key players the receptor at, connected with this Erik Monika and the Basis for the Five Prime Head of sowas Vreni ging, got Srebrenica at the point and the firing comes into the crowd because of the blitz. Anti crooked Annelie. Willi Claus Die erste Zeit. And der der Claudis formt and Stable Release stand or Second Century Hammers Daisy. Games, goal built Now this Simply Fight go DF 2 part ways leading to the activation of the Central to Seim in Secondary Hermes of this joke rhomben. Who on the extrinsic Part 3 Andi Hefti Intrinsic Part Way. Bose LED Warrior different cooperation between Sony goalkeeper in in the Coming slides Grad intensive lie Bost lie to the Formation of Thrombin their ex in victory party is scratchy ice by using this in front of people and table fakter because the intensive masri is Start with Surface after fishing surface and factor twelve. Groß L Thrombin and Rhomben is also formal clothing. Triggers Formation of Farben from Fibrin Annette Gips, really stay Clothing Fail principle as with stack The plot initially forms at Blitz. That's the process. I have us After the Fight only quietly be Cold Blood Manager behind sheet, Dat is activated both sent Gold plus Manager activator leading to plasmen in plasmas will result to fail brennt frei, bells and leading to five releases and so cold prey, bring decoration products and most famous manu will come to dat japaner miete. This presentation is the Deimer will this decoration product of fibrin? And of course all wishes to be balance 2 der sehr wohl an sein Auto like komplex Switch can stop the process because it starts and. The reason is the good Seals Danny test stops or a Counter Mechanisms and Enzymes Like Voice Traffic Light Antithrombin by Kenan Bein, Thrombin and Not only that was the protein CEA importing Espace re or the tissue factor party. Please I will not say a block care regarding part w. So the table. Magnesium Switch because song Turtur stop of the Calculation? How does the YES Simplified look here, here is a new cartoon, which they all the pen and ensheim they want them like you of Numbers I thrombin in the middle of all and here Correlation factor will be yes great Clean Lambert belongs at all factor Twelve, which is our factor tender is the factor eleven, the factor no factor. 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And that's so gentleman contained that works or discovery on the in Inside of the Brussels Istanbuls working properly you have hyper cock ability that can happen if something is not in balance? Im Oldies an Times or you have state of blood flow that means? For example, one might of ordoff the economy class syndrome and peoples it too long. Cross Legs The Blood will Not Flow, acid should be und das is called Venus states and that can cause as rom bes. Because Heiko Ability ken FSS reasons for the Smart Bialik, Nancy Sepsis or Thrombo Filia is this Certain acquired or nowz inherited and Information then you have the omitte dis function net can Cam no picture youtube stromae sorry mini pancho? Boah, Sklerose Swiss made most popular and well known cause of exile is function and the main reason why people get a hug and venus.de cette meintest du bist a reputation nagisa qualcomm and condition and the elderly. Rhinos abstraction yes, youtube tumor obesity and the economy class syndrome is immobility will know also lead to chose from bes because Hermes is the balance balancing Act you have on the one hand. Thrombosis is the formation of the Plot. Jutta Handy, helf prices the dissolution of the cloth f. European stock exchanges healthy that stu process is a in balance. I write Annelies is. Ober acting weil or from both is our acting because patients having this problem will help leading risk while befinden seri round or the thrombosis Sparks over acting. Unfolded in Hit for Recent bis Punktes on robotics risk. Will Robert Berlins and the most known conditions for playing? Famous but not that common is hemophilia a or BWSA is the selec of factor eight and b, is the tasty factor no. Marble come from Wille Brand they audibly from the puppy factor. How much does only Dina von Willy Brandt have factor? He doesn't have a motorcade bleeding to Edith, who comes from Willy Brandt Factor Taiwan with Juste reduction to the on the evening of Hildebrand Factor in The Blood bist and Most Common Bleeding Disorders. When percent of the General population en hewing lose normau Vorbild ground levels and of course, Perry o, poster Tree, Bleeding can also Happen Baris wiesen, so this Main reasons why people. Hang up and in critics of the Peri and Post Server Reading Something Why in The Hospital is on when is electrophoresis, Drie, Wei correlation or Ms Daisy System is @least enemy testet to know if patient as the Problem? Thuringia the operation welch mei Knopfi, no Niad denn Herr Thrombosis, Herr The Venus von Pampel Muse um. This is very most 2 Most Common City brain by Bosses. 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What is Embolos and the brain the region of the bridges getting its nutrition and sugar? Both Brussels will be blocked and der and new ones every sensitive to the loss of oxytocin and and energy supply. So he wants, the broad quickly. Networking UC the symptoms of stroke people loose, who have relatively speak or is. Moving problems and many other things. People outside the? The formation is the Hard Egg Hephata Wissler Roses will omitted this problem with Canon at this fertik blocks can rupture and the what is in the blocks a is too active blade so much violent is this western The Round your heart, the Connerys Day and Effiz who David got this plaque rupture and the places Activated and Devil formed Claude unloaded. Cortana Riri so that hard it's the hard marcel kenobi, get cannot get edge boxing and LG game so dat ja net. Where is the hard text or the hard is not working properly anymore, so no Boss conditions? Robotic actions can be kann be lead to death? Is the other Twitter popular smiley. Border common risk factors to develop from bosses. If I see you here. Family history pregnancy is always. Société third party. Navigation on the hometown Existem Josef. Immobility 2 have Tobi in in in the Hospital Long Time lay in the Bad Jav da area is service factor card was codesys. Just as he inflammatory conditions like Verona Seite coping with the soviet inflammatory conditions can lead to thrombosis well nauen symptom in combination patients sartori ja Asset Delon Hospitals Day and postulate castoren based therapies it is known that the pill for women to ss konzeptes can cause high risk of fortran bosses. So what is the price on hemostasis sda Agnostics first is Usses Risk, Ida s amanis, robotik or bleeding risk, especially, priet surgery, then monitoring in summer in Hesse condition matchs Lite, bleeding or thrombosis so hotter higher risk for that people typically treated and dies essayist serve to monitor da treatment is properly working and. Monitoring and allowance people and ideas si das ding is fine one patient. We came to the shepherds before Basic, Calculation Tests, Half Prothrombin Time, the activated partial thromboplastin time I'm, the Rhombi Time and Final i die The Management of om, Fibrinogen concentration CD All the Old Wolf the Main players of Secretary Hermes thesis. First program time changes is graf like Use Early Ja n Thrombin Time will address the Extrinsic Patri or tables facters and the far contain stic factor by thrombi program will end peri grind of NT you can here yes fish, fake, thromboplastin calcium nnr typically @this today Sir. The plasma and June first song Use Citrate Plasma before rabbit testing is the typical Alessandro medium because i use for example, serum that will not work because all the calculation and sam's vinohrady be out because serum is clotted. It's plasma, widgets, Pink Lotte ten ten nsd superlative. The has so Init Site rescues Plasma Ortho Messer Corporation process this now then here, please know Yellow here how fierce process tables. Added to the dude patient, plasma clothing form trees. Here Lance or the True Light Control through anymore is still a bit muddy said before antenna knife set in Testor into a system, so the tickets sampling called Clotting Time. Anni Fanny on this. Factors involved in that? Extrinsic Part we eat sambo and not working properly list Test will pick it up? And to detect platform Auto just. 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Of the programming time you have the so called disseminated intra was cola calculation that this body white correlation process and dat is open, in sepsis and can be ro so fatal and yet large internship office and everybody everywhere clothing is herrlingen body and of course if I am connects him decoration products can also so blocked because the inhibit correlation. Did he come out in the Very High concentration something without Hand of note should be let? Antiquarian is the hot effect on the pity but these strong effect and the EPTT Bedwell address in minute. And uh lupus anticoagulans. This will be tried out some of the Future Lectures. The also so the LPT is mausetot condition. Before the petticoats is Use in the Clinic in ergo back for minute. Before the Screening of K Antonis. Sing the Quality International Normalized Ratio, so now it's completely off like in All Regions and Labs, and that's the family man here. The one year the Ptf Pensiones is the truth beider.pt Offer Pult normal plasma. Because they as i ent stan for international sensitivity Index en dat is typical use for its no no in the C invite them to Round One endings fine folk traffic light for patients receiving weapon urine is ok, which is in therapeutic window with concentrer NANA on bit minen tuot risotto slightly Paula with. This is just Butler before the Management of k antagonist patients. Now I'm waiting for people who are waiting for days. American hardware sets bit Higher and reasons for anticoagulation can be thrombosis hs the pension bosses or a pulmonary harpsichordist mitri talk built early yes. Annette jetzt trade also was one calls it before bavarian. Do you have the Activated partial thromboplastin Time that addresses die? Intrinsic Part Restarting the Surface Contact Anita Quartet Julia Faktor Trave Lite Download goes every or knife in your pocket? Pudding Site Reddit Plasma Yes, Mr. Voßkuhle President Erwin activated June Dead Surface of and This is Supi Isaac Kaolin Micro Nice, Silicon or Electric Acid and Explorer you are Calcium dis will start reaction the clothing reaction, which can be measured? Photo Optical Grandma Canikli. Lenggries Tittys Observe deficiency in factor twelve, so olfactory Wollfactory Eleven factors a factor @ Butlers factor X factor five end of Cross Prothrombin and fibrin roses without HS part factor when? And. Quick mobile phone everyone can do something different. The hemophilia B with this deficiency and factor no and hemophilia a user deficiency in factor et. Ah, the factor time, no crisis the IPT how should know Node in The pts Light your happiness? Pro Long The Act the Dogs here mainly the One Door War direct line heating. Thromben mistrusts Amiga, because of Cross if again behavior connect how big is Need to form the God? Since that's just likes? The Sacred International compilation Pall Faktors A Consumer today also in Impact DAPTT. And lupus anticoagulant. Also at Auto Moody's from the Body Forms Anti Bodies Agent as border river Philippes Annette Kurs. Ursula propagation of the of the clotting time all do it is not the bleeding condition based on butik disorders. Um, an Logical Body? This is the effect in the tests still in vivo and Forty. First of all, the IPT is not sensitive enough the 2 pts to Monitor is. Because what is the name of bomb sharing at Hyundai Rekli Putz, Thromben and Calcium in side rated Plasma Samples again you Magic Magic Club Formation Foto Optik Lyom, Canikli, Densidad. This this process is Vicky confess monitor factor filtin, ugly rest, influence and this this conditions can we knife musicals thrombin time now really something like an mine she is without Something wrong we fight Bridget online? Spotify brings generation. Net. Candy in Christ I want Mr. Japanese Deficiency Solo concentration or diffusion of high bridge in happening because it acts on thromben dabigatran please directly blocks Robin thrombin anti parties like sometimes know beer conditions partition relatively linear going out high concentrations of iron decoration products. An deinen bekannte verbilligen and it's is one of the key and times in the calculation process 2 will shortly talk about it fabriieren ez glei kaputt in der circular the blood in very high concentrations Instagram perlit arranged it. Blood vessels to Stop Excessive bleeding exit cross linked together with the players first but an forming fibrin autofit. Your Vivienne. So you have the gate in the in the audio of the song and the Early as Lights. Now many function will yes the this Cross Linking of the blood the base set for the firing it can leg thrombosis calls bolit Cent matic activiti reset counter mechanism and his regulatory function with this portant. Before the Balance of the Corporation sofsky Protein the Game is bombing in the role process that my changes in Finnish function or concentration is a no. Such a house is your complaint she has Different Ways or Method you on this Gold Klaus reports users from bin activator 2 Marie similar partnerstogether concentration will moreover thrombin Time javder.pt 3 Fiji connects and essays that so Conti mature Chemnitz Immunology always Logical meaning that you have? And Anti Body Rich Test 2 Briten and New Measure the plotting 2 that anti body and gravy matrix review the very old measure because. Something is not used in clinical practice now days. Can you have to come? News will blur this Klaus Klaus Method bobsledder already determination in the functional assay. Concentration is in exchange li proportional to this thrombin time of diluted plasma and reference. Horst ends curvys is why TF like a Standard of British any form calibration Cologne earlier medium use to read out the pageant concentration in your. Paint sample so complains of optics lio Mechanically and Again will Bayer Klopp formation develop them here Like it is discourse inverse karate taut looks Like and the no news of calibration opened u read out the verbingen concentration video plasma traffic light? It's safe. Because the haelfte.pt the series connect Curse. We know this dieroutine.pt measurements. Creation and its derivat for the change in optical density compared to the calibration curve, so geese calibrate can know before wikipedia calibration curve again using that kalibrationskurve read out. The favorites concentration in the plasma of your patient. So what can lead to abnormal? Fabrizio have calculation Disorders Called whistle Pro Jenny Mia so that Homo sei kiffen ist jetzt inherited Jaf High per No, Heiko Pfeiffer, Nadine Mi so first to bles? Cheapen. If the. Adorno spend and Roll designs Edith Fibre Digital Mia the functional factory in Words, own fake bike acquis a Heiko Friebe called Mia and this fucking wants Mia Weekend osoby acquired in Not Continental minus Inherited. So. Functional industries, concentration and Nbv and in pregnancy. Pa. Face Response meaning Information this is your cupro ball in State. I think I got to whatsapp. Lies and cross Link Fibre is built from five religion. And I see this people give handjob or food example, how three dimension and match is forming because Mrs. Panasonic 2 sides kicks. So offers new get acquainted form dis dis inter action zone you here, which is cross linking and forming release complex Fibre Smash Stable Eisinger Claude. Is that because how should fit half is lonely plasmas heard? Listen to slides and Dis placement Mediathek Liebig of Crossing fibrin do you love different molecules and the most common and typical? When is it so cold? D Dimer yes. The lady is my parameter now still the classic. Clothing essay but is maybe the most ja must combi test parameter so folk traffic light touring the pandemic in browser key parameters, combinations measured, qc ft Herr an activacion of clock formation in which in the body so the Damer Issa Issa Berry. Central monika.uk dat in the plot is concentration illidan immunology kli, who helped me into bed cheering. Tchibo die offen enhanced put on a surface of an offer bytow. Bodies, Anti Bodies and then it's the lady Monika and Not one comes off. This you get money or the speed camp Claude because just the Anti Barcelona or articles in Hems ja mashed Better in a photo optimat in the photo meta. Forget. The Half Life of the Deimer is and enormous condition This eight hours. And dat is much longer if ader indicators of last like thrombin activation slick the thrombin antithrombin complex ear forms the prothrombin fragment F One plus 2 witches if prothrombin is converter to active thromben. Now Wire The Kidney's survival Clarence clears up FF kidnapping. This will also be like Opus will be in the levels yes. I will comprise of different, so the then still One Molecule, which are allowed the structures but it can be measured easily with red always logic Test and enjoyed it you? At the norms it comes to the box member Ute Three per Cent of the woman bin hin present is converted into file burn would see in t news li. End ring of the Base Level of the Queen in New York, New Blood. Do you have fickle conditions? Morn, so you can Volkswagen with youtuber Access Cloud Formation. I throw Clothing New Body, which am on Maffei, so fashion creation and displays to higher levels of D dimer I want to know like Match so the lady in the concentration camp of is a in Christ clot formation in your body happening. Conditions would be this, can help is is. How does the battery become yes or many reasons why? I would have buck formation was the Daimler no Bmbh, that was now open, complains full example. It also belongs to interrogation, because Mr. Flotow Klotz am form. This is the condition ready then very high world song is Use taser, so an indicator of dis condition is just happening in the game, so the Dalma, is May. Kee indicator Dead a Passion it. An increase cloud formation in vivo. And is it the second keyboard here? Far clinical applications for tidal, mud Esting throws the she yes, she we infections like ruby with over soul so has except like in crisis the deimer levels goes now heiern acute with cable infection in Kay Seri atherosclerosis greeting light? God am, forms cerebrovascular excellence in Progress of Stroke in Cancer in Paris, Aartal Disease, in Art 11 Ablation, which, so knife that she ok How Strong is there defective Penny is also so. Antiquarian Rated in Aortic Aneurysm hs. Anticoagulation sarapi sometimes and of course if you have an end of thrombus in your body not only in the hardest. By the way, from base or pulmonary embolism to discount Osoby Sign Wursti Deimer and imperial in dat case maybe the key application of die deimer edis use for the exclusion of dies yes also say I want for example, page and come uldu Hospitals essor UVP ein, in the La Kreuz gays. What did Hospital? This is just measures, the Daimler Level tussi IF, who means beer the Brembo this present because it is present the dahmers high but it is not present then the, the Metal is normal can be excluded. This what the Key application of D dimer in Cologne praxis to really to exclude y Hass by Bose Sony the Play Rose Soul Pulmonary Embolism Song. Or Computer take home points of the complex, subject testing. Hermes is built balance can be i go into the direction of thrombosis or bleeding? And decorations tests albert different ones to really given idea first idea what an cyber what player in der complex process might be not der interviewer mount or not functioning as it should be händ dis dis. Correlation of the OSC develop the Top Leading tidying up Poses Can we inheritauto.com Chanel or May be quiet? And final for this @the purpose of die gnostik testing a this is to assess the risk of bleeding einen hermes thesis thrombosis sorry so bleeding verbotes riskassessment dann to Monitor. This is on the phone sorry to monitor whats happening. If Ursula Keffer rapide an spreading of bosses too just and Monitor dat treatment, so der will be no salty facts. Auf der treatment and patients are fine and the company tastes as in the first line the program and I'm deactivated Party Instrument time. 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10:13 11.11.2022 10:14 10:15 10:16 10:17 10:1 10:18 10:19 10:20 10:21 10:22 10 10:23 10:24 11 10:25 12 10:26 10:27 13 10:28 14 10:29 10:30 10:31 10:32 15 10:33 10:34 16 17 10:35 10:3 18 10:36 19 10:37 10:38 20 21 10:39 10:40 22 10:41 23 2-3 2.3-3.5 10:42 24 25 10:43 26 10:44 27 10:45 28 29 10:46 30 10:47 31 10:4 10:48 90 80 70 60 32 33 10:49 34 10:50 35 10:51 36 10:52 10:53 10:54 37 10:55 10:56 38 10:57 10:5 39 10:58 Rechner, Andreas SIEMENS Healthineers Introduction to Hemostasis Dr. Andreas Rechner Learning Objectives What is Hemostasis Describe the different stages of coagulation Describe the clinical indications for a hemostasis assessment Describe the most commonly ordered assays in hemostasis Hemostasis - What Is It? Hemostasis is the mechanism that ensures that blood in an intact circulatory system remains fluid, but coagulates spontaneously in response to injury. Hemostasis = cessation of bleeding (Greek) Haem = blood Statis = standing, stoppage Synonym: Coagulation What Are The Normal Stages of Coagulation? Modified from Bhat R et al. Hematol Oncol Clin North Am. 2017;31(6):1105-1122. Primary Hemostasis Adhesion and aggregation Secondary Hemostasis Tertiary Hemostasis Activation of clotting factors Fibrin cross linking & fibrinolysis and fibrin formation In-vivo hemostasisnal Stages of Coagulation? Mitchell In-vivo hemostasis Platelet adhesion: high shear stress: requires vWF Platelet Platelet (monolayer) vWF Endothelial injury Collagen Platelet activation: shape change Granule secretion ADP, TXA2 fibrinogen Thrombus development Of lesser importance in platelet aggregation: GPIb binds vWF Secondary Hemostasis simplified Extrinsic pathway Initiator: tissue factor (TF) surface + FXII F1+2: Prothrombin fragments 1 and 2 TF: tissue factor TFPI: tissue factor pathway inhibitor FXII: coagulation factor XII PAI: plasminogen activator inhibitor tPA: tissue plasminogen activator Thrombin Clot formation Fibrin fibrils tPA Plasmin Plasminogen Fibrinolysis Fibrin degradation products (FDP) D-dimer F1+2 TFP Antithrombin Protein C/Protein S PAI Molecular level Fibrinogen Fibrin Prothrombin Xa Va Xa IX uPA XI Fibrin Clot FDP VII TF Coagulation cascade Surface Contact IXa Tissue damage Ca2+ Extrinsic Common Intrinsic Inactive factor Active factor Ca2+ Calcium PL Platelet phospholipid Vit. K-dependent factors Fibrinogen -> Fibrin Stable Fibrin Clot Calcium E domain D domain Secondary Hemostasis (Plasma Coagulation System) - Intrinsic Pathway Collagen activates the surface-sensitive factors XII and XI (contact activation). Factor Xlla activates prekallikrein to kallikrein, which, together with HMWK Activating surfaces (high molecular weight kininogen) as a cofactor in an amplification loop, Activation within minutes Subendothelial collagen When HMWK is present, FXlla activates additional FXI to FXIa, HMWK · which activates FIX to FIXa in the presence of calcium ions. · FIXa activates FX to FXa. This activation is accelerated 200,000-fold by FVIlla (cofactor). FXa forms a cornplex (prothrombin activator complex) together with FVa Tenase (cofactor), calcium ions and phospholipids. Like FVIlla, FVa has no enzyme complex activity, but instead serves to speed up reactions by a factor of 100,000. This prothrombin activator complex then cleaves prothrombin (factor II)' to form thrombin (Flla) and the prothrombin fragment 1+2 (F1+2) activator · Common pathway of intrinsic and extrinsic pathways FX FXII is activated in-vitro by glass, kaolin, celite or ellagic acid. FXa Activation within seconds Tissue factor (TF) is released from injured tissue. Endothelial damage Endothelium Together with phospholipids, tissue factor is formed, which, as a cofactor together with FVIla, then activates FX to FXa > Common pathway of intrinsic and extrinsic pathways What is important here is that a small amount of FVlla must already be present in order to initiate the coagulation cascade (release of TF). However, as soon as FXa is formed, the pathway itself is amplified to convert FXa together with the tissue factor FVII to FVIla. Virchow's triad Hypercoagulability Endothelial dysfunction Stasis of blood flow Endothelial Dysfunction Trauma or surgery Malignancy Venipuncture Sepsis Atherosclerosis Thrombophilia Inflammation Venous Stasis Atrial Fibrillation Venous Obstruction (e.g ., tumors, obesity) Immobility or paralysis Hemostasis is a Balancing Act Healthy Thrombosis Bleeding Risk Thrombosis Risk Diseases related to disbalanced coagulation Bleeding Hemophilia A or B Hereditary disease with a strong bleeding tendency Requires life-long medication and care Von Willebrand Disease (VWD) Most common bleeding disorder ranging from mild (type 1) to severe (type 2s, type 3) Peri- or post-surgery bleeding Due to medication such as anticoagulants or anti- platelet drugs Numerous other reasons, hereditary or acquired Venous Thromboenbolism Deep Vein Thrombosis (DVT) Pulmonary Embolism (PE) Stroke Thrombus blocking arterial blood flow to the brain Heart attack Thrombus in the coronary arteries of the heart Common risk factors for the development of thrombosis Due to a number of factors, critically ill patients are at high risk of developing clots. Several other comorbidities and triggers increase a patient's risk, including: Diabetes Immobility Cardiovascular disease Estrogen-based Severe therapy inflammatory conditions Pregnancy Hospital stay Family history Surgery Purpose of Hemostasis Diagnostics Assess Risk Is there a risk of hemorrhaging or thrombosis, for example prior to surgery? Monitor Progress How is the hemostasis disorder progressing? Adjust and Monitor the Therapy Correct dosage of medications? Examples: phenprocoumon (Marcumar®, Falithrom®), heparin, acetylsalicylic acid (e.g. aspirin), DOACs (rivaroxaban, apixaban, dabigatran, etc.) The four Basic Coagulation Tests ics Test Abbreviation Comment Prothrombin time PT Functional test of extrinsic and common pathway Activated partial thromboplastin time APTT Thrombin time TT Functional test of the common pathway Fibrinogen Concentration Fib Functional or quantitative measurement (depending on the methodology) Prothrombin Time (PT) Ca2 Tissue factor (thromboplastin) Ca2+ TF + VIIA Xa + VA Clot V ca Clot Detection Systems Mechanical Magnet Clotting time (secs) Photo-optical Optical Sensor Viscoelastic Tracking + numeric result Increased PT: deficient function or concentration or inhibition of: vit K dependent Increased PT Liver disease Decreased clotting factor production/potential vit K malabsorption (if severe: aPTT prolonged) Vit. K antagonists Warfarin (Coumadin, blocks carboxylation) DOACs In particular direct Fxa-inhibitors such as Rivaroxaban, apixaban, edoxaban Disseminated Intravascular Coagulation (DIC) Factor consumption Fibrin/fibrinogen degradation products Inhibits coagulation (occursw/ DIC) Note RE: Heparin: aPTT is more sensitive to heparin RE: Lupus anticoagulant (LA): aPTT is a better test for LA Increased PTion of PT -> International Normalized Ratio (INR) ISI Ptpa Ptpatient INR = (pooled normal) ISI = International Sensitivity Index of the thromboplastin (thromboplastin = TF + PL) ISI - generally between 1 (human tissue factor reagents) and 2 (rabbit tissue factor reagents) Standardization of PT -> International Normalized Ratio (INR) Ptp PT (pooled normal) How is the PT/INR used? Titrate warfarin dose to achieve a "target" INR Normal PT/INR Target for anticoagulation Mechanical heart valve Reason for anticoagulation Tx of DVT or PE Activated Partial Thromboplastin (aPTT) Phospholipids (cephalin) contact activator (e.g. Kaolin, micronized silica or ellagic acid) Ca2+ Xia + IXa VA + VA deficient function or concentration or inhibition of: Increased aPTT: ›def: hemophilia B (XLR) vit K dependent VIII > def: hemophilia A (XLR) bound by VWF Increased aPTT: at can increase aPTT Other factors that can increase aPTT def: hemophilia C (AR) Heparin In particular direct thrombin inhibitors such as Dabigatran Inhibits coagulation (occurs w/ DIC) DIC Lupus anticoagulant (LA) Anti-phospholipid autoantibodies; aPTT is a better test for LA than PT RE: Vit K antagonists: warfarin; PT is a more sensitive test; warfarin overdose: prolonged aPTT generation Thrombin Time > functional measurement of fibrin Thrombin, Activation Monomer Soluble Polymerization Fibrinopeptides A&B Clot Formation Thrombin Time can be increased by: Fibrinogen deficiency Low concentration, dysfunction or inhibition Heparin is administered for anti-coagulation - inactivates lla (thrombin), etc. Dabigatran Direct oral anticoagulant for anticoagulant therapy directly inhibiting active Thrombin antibodies May develop following operating room exposure to bovine thrombin Function of Fibrinogen Glycoprotein that circulates in the blood Occlude blood vessels to stop excessive bleeding It crosslinks platelets at the site of injury Is subsequently converted fibrin fibrils forming a three-dimensional mesh occluding the injury Can bind thrombin and abolish its enzymatic activity This regulatory function is important for the balance of the coagulation system Cleavage D Domain Y Chain E Domain Fibrinopeptide A How is fibrinogen measured? Assays Clauss A functional assay based upon the time for fibrin clot formation PT-derived Fibrinogen Assays A derived fibrinogen based upon the prothrombin time Immunological An immunological method which measures fibrinogen antigen rather than functional fibrinogen Gravimetric A method based upon clot weight Clauss method of fibrinogen determination (most common method) Clauss Technique Functional assay Fibrinogen concentration is inversely proportional to the thrombin time of diluted plasma A reference (standard) curve is prepared using known fibrinogen concentrations (diluted 1:5-1:40) vs the respective thrombin time Log 50 Sec 40 25 50 75 100 125 150 175 200 Log Fibrinogen, mg/dL Patient Sample PT-derived fibrinogen curve determination (most common PT-derived fibrinogen curve A routine PT is performed on the patient's platelet poor plasma and the Fibrinogen derived from the change in optical density compared to the calibration curve. The derived Fibrinogen is a simple and inexpensive test and is widely used. However, the test can give misleading results in some disorders and is not recommended for routine laboratory use. Vessel Damage [Contact Phase] Extrinsic Pathway Vascular Injury Tissue Factor [TF] Factor X Fibrinogen [I] FIBRIN Monomer FIBRIN Polymer Cross-linked FIBRIN Abnormal fibrinogen .... Low functional fibrinogen concentration Congenital disorders Afibrinogenemia Homozygous Def Hypofibrinogenemia Heterozygous Dysfunctional fibrinogen Acquired disorders Liver disease, Consumption (DIC), thombolytic therapy Liver disease, Hepatic malignancy Increase functional fibrinogen concentration Pregnancy, estrogen, Acute phase response Procoagulant state Fibrin monomer Cross-linked fibrin Pregnancy, estrogen, Acute phase response Procoagulant state Cross-linked fibrin is built from fibrinogen Cross-linked fibrin is built from fibrinogen -mediated cleavage of cross-linked fibrin molecules a) fibrinogen, b) non cross-linked soluble fibrin and d) cross-linked, soluble or non-soluble fibrin YD XXD nent) should be considered as a specific FDP that is recognized by most of the reagent antibodies us Cross-linked fibrin ratory assessment of thrombosis. D-dimer is the final product of the plasmin-mediated cleavage - Fibrinolysis is initiated to degrade the clot: Plasmin cleaves b) non cross-linked fibrin, c) YY XY XX Only fibrin polymers that have undergone factor XIII-mediated cross-linking will produce fragments containing covalent bonds between two adjacent D domains (i.e. D-dimer). Therefore, D-dimer (DD/E fragment) should be considered as a specific FDP d) Pathological conditions nger than ler are Conditions with an interrupted blood flow (e.g. VTE), Clearance by the renal metabolism and tend to produce shorter fragments Cor e total entering the fibrinolytic pathway Clinical samples - D-dimer antigen Normal conditions Half-life ca. 8 hours i.e. much longer than The longer the fibrin degradation is progressing, the the thrombin antithrombin complex (TAT) smaller are the fragments (10-15 min) or F1+2 (1.5 h) the reticulo-endothelial system Conditions with a maintained flow (e.g. DIC) are D-dimer in the patient comprises multiple considered to produce longer fragments: Clinical plasma fragments of different molecular weight from DIC patients contain large amounts of high Concentration correlates with the total molecular weight crosslinked fibrin derivatives, whereas thrombolytic activity in the body fragment D-dimer represents only a minor fraction of total D-dimer antigen Approx. 2-3% of fibrinogen is converted into fibrin which instantaneously is Favresse J, et al. Crit Rev Clin Lab Sci 2018:55:548-577 Fibrinolysis is initiated to degrade the clot: Plasmin cleaves c)_soluble fibrin and that is recognized by most of the reagent antibodies used in the laboratory assessment of thrombosis. - The longer th ller are (1.5 h) ditions with a ro nen Favresse J, et al. Crit Rev Clin Lab Sci 2018;55:548-577 Clinical applications proven or considered for D-dimer testing Disseminated intravascular coagulopathy (DIC) Peripheral artery disease (PAD) Severe infections, e.g. COVID-19 Atrial fibrillation (AF) Acute myocardial infarction (AMI) VTE Acute aortic dissection (AAD) Coronary atherosclerosis (CAD) Aortic aneurysm (AA) Cerebro-vascular Accidents (CVA) Progressing ischemic stroke DVT/PE exclusion Cancer Anticoagulation (AC) therapy Wells PS. J Thromb Haemost 2007;5:41-50 CLSI. Quantitative D-dimer for the Exclusion of Venous Thromboembolic Disease; Approved Guideline. CLSI document H59-A. Wayne, PA: Clinical and Laboratory Standards Institute; 2011. Thachil J, et al. Meth Mol Biol 2017; 1646:91-104 Zhang L, er al. Int J Lab Hem 2018: 40:503-507 Soomro AY, et al. Eur Heart J 2016; 2:175-184 Golledge J, et al. Eur Heart J 2011: 32:354-364 Suzuki K, JTH 2018; 16:1442-4 Take Home Points Testing Hemostasis is a balance between clotting (thrombosis) and bleeding Coagulation consists of three stages (primary, secondary and Tertiary) A Coagulation disorder can be inherited as well as acquired Final thoughts · Purpose of Hemostasis Diagnostic testing . Assess the risk for bleeding or thrombosis? Monitor: How is the hemostasis disorder progressing? · Adjust and monitor the Therapy Key parameters to assess: · - PT, APTT, Fibrinogen, TT AND D-dimer Q&A Contact information: John V. Mitsios, PhD Email: johnmitsios@siemens-healthineers.com Andreas Rechner, PhD Email: andreas.rechner@siemens-healthineers.com D-Dimer