Hemostasis

Fibrolytic processes

Primary System

Procoagulants

anticoagulants

Thrombi

PLATELETS 3 Pathways 1. Intrinsic 2. Extrinsic 3. Common

Secondary System

Fibrin

Thrombin

Coag Factors

Excess Bleeding 1. Blood vessel damage (papercut) 2. Aneurysm BV rupture 3. ABNL PLT function & aggregation Coag Function quantities Acquired/Inherited

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4-2-13 Ch 24 MUST KNOW Table24-8 You must know the plt structure (ch 24 pp548) Nomenclature Roman numerals Table 24-13 All 3 pathways and Factors involved with Extrinsic Intrinsic Common Normal plt range is 150-400x109/L PLT =Megakaryocyte cell fragments Megakaryoblast Promegakaryocyte Megakaryocyte Megakaryocytes undergo endomitosis Normal gametes are 1N Somatic 2N Megakaryocytes can split several time in self to give 16N or greater Megakaryocyte buildup of granules then split up 3pathways 1. Extrinsic 2. Intrinsic 3. Common Hemostasis is a balance; it uses Platelets and Coag factors There is the primary system and secondary system 2 ways to activate the system: a tissue cut, intravascular due to drugs cancers, weird proteins in circulation Hemostasis: a combination of blood vasculature, PLT and what they do and Coagulation factors Pro coagulant enhances the coagulation .When in circulation they cannot coagulate until they are activated. Once activated they activate coagulation factor Anticoagulants in lining of the vessels heparin and other anticoagulants prevent clotting of blood in circulation. When there is a cut the PLT will become aggregated Secondary system is the COAG factors To stay fluid everything must stay balanced Fluidity: consists of the anticoagulants, profibroinolytic system, and PLT If too much procoagulaatns = clots If plt do not work then you can BLEED Excess bleeding (acquired or inherited) Vasoconstriction=if blood vessel damage and the vasculature is not constricting. Vasoconstriction plays more of a role in smaller cuts than larger cuts due to able to contain a small cut more easily Aneurysm = blood vessel rupture, need surgery to make sure it stops bleeding ABNL PLT function ABNL PLT aggregation (PLT come together too loose and break apart) Decreased Coagulation function/quantity (hemophiliacs & factor 8) Decreased Coagulation Granules Pathologic Thrombus In the lab determine if it is it a pathologic thrombus or natural?

Hemostasis Thrombi if in the vessels will block the vessel If pathologic Strokes heart attack or kidney failure What is occurring in the body ThrombinFibrinplatlet plug that help seal up the hole Fibrinolytic process that occurs in the body to stop the buildup of the PLT Body has fibrinolytic system and anticvoagulants to prevent clots and aggregation of the blood If the system is not in balance, too many fibrinolytic process going on or too much anticoag the patient will have bleeding (if procoag not working) Look at PLT aggregation and vasoconstriction When you are cut what is exposed? The tissues are exposed. Tissue factor is released and collagen is released. Collagen and tissue factor are the two main reasons why PLT start to aggregate. Inside the PLT are granules and tables that are released. PLT when in contact with tissue factor and collagen PLT release their content (orgasm) starts PLT orgy and police come in and break up the party (fibrinolytic system). Fibrinolytic process stops the platlet party and begin heeling process. PLT in secondary system 3 pathways Intrinsic (how the Pathway begins) Extrinsic (how the pathway begins) Common( where both intrinsic and extrinsic lead into; similar to the MAC for complement) Hemostasis a process by which blood fluidity is maintained. The arrest of bleeding at the site of tissue damage is facilitated by 3 events. Vasoconstriction PLT aggregateion Blood Coagulation What is the primary system? Whatis the secondary system? The effectiveness depends on the type and degree of injury & ability to vasoconstrict, the ability of the plt and their activity. Whether it it is the Ability of PLt to aggregate, the vasoconstriction or coagulation factors there are 2 ways this is affected pathologyically, inherited or acquired dysfunction. All of the blood factors and their relation to the function as enzymes or as cofactors and antigenic concentrations meaning Procoagulant vs Coagulant Each coagulation factor by self is not able to coagulate the blood. Coagulation by the blood factors is dependent on the activation of the coagulation factor by platlets or other stuff in circulation Normal presence of inhibiters and circulating anticoagulants, if not present then this leads to formation of clots at inappropriate times A process of formation of a clot will result in fibrinolysis , the dissolution of the form and stability of the clot. Tissue repare will occur as the clot is broken down. Hemostatis checks and balances . If not balanced then there will be either bleeding or clots Hemorrhaging can occur with disease, BV rupture, abnormaility in the blood, decrease in facors, acquired/inherited deficiency in PLT, drugs or liver disease Most coagulation factors in liver. If liver is diseased then there will be ap problem with coagulation factors as the liver makes coagulation factors Kidney disease will lead to RBC produced as it makes EPO

Hemostasis Clot /thrombus at in appropriate time (pathologic) Formation of clots, stops blood flow & Leads to strokes Causes of clot Fibrinolytic system is not working. PLT party goes on all night long and PoPo doesnt come around to break up the party. Sometimes the PLTs can leave the original party and have an after-party, A piece of the clot leaves to cause further problems in your vessels leading to stroke Inhibitors (something in circulation that is going around an inhibition the anticoagulants) Hypoercoagulable state (deficiencies in naturally occurring anticoagulants) 2 main tests to check for clotting time PT PTT It is difficult to predict the risk or anticipate development of a thrombus, people with heart attack will be given blood thinners :P anticoagulants eg : warfarin Cumadin What happens when you are cut? 1. Blood and PLT come out of cut 2. PLT try to form a plug (adhesion) PLT attracted to collagen and tissue factors relased by the endothelial 3. PLT aggregation (excitement) PLT start getting excited and releasing content 4. Fibrin comes in and makes fibrin clot, party starts getting crazy 5. Policia! Stop the party an dissolution of the clot 6. Healing What released the collagen? Endothelial Hypocoagulable means excess bleeding inherited or acquired What factor is associated with a hypocoagulable state? Factor 8 is the main factor but any missing factor is going to affect the ability of the person to forma aclot DIC Disseminated intervascular coagulation. Inappropriate time of formation of clots throughout the body. Causes incude cancer, preganancy, Drugs, Bacterial cell walls. Anticoagulants/Blood thinners :P warfarin Cumadin (rat poison) Cause Over coagulation of the patient easily reversible by giving Vitamin K or eating greens can be inhibited by diet high in spinach/broccoli able to be monitored with lab tests Newer anticoagulants are not easily reversible, note easily monitored by the lab tests. Plavix take with asprin. Lupus Anticoagulans (MISNOMER) Has no association with lupus and does not act as an anticoagulant Anticardiolipin If you have lupus anticoagulant you will make clots Hemostatic protein abnormailityies can be seen in after surgery , cancer and pregoo PLT abnormailities seen in Diabeties High cholesterol Both can coat the PLT and RBC membrane not allowing it to work Meyloproliferative disordres abnormalities see dysfunctional PLT , very big plt or plt that do not work

Hemostasis Heparin Induced thrombocytopenia HIT . When apatient with clot or stroke is give Heparin IV . Sometimes heparin can make PLT count go down The patient is on anticoagulants with a reduced PLT count the patient can start to bleed. Clot formation Artificial surface in Blood vessles (stent) Angioplasty (balloon) ABNL blood vessles (high cholesterol buildup) Too much cholesterol in vessles leads to Heart Attack Hemostasis 2 parts Primary & Secondary . Primary is vascular and PLT. . Secondary is the coagulation factors. With secondary occurs in cascade fashion (similar to complemen) . PLT cascade 1. Initiation occurs beginning with PLT and release and Factors come in 2. Activation of X (10) everything comes into factor 10 . After Facotr X all the other factors work together to make clot 3. Formation of thrombin 4. Fibrinolysis insoluable part Cyclic fashion The moment that the Party begins Police in circulation making sure it doesnt get too crazies Basic Events that happen Primary stage 1. Vasoconstriction 2. PLT adhesion 3. PLT aggregation Fibrin and Plug formation Fibrin stabilization ( CLOTstabilizer is Factor XIII) Vessle trys to constrict but it is also cut reeaseing collagen and tissue factor. The njury breaks the smooth muscle lining Exposing collagen, A surface will promote formation of plug for PLT to start coming in Other happenings : serotonin aka 5hydroxytryptamine (PLT) & thromboxaine A2. These are 2 stimulants of PLT and are inside the PLT themselves. Endothelium is released form broken endothelial cells PLT come in and are excited by the collagen and relase their contens (Thromboxaine A2 and seratonin). Tissue factor AKA factor III Factor III(aka tissue factor) works with factor VII Upon exposure Factor III finds factor VII and make a complex of tissue factor and factor VII which starts the extrinsic pathway which will eventually go down to Factor X Vessle injury initiates Fibrinolysisi (popo) AKA Endothelial cells release tissue plasiminogen activetors (police) 4-3-13

Hemostasis

What are the 5 components involved in the hemostatic system Vasoconstriction/Blood vessles Platelets Fibrinolysis Coagulation factors Coagulation inhibitors (anticoagulants/blood thinners) If you have a cut what is reasesd? Tissue factor and Collagen Ouside of PLT membrane have glycophorins Glycophorin 1A the receptor on PLT that reacts with collagen and helps it stick Von Willambans Factor A complex molecule released by PLT PLT to stick to VWF .with glycophorins GP1B GP2Band GP3A PLT use these glycophorens to stick to the membrane to start the party Other names are Alpha 2B Beta 3

Skin layer is Cut Relases of Tissue and collagen

Hemostasis

GP1B likes VWF:r Ristociten the VWF secreted by PLT alpha granules

GP1B GP2B and GP3A All react with VWF but will have a better reaction when: GP1B likes it more when it is VWF:r ristocitin derived from PLT granules GP2B and GP3A like it when it is near fibrinogen

PLT LOVE Von Willibrans Factor. They stick to it using GP1B GP2B Fibrinogen Receptors GP3A PLT use on outside membrane to Stick to stuff Alias IIb 3

PLT use GP1A to stick to Collagen

PLT and GP5A likes thrombin

This occurs in subendothlial part of vessel and this is how PLT stick to Collagen and VWF Bernards Soliae problem with GP1B PLt do not stick to to lack glycophorin Glazmans Thrombobastimia associated with GP2B and GP3A GP2B and GP3A are also receptors for fibrinogen What does fibrinogen do makes fibers that hold PLT together if not the platlets will fall apart. Glycophorin GP3A and GP2b grab fibrin allowing PLT to stick tohether more firmly ans change shape and relase content. VWF located on Sub endothelium of vessel , GP on PLT Fibriniogen receptors need to be there for PLT to aggregate.

Hemostasis

Fibrinonectin Collagen Thrombin ADP VWF Factors affecting PLT stickiness Thrombin ADP

PLT Dense Granules lpha granules Microtubles system Get the granules in and out GP membrane Mitochondria & glycogen Granules Lysosomes Folded surface Surface area to react Glycophorins associated with initial PLT adhesion GP1A GP1B GP2B GP3A PLT has a dense tubular system associated with the membrane that forms a circle around the PLT. Site for arachadonic acid metabolism helps platlets stick like a sticky spider web. Affected by aspirin which doesnt allow PLT to stick

Acts as calcium sequestering if it needs calcium .

6 released contents of the Alpha Granules 1. PLT Fibrinogen When they get excited and not enough fibrin they relasse alpha grnaules with fibrinogen to make their own 2. PLT derived GF PDGF stimulate production of more PLT 3. VWF:R . PLT make their own version of Von Willabrams Factor that is a receptor 4. Beta thromboglobulin 5. PLT Factor IV a heparin neutralizer Want to neutralize the anticoagulants to form the clot 6. Fibrinectin Dense granules contain ADP ATP Serotonin/ 5hydroxystryptamine Calcium : if there is not enough Calcium floating in subendothelium near cut the PLT will make its own calcium from the dense granules Remember that anticoagulants like EDTA and NAcitratite bind Calcium Coagulation cascade needs calcium in order to form a clot. PLT seening collagen will throw out content calling out its PLT homies for a crazy party. Relases nticoagulant neutralizers , makes calcium to start the clot process.

Hemostasis

3 natural inhibtiors of PLT to prevent formation of clots at wrong time 1. NO Nitric Oxicde from endothelial cells & macrophages 2. Prostacycline From endothelial cells 3. CD39 Ectonuclitidase. Acts as an inhibitor Prevents PLT aggregation, by acting like an ADPase & cant interact with cell wall of vessles If no ADP then the PLT cant aggregate Von Wilabrams Factor Relased under Stress Excersise INfustion of DD ADP VWF is in the PLT and in the subendothelial . Humans have a tendancy to store VWF Weibel Palade Bodies : store VWF In the book Serotonin is 5hydroxytryptamine 4-8-12 Coagulation cascades Primary hemostasis cosists of vasococnstriction and plt stuff Secondary hemostasis deals with coagualtion factors Know where the coag factors are are at Produced mostly in liver and circulatin as inactive precursor form, roman numerals Add an A to designate an active form which acts an an enzye to catalyze other reactions. 7 circulates as unactivated form, when 7a then acitive form These factors are categorized as Substrate substance that enzyme acts on if you have a factor 3 that acts on 7 then 7 is a substrate of 3a Zymogen enzyme precursor conversion of zymogen to enzyme is either a serine proteases (II, VII,IX,X,XI, XII) use serine as active site and cleave the peptide, or create covalent bonds Cofactor aid in acitivation Calcium 3 groups : Prothrombin fibrinogen Contact group The ultimate goal of hemostastis: stop bleeding by formation of platlet plug To get fibrin (hold together) need to go down to thrombin and fibrin need to know which factors go into what grouping 13 Factors PLT have to be in adequate # and function Participate in hemostasiss by? Collagen attractant and attachment using plts glycophorins, VW hooking factor. Negative chagege with phospholipids, release of substances, Attract more plat and release serotonin which induces vasoconstriction. Has plt membranes for glycoproteins, When you cut yourself tissue factor and collagen

Hemostasis are released causing the start of the cycle.

Hemostasis

Factor 8 has 2 components the factor 8C and VWF . VWF is bigger and carries but 8C is the part that take Use PT to detect Extrinsic PTT for intrinsic If problem with common factor both will decreases MUST KNOW the seconds of the reference ranges for the test table-9 Test rr PT 11-13s aPTT bleeding time 2.5-9.5 min Thrombin time 15-22 reptililiase time 18-22 Factor 3 Starts the Extrinsic pathway Tissue factor is released from the tissue damage & collage attracts plt and tissue III starts extrinsic. In the presence of calcium and factor VII vit K dependant and initiates serine proteases increased levels in MI

Hemostasis Intrinsic factor starts with collagen & factor XII (heagaman factor) XII is a contact factor that is heat activated or activated when it binds to negative surfaces like collagen Autoactivates , can self activate Collagen +XII XIIa XIIa in the presence of HMW kninogen and PK it goes to activate XI (very fast) If no HMWKiniogen or PK it can still go to activate XI but it proceeds very slowly XI Plasma thrombosplastin antecedent, contact factor, circulate in blood and is complexed with HMWK Hemophilia C associated with deficiency in XI

VIII produced by mega karyo and endothelial cells IX XI

Hemophilia A Christmas hembphilia B vit K dependant Hemophilia C

In the presence of cacium(IV) XIa activates IX Complex (III IV and VII from extrinsic) help go to thrombin by working on factor IX Factor IXa goes to X (common) bu ti needs help from factor VIII VII goes back to intrinsic to help IX VIII goes back to C VII VWF X Xa X can be activated by VIIa Complex from extrinsic and IXa complex from intrinsic Factor v proaccelerin /labile , diminish at RT , consumes during clotting attaches to PF3 and III X activates II/prothrombin with V, changes to thrombin IIa Thrombin responsible for conversion of fibrinogen to fibrin Formation of the Fibrin polymer: fibrin has little stickys sticking up on it thrombin reacts on the monomers & will spontaneously react to make a fibrin polymer VVa activates itself spontaneously Xa + spontaneous Va both act on II IIa IIa very important!!!! IIa firstly goes to fibrin Fibrin is factor I and thrombin IIa makes the monomers which are activated Ia which are the monomers which spontaneously make polymers. Polymers make stable clot, what is the stabilizer? XIII fibrin stabilizing in the presence of Ca How does XIII to XIIIa by thrombin. Thrombin works on fibrin substrate & also works on prothrombin and thrombin II and IIa . Thrombin also goes to the VIII to speed things up andthrombin also goes to XI to help speed things up. XI to X occurs on plt surface HMWK and XII can go back to stimulate VII and VIIa

4-10-12 How many systems of hemostasis? Primary and secondary system of hemostasis Primary Platelets in the veins /vasosconstriction Secondary consists of the coagulation factors ,put it together How does the body normally inhibit us from turning on the systems without reason?

Hemostasis

Good reasons: tissue Damage Deactivation of circulating anticoagulants and processes Disease states Cancer/drugs/Birth control The body has processes to inhibit clotting and stay fluid in the vasculature

Basement membrane
When the basement membrane is cut or damaged this will trigger the body to release tissue factor and collagen. Endothelial cells will release a coagulation factor that is not released by the liver (factor8/von willabrams factor) 6 ways a normal intact membrane functions / prevents pLT adhere antithrombins 1. NO nitrous oxide 2. ADPdiphosphatase 3. PGI2 When plt are able to adhere and aggregate will call other platlets and make fibrin Anticoagulation has 3other things 4. Heparin sulfate 5. Antithrombin3 doesntlike thrombin 6. Thrombomodulin regulates thrombin Heparin has a receptor site for antithrombin 3 and when they come together they inactivate thrombin Antithrombin chews up thrombin Heparin sulfate + antithrombin3 complex inactivates factor Xa and IXa What does thrombin(IIa) do ? promotes XIIIXIIIa promotes fibrin monomers helps V and VIII The heparin sulfate antithrombin3 complex stopsthromibnfromgoing and helping formthe fibrin monomers to forma clot

Hemostasis Thrombomodulin receptor : regulates thrombin acts as a safty if antithrombin doesnt get all.thrombomodulin is safty net. Activates protein C which digests circulating factors Va and VIIIa TPAtissue plasminogen activator Endothelial cells produce NO PGI2and ADPdiphosphate & TPA

Thrombomodulin Receptor

Endothelial cells want to stop platelet aggregation and make sure that the plasma factors are not working. The ultimate goal of coagulation factors is to produce fibrin from fibrinogen. TPA converts plasminogen to plasmin Plasmin digests and break down fibrin to fibrin degradation products FDP seen in DIC ,very bad thing do not want to see when it should not be in the circulation Normally in the body coagulation systems are circulating as inactive forms 1:36

C T C
Protein C Thrombin