BLD 324 NOTES
BLD 324 NOTES 324
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This 11 page Class Notes was uploaded by Kayln Smith on Sunday February 15, 2015. The Class Notes belongs to 324 at Michigan State University taught by B. Zhang in Fall. Since its upload, it has received 129 views. For similar materials see BLD in Biomedical Sciences at Michigan State University.
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Date Created: 02/15/15
BLD 324 NOTES De ne Hemostasis Hemostasis the sum of all coagulation related mechanisms that allow blood to circulate freely in the blood vessel while also allowing for clot formation at the site of injury Primary Hemostasis Platelets Activated by desquamation and small injuries to blood vessels Involves vascular intima and platelets Rapid short lived response Procoagulant substances exposed or released by damaged or activated endothelial cells Secondary hemostasis Coagulation Factors Activated by large injuries to blood vessels and surrounding Ussues Involves platelets and coagulation system Delayed long term response Tissue factor exposed on cell membranes More stable Hemostasis Overview Pg 3 Anticoagulant properties of intact vascular intima Endothelial cells form a barrier between blood and collagen Anticoagulant properties of intact endothelium Composed of rhomboid cells presenting a smooth contiguous surface Secretes the eicosanoid platelet inhibitor prostacyclin Secretes vascular relating factor nitric oxide Secretes the anticoagulant glycosaminoglycan heparin sulfate Secretes coagulation extrinsic pathway regulator tissue factor pathway inhibitor Maintains cell membrane thrombomodulin a protein C coagulation control system activator Procoagulant properties of the damaged Vascular lntima Structure Procoagulant Property Smooth muscle Induce cells in arterioles vasoconstriction and arteries Exposed Binds VWF and subendothelial platelets secrete collagen VWF Damaged or Secrete activated endothelial cells adhegon molecules P Exposed sleectin lCAMs smooth muscle PECAMs cells and broblasts Tissue factor exposed on cell membranes Endothelial cells Tissue factor is in in ammation induced by in ammation Fibrinolytic Properties of Vascular lntima Secrete TPA Tissue plasminogen activity can activate plasminogen dissolbing the clot pgS Adhesion VWF binds platelets via GPllbIXV receptor Bernard Soulier syndrome Aggregation Fibrinogen binds to GP llbllla receptors and crosslinks platelets Glanzmann thrombasthenia Secretion Platelet membrane integrin receptor site PLT Collagen binding site Basement membrane PgS coHagen Platelet Granule Platelet alphagranules Contents Large molecules 8 thromboglobulin Factor V Factor Xl Protein S Hbdnogen Von Willebrand Factor Platelet factor 4 Heparin Inhibitor Platelet derived growth factor Platelet Sigma Granules Dense Bodies Small molecules Adenosine diphosphate activates neighboring platelets Adenosine triphosphate Calcium Serotonin vasoconstrictor Thromboxane BZ A Stable measurable plasma product that is reduced in aspirin therapy PROCOAGULANTS PLASMA PROCOAGULANT SERIN E PROTEASES Prothrombin ll Thrombin Ila Fibrinogen V VII etc PG 6 Other plasma procoagulants Not serine proteases Hbdnogen Factor XIII Phospholipids Calcium Von Willebrand Factor Procoagulants Nomenclature Activated factor indicated by quotaquot behind the numeral Fibrinogen I prothrombin II TF III calcium IV VWF carries factor VIII Prekalilraine Fletcher factor and high molecularweight kiniogen Fitzgerald factor HMWK Platelet factor 3 PF3 Phosphatidylserine Classi cation Serine proteases and cofactors Seryl residue at active sites Hydrolyze peptide bond Bind to cofactors Other plasma procoagulants FACTOR 8 VONWILLEBRAND FACTOR VWF Vitamin K Dependent Prothrombin Group Procoagulants Regulatory Proteins Prothrombin ll Protein C VII Protein S IX Protein Z X Vitamin K Dependent Prothrombin Group All resemble prothrombin 1012 glutamic acid units near amino termini VitK is a cofactor for ycarboxylation ycarboxylation allows binding of Ca2 Ca2 binding permits binding of phospholipids Wa rfa rin Can inhibit the activity of coagulation Factor IIVIII IX X Von Willebrand factor Factor VIII Complex Glycoprotein produced by endotheia cells and megakaryocytes Stored in agranules and Weibel Paade bodies Circuate in plasma Platelet membrane binding site GP IbVix Platelet membrane binding site GP llbllla Collagen binding site PG7 Fibrinogen structure and brin formation Cleavage of brinogen results in clot formation Fibrinogen is the precursor of brin Enzyme Serine protease Thrombin cleaves brinogen to brin monomer Fibrin monomers aggregate to form soft clot Factor Xlll catalyzes formation of stabilized brin by cross linking Release of vasoconstrictos Fibrinogen 3 polypeptide chains A By Coagulation PathwaysPG8 Tissue factor extrinsic pathway is activated by tissue factor Fromation of 3 complexes AP39ITPT activated partiesl thromboplastin time Factor Xl intrinsic pathway is activated by thrombin and contact factors Contact factor complex Factor Xlla HMWKA Fitzgerald preK Fletcher PT Prothrombin time Not test for factor IX and VIII Common pathway factor X V Prothrombin First complex Vlla tissue factor phospholipid and Ca 2 FunctionCleaves IX and X Second complex lXa Vllla phospholipid and Ca 2 I Function Cleaves X called tenase Third complex Xa Va Phospholipid and Ca 2 I Function Cleaves prothrombin called prothrombinase In Vivo cell based coagulation PG 8 Initiation TFL ll activates IX and X Xa Va activates thrombin lX activation does not proceed Ampli cation Platelets and VII VWF spill Platelets activated by thrombin and collagen Thrombin also activates V Vlll Xl Propagation Thrombin can stimulate coagulation AND inhibit too much clotting Activates TFI Cleave brinogenpepetides A and B from brinogen Prothombotic regulatory role Feedback ampli cation to stimulate its own formation by activating factors V VIII XI Activate factor XIII to crosslink and stabilize brin clot Antithrombotic Bind to thrombomodulin Activate protein C Vit K dependent II VIII IV X Anti brinolysis Activateds TAFI Principle Regulators of Coagulation TFPI antithrombin protein C pathway Inhibit procoagulants to prevent excessive clot formation De ciency associated with venous thromboembolic disease Coagulation Regulation TFPI Inactivate Xa Bind to TF VIIa to prevent activation of additional Xa Protein S is a cofactor Coagulation Regulation Protein C After binding trhrombomodulin thrombin activates protein C Free protein S binds and stabilizes activated protein C Activated protein C protein S complex digests and inactivates factors Va and Villa C4bBP is an acute phase reactant in ammation increased thrombosis Recurrent benous thromboembolic disease Protein C or S de ciency or mutation Factor V mutation Compromise down regulation of Van ad VIIIa Coagulation Regulation serpins Serine Protease Inhibitors Antithrombin heparin cofactor II ZPI protein C inhibitor Heparin and thrombin HMW high molecular weight unfractionedl inactivate thrombin LMW Low molecular weight fractioned l Inactivate factor Xa Hepa ne Enhances activity of thrombin Fibrinolysis Final stage of coagulation Hydrolysis of brin by plasmin dissolbes brin Excessive Bleeding Inadequate lot extension and thrombosis Activated by TPA Tissue plasminogen activator Urokinase Inactivated by PAI1 Plasminogen activator inhibitor 1 a2 Antiplasmin TAF Thrombin activated brinolysis inhibitor Ddimer immunoassay Identify chronic and acute DIC Rule out venous thromboembolism Hemostasis specimen collection Whole blood sodium citrate 32 91 anticoag plasma 14 or 15 Adjust if Hct gt 55 Volume of citrate 183 x 10393100hctx vol Short sample Order of draw Specimen handling 0 Well mized whole 0 Plasma Always plastic 0 Covered o Hemolyzed or lipemic Specimen storage keep at room temperature 1824 decrees C Whole blood Plasma 24 Degrees C 2 hrs 70 degrees C 6 ms months PRva PPP platelets poor plasma Blood culture tube Glass or plastic non additive Coagulation tube Serum tube EDTA tubes ESR tubes CHART ON PAGE 3 Hemostasis Specimen Collection Patient management 0 Fast or not l does not need to be fast Drugs Aspirin Inhibit production of prostaglandins can cause bleeding Warfarin Coumadin can impact test must stop atleast a week before Hemostasis Collection Errors Short draw Whole blood volume less than 90 of required volue or less tha manufacturer speci ed minimum Clot in specimen each specimen must be visually inspected prior to centrifucationl the presence of even a small clot requires that the specimen be recollected Visible hemolysis hemolysis pink or red plasma indicates in vitro activation of platelets and coagulation and results will be unreliable Lipemia or icterus Optical instruments may not measure clots in cloudy or highly colored specimens The scientist automatically shifts to the use of a mechanical instrument Prolonged tourniquet application stasis evaluates the concentration of Von Willebrand Factor and factor VIII and shortens the measured time on clot based tests Specimen storage at 1 degrees C to 5 degrees C Storage at refrigoratro temperatures causes precipitation of large von willebrand factor multimers and destroys platelet integrity Specimen storage at more than 25 degrees C Storage at above standard room temperature causes coagulation facor Vlll deterioration Platelet Function Test Bleeding Time In Vivo BP cuff pumped uip to 40 mm Hg Standardized incision in forearm start stop watch 1mm in depth 0 Filter paper absorbs blood every 305 0 Stop time when no more blood detected 0 Prolonged normal 29 min Von Willebrand disease Vascular disorder Drugs Platelet Function Test Bleeding Time In Vitro PFA 100200 Blood aspirated through an aperture in a membrane coated with collagen epinephrine or collagen ADP Platelet plug occludes aperture Drop in ow rate is monitored Closure time full occlusion of aperture is reported Platelet Function Test Aggregation studies Using PRP Citrate anticoagulated PRP Constant stir in a 37 degree celcius cuvette Light is sent through the cuvette Light transmission absorbance is recorded Increased transmission Decrease optical density as aggregation occurs Platelet Function Test Aggregation Studies using Whole Blood Platelet aggregometry 11 saline whole blood suspension Constant stir in a 37 degree celcius cuvette Add agonist Suspend a pair of DC electrodes Aggregated platelets at the electrodes impeded DC current 0 Increased impedance is ampligied and recorded Platelet lumiaggregometry whole blood or PRP 0 Measure both aggregation and secretion Thrombin is rst added to induce secretion Platelet Aggregation Studies Clinical Uses 0 Von Willebrand disease VWD Ristocetin induced platelet aggregation RIPA test Corrected by exogenous VWF Not corrected by exogenous VWF Aggregation with low ristocetin concentration ZB VWD Poor predictive values used together with other tests 0 Different agonist responses in various circumstances NSAIDS decreased or no response to arachidonic acid or collagen Platelet release secretion defects Decreased or no response to all except for thrombin Storage pool de ciency Decreased or no response to thrombin only Platelet membrane defects Glanzann Thrombasthenia Decreased response to al except for thrombin or modest response to arachidonic acid Acquired platelet disorders Heparin induced thrombocytopenia with thrombosis Qualitative Measuremeny of Platelet Markers o Antiplatelet factor 4 HIT screening immunoassay o B thromboglobulin and PF4 CATD tubes blue top Thrombotic stroke or coronary thrombosis o Thromboxane A2 11 dehydrothromboxaine 82 Monitor aspirin therapy Aspirin resistance Coagulation Tests Use PPP ad calcium to overcome anticoagulant Generalities Endpoint is polymerized brin No test assesses factor XIII Adding activator of a given factor is able to initiate coagulation at that factor and evaluate all the factors after it down to polymerized brin The time to form a clot is determined and is dependent on Procoagulants Anticoagulants These are functional assays depend on adequate amounts had normal function structure of all factors Abnormalities are detected by prolonged times unable to detect abnormalities that result in shortened times increased clotting tendency Prothrombin time PT 126146 5 Time needed to clot plasma after addition of TF and Ca 2 Prolonged with de ciencies of factor VII X V II I Used mostly to monitor oral anticoagulant therapy Example IN R PTpatient Geometric mean of normal For patients with a stable anticoagulation response Activated Partial Thrombin Time a PTT 26385 Time needed to clot plasma after addition of platelet lipid substitute and Ca2 Reagents Prolonged with de ciencies of factor XII XI IX VIII X V II PTT Mixing Studies Lupus Used mostly to monitor therapy Uses 0 Initial detection of LA 0 Detect other speci c inhibitors Procedure Do TCT if P39IT is prolonged Neutralize heparin of TCT is prolonged Mix Patient plasma PNP Ratio 11 Perform new P39IT Coagulation factor de ciency is presumed if this new PTT is corrected within 10 of PMP PTT or within references patient is bleeding If P39IT corrects make a new mixture and incubate at 37 degrees C 12 hrs If fail to correct and bleeding do factor presence of inhibitors factor VIII activity assay If P39IT of initial or incubated mixture fails to correct and no bleeding suspect LA LUPUS ANTICOAGGULANTS Thrombin Clotting Time 0 Time needed to clot plasma after addition of thrombin and TCT 15205 Ca 2 0 Length of time is proportional to the amount of functional b nogen Uses To determine if heparin is present when P39IT is prolonged or before considering diminished or abnormal b nogen Fibrinogen Assay 250 o Quantitation of brinogen 400 m9 dL Based on standard curve using dilutions of a known brinogen o Relies on a variation of TCT time needed to clot plasma after addition of thrombin and Ca 2 Length of time is proportional to the amount of functional b nogen Signi cance Prolonged with quantitative de ciencies or qualitative abnormalities of brinogen Single Factor Assays c When to perform P39IT based Prolonged P39IT with normal PT and TCT Exclude heparin LA or a factor speci c inhibitor Factor VIII lX or Xl de cienty mostly done on previously diagnosed to monitor therapy Prolonged P39IT of factor VIII depleted PPP reverts to normal if normal PPP added 0 PT based Prolonged P39IT and PT with normal TCT Excludes liver diseases vtK de ciency DIC warfarin Factor V or X de ciency Factor Xlll Assay Bleeding and poor wound healing Normal P39IT PT Platelet count brinogen level 5mol L urea solubility test Tests of Fibrinolysis 0 Quantitative D dimer assay Immunoassay Rule out thromboembolic disease Detect and monitor DIC FDP Immunoassay Plasminogen chromogenic substrate assay Decrease in Thrombolytic DIC Hepatitsi Cancer Hepatic de ciencies Increase in In ammation pregnancy hemorrhage systemic brinalysis TPA assay Enzyme immunoassay Decrease increase risk of MI stroke DVT PAI1 assay 0 Euglobulin clot ysis time test Dissolved lt 2 hrs Clot remains gt10hrs
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