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Coagulation
| Question | Answer |
|---|---|
| Specimen collection and handling for coagulation tests: anticoagulant/tube type and type of specimen | • Sodium citrate (Ca++ is necessary for both coagulation and platelet aggregation studies) • Whole blood-anticoagulant ratio = 9:1 • Use siliconized glassware b/c glass activates Factor XII & plts will adhere to the glass |
| Specimen collection and handling for coagulation tests: hemolyzed and lipemic | • Hemolyzed samples should NOT be used for platelet aggregation studies because RBCs contain ADP • Lipemic samples may cause problems with coagulation and aggregation (may obscure changes in optical density) |
| Specimen collection and handling for coagulation tests: can this be drawn first | • NOT be drawn 1st when using vacutainers b/c contamination with tissue thromboplastin (activates coagulation) as needle pierces skin (only test ordered dead tube) |
| Platelets | • Produced from megakaryocytes • Life span 9-12 days • 150,000-400,000/mm^3 |
| Platelets distribution | • 30% spleen • 70% peripheral blood |
| Functions of platelets | • Initial arrest of bleeding and formation of the platelet plug by Adhesion Aggregation Localization of the platelet plug Assembly and localization of the fibrin clot |
| Functions of platelets: adhesion | • Glycoprotein Ib binds to exposed collagen • Requires von Willebrand’s factor • Results in release (secretion) of ADP and other granule components (including factor V and fibrinogen) |
| Functions of platelets: aggregation | • Other platelets are stimulated by ADP to undergo shape change(disc to sphere to pseudopods) exposing the glycoprotein IIb/IIIa complex which binds fibrinogen • Fibrinogen binding links the platelets; the first (and reversible) phase of aggregation |
| Functions of platelets: localization of platelet plug | • Secreting platelets release arachidonic acid which converts to prostaglandin (becomes Thromboxane A2) • Arachidonic acid is processed by adjacent endothelia cells to form platelet-inhibiting prostacyclin Plt plug limited to the injury site |
| Functions of platelets: assembly and localization of the fibrin clot | • Plt release fibrinogen, factor V, factor VIII • Fibrinogen is bound on the plt surface during aggregation • Factor VIII is bound to the plt surface with von Willebrand’s factor • Shape change exposes plt membrane phospholipid(template for factor 3) |
| Contact factors | • XI • XII • PK • HMWK |
| Prothrombin facotrs | • II • VII •IX • X |
| Fibrinogen facotrs | • I • V •VIII • XIII |
| What factors are absorbed by Al3OH/BaSO4 | Prothrombin factors |
| What factors are Vitamin K dependent | Prothrombin factors |
| What factors are consumed in clotting | Fibrinogen factors and factor II |
| What factors are found in serum or plasma | • Contact and prothrombin factors are in both serum and plasma • Fibrinogen is only in plasma |
| Plasma coagulation factors: Functions | • Substrate- factor I (fibrinogen) • Cofactors- accelerate enzymatic reactions Factors III, V, and VIII Factor HMWK (high molecular weight kininogen) |
| Plasma coagulation factors: Enzymes | • Serine protease- cleave peptide bonds (factor II, VII, IX, X, XI, XII) • Transamidase- XIII only |
| Characteristic of coagulation proteins: Contact proteins | • Factors XII, XI, PK (prekallikrein), HMWK • Participate in the initial phase of the intrinsic system • NOT consumed during clotting (found in both serum and plasma) • NOT absorbed by Al3OH/BaS O4 • NOT vitamin K dependent |
| Characteristic of coagulation proteins: Prothrombin proteins | • Factors II, VII, IX, X • Vitamin K dependent • NOT consumed during clotting (except II) • Present in fresh and stored plasma and serum • Absorbed by Al3OH/BaSO4 |
| Characteristic of coagulation proteins: Fibrinogen proteins | • Factors I, V, VIII, XII • Consumed during clotting (therefore not in serum) • NOT absorbed by Al3OH/BaSO4 • Increase in acute phase (pregnancy and inflammation) |
| Turn it on: Stabilized crosslinked fibrin | • Activated intrinsically by the collagen (via factor XII) contact system • Activated extrinsically by disrupted endothelia cell membrane (tissue factor or tissue thromboplastin) complex with factor VII to directly activate factor X |
| Cofactors: Stabilized crosslinked fibrin | • VIII bound with IXa by Ca+ to Plt phospholipid membrane • They activate X (in the common pathway V is the cofactor to Xa in a similar arrangement with Ca+& Plt factor 3) • This prothrombinase complex converts prothrombin to the active thrombin |
| Thrombin: Stabilized crosslinked fibrin | • Cleaves peptides off of the molecule to form fibrin which polymerizes to form insoluble fibrin strands • Thrombin also activates factor XIII which crosslinks the fibrin strands at the “D” region (birth of the D-dimer) |
| Other functions of thrombin | • Feeds back to “potentate” factors V and VIII • Recruits and aggregates platelets • Turns on endothelial cells thrombomodulin (receptor/activator for protein C and protein S system) to inactivate factors V and VIII |
| Turn it off: Stabilized crosslinked fibrin | • Heparin sulfate on the endothelial cell binds antithrombin III which inactivates the activated serine protease • Activated protein C and its cofactor protein S (when bound to its receptor/activator thrombomodulin) inactivates factor VIII and V |
| Turn it on: Fibrinolytic system | • Activated intrinsically by collagen via Factor XII/contact pathway that initiates intrinsic clotting or extrinsically by tissue plasminogen activator (TPA) • Activators convert the precursor plasminogen to plasmin |
| What does it do? Fibrinolytic system | • Plasmin cleaves fibrin strands to soluble fragments of fibrin (fibrin degradation products are X, Y, D, or E) • Can come from fibrin clot (fibrinolysis) or from unclotted fibrinogen (fibrinogenolysis) • D-dimer from crosslinked clot (clot specific) |
| Turn it off: Fibrinolytic system | • TPA inactivates by tissue plasminogen activator inhibitor (TPAI)- stops activation • Active plasmin inhibited by Alpha-2 Plasmin Inhibit if it escapes the area of the clot. This prevents fibrinogen-olysis |
| Excessive and inappropriate fibrinolysis | • Disseminated Intravascular Coagulation response to excessive clotting • Liver disease (activators are not cleared and the inhibitors are diminished) • Complications of cancer of surgery of the prostate or urinary tract where urokinase into circulation |
| Prothrombin Time (PT) | • Screen for extrinsic and common pathways • Measures I, II, V, VII, and X • Monitors oral anticoagulants (Warfarin, Coumadin) • Reagent- tissue thromboplastin and CaCl2 • Sensitive to Vitamin K factors • International Normalized Ratio: INR |
| Prothrombin Time (PT) reference range | <14 seconds and INR: 2.0-3.0 |
| Activated Partial Thromboplastin time (APTT) | • Screen for intrinsic and common pathways • Measures all factors EXCPET VII and XIII • Monitors heparin therapy • Reagents- activators (kaolin, celite or ellagic acid), platelet phospholipid (PF3) and CaCl2 |
| Activated Partial Thromboplastin time (APTT) reference range | 20-40 seconds • Therapeutic goal: 1.5-2.5 times “normal” or use Heparin Response Curve |
| Remember: monitoring by PT and APTT | • APTT=2 T's together remind you of an "H" =Heparin • PT= Coumarin, Vit K factors |
| Fibrinogen assay | Quantitative measure of Factor I |
| Fibrinogen assay reference range | 200-400mg/dl |
| Thrombin Time (TI) | • Does NOT measure defects in intrinsic/extrinsic pathways • Affected by decreased fibrinogen levels and presence of heparin and other anti-thrombins |
| Thrombin Time (TI) reference range | <20 seconds |
| In vivo aggregating agents: | • ADP • Collagen • Epinephrine • Thrombin • Serotonin • Arachidonic acid • Ristocetin • Snake venom • Antigen-antibody complexes • Fibrin degradation products (FDPs) |
| In vitro aggregating agents: | • ADP • Collagen • Ristocetin • Epinephrine • Thrombin • Arachidonic acid |
| Remember: Platelet adhesion disorders | • Wimpy Willie (von Willebrand's disease) = ↓ factor VIII and ↓vWF • Super Bernie (Bernard-Soulier)= GAINT platelets |
| Substitution of absorbed plasma and aged serum in PT and APTT test | • Aged serum (VII, IX, X, XI, XII) • Absorbed plasma (V, VIII, XI, XII, XIII) |
| Remember: Absorbed Plasma Vs aged serum | Absorbed Plasma is a young team that is going to win. They have a v-8 engine (V+VIII). the 4th member is is remembered by adding V+VIII=XIII. XI and XII are on both teams |
| Remember: absorbed plasma Vs Aged Serum | Aged Serum is an old team. Remember number your fingers starting with your left thumb. Hold you right thumb over the middle finger of your right hand. The members are the fingers remaining extended on your righr hand (VII, IX, X) XI and XII are on both. |
| Fibrinolysis testing | • Fibrin/fibrinogen degradation (split) products (FDP/FSP) Latex beads coated with anti-fibrinogen Positive screen in DIC • Latex D-dimer- monoclonal antibody to crosslinked D fragment; positive in DIC, deep vein thrombosis and pulmonary embolism |
| Hemophilia A: Inherited disorders | • Deficiency of Factor VIII • Sex linked recessive- almost exclusive to men • Spontaneous bleeding into joints • Treat with commercial Factor VIII |
| Hemophilia B: Inherited disorders | • Deficiency of Factor IX • Sex linked recessive- almost exclusive to men • Clinically identical in inheritance and symptoms to Hemophilia A • Treat with Factor IX concentrates |
| Hemophilia C: Inherited disorders | • Deficiency of Factor XI • Incomplete autosomal recessive • Wide range in clinical severity • High incidence in Ashkenazi Jews • Only contact factor associated with bleeding |
| von Willebrand’s Disease: Inherited disorders | • Primary defect in the vWF Factor • Usually secondary deficiency of VIII • Autosomal dominant-boy/girl affected = • Plt adhesion defect with prolonged bleeding time • Treat with cryo or DDAVP (drug); Factor VIII concentrates do NOT contain vWF |
| Factor XIII deficiency: Inherited disorders | • Autosomal recessive • NOT detected by common coagulation tests • Results in a significant bleeding disorder • Detected with 5M urea test |
| Lupus anticoagulant: Acquired disorders | • Directed against phospholipids • Seen in Lupus Erythematosis also seen in malignancies, infections, drugs therapy, and other autoimmune disorders • Use Plt neutralization techniques to confirm presence |
| Factor VIII inhibitor: Acquired disorders | • Most common specific inhibitor • APTT mixing studies differentiate factors deficiency from inhibitor • If corrected by normal plasma, a factor deficiency is indicated • If NOT corrected, an inhibitor should be investigated |
| Vitamin K deficiency: Acquired disorders | • Functional deficiency of factors II, VII, IX, and X • PIVKA molecules present but not functional • Vit K originates from diet and bacteria in gut • Seen in poor diet and with broad spectrum antibiotic use |
| Liver Disease (depending on severity or stage): Acquired disorders | • Deficiency of Factors I, II, V, VII, IX, and X • Factor VII deficiency most pronounced • Decreased clearance of plasminogen activators • Increased FDP due to fibrin(ogen)olysis |
| Disseminated Intravascular Coagulation (DIC): Acquired disorders | • Secondary to sepsis or obstetric complications • Thrombotic occlusion of microcirculations • RBC fragments • Consumption of platelets and factors I, V, VII • High levels of FDP and D-dimer |
| Thrombotic Disease: Arterial Event | Platelet driven (atherosclerosis, prosthetic heart devices) |
| Thrombotic Disease: Venous Event | • Blood flow problems (superficial or deep vein thrombosis) • Clot inhibitor deficiency (about 20%) • Factor V Leiden |
| Venous Event clot inhibitor deficiency- Antithrombin III (ATIII) | • Principle antagonist of active coagulation proteases • Produced in the liver • Activated by heparin sulfate on the endothelial cell and by heparin as therapeutic drug |
| Venous Event clot inhibitor deficiency- Protein C | • Vitamin K dependent serine protease • Activated by thrombomodulin on the endothelia cell • Requires Protein S cofactor • Inactivates Factor V and VIII |
| Venous Event clot inhibitor deficiency- Protein S | • Vitamin K dependent • Cofactor for Protein C • Bound and free state • Only free protein S is functional so measure total and free |
| Thrombotic Disease: Venous Event- Factor V Leiden | • Mutant factor V • Resists the action of Protein C/S • Activated Protein C resistance test |
Created by:
evk2369
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