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74 Cards in this Set
- Front
- Back
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Q: Describe the coagulation system.
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-this system involves the sequential activation of many inactive proteins normally present in the bloodstream, the ultimate result is the formation of a fibrin clot, which deposits on the platelet plug to arrest bleeding from damaged vessels, there is a transformation of inert coagulation factors into active enzymes
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Q: What are the different components of the coagulation system?
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-there is an intrinsic pathway, extrinsic pathway and common pathway
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Q: What are the coagulation factors used in the coagulation system?
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-twelve factors plus-prekallikrein and HMWK
-most made in liver, vWF in endothelium -most are proenzyme to enzyme conversions except I, III, IV, VI |
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Q: Which of the coagulation factors are vita K dependent?
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-II, VII, IX and X
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Q: What are the unique factors to the intrinsic pathway?
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-VIII (Ca2+, platelet factor III), IX, XI, XII
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Q: What are the lab assays used to study the intrinsic pathway?
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-activated plasma thromboplastin time (aPTT)
-can also detect abnormalities in prekallikrein, HMW kininogen, factors in the common pathway, circulating inhibitors |
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Q: What are the steps involved in the intrinsic pathway?
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-Factor XII (Hageman Factor) -> XIIa (via HMWK collagen)
-XIIa activates XI to XIa and turns prekallikrein to kallikrein -XIa activates IX -thrombin activates VIII -IXa and VIIIa activate X with Ca2+ |
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Q: Describe the extrinsic pathway. What factors are unique here?
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-is the major initiator of coagulation cascade
-unique factors include III (tissue thromboplastin which is factor VIIa-tissue factor complex) and VII |
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Q: What are the lab assays used to study this pathway?
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-prothrombin time (which is also used to detect problems in the common pathway)
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Q: What are the steps involved in the extrinsic pathway?
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-tissue injury leads to formation of tissue factor (thromboplastin)
-thromboplastin activates VII -VIIa activates X with Ca2+ joining the intrinsic pathway |
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Q: What steps are involved in the common pathway?
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-X becomes activated to Xa
-thrombin activates V -Va + Xa + Ca2+ activates II (prothrombin) to IIa (thrombin) -thrombin activates both factor XIII (with Ca2+) and I (fibrinogen) to fibrin -XIIIa stimulates fibrin (monomer/polymer) to form a stable fibrin polymer |
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Q: Where does the coagulation cascade take place?
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-these components are typically assembled on a phospholipid complex and held together by Ca2+ ions
-this allows clotting to remain localized to sites where such assembly can occur (on the surface of activated platelets or endothelium) |
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Q: What are the functions of thrombin?
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1. activates factor VIII
2. activates factor V 3. activates factor XIII 4. activates factor I (fibrinogen) 5. induces platelet aggregation and secretion of TxA2 6. activates endothelium to generate leukocyte adhesion molecules 7. activates endothelium to generate t–PA, NO, PGI2 and PDGF |
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Q: What is the mechanism of function of thrombin concerning local vasculature?
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-most of these effects are induced via binding to a family of protease-activated receptors (PARs) that belong to the seven-transmembrane G-protein-coupled receptor family
-activation of receptors is caused by clipping the extracellular end of the thrombin receptor via thrombin, this conformational change activates associated G protein |
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Q: What are the anticoagulants that keep the coagulation cascade restricted to the local site of injury?
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-antithrombins, proteins C and S, and tissue factor pathway inhibitor (TFPI)
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Q: Describe antithrombins and their role as an anticoagulant.
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-inhibit the activity of thrombin and other serine proteases (factors IXa, Xa, XIa and XIIa), antithrombin III is activated by binding to heparin-like molecules on endothelial cells hence the clinical usefulness of administering heparin to minimize thrombosis
-in the presence of heparain, thrombin is pimary target |
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Q: Describe proteins C and S as anticoagulants.
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-they are two vitamin K-dependent proteins, are characterized by their ability to inactivate factors Va and VIIIa, the activation of protein C by thrombomodulin was described earlier
-protein C activated by binding of thrombin to thrombomodulin, proteins S enhances activity |
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Q: Describe tissue factor pathway inhibitor (TFPI).
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-a protein secreted by endothelium (and other cell types), complexes to factor Xa and to tissue factor-VIIa and inactivates them to rapidly limit coagulation (mediates feedback inhibition), DEC activation of factors IX and X
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Q: Describe the fibrinolytic cascade.
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-limits the size of the final clot by generating plasmin
-plasmin is derived from enzymatic breakdown of its inactive circulating precursor plaminogen either by a factor XII dependent pathway or by two distint types of plasminogen activators (u-PA or t-PA) |
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Q: Describe inhibitors of the fibrinolytic system.
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-tissue factor pathway inhibitor, antithrombin III, protein C, protein S, thrombomodulin
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Q: Describe activators of the fibrinolytic system.
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-thrombin, kallikrein, tissue plasminogen activator, urokinase, streptokinase, staphylokinase
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Q: Describe u-PA.
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-urokinase-like PA, present in plasma and various tissues and capable of activating plaminogen in the fluid phase
-plasmin converts the inactive pro-urokinase precursor to the active u-PA molecule creating an amplification loop |
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Q: Describe t-PA.
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-synthesized principally by endothelial cells and is most active when attached to fibrin, is a more useful therapeutic agent because it targets the fibrinolytic enzymatic activity to sites of recent clotting
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Q: What else can activate plasminogen?
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-streptokinase
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Q: What is the function of plasmin?
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-breaks down fibrin and interferes with its polymerization, the resulting fibrin split products (FSPs or fibrin degradation products) can also act as weak anticoagulants
-plasmin doesn’t distinguish between fibrinogen and fibrin |
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Q: What do FSPs do?
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-INC vascular permeability and interferes with thrombin induced fibrin formation
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Q: What happens with elevated levels of FSPs?
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-usually measured as D-dimer
-useful for diagnosing abnormal thrombotic states such as DIC, deep venous thrombosus, or pulmonary thromboembolism -any free plasmin rapidly complexes to alpha2-plasmin inhibitor and is inactivated |
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Q: What do plasminogen activator inhibitors (PAIs) do?
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-released by endothelial cells to block fibrinolysis by inhibiting t-PA binding to fibrin, is a pro-coagulant
-INC by thrombin as well as certain cytokines and probably play a role in the intravascular thrombosis accompanying severe inflammation |
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Q: Describe prothrombin time.
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-most frequently performed coagulation test, uses tissue thromboplastin and ionized calcium
-when these reagents are added to citrated plasma, these substitute for tissue factor to activate factor X in the presence of factor VII without involving platelets or the procoagulants of the intrinsic pathway |
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Q: What does pro time look at?
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-to get normal PT value, plasma must have at least 100 mg/dL of fibrinogen and adequate levels of factors VII, X, V and prothrombin
-evaluates extrinsic system (II, VII, as well as I, V, and X), doesn’t evaluate intrinsic factors or platelets |
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Q: What do elevated PTs mean?
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-prolongation of the PT as an isolated finding when the PTT (partial thromboplastin time) is normal occurs only in factor VII deficiency
-prolongation of PT and PTT can occur for a variety of reasons, including very high heparin levels, fibrinogen, multiple coagulation factor deficiencies, oral anticoagulation therapy (coumadin), liver disease, vitamin K deficiency and deficiencies of factors in the common pathway (factor V) |
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Q: What is the activator and endpoint of PT?
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-activator is complete tissue thromboplastin (tissue factor + phospholipid (platelet substitute) + calcium)
-endpoint is the fibrin clot |
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Q: Is PT standardized?
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-YES, by international normalized ratio (INR), developed fro patients receiving stable oral anticoagulant therapy
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Q: Describe activated partial thromboplastin time (aPTT).
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-plasma is removed and placed in a sample tube, it is then recalcified and a reagent containing surface-active factors such as kaolin and phospholipid is added
-kaolin enhances the speed of contact activation while the phospholipid provides a surface on which the coaguatlion enzyme substrate reacions can occur -time taken for the clot to form is the aPTT |
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Q: What does the aPTT evaluate?
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-assesses the intrinsic coagulation and common coagulation pathway
-this test measures the presence of factors VIII, IX, XI and XII which must all be present at adequate levels to have a normal aPTT, factors I, II, X, V, prothrombin, and fibrinogen must also be present, VII is not needed because the test bypasses extrinsic pathway (also doesn’t evaluate platelets) |
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Q: What is the activator and endopoint of aPTT?
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-activator is incomplete tissue thromboplastin (phospholipid (platelet substitute) + calcium + contact activator (XII))
-endpoint is fibrin clot |
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Q: When is aPTT abnormal?
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-heparain, factor deficiencies (hemophiliac) and inhibitors
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Q: Describe thrombin time (TT).
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-a tests that assesses fibrinolytic pathway activation, because this results in the release of plasmin which cleaves fibrin and fibrinogen, fibrinogen may be DEC or the fibrinogen degradation products so released may competitively inhibit thrombin/fibrinogen interaction
-consequently if circulating fibrin degradation products are present, this competitive inhibition of thrombin/fibrinogen interaction may prolong the thrombin time -activator is thrombin |
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Q: When is TT abnormal?
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-low fibrinogen, inhibitors FDP, fibrinolysis, heparain
-hypofibrinogenemia, dysfibrinogenemia, heparin, fibrin split products |
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Q: Why would different coagulation assays be mixed?
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-done to see if the abnormality can be correct, take normal plasma and mix with patient plasma and studies are rerun
-if abnormality correct then most likely a factor deficiency -if abnormality doesn’t correct then think inhibitor or anticoagulant |
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Q: Describe the mixing studies.
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-used to confirm either deficiency or presence of inhibitor or anticoagulant, add different agents to the patient’s plasma to see what corrects the abnormality
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Q: Describe the D-dimer assay.
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-when fibrin but not fibrinogen is cleaved by plasmin, neoantigens are released, in this case two D fragments from the gamma crosslinkage site of fibrin
-the test uses a monoclonal Ab directed against the DD fragment (D-dimer), not specific for fibrinogen and therefore identifies plasmin action on cross-linked fibrin in a local or disseminated action |
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Q: Where are D-dimers found?
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-found in over 90% of patients with thrombotic or thromboembolic disorders
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Q: How is the D-Dimer assay measured?
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-semi-quantitative (monoclonal Abs to D-dimers bound to latex particles) or quantitative (EIA)
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Q: What are some general points concerning the coagulation assays?
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-virtually all factors or protein degradation products can be checked individually using specific assays (immunologically or based on activity studies)
-test specificities may overlap (multiple tests may be required |
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Q: What are some problems with coagulation assays?
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-appropriate anticoagulant proportions and mixing are critical
-specimens deteriorate, especially labile factors (3 hours RT or 6 hours 4C for aPTT) |
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Q: Describe Hemophilia A.
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-is a factor VIII deficiency or malfunction, most common hereditary disease associated with serious bleeding, inherited as an X-linked recessive trait
-exhibits a wide range of clinical severity that correlates with level of factor VIII functioning, severe (<2%, 2/3 of cases), moderate (2-5%), or mild (5-10%) |
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Q: What does factor VIII do?
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-serves as a cofactor for factor IX in the activation of factor X in the coagulation cascade
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Q: What is the clinical presentation of Hemophilia A?
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-tendency toward easy bruising (esp. after slight trauma) and massive hemorrhage after trauma or operative procedures, spontaneous hemarthrosis (hemorrhage at regions subject to trauma (particularly joints)), bleeding in GI tract, urinary, oral, intracranial
-petechiae are absent |
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Q: What lab findings are associated with Hemophilia A?
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-normal bleeding time, platelet count, and PT
-prolonged aPTT pointing to abnormality of the intrinsic coagulation pathway -factor VIII specific assays are required for diagnosis |
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Q: Why do patients bleed with hemophilia A?
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-with factor VIII deficiency, fibrin deposition is inadequant to achieve hemostasis
-the extrinsic pathway is done to produce an initial burst of thrombin activation -have inadequate coagulation and inappropriate clot removal |
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Q: What is the treatment for Hemophilia A?
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-infusion of factor VIII (virally inactivated), may be recognized by Abs, can give recombinant concentrate (Recombinate, Kogenate, Bioclate)
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Q: What are some complications of Hemophilia A?
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-hepatitis and AIDS
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Q: Describe hemophilia B (Christmas disease).
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-have severe factor IX deficiency, is clinically indistinguishable from Hemophilia A (since both factor VIII and IX function together to activate X), severity, tests used and complications are all also the same as Hemophilia A (except assay for factor IX)
-inherited as an X-linked recessive disorder |
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Q: What is vitamin K needed for?
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-required cofactor for a liver microsomal carboxylase that is necessary to convert glutamyl residues in certain protein precursors to gamma-carboxyglutamates
-clotting factors II, VII, IX and X and prothrombin all require carboxylation of glutamate residues for functional activity because carboxylation provides Ca2+ sites which allows them to interact with phospholipid surface |
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Q: What is the source of vitamin K?
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-premade in plants, formed in gut by bacteria
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Q: What happens with vitamin K deficiency?
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-major consequence is bleeding diathesis (unusual susceptibility to bleeding)
-usually takes 3 weeks to deplete normal reserves, found in newborns as well as in coumadin therapy, may be found in liver disease |
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Q: What are the lab findings associated with vitamin K deficiency?
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-have a prolonged PT and aPTT
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Q: What does antithrombin do?
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-antithrombin is a serine protease inhibitor of thrombin (and impairs its ability to clot fibrinogen), factors IXa, XIa and XIIa and plasmin
-it is produced by the liver and is part of the serpin family of inhibitors (alpha2-antithrypsin) |
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Q: Describe antithrombin deficiency.
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-leads to INC risk of thrombosis, often tends to be venous thromboses
-assays for antithrombin may determine immunologically the amount of AT protein present or may use a functional assay of the ability of the protein to inhibit thrombin/fibrinogen interaction |
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Q: Describe factor V Leiden (resitance to activated protein C).
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-patients have an inherited mutation of glutamine for arginine at #506 of factor V, factor V becomes resistant to activated protein C and leads to INC risk of thrombosis
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Q: What happens when activated protein C is added to an aPTT system?
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-the PTT is prolonged because of the inactivation of factors VIIIa and Va, subjects with APC resistance do not experience this prolongation and may have shorter PTT values
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Q: Describe prothrombin 20210.
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-inherited mutation where there is a single nucleotide substitution of guanine for adenine of the prothrombin gene
-get a three fold INC risk of thrombosis |
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Q: Describe hyperhomocytsteinemia.
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-can be an inherited or acquired disease that leads to INC risk of arterial and venous thrombosis, is an independent risk factor for atherosclerotic vascular disease (may be as significant as elevated cholesterol), get inhibition of antithrombin and thrombomodulin
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Q: Describe homocysteine.
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-a sulphur containing amino acid that is formed during metabolism of methionine and is an integral component of folate and cobalamin metabolism
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Q: Describe antiphospholipid antibody syndrome.
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-there are two main antiphospholipid Abs (lupus anticoagulant and anticardiolipin Ab)
-get inhibition the phospholipid interaction with the coagulation proteins and get venous and arterial thrombosis -get prolonged aPTT and may also get prolonged PT (don’t get correction with normal plasma as you would with a coagulation factor deficiency, so an inhibitor is present) |
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Q: Describe deficiencies of protein C and S.
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-protein C and S are vitamin K dependent and synthesized in the liver, they play a role in inhibiting Va and VIIa, deficiency leads to INC risk of thrombosis
-used immunologic assays or functional assays using chromogenic substrates to see if there is deficiency |
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Q: What is the function of coumadin?
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-an anticoagulant that prevents thrombosis and embolism in some disorders, it inhibits vitamin K utilization and affects factors II and VII more than IX and X
-have to monitor PT when giving patients coumadin, have a therapeutic goal of a PT prolonged 2-3 times INR, equilibration time = 5-10 days |
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Q: What is the function of heparin?
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-acts as an antithrombin and inhibits other factors (especially IX and X), synthesized in the liver, get normal anticoagulation at 60% activity level but thrombosis is probable at <60% activity
-requires antithrombin III as a cofactor -needs to be monitored with aPTT, therapeutic goal of 1.5-2.5 times normal -is the anticoagulant of choice in pregnancy |
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Q: Where is heparin found in the body?
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-stored within secretory granules in mast cells and released into the vasculature at the site of injury
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Q: What is the anticoagulant mechanism of action for heparin?
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-heparin binds to antithrombin causing a conformational change, antithrombin then inactivates thrombin and factor Xa
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Q: Describe lupus inhibitors.
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-are anti-phospholipid Abs that interfere with phospholipid reagents, get artificial prolongation of phospholipid-dependent tests (aPTT)
-results in thrombosis rather than bleeding in vivo, won’t correct with mixing study |
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Q: Describe factor VIII Ab.
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-seen in hemophiliacs and collagen vascular diseases, initially corrects with mixing study, then reverts to abnormal
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Q: Can coumadin be given to pregnant women?
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-NO, can lead to congenital malformations, bleeding and fetal bone malformations
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