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103 Cards in this Set
- Front
- Back
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hemostasis |
sealing of blood vessel *stops blood flow *complex system of activators and inhibitors *maintain blood fluidity *abnormal - excessive clotting (clotting w no injury or injury but too much clotting) |
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normal endothelium prevents hemostasis (sequence in normal hemostasis) |
*provides a physical barrier *secretion products that inhibit platelets (nitric oxide and prostaglandin I2 ) |
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vascular injury results in... (sequence in normal hemostasis) |
*vasoconstriction - transient event - slows blood loss and slows local blood flow *vasoconstriction caused by: - neural reflex action - local secretion of constriction factors - thromboxane A2 in small vessels |
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primary hemostasis (sequence in normal homeostasis) |
*platelet event (primary platelet plugs over the site of injury) involves: *adhesion - bind to exposed subendolium collagen *activation - spit out granules *aggregation - indirectly bind to each other to seal off injury and prevent blood loss |
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secondary hemostasis (sequence in normal homeostasis) |
*biochemical event *platelet plug is solidified through interaction between platelet membrane, enzymes, and coagulation factors *goal = generation of fibrin |
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fibrin |
*circulates in inactive form *insoluble strand-like protein forms mesh around platelet plug *stabilizes the platelet plug |
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tertiary hemostasis (sequence in normal homeostasis) |
*regulatory proteins keep coagulation cascade at site of injury ONLY *coagulation cascade activity ceases once enough fibrin has been generated *clot is dissolved through proteolysis |
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two types of hemostatic problems |
*bleeding: inability to form platelet plug or problems with fibrin *thrombosis: lose ability to regulate those system; inappropriate clotting (too much or when we don't need it -- can move to other parts causing stroke, heart attack, etc.) |
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localized vs. general bleeding |
*an important tool in ruling out the cause of hemorrhage *localized: trauma or acute injury *generalized: some underlying defect in the primary or secondary hemostatic system (coagulopathy - inability to form a clot) |
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mucocutaneous vs. anatomic bleeding |
mucocutaneous
*issue with platelets (not enough or issues within themselves) *bleeding in mucous and skin membranes (nose bleed, menstrual bleeding) *primary hemostatic defect anatomic *bleeding in joints, body cavity, muscles, CNS *secondary hemostatic defect (issue with coagulation factor deficiency) |
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thrombosis |
*occlusion of a blood vessel after injury *occlusion can: -be localized or travel (thromboemboli) -grow suddenly or slowly |
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Process of Hemostasis |
1. Vascular injury 2. Adhesion (and activation) 3. Aggregation (primary hemostatic plug) 4. Fibrin formation via cascade (secondary hemostasis) 5. Fibrinolysis and healing |
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Vascular Intima |
*endothelial cells *innermost lining of blood vessels *smooth surface that promotes the fluid passage of blood (keeps turbulent flow from happening so RBCs don't bump into each other) |
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Procoagulant Properties of Vascular Intima |
*Step 1. Vasoconstriction (smooth muscle contracts; vascular lumen narrows; blood flow to injured site is minimized) *Step 2. exposure of collagen (basement membrane); allows platelets to bind *Step 3. von Willebrand factor (adhesion of platelets) *Step 4. injured endothelial cells expose tissue factor (initiation of coagulation cascade to create fibrin) |
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Platelets (thrombocytes) |
*Cellular fragments *Light blue with red-purple granules when Wright's stain is used *Lifespan of 8-9 days *1/3 are stored in the spleen and released into circulation as needed *production controlled by thrombopoeitin (stems cells to differentiate into megakaryocytes) |
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Role of platelets |
*surveillance of vascular integrity *formation of primary hemostatic plug *platform for secondary hemostasis *healing |
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Platelet anatomy |
*peripheral zone with glycoprotein recepts *structural zone with contractile microtubules *organelle zone with granules *membrane with open canalicular and tubule systems (granules released once activated) |
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Platelet function |
*adhesion to basement membrane collagen directly or via vWF *activation: - shape change - exposure of GP IIb/IIIa and other receptors - TXA2 synthesis |
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Resting platelets |
*2-4 micrometers *oval/disc shape *contains two distinct zones: - hyalomere - granulomere |
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Activated platelets |
*large number of pseudopods (spiky) develop *granules are expelled |
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Granulomere contents |
*Two major types: - α (alpha) granules - 𝛿 (delta) granules (dense bodies) |
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Alpha granules |
*contents play an important role in platelet adhesion, blood coagulation, and the initial phase of vascular repair |
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Dense / delta granules |
*adenine nucleotides *Ca2+ - coagulation cascade *Histamine - increases vascular permeability *Serotonin - spasms in vessel *Epinephrine - constriction *contents facilitate platelet aggregation and vasoconstriction at the site of vessel injury |
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Platelet adhesion |
*Initial phase of primary hemostasis *Within veins: -platelets bind directly with collagen via receptor GP Ia/IIa *Within arterial and capillary circulation: -vWF binds to collagen -platelets bind to vWF via GP Ib/IX |
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vonWillebrand Factor (vWF) (platelet adhesion) |
*Glycoprotein *Endothelial cells, stored in Weibal-Palade bodies *Function: forms bridge between exposed collagen and GP receptor (Ib/IX) on platelet surface |
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Platelet activation |
*adhesion to vessel wall causes activation *exposure of GP IIb/IIIa receptor (important for aggregation) *release of α and 𝛿 granules initiated by increase in Ca2+; granule membrane fuses w membrane of open canalicular system *results in: synthesis and release of TXA2 and platelet activting factor (PAF) and ADP and Ca2+
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Platelet Aggregation |
*Mediated primarily by fibrinogen - binds to GP IIb/IIIa on adjacent platelets - occurs after activation *Aggregation leads to the formation of the primary platelet plug |
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Laboratory Tests |
*platelet quantitative measurements - platelet counts * platelet qualitative measurements - platelet morphology - bleeding time - platelet aggregometry tests |
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Deficiencies of platelet adhesion |
*vonWillebrand Disease *Bernard-Soulier Syndrome |
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vonWillibrand Disease (vWD) |
*Conditions that affect synthesis of vonWillibrand Factor (vWF) *Type I: most common, quantitative (mild-moderate), mild or moderate mucocutaneous bleeding *Type 2: qualitative; structure of glycoprotein vWD, autsomal dominant *Type 3: quantitative; severe deficiency - little to none; decreased factor VIII; autosomal recessive |
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vonWillibrand Laboratory Values
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*platelet count: normal *bleeding time: prolonged *prothrombin time (PT): normal *activated partial thromboplastin time (aPTT): variable (Type III - abnormal) *vWF: decreased *Factor VIII: normal or decreased |
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vonWillibrand Diagnostic Tests |
*vWF antigen assay: >30 IU/dL; diagnostic *collagen binding assay *Factor VIII levels - to see if they have type 3 |
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vWD treatment |
*avoid anti-platelet agents (particularly Aspirin, prevents clumping) *DDAVP: first line of treatment (type 1), anti-diuretic; stimulates release of vWF from endothelial cells *vWF concentrates: intravenous; combination of vWF and Factor VIII *component therapy: fresh human plasma, cryoprecipitate (coagulation & vWF factors) |
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Bernard-Soulier Syndrome |
*AKA "large platelet disease" *thrombocytopenia, large platelets, mucocutaneous bleeding *Autosomal recessive *Quantitative and qualitative defect in GP Ib/IX complex |
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Clinical Manifestations of Bernard-Soulier Syndrome |
*Severe bleedings - Purpura: hemorrhages underneath the skin - Epistaxis: nose bleeding -Gingival bleeding: bleeding of the gums -Menorrhagia: increased menstrual bleeding |
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Bernard-Soulier Syndrome Laboratory Values |
*Bleeding time: prolonged *Platelet count: decreased (due to platelet survival time) *Diff: giant platelets(5-8 micrometers) * Platelet aggregation: - absent with bovine vWF or ristocetin - reduced with thrombin - normal with ADP, collagen, epinephrine |
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Bernard Soulier Syndrome Treatment |
*Avoid anti-platelet agents (aspirin) *Platelet transfusions *DDAVP *Recombinant factor VIIa |
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How does aggregation occur? |
*platelets clump indirectly with fibrinogen to form primary platelet plug *doesn't bind directly *IIb/IIIa allows for them to bind to fibrinogen |
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Glanzmann Thrombasthenia |
*autosomal recessive *quantitative or qualitative defect in IIb/IIIa complex *severe and debilitating bleeding episodes |
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Glanzmann Thrombasthenia Laboratory Values |
*platelet count: normal (doesn't play a role in platelet lifespan) *bleeding time: prolonged *platelet aggregation: -normal with ristocetin and vWF - abnormal with ADP, collagen, or epinephrine |
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Glanzmann Thrombasthenia Management |
*avoid anti-platelet agents *platelet transfusions *recombinant factor VIIa |
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Three types of deficiencies of platelet secretion |
* α granule deficiency * 𝛿 granule deficiency * other storage pool disease |
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Dense Granule Deficiency |
*autosomal dominant *abnormalities in platelet aggregation due to lack of proper ADP release |
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Alpha Granule Deficiency |
*AKA "Gray Platelet Syndrome" *Autosomal recessive *lifelong mild bleeding with thrombocytopenia and enlarged platelets |
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Other Storage Pool Diseases (2) |
*Alpha and Dense Granule Deficiency - autosomal dominant *Quebec Platelet Disorder - autosomal dominant - stored platelet plasminogen is converted to plasmin (degrades the clot that formed) |
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Secondary Hemostasis |
*Formation of fibrin by means of the coagulation cascade *Circulating coagulation factors acting as enzymes and cofactors, Ca2+, and platelets *defects in cascade lead to more serious bleeding *involves a series of zymogen activation reactions *at each stage, precursor protein is converted to an active protease by cleaveage of one or more peptide bonds |
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Components involved in zymogen activation reactions of secondary hemostasis |
*a protease - active enzyme (cleaves a few amino acids off of zymogen to activate) *a zymogen *a non-enzymatic protein cofactor *Ca2+ *organizing surface |
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3 pathways of coagulation cascade |
*Intrinsic -high-molecular weight kininogen (HMWK), prekallikrein, and Factors XII, XI, IX, VIII -factor VIII acts as a cofactor for the factor IX-mediated activation of factor X *Extrinsic -tissue factor (III) and factor VII activate factor X *Common -factor X-mediated generation of thrombin from prothrombin; Factor V acts as a cofactor -production of fibrin from fibrinogen |
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The main pathway for initiation of coagulation is... |
*extrinsic pathway *intrinsic pathway acts to amplify the coagulation cascade |
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Intrinsic Pathway |
*factors circulate in inactive form *source of phospholipid is platelet membrane *initiation requires exposure to negatively charged surfaces (contact phase) *formation of the primary complex on negatively charged surface by HMWK, prekallikrein, and Factor XII *XII is activated; prekallikrein is converted to kallikrein XIIa > XI > XIa > IX > IXa along with its cofactor VIIIa activate X |
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Extrinsic Pathway |
*tissue factor (TF/III) not normally found in blood *Source of phospholipid is TF *Initiation requires release of TF into circulation *Initiation bypasses contact phase *exposure of tissue factor *TF is expressed by endothelial cells, subendothelial tissue, and monocytes *TF/VIIa complex activates factor X |
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Common Pathway |
*Factor Xa, in the presence of Factor Va, Ca2+ and platelet phospolipid activate prothrombin to thrombin *Thrombin cleaves fibrinogen to form soluble fibrin monomers polymers *Thrombin also activates factor XIII, which, together with Ca2+, crosslinks and stabilizes the soluble fibrin polymer, forming cross-linked (insoluble) fibrin |
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Thrombin |
*Activation of Factor XIII *Activation of Factor XI *Activation of Factors V and VIII > cofactor |
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Cofactors: Vitamin K |
- factors II (prothrombin), VII, IX, and X, as well as Proteins C, S, and Z (anticoagulant proteins) - post-translational modification: cofactor for y-glutamyl carboxylase that adds a carboxyl group to glutamic acid residues so that VII, IX, and X can be activated |
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Cofactors: Substances required for coagulation cascade |
*Ca2+ and platelet phospholipid *required for the tenase (IXa - VIIIa) and prothrombinase (Xa - Va) complexes to function *Ca2+ mediates binding via the terminal gamma-carboxy residues on Factor Xa and IXa to the phospholipd surfaces expressed by platelets *Ca2+ is also requird at other points in the coagulation cascade: XIIa + Ca2+, XI, XIa |
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Laboratory Testing |
*We cannot mimic the coagulation cascade as it is found in vivo (in the body) *Series of in vitro tests: prothrombin time (PT), activated Partial Thromboplastin Time (aPTT), Thrombin time (TT) *Each measure the time elapsed from activation of the coagulation cascade at different points to the generation of fibrin |
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Prothrombin Time (PT) |
*Measured in seconds (normal reference range 10-14 seconds) *Time necessary to generate fibrin after activation of Factor VII *Measures extrinsic and common pathways (Factors VII, V, X, prothrombin, and fibrinogen) *More sensitive than the aPTT for deficient levels of factors |
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Activated Partial Thromboplastin Time (aPTT) |
*Measured in seconds (normal 25-35 sec.) *Time necessary to generate fibrin from initiation of the intrinsic pathway and common pathway *abnormal with decreased quantities of factors of the intrinsic and common pathways *prolonged if a patient has less than approximately 30% normal activity |
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Thrombin Time (TT) |
*Measured in seconds (14-16 seconds) *Time of the reaction of fibrinogen to fibrin in the presence of thrombin *if clot formation is prolonged = quantitative or qualitative fibrinogen defect |
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Factor Assays |
*Directly measures % concentration of factor *Two methods to determine specific factor activities: 1. ability of the patient plasma to correct the prolonged clotting times of deficient plasma 2. chromogenic substrates |
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Factor Assays: Chromogenic Assays |
*Ability of the factor to cleave a chromogenic-linked substrate is assessed - example: factor VIII chromogenic assay *factor VIII in the patient sample is activated by a reagent containing thrombin and activated IX *VIIIa and IXa activate X *activity of Xa is assessed by hydrolysis of a chromogenic substrate *the intensity of color produced is proportional to the activity of Xa and thus to VIII activity |
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Factor Assays: Clotting Assays |
*Ability of the patient's plasma to normalize prolonged coagulation time of specific factor-deficient plasma *the clotting time of the patient in factor-deficient plasma is compared to a standard curve *activity of the coagulation factor being measured is reported as a % of the standard pool |
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Hemophilia A cause (most common) |
*deficiency in Factor VIII *Factor VIII: - carried in peripheral circulation by vWF (to stabilize VIII) - activated by thrombin *deteriorates at about %5/hr at RT (falsely prolonged aPTT if you leave it out) |
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Hemophilia A genetics |
*X-linked recessive *Occurs in males and homozygous females |
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Hemophilia A physical manifestations |
*anatomic bleeding into joints, muscles - hemarthrosis: rapid joint swelling (knee, elbow, etc.) - bleeding in CNS, GI tract, and kidneys |
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Hemophilia A laboratory diagnosis (PT, aPTT, TT) |
VIII > intrinsic pathway PT: normal aPTT: prolonged thrombin time: normal |
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Factor VIII Activity Level |
severe: < 1% (<1 IU/dL)
moderate: 1-5% (1-5 IU/dL) mild: 5-30% |
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Hemophilia A treatment |
goal: increase factor VIII *recombinant factor VIII (genetically engineered) *DDAVP (antidiuretic hormone) *Factor VIII concentrate (fresh plasma) |
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Hemophilia B |
*Factor IX deficiency (Christmas Factor) *X-linked recessive treatment: IV administration of IX concentrates |
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Hemophilia B tests (PT, aPTT, Factor IX?) |
PT: normal aPTT: prolonged Factor XI: decreased |
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Hemophilia C |
*Factor XI deficiency *autosomal recessive trait (chromosome 4) *rare for spontaneous or joint bleeding |
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Hemophilia C laboratory values (PT, aPTT, Factor XI) |
PT: normal aPTT: prolonged XI: decreased |
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Hemophilia C treatment |
*rarely required *fresh frozen plasma *factor XI concentrates in Europe (illegal in USA) |
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Circulating Inhibitors |
*exogenous factor concentrates can produce alloantibodies -develop in approx.20-30% w severe Hemo. A |
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Circulating Anticoagulants |
*causes excessive clotting (in-vivo) *anti-phospholipid (in-vitro) *prolonged aPTT *Associated with thrombosis / thrombocytopenia (increases risk of bleeding)
Type: -Lupus anticoagulant (LA) - Anti-cardiolipin antibody (ACA) |
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Mixing Studies - patient plasma that has prolonged aPTT |
*Add normal plasma 1:1 ratio -Prolonged aPTT: circulating coagulant -Normal aPTT: factor deficiency |
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Bethesda Assay |
*Quantitate the concentration of a factor VIII inhibitor *Bethesda unit = amount of inhibitor that will inactivate the half of a coagulant during the incubation period |
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Tertiary Hemostasis |
*Regulatory proteins keep coagulation site at site of injury *Coagulation cascade activity ceases *Clot is dissolved through proteolysis |
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Fibrinolysis mechanism |
*tissue plasminogen activator (tPA) is released from vascular endothelial cells (stimulated by tissue damage and bradykinin) *tPA binds to plasminogen within the clot, converting it into plasmin; requires fibrin *plasmin lyses both fibrinogen and fibrin in the clot |
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Fibrinolysis |
*The enzymatic dissolution of cross-linked fibrin polymers -plasminogen activated into plasmin *also breaks down fibrinogen and factors V and VIII |
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Other plasminogen activators |
*Urokinase *Factor XII *Kallikrein |
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Fibrin degradation products |
*fragments of fibrin breakdown *X, Y, D, E, D-D (D-D made from breakdown of blot clots) |
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D-Dimer Assay |
*Latex agglutination assays -measures binding of an antibody to a D-dimer fragment |
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Inhibitors of Fibrinolysis |
*Plasminogen Activator Inhibitor 1 (PAI-1) -secreted from endothelial cells, inhibits tPA *Alpha-2-plasmin inhibitor - rapidly and irreversibly binds free plasmin |
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What are the factors that feed the cascade? |
VII, XII, XI |
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Coagulation cascade inhibitors |
*Tissue Factor Pathway Inhibitor (TFPI): shuts down extrinsic pathway, inhibiting TF *Antithrombin (AT): thrombin and contact activation pathway (IX, X, XI, XII) - heparin binds to antithrombin and changes shape, giving AT a higher affinity for the factors it needs to break down |
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Proteins C & S |
*Vitamin K dependent *Thrombin activates thrombomodulin -this complex activates the Protein C zymogen -activated protein C (APC) binds with Protein S -Protein C-S complex inactivates Va and VIIIa |
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Antithrombin deficiency |
*autosomal dominant or acquired *quantitative or qualitative defect *predisposition to venous and arterial thrombotic disease - deep vein thrombosis (DVT) - pulmonary embolism (PE) |
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Antithrombin deficiency treatment |
*acute: IV heparin, followed by oral anticoagulant therapy (warfarin) *ongoing thrombosis: antithrombin concentrates until therapeutic dose of oral anticoagulant is achieved *prophylaxis: antithrombin concentrates |
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Protein C deficiency |
*autosomal dominant or acquired *quantitative or qualitative *manifestations - DVT, PE - warfarin-induced skin necrosis - neonatal purpura fulminans |
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Protein C deficiency treatment |
*protein C concentrate *life-long anticoagulant therapy |
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protein s deficiency |
*autosomal dominant or acquired * quantitative or qualitative *DVT, PE, WISN, NPF |
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Disseminated Intravascular Coagulation (DIC) |
-acquired disorder of hemostasis -generalized activation of coagulation and fibrinolytic systems - thrombin and plasmin produced at a rate that exceeds ability of inhibitors to neutralize them - complication of another disease process |
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DIC is characterized by: |
*consumption of coagulation factors and platelets *generation of thrombin *widespread deposition of fibrin in small vessels *increased formation of FDPs |
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DIC Etiology |
*primary disease introduces Tissue Factor or Tussue Factor-like substances (extrinsic pathway) into the circulation |
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DIC: Acute vs. Chronic |
Acute: -80-90% -sudden exposure of blood to TF-like substances -compensatory hemostatic mechanisms are quickly overwhelmed Chronic: -10-20% -blood is continuously or intermittenly exposed to small amount of TF (slow) - compensation: not overwhelmed |
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Clinical Conditions Associated with Development of DIC |
*Infections - most common (fungal, viral, etc.) *Pregnancy (retained placenta, septic abortion) *Massive tissue injury (burns, head injury, etc.) *Snake Bites (activate X, prothrombin, fibrinogen) *Malignancies (acute promyelocytic leukemia, adenocarcinomas) |
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DIC Pathophysiology |
*Systemic generation of thrombin *Fibrin clots trap platelets = larger clots *thrombocytopenia *endothelial cells release tPA *on-going generation of plasmin *excessive fibrinolysis = fibrin degradation products (FDP) *coagulation inhibitors antithrombin and thrombomodulin are overwhelmed: more clotting |
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Manifestations of DIC |
*renal failure *neurologic dysfunction *liver failure *respiratory failure *skin necrosis, gangrene *bleeding *jaundice *Mortality: 50-60% |
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Clinical Aspects of DIC |
*Bleeding (at 3 or more sites) *Microvascular thrombosis - predominant in chronic DIC - fibrin strands obstruct microvasculature * Microangiopathic hemolytic anemia - RBCs become fragmented resulting in intravascular hemolysis |
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DIC Laboratory values |
*platelet count: decreased *PT: prolonged *aPTT: prolonged *fibrinogen: decreased *d-dimer: increased |
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DIC Laboratory Diagnosis |
* >90% certainty: - PT, fibrinogen, and platelet count are abnormal OR - 2 out of 3 tests are abnormal with elevated FDP (d-dimer) |
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DIC treatment |
*most important: primary condition *DIC with bleeding requires replacement therapy (platelets, RBCs, cryoprecipitate, FFP) *DIC with thromboemboli requires heparin |
