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65 Cards in this Set
- Front
- Back
What is hemostasis?
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A combination of cellular & biochemical events that function in harmony to 1. keep blood liquid in veins & arteries; 2. prevent blood loss by thrombi formation; & 3. re-establish blood flow during the healing process.
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Cellular elements of hemostasis.
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- Vascular intima (blood vessels)
- Blood platelets - RBCs - Lymphocytes - Monocytes |
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Enzyme systems of hemostasis.
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Coagulation/fibrinolysis mechanisms.
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Mechanism of primary hemostasis.
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Activated by small injuries to blood vessels or damage to endothelial cells--> blood vessel contracts to seal the wound and platelet plug formation.
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Characteristic of primary hemostasis d/o.
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Mucous membrane hemmorhages.
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Mechanism of secondary hemostasis.
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- Is triggered directly or by primary hemostasis & is necessary to control bleeding from large wounds incurred through trauma, surgery, or dental procedures.
- Coagulation cascade resulting in the formation of cross-linked fibrin. |
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Primary procoagulant roles of the blood vessel.
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Constrict & provide collagen & other compounds to activate clotting.
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Anticogulant properties if intact endothelium.
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- Cells are rhomboid, presenting a smooth, contigious surface
- Secretes prostacyclin: plt. activation inhibitor - Secretes nitric oxide: counteracts vasocnstriction - Secretes heparan sulfate: slows coagulation by acivating antithrombin. - Secretes tissue factor pathway inhibitor (TFPI): inactivates coagulation factor VIIa & controls the tissue factor pathway. - Maintains cell membrane thrombomodulin, protein C coagulation control system activator. |
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Fibrinolytic properties of the vascular intima.
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Secretes tissue plasminogen activator (TPA) w/c binds fibrin & triggers the activation of plasminogen--> plasmin w/c digests the thrombus & re-stores blood flow.
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Release process of platelets into peripheral circulation from the bone marrow.
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Megakaryocytes cytoplasmic fragments extend through the endothelial cells, lining the sinusoids, into blood & then shed platelets.
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Platelet ultrastructures.
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- Membrane resembles any biologic membrane; a bilayer composed of proteins & lipids.
- Platelet membrane supports categories of receptors that support the initial phases of plt. adhesion & aggregation. |
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Most important adhesion receptor.
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GP Ib/IX/V= vWF receptor (CD42)
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Receptor for fibrinogen.
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GP IIb & IIIa- "hidden" receptor in resting plt.; required for plt. aggregation.
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Platelet structural zone.
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- Consists of microtubules & a network of proteins (maintain plt. shape & contract on activatin to encourage expression of alpha-granule contents)
- Actin is the most abundant protein. |
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Function of platelet granules.
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Serve as storage sites for proteins & other substances essential for platelet function.
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Dense bodies (delta granules).
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Appear more dense in electron microscope preparations- contain mediators of plt. function & hemostasis that are not proteins (ADP, serotonin, ATP, Ca+ & Mg+).
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Alpha granules.
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- Most numerous plt. granule contains hemostatic & non-hemostatic proteins.
- Some are synthesized by the plt (vWF & Factor V). - Others sre absorbed/endocytosed from the plasma (fibrinogen, Ig, albumin) - Some alpha granule contents are found exclusively in plts (i.e., PF4, PDGF, PAI-1) |
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Function of platelet derived growth factor (PDGF).
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Stimulates smooth muscle to multiply & replace the damaged cells (allowing the vessel to heal).
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Primary hemostatic plug.
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Is the result of the transformation of plts from an inactive (non-adhesive) to an active (adhesive) state.
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Events involved in the normal formation of primary plug.
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1. Adhesion
2. Aggregation 3. Granule secretion 4. Secondary hemostasis |
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Platelet adhesion.
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- 1st step in primary plug formation.
- Attachment of plt. to collagen fibers in subendothelium (directly in low shear stress areas) - Requires the presence of vWF & the GPIb/IX/V receptor (in high shear stress areas to "carpet" the injury site. - Does not include the secretion of granules. |
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Agonist.
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- Substances that stimulate & activate platelets.
- Collagen, Thrombin, ADP, Epinephrine, Thromboxane A2 |
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Platelet aggregation.
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- Attachment of platelets to each other.
- Required the active conformation of the GPIIb/IIIa receptor. - Part of primary hemostasis (plt-vWF plug) |
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Platelet secretion.
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- Plt granule content d/c into the surrounding area.
- Requires ATP. - Delta granules release ADP & Calcium necessary for fibrinogen attachment & secondary hemostasis. - Release of alpha granules --> secondary hemostasis. |
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Other blood cells role in coagulation.
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- RBCs: add bulk to fibrin clot.
- Lymphocytes & monocytes: provide tissue factor that triggers coagulation in inflammation. |
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Serine proteases.
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- Proteolytic enzymes: Factor 2, 7, 9, 10,11, 12, & pre-Kallikrein.
- Function in harmony to form a fibrin clot (secondary hemostasis). - Absence of a single plasma procoagulant --> lifelong hemorrhage, chronic inflammation, transfusion dependence. |
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Coagulation system.
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- Activation of procoagulants is localized to the site of the injury.
- Occurs on the surface of the plts/endothelial cell membrane phospholipids (not in fluid phase). |
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Fibrinogen (Factor I).
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- Ultimate substrate (acted upon by the enzyme thrombin) of the coagulation pathway.
- The only coagulation protein that does not become an activated enzyme. - Forms the primary structural protein of the fibrin clot. - Refrence range: 200-400mg/dL |
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Zymogens.
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Enzymes that circulate in an inactive form.
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Cofactors.
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- Bind specific serine proteases--> stability & increased reactivity of enzyme.
- Tissue factor, Factor 5, 8, & high molecular weight kininogen (HMWK). |
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Factor XIIIa.
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The only coagulation protein w/ transglutaminase activity- form stable, covalent, fibrin cross links.
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Vitamin K dependent.
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- Prothrombin (Factor II)
- Factor 7, 9, & 10. - Regulatory proteins: protein C & S. |
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Vitamin K.
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- Fat soluble vitamin (quinone) found in green leafy vegetables, fish, liver.
- Synthesized by some Gram negative bacteria. - Catalyzes glutamic acid--> y-carboxyglutamic acid reaction. |
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Prothrombin group proteins.
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Essential post-translation modification= glutamic acid--> y-carboxyglutamic acid (critical for calcium binding properties of Prothrombin group proteins)
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Vitamin K deficiency.
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- Vitamin K dependent procoagulans released from the liver but unable to participate in coagulation.
- Non-functional; lack COOH group that binda calcium. |
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Vitamin K antagonist.
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Warfarin/Coumadin (oral anti-coagulant therapy).
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Fibrinogen group proteins.
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- Fibrinogen (Factor I), factors V, VIII, & XIII.
- Acted upon by thrombin. - Have the highest molecular weights of all factors. - Not found in serum; consumed during clotting. |
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von Willibrand Factor (vWF)
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- Provides receptor sites for plts (adhesion) & collagen.
- Transports the procoagulant factor VIII. - Synthesized in megakaryocytes (alpha granules) & endothelial cells. |
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Factor VIII.
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- Labile deteriorates rapidly; depends on vWF for stability.
- Hemophilia A: decreased factor VIII w/ normal vWF levels. - von Willebrannd Dz: decreased vWF & factor VIII. |
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Contact factor complex.
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- Factor XI, XII, high molecular weight kininogen (HK), & prekallikrein (PK).
- Requires a negatively charged surface for activation (glass, kaolin, ellagic acid). - Does not require calcium. - Do not appear to play a major role in vivo except factor XI. |
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Factor XI activation pathway.
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- Activated by thrombin.
- Factor XIa activates fatcor IX--> fibrin stabilization by fatcor XIIIa. - Essential to normal coagulation. |
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Four coagulation cascade interacting sets of reactions.
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- Complex formation on phospholipid membranes- coagulation occurs on cell surface membranes.
- Intrinsic pathway - Extrinsic pathway - Common pathway |
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Procoaguant complexes assemble on the PL membrane.
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- First complex (extrinsic Xase)
- Second complex (intrinsic Xase) - Third complex (prothrombinase) |
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Tissue factor pathway: first complex
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Membrane receptor for factor VIIIa (in the presence of PL & Ca2+)--> activation of factors 9 & 10.
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Tissue factor pathway: second complex
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- Factor IXa binds factor VIIIa on PL surface & also activates factor X.
- Factor Xa binds Va on PL surfaces. |
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Tissue facor pathway: third complex
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- Factor Xa/Va complex activates prothrombin= thrombin.
- Thrombin leaves fibrinogen--> fibrin monomer--> polymer - Factor XIIIa stabilized fibrin polymer. |
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Thrombin
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- Chief protease of coagulation.
- Primary fn.: Cleave fibrinogen molecule--> fibrin monomer. - Add'l fns.: activates factors V, VIII, XI (amplifies coagulation); activates factor XIII; initiates activation of plts (agonist); activates protein C pathway; activates thrombin activable fibrinolysis inhibitor (TAFI) |
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Tissue factor pathway inhibitor (TFPI).
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- Regulatory mechanism.
- Factor VIIa/tissue factor (first complex)--> activates factor 9 & 10. - Factor Xa reacts w/ first complex to bind TFPI--> inactivates factor VIIIa--> short lived factor VIIa/tissue factor complex. |
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Protein C regulatory system.
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- Thrombin-thrombomodulin complex--> activates protein C system.
- Activated protein C (APC) binds free plasma protein S--> inactivates Va & VIIIa. |
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Protein S.
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- Binds to & stabilizes APC (cofactor).
- Vitamin K dependent. - Only free plasma protein S can serve as APC cofactor. |
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Antithrombin.
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- Serine protease inhibitor.
- Binds & neutralizes thrombin, fatcors IXa, Xa, XIa, & XIIa. - Requires heparin for effective anticoagulant activity. |
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Other serine protease inhibitors.
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- Heparin cofactor II
- Alpha2- macroglobulin. |
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Plasminogen
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- Single chain protein that binds to fibrin during polymerization.
- Converted to plasmin by bound TPA or urokinase. - Also binds plasma alpha2-antiplasmin, w/c rapidly & irreversibly binds & inactivates free plasmin (prevents systemic activity). |
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Plasmin
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- Serine protease that systematically digests the fibrin polymer.
- Capable of digesting fibrinogen & fatcors V & VIII (known as primary fibrinolysis). |
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Fibrinolysis.
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- Final stage of hemostasis; begins few hours after fibrin polymerization.
- Function: reduce thrombus/clot & re-stre normal blood flow during vascular repair. - TPA binds to fibrin--> activates plasminogen forming plasmin--> plasmin systematically degrades the fibrin clot into fragments (fibrin degradation product). |
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Tissue Plasminogen Activator (TPA)
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- Binds to fibrin during polymerization.
- Initiates fibrinolysis by convering plasminogen--> plasmin. - Free TPA circulates bound to inhibitor & cleared from plasma by the liver. - Lyses the clot rather than prevents future clots. - Synthetic TPA used clinically to dissolve clots/thrombi in stroke pts. |
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Urokinase
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- Plasminogen activator
- Binds to fibrin during polymerization but does not bind firmly like TPA--> relatively minor physiologic effect. |
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Plasminogen Activator Inhibitor-1 (PAI-1)
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- Fibrinolysis inhibitor
- Prevents activation of TPA & urokinase. |
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Thrombin Activable Fibrinolysis Inhibitor (TAFI)
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- Activated by the thrombin-thrombomodulin complex.
- Prevents the binding of TPA & plasminogen to fibrin. - Link between coagulation & fibrinolysis. - Decrease thrombin production reduces activation of TAFI--> - Increase thrombin generation increases the activation of TAFI--> |
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Fibrin Degradation Products.
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- Inhibits hemostasis by preventing plt activation (primary) & fibrin polymerization (secondary).
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D-dimer (D-D fragment)
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- A specific marker for thrombosis.
- Used to identify DIC. - Also used to rule out venous thromboembolism: deep vein thrombosis (DVT) & pulmonary embolism (PE). |
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Unique to the intrinsic pathway
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Factors 12, 11, 9, & 8
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Unique to the extrinsic pathway
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Tissue factor & factor 7
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Coagulation factors consumed during clotting
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Fatcors 1, 3, 5, 8, & 13
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Factors in Common Pathway
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Factors 10, 5, 2, & 1
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