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87 Cards in this Set
- Front
- Back
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What are the 3 main steps in Hemostasis?
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1. Initial vasoconstriction
2. Primary hemostasis 3. Secondary hemostasis |
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What does primary hemostasis consist of?
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Platelets and the vasculature
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What does 2ndary hemostasis consist of?
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Coagulation factors/Fibrin glue
Anticoagulant proteins |
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What are the platelet receptors for collagen?
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GP Ia/IIa
GP VI |
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What is the platelet receptor for fibrinogen?
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GPIIb/IIIa
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What is the platelet receptor for von Willebrand factor?
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GPIba
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What receptor has to bind its substrate first in order for platelets to form a clot against a vessel wall? What is the result of binding?
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vWF on the vascular wall has to bind GPIba which results in ADHESION.
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What receptor has to bind its substrate after adhesion? What is the result?
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Fibrinogen binds to GP IIb/IIIa resulting in aggregation of more platelets.
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What is in the Dense Granules of platelets? (4 things)
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-Calcium
-ATP -Seratonin -ADP |
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What is in the Alpha granules of platelets?
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-Coagulation factors
-Growth factors -Platelet factor 4 (PF4) |
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What coagulation proteins are in the alpha granules of platelets?
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-Factor V
-Fibrinogen -vWF |
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What growth factors are in the alpha granules?
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-PDGF
-TGF-beta |
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What membrane lipid molecule is essential for platelets to function?
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Phospholipid
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What cleaves phospholipid from the platelet surface?
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PLA2
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What stimulates PLA2 activity?
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Calcium
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What is the result of PLA2 cleaving phospholipid from the membrane?
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Arachidonic acid is released into the platelet cytosol.
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What enzyme acts on AA and what is the product?
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Cyclooxygenase 1 - produces PGG2
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What is the ultimate endproduct of AA metabolism in platelets?
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Thromboxane
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What is thromboxane?
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A potent stimulator of platelet aggregation.
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How does thromboxane achieve platelet aggregation?
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By decreasing cAMP
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What is an inhibitor of thromboxane that acts by increasing cAMP in its face?
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Prostaglandin I2
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What drug inhibits COX1?
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ASA - acetylsalicylic acid
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What are the Galpha-q protein coupled receptors on platelets for?
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Binding to specific platelet agonists
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What are 4 agonists that bind the Gaq-protein coupled rec's on platelets?
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-Serotonin
-Thrombin -ADP -Thromboxane |
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What do the GPC receptors do?
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Stimulate PLCbeta
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What are the 2 results of PLCbeta activation?
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-Calcium release from the dense tubules
-Protein kinase C activation |
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What are the 3 end results of calcium release and PKC activation?
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Ca: Integrin activation and granule secretion
PKC: cytoskeletal rearrangement and shape change |
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What is the first step in platelet adhesion?
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vWF binding to exposed collagen and getting activated
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What happens after vWF binds exposed collagen?
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Platelets bind vWF via GP1b and that activates the platelets
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What are 4 things that activated platelets do?
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1. Change shape
2. Express IIb/IIIa 3. Express membrane procoagulant 4. Release their granules |
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What is the result of platelet adhesion and activation?
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A film of activated platelets adhering to the exposed collagen
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What binds to the GPIIb/IIIa on activated platelets?
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Fibrinogen
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What platelet agonist is responsible for increasing GPIIb/IIIa expression on platelets?
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ADP
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How does fibrinogen binding platelets allow for aggregation?
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It creates bridges for platelet coherence.
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So what is the result of platelet adhesion and aggregation?
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The formation of the primary platelet plug.
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Is that enough to stop bleeding?
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No; you also need GLUE
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What is the ultimate goal of the coagulation cascade?
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Thrombin activation
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What does Thrombin stimulate?
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-Platelet aggregation
-Fibrin polymerization -Endothelial cells to produce tPA and PGI2 and NO -Lymphocytes -PDGF secretion from EC's and monocytes -Neutrophil chemotaxis |
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What is the general response of endothelial cells to thrombin?
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Inhibition of coagulation to provide the needed balance that prevents hypercoagulation.
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What type of proteins are the clotting cascade proteins?
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Serine proteases - in zymogen forms
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What is the goal of the clotting cascade?
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To generate thrombin
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What is the body's mechanism for ensuring that Thrombin isn't just free floating and activated randomly?
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It has placed it at the end of this complicated clotting cascade
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Why is it good that there are so many twists and turns in the clotting cascade?
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It provides many places for regulation of thrombin activation.
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What is the requirement for Thrombin to be activated?
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It must occur on SURFACES
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On what surfaces does Thrombin formation occur?
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Platelet surfaces
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What is the exact component of platelet surfaces required for Thrombin activation?
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Phospholipid
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What also requires phospholipid in order to be activated?
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Factor X
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What is the primary mechanism for starting thrombin generation and the clotting cascade?
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The activation of Fx 7 by Tissue factor and calcium.
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Where is Tissue factor found?
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On multiple cells including monocytes and vascular endothelial cells
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Once factor 7a is generated what does it activate?
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Factor Ten
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What does Factor Ten activate?
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Prothrombin
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Can Fx 10 activate Prothrombin by itself?
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No; it requires Calcium, 5a, and phospholipid on platelet surfaces
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What else can activate Fx 10 other than Fx 7a?
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Tenase
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What is Tenase?
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Factor 9a
Calcium 8a Platelet phospholipid |
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Where does Factor 8a come from?
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It is carried in the bloodstream on vWF
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What activates Fx 9?
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Factor 11a
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What activates Fx 11a?
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Factor 12a
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What activates Fx 12?
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PK and HMWK
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If it is required that Fx 10 and Thrombin be sitting down on surfaces in order to be activated, how does the body enable them to sit down?
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By gamma carboxylating them - they are Vit K dependent
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What are the vit K dependent factors?
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2 (thrombin)
7 9 10 Proteins C and S |
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What are Proteins C and S?
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Anticoagulants
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What does gamma carboxylation of glutamic acids on the Vit K dependent proteins allow?
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For them to recognize and bind to lipid on phospholipid surfaces of platelets.
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What else is required for the factors to sit down on platelets? Why?
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Calcium - it neutralizes negative charges on both the proteins and the membrane.
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What does Thrombin do once it's activated by Tenase?
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It's free to bump along the membrane and do its thing.
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What is the purpose of Thrombin (two things)?
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1. Form Fibrin
2. Activate platelets |
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How does Thrombin form Fibrin?
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By cleaving Fibrinogen
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What else can Thrombin cleave and activate?
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Factors 5, 8, and 9 to amplify the clotting cascade.
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Once Thrombin has cleaved Fibrinogen into fibrin, what crosslinks the fibrin?
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Factor 13
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What does Fibrinogen look like in its native form?
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An E domain with 2 D domains and fibrinopeptides A and B attached to the E domain.
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What does Thrombin do to Fibrinogen?
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Cleaves off the fibrinopeptides A and B
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What does Fibrin look like after Fibrinopeptides A/B have been cleaved off?
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Fibrin monomers of D and E domains
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What do Fibrin monomers do?
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Self-assemble into fibrin POLYMERS
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What crosslinks the fibrin polymers to stabilize them?
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Factor 13
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What activates Factor 13?
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Thrombin
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What do you want to have happen after Primary and Secondary hemostasis mechanisms?
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Healing - Fibrinolysis
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What is the dominant molecule that does fibrinolysis?
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Plasmin
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So what are the 3 big players in hemostasis?
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-Thrombin
-Fibrinogen -Plasmin |
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What is Plasmin generated from? What activates the process?
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Plasminogen; activated by Tissue Plasminogen Activator (tPA) secreted by endothelial cells
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What are 2 other things in addition to tPA that activate Plasmin?
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-Streptokinase
-Urokinase |
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What is Plasmin and what does it do?
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A serine protease that chops up fibrin clots.
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What gets released after fibrinolysis by plasmin?
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-Plasmin floats away
-Fibrin degradation products (FDP's) |
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What binds free plasmin after it's done chopping fibrin clots?
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alpha2-antiplasmin
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What is PAI and what does it do?
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Plasminogen activator inhibitor - it prevents tPA from activating too much plasminogen.
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What is the main hemostasis Police Force that makes sure everything stays in balance?
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Endothelial cells
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What on EC's stimulates clotting during inflammation?
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Exposure of membrane-bound tissue factor to activate the Extrinsic pathway
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What on EC's stimulates clotting during tissue injury?
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Exposure of collagen which binds vWF and platelets; platelets then act as the surface for clotting factor activation.
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What are are 6 things that EC's express or secrete to PREVENT thrombosis?
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-Heparan
-Antithrombin -Thrombomodulin system -PGI2, NO, tPA |
