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87 Cards in this Set

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