Which layer of the blood vessel could you find collagen fiber and tissue factor?
Subendothelial layer
What is the significance of the subendothelial layer of the blood vessel?
Promotes coagulation with collagen fiber and tissue factor when exposed to blood (often due to injury to blood vessel)
Collagen -> activate platelets
Tissue factor -> activate coagulation pathway
All blood vessels are lined by a flat sheet of ______; intact surface is _______ (characteristic relating to clotting)
Endothelial cells
Antithrombotic
How does endothelial cell achieve thrombo-resistance?
It forms a physiologic barrier between circulating platelets and clotting factors, and subendothelial substances (collagen and tissue factors)
What are the two potent vasodilators produced by endothelial cells?
Prostacyclin (PGI 2)
Nitric oxide (NO)
T/F: vasodilators Prostacyclin and nitric oxide inhibit platelet function
True; these are produced by the endothelial cells, one of the ways that endothelium exhibit thrombo-resistance
Endothelial cells produce anti-______, anti-______ and pro-_____
Antiplatelets (ie NO and PGI2)
Anticoagulant
Profibrinolytic (ie t-PA)
In response to an injured blood vessel, vaso____ occurs
Constriction
What are the three mediators released by platelet in response to vessel injury?
Platelets secrete:
Serotonin
Thromboxane A2
Epinephrine
Epinephrine and serotonin are vaso____
Constrictors
Prostacyclin and nitric oxide are vaso_____, produced by _____. Epinephrine and serotonin are vaso____ released by _____.
Vasodilators produced by endothelial cells
Vasoconstrictors produced by platelets
What is the mechanism that leads to platelets getting activated when there is injury to the vessel?
Exposure of blood to subendothelial collagen and tissue factor activates platelets and coagulation pathways
Primary hemostasis involves which cell?
Platelets
In primary hemostasis, platelets first _____, then changes shape to ____. Once that occurs, platelets release _______, thereby ______ other platelets and aggregate
Adhere to the collagen
Activate themselves by making thromboxane
ADP from granules and thromboxane (produced by platelets)
Recruit and activate
Life span of platelets is ____ days
7-10
What are the two platelet cytoplasmic granules?
Alpha granules contain fibrinogen and clotting factors V and VIII (5 and 8)
Platelet receptors Gp1a-2a (glycoprotein), and Gp VI bind directly to subendothelial collagen tissue
Platelets adhesion to collagen indirect (major site) way:
Platelets bind indirectly to collagen tissue (subendothelial layer) via GP1b to von Willebrand factor secreted by endothelial cells
What is the major substance needed for platelet adhesion that is secreted by endothelial cells?
Von Willebrand factor
How is thromboxaneA2 produced?
Upon adhering to collagen, platelets will change shape (activating Gp2b/3a) and this shape change exposes phospholipid membrane which is precursor to thromboxane synthesis
T/F: When blood reaches subendothelial collagen, platelets get signaled to come bind to the endothelium
False; platelets binds to the subendothelial collagen via GP1b to vWF, as well as to collagen directly via GP6 and GP1a and 2a
Thrombin is factor___, and this causes vaso_____
IIa
constriction
Major stimulators of platelet activation:
Thromboxane A2
ADP (From dense granule)
Thrombin (formed from phospholipid membrane, like TxA2)
What receptor on the activated platelets form bridging crosslinks with fibrinogen?
GP2b/3a
vWF can also help to form these bridging crosslinks in high shear blood flow conditions
What is the significance of crosslinking fibrinogen via GP2b/3a?
Leading to platelet aggregation
What can inhibit platelet aggregation?
Nitric oxide and prostacyclin produced by endothelial cell inhibit platelet aggregation and cause vasodilation
Most clotting factors are made in the _____
Liver
Liver needs _____ to make 4 clotting factors:
Vitamin K
Factors II, VII, IX, X.
What are two natural anticoagulants formed by the liver requiring Vitamin K?
Protein C
Protein S
T/F: Clotting factors circulate in the blood in the active form
False-mostly; circulating clotting factors are in inactive form. Except actually for Factor VII (7) that one is actually in its active form In the blood
T/F: vitamin K dependent clotting factor needs vitamin K to be oxidized so the precursor molecule (glutamic acid) gets de-carboxylated and this allows a calcium molecule to interact with it to anchor the factor to phospholipid membrane of activated platelets
False; glutamic acid gets carboxylated.
Secondary hemostasis:
Formation of a fibrin clot- cement platelet plug in place
Coagulation cascade: contact activation pathway is ____ pathway. Tissue factor pathway is the ___ pathway.
Intrinsic
Extrinsic
Tissue factor is factor ___. Calcium is factor ___
III
IV
Extrinsic and intrinsic pathways converge at the activation of factor _____ into the ___ pathway which activates ____ and leading to ___
X
Common
Ia
Cross-linked fibrin clot
Extrinsic pathway: Factors _____
VII and Tissue factor (III)
Intrinsic pathway: factors____
XII
XI
IX
VIII
What is the Hageman factor?
Factor XII, part of the intrinsic factor
T/F: the intrinsic pathway is the most physiologically relevant pathway for the initiation of coagulation
False; the extrinsic pathway is, not the intrinsic pathway. Extrinsic pathway is activated by tissue factor (F III) expressed at sites of injury vs intrinsic pathway is when blood interacts with a negatively charged surface like glass
Warfarin is monitored via ___ coagulation tests reported as____, associated with ____ pathway
PT
INR
Extrinsic
T/F: The intrinsic pathway should not be completely ignored even though it is relatively unimportant, but patients with coronary catheter and other blood-contacting medical devices could likely have activation of this intrinsic pathway
True
Blood clotting can be prevented by _____
Calcium chelators such as EDTA
In initiation phase, small amount of thrombin are formed, what do these thrombin go on to make?
Mainly Factors 5a, 8a, 11a and up-regulation of platelets
Tissue factor pathway inhibitor would disrupt which phase of coagulation?
Initiation phase would be turned off
Following the initiation phase comes the ____ phase, which takes place on _____.
Amplification
Activated phospholipid membrane of the platelets
Major cofactor of intrinsic tenase is ______
Factor 8a
In amplification phase, Factor ___ from _____ tenase comes to the intrinsic tenase, requiring cofactor _____. And this would produce factor _____ which goes to the ________ , joining factor ____ which leads to ___ burst
Factor IX
Extrinsic
Factor VIIIa
Factor Xa
Prothrombinase
Factor Va (co-factor/accelerator)
Thrombin
4 main things needed for thrombin burst during amplification phase:
Factors 5a, 10 a, 2a
And calcium
Formation and growth and stabilization of fibrin clot is the _____ phase
Propagation
Function of thrombin in the propagation phase?
Convert fibrinogen to fibrin
Activates factor XIIIa
Which factor is in charge of crosslinking fibrin polymers?
Factor XIIIa
Co-factor, enzyme and product of Extrinsic tenase, intrinsic tenase and prothrombinase:
Extrinsic tenase: tissue factor, Factor VIIa, Factors IXa and Xa (co-factor, enzyme, product)
Intrinsic tenase: facot VIIIa, Factor IXa, Factor Xa
Prothrombinase: Factor Va, Factor Xa, Thrombin (Factor IIa)
How does fibrinolysis occur?
Endothelial cell makes plasminogen activator (t-PA) which activates fibrinolysis
How does plasminogen gets converted into plasmin?
Upon binding to fibrin, it can be converted to plasmin by plasminogen activator (t-PA)
T/F: Plasminogen is a zymogen of plasmin that is produced in the kidneys
False; it is produced in the liver and circulates in the blood in a form that is activation-resistant
What is the function of alpha2-antiplasmin?
Pick up free plasmin that has escpeted the site
What is D-dimer?
It is a fibrin degradation product. That’s why we test for D-dimer to see whether there is clot
Thrombin can activate Protein _____, which is a natural____. And it will bind to co-factor Protein _____ forming a complex which will inactivated Factor _____ and Factor _____. This will lead to inhibition of further blood coagulation
Protein C
Anticoagulant
Protein S
Factor VIIIa
Factor Va
Thrombin can bind to _____ expressed on the endothelial cells, which will inactivate thrombin, and activate ____
Thrombomodulin
Protein C (a natural anticoagulant)
Antithrombin III binds to ____ on endothelial cells and inhibits the activity of ______ and factors ___, ____, ___, _____.
Heparan (heparin-like molecules)
Thrombin
IXa, Xa, XIa, and XIIa
What are the 7 ways of controlling blood clotting?
1 factors activation is restricted to sites of exposed phospholipids
2 Antithrombin III presence to inhibit thrombin and 9a, 10a, 11a, 12a
3 Thrombomodulin binds and inactivate thrombin
4 activating protein C and S which inactivate Va and VIIIa
5 endothelial secrete Tissue factor pathway inhibitor that inactivate factor 10a and TF-VIIa complexes
6 endothelial secretion of NO and prostacyclin inhibit platelet aggregation
7 activation of fibrinolysis by endothelial secretion of TPA
