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2: Coagulation/ amplification/testing of hemostatic lectures
October 18 Lectures
36
Immunology
10/22/2011

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Term
the purpose of the coagulation cascade is to catalyze rapid formation of a fibrin clot through generation of the potent enzyme called:
Definition
thrombin
Term
blood coagulation is under tight control so that the area of clot formation is limited to the
Definition
area of injury
Term
the 6 main components of the coagulation system are:
Definition
1) the ultimate substrate, fibrinogen
2) cofactors
3) vitamin K dependent proteins (VKDPs)
4) initiators
5) calcium
6) phospholipids
Term
formation of a fibrin blood clot results when the enzyme _____ is generated
Definition
thrombin
Term
thrombin
Definition
this enzyme is able to cleave 2 small peptides from the fibrinogen molecule forming fibrin monomer which can then dimerize and mutimerize to form a large lattic like protein.
Term
how does the generation of thrombin occur
Definition
it occurs after a series of enzyme linked, phospholipid dependent reactions iccur on cell surfaces (PLT's, monocytes, endothelial cells, etc)
Term
tissue factor
Definition
immediately after injury, this is exposed at the site, and then this rapidly binds to factor 7a present in the blood
Term
When tissue factor is bound to 7a, the complex is able to convert the zymogens ____1____ or ____2____ to their respective ezymes factor ___3____ or ____4_____
Definition
1) factor 10
2) factor 9
3) factor 10a
4) factor 9a
Term
Factor 5a
Definition
this is a cofactor that when added to factor 10a, is able to convert the substrate prothrombin to the enzyme thrombin
Term
what is the alternate pathway that factor 10a can be generated?
Definition
if factor 9a acts with its cofactor factor 8a (with inactive factor 10)
Term
What are the 2 ways that you can make active factor 9a?
Definition
1) add factor 11a to inactive 9
2) add tissue factor/7a complex to inactive factor 9
Term
what are the two ways to make factor 11a?
Definition
1) thrombin acting on factor 11
2) IN VITRO- add factor 12a, prekallikrein, and HMW kininogen
Term
Properties of Tissue factor
Definition
-a 47 kD integral membrane lipoprotein
-expressed under basal circumstances by a number of cells including vascular smooth muscle cells, pericytes, fibroblasts, brain astrocytes, epithelial cells in lungs, cardiomyocytes in heart, placental trophoblasts, etc)
Term
blood borne TF
Definition
-there is a TINY amount of circulating TF in blood
-may be in form that's not functionally active (encrypted) and may be associated with membrane microparticles derived from endothelial cells, vascular SM cells, leukocytes, and monocytes. this may be important in thrombosis developing with mittle endothelial damage
Term
Decryption of microparticle TF
Definition
circulating microparticle TF (encrypted) binds to/is transferring to activated platelets by interaction between PSGL1 (p-selectin glycoprotein ligand 1) on microparticle and P selectin on platelet. This 'decrypts' TF activity.
Term
what are the vitamin K dependent proteins?
Definition
factors: 2,7,9,10
Term
carboxyglutamic acid
Definition
is an uncommon amino acid introduced into proteins by a post-translational carboxylation of glutamic acid residues. This modification is found, for example, in clotting factors and other proteins of the coagulation cascade. This modification introduces an affinity for calcium ions. In the blood coagulation cascade, Vitamin K is required to introduce gamma-carboxylation of clotting factors II, VII, IX, and X.

Term
gamma-glutamyl carboxylase
Definition
this reduces vitamin K, and allows for carboxylation on gamma carbon of glutamic acid when dealing with vitamin K dependent proteins function
Term
what factor is needed to go from prothrombin to thrombin?
Definition
factor 5a
Term
Amplification occurs mainly as result of this enzyme's ability to 'activate' a number of other coagulation factors and stimulate platelets
Definition
thrombin
Term
what are the negative controls of coagulation?
Definition
-serine protease inhibition
-degradation of cofactors
-inhibition of TF
-inhibition of platelet activation
-vWF proteolysis
-phospholipid surface sequestration
Term
fibrinolysis
Definition
clot dissolution that ensures that vessel patency is reestablished (a fibrin clot, the product of coagulation, is broken down.Its main enzyme plasmin cuts the fibrin mesh at various places, leading to the production of circulating fragments that are cleared by other proteases or by the kidney and liver.)

Term
endothelium
Definition
plays a critical role in inhibiting clot formation under 'resting' conditions
Term
thrombin
Definition
this cofactor is able to activate the cofactors, 5 and 8, to factors 5a and 8a through limited proteolysis, significantly enhancing the two cofactors' ability to act on proteolytic activity of factors 10a and 9a respectively.
Term
activation of factor 11 to 11a can occur by 2 pathways:
Definition
1) thrombin can convert factor 11 to lla by limited proteolysis (most important of the 2 pathways)
2) IN VITRO (NOT IN VIVO): activation by contact factors (factor X11a, prekallikrein, and high molecular weight kininogen)
Term
Factor 13
Definition
thrombin is able to convert this factor to its active form which can then chemically cros link fibrin to form an insoluble clot
Term
thrombin
Definition
most potent platelet activator known
Term
name the several naturally occuring anticoagulants:
Definition
1) antithrombin (aka antithrombin-III)
2) protein C
3) protein S
4) tissue factor pathway inhibitor

all these molcules inhibit serine proteases, cofactors, and the initiator (TF)
Term
does an anticoagulant do?
Definition
these inhibit serine proteases, cofactors, and the initiator TF
Term
fibrinolysis
Definition
occurs when plasminogen activators convert plasminogen to active enzyme plasmin
Term
Endothelial cells express/secrete these 5 things which all inhibit coagulation, inhibit platelet function, and/or cause vasodilation
Definition
1) thrombomodulin
2) prostacyclin
3) heparin like molecules
4) protein C receptor
5) NO
Term
ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin like domains)
Definition
cleaves the highest molecular weight forms of vWF into smaller forms that circulate (decreasing vWF activity)
Term
Bleeding Time Test and Platelet function studies
Definition
used to assess primary hemostasis
Term
Bleeding time test
Definition
this is infrequently used due to test result variability and poor correlation with bleeding
Term
PTT and APTT
Definition
The partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT or APTT) is a performance indicator measuring the efficacy of both the "intrinsic" (now referred to as the contact activation pathway) and the common coagulation pathways. Apart from detecting abnormalities in blood clotting, it is also used to monitor the treatment effects with heparin, a major anticoagulant. It is used in conjunction with the prothrombin time (PT) which measures the extrinsic pathway. These are useful, however, the reactions in the test tube do not reflect how events occur in vivo.
Term
Thrombin time
Definition
measures the conversion of fibrinogen to fibrin