12-04 L3 Regulation of Coagulation Flashcards
In platelets (define)
thromboxane A2
- the potent mediator of platelet aggregation and vasoconstriction
In endothelial cells (define)
activation of endoperoxide PGI2
- major inhibiotr of platelet aggregation and vasodilator
- htus the endothelium counterbalances the release of thromboxan A2 (by the stimulated palatelets by basla secriont of PGI2)
Arachidonic acid metabolism is central to the counterbalancing effect of what?
central to the counterbalancing effect of PGI2 on Thromboxane A2
what is the main inhibitor of coagulant activity?
- what does it contain?
- what does it act on?
- TFPI (tissue factor pathway inhibitor)
- conatins kuntiz-type protease inhibitor domains
- neurtalizes 7a and 10a by a feedback mechanism
MOA
Antithrombin III
_ _ enhanceds the activity (inhibition)of AT3 on a certain cofactor _ ._
- 2a (thrombin), 9a, 10a, 11a, 12a, kallikrein
- 2a inhibition is enchanced by heprain
Heparin
MoA
- indirect effect on thrombin via AT
- Acts like a catalyst in an enzymatic reaction
Anti-protein C inhibits what else?
- activation of TAFI
(additional anti-coagulant/profibrinolytic effect)
Protein C
half-life
activated by what
- Vit K dependent
- half-life: 6 hours
- activated by 2a (R169–>L170 cleavage) in complex with cell-surface cofactor TM, which can be modulated in part by EPCR
Protein C exerts irreversible proteolytic inactivation of what 2 compounds?
- Va
- VIIIa
Protein C
cofactors
- PS, Phospholipids, V, HDL, glycosphingolipids
APc is inactivated by what?
- protein C inhibitor (PAI-3)
- alpha1-antitrypsin
- alpha2-macroglobulin
Proetin S
serves as a co-factor for who?
possesse what unique attribute
- co-factor for APC
- possesses APC independent anticoagulant activity
- direct & irreversible binding to Va
- competition with Xa
TM
Thrombomodulin
non-enzymatic cofactor that accelerates PC activation by IIa
TM-bound IIa
- loses its ability to cleave/clot fibrinogen and/or activate platelets
- TM-bound 2a is inactivated by protease inhibitors more easily than free 2a
EPCR
(endothelial protein C receptor)
- enhances the rate of PC activation by 2a/TM (by 5-fold)
Fibrin(ogen) degradation products
- d-Dimers levels: an indirect measure of coagulation activation in the clinic,
- helpful in diagnosiing DIC
tPA (tissue-type plasminogen activator)
- a major endogenous PA activator,
- glycoprotein secreted mainly by endothelial cells
- its assmebly with plasminogen is fibrin dependent
12a-Kallikrein-HMWK system:
- the second major endogenous PA activator
u-PA (urokinase type PA)
- a potent PA activator produced by renal epithelium mac and some tumor ells
- has lower affinity to fibrin compared to t-PA
- its activation of plasminogen is fibrin-independent
streptokinase
- an exogenous PA activator, product of hemolytic streptococci
*
Activation receptors
u-PAR
- expressed on many cell types including endothelial cells
- bound u-PA maintains its activation capability
Activation
Annexin 2
- possesses binding affinity for plasminogen and t-PA (but not u-PA)
Name the 3 general inhibitors of Fibrinolysis
- plasmin inhibitors
- plasminogen activator inhibitors
- Clearance receptors
plasmin inhibitors
inhibitor of fibrinolysis
- serpin: alpha2-plasmin inhibitor
- non-serpin: alpha2-macroglobulin
- Nexin: broad specificity protease
Clearance receptors
inhibitors of fibrinolysis
- LRP, mannose receptors play a major role in the clearance of ‘t-PA-PAI-1’ complex
TAFI
Thrombin-activatable fibrinolysis inhibitor
- what is it
- actiavted by what
- moa
- Plasma carboxypeptidase: a potent inhibitor of fibrinolysis
- actiavted via limited proteolysis by 2a
- Down-regulates t-PA induced fibrinolysis (was shown to prolong endogenous clot lysis in vivo
Name 4 disease that are hereditary resistance to APC
- Factor V leiden (R506Q)
- Factor V cambridge (R306T)
- Factor V hong kong (R306C)
- Primary pulmonary embolism (less freq)
prothrombin G202010A gene alteration
- MOA
- clincial manifestaion
- having _ _ increased likelihood of this disease
-
modified 3’-UTR of prothrombin mRNA leads to the mRNa increased stability and augments its translation
- elevated synthesis and secretion of prothrombin
- Clinical manifestaions: thrombosis in unusual sites (hepatic, portal, cerebral sinus)
- arterial thrombosis incsreased likelihood of carring Prothrombin G20210A
Protein C def
- Type I
- Type II
- clinical features
- Type I: low levels and activity
- Type II: normal levels but altered/decreased activity
- clinical features: _ superfical/deep venous thrombosis,_ unusal sites (cerebreal, mesentery)
Protein S
- Type I
- Type II
- Type III
- clincal manifestations
- Type I: low levels and activity
- **Type II: **normal levels/imparied activity
- Type III: low free levels, total protein levels in low-to-normal range)
- clinical manifestations: DVT/PE (pulmonary embolism)
Antithrombin def
- Type I
- Type II a,b,c
- most common symptom
- Type I: low antigen/activity in the presenc and absence of heparin
-
Type II: normal antigen/impaired activity
- IIa: reactive site mutations
- IIb: heparin binding site mutations
- IIc: pleiotropic mutations
- Most common symptom: venous thrombosis of the lower extremities at early age peaking at the 2nd decade of life.
most common symptom of antithrombin def
- venous thrombosis of the lower extremities
- at early agepeaking at the 2nd decade of life
