12-04 L3 Regulation of Coagulation

Question 1

In platelets (define)

thromboxane A2

Answer 1

• the potent mediator of platelet aggregation and vasoconstriction

Question 2

In endothelial cells (define)

activation of endoperoxide PGI₂

Answer 2

• 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)

Question 3

Arachidonic acid metabolism is central to the counterbalancing effect of what?

Answer 3

central to the counterbalancing effect of PGI₂ on Thromboxane A₂

Question 4

what is the main inhibitor of coagulant activity?

• what does it contain?
• what does it act on?

Answer 4

• TFPI (tissue factor pathway inhibitor)
  
  • conatins kuntiz-type protease inhibitor domains
  • neurtalizes 7a and 10a by a feedback mechanism

Question 5

MOA

Antithrombin III

_ _ enhanceds the activity (inhibition)of AT3 on a certain cofactor _ ._

Answer 5

• 2a (thrombin), 9a, 10a, 11a, 12a, kallikrein
• 2a inhibition is enchanced by heprain

Question 6

Heparin

MoA

Answer 6

• indirect effect on thrombin via AT
• Acts like a catalyst in an enzymatic reaction

Question 7

Anti-protein C inhibits what else?

Answer 7

• activation of TAFI

(additional anti-coagulant/profibrinolytic effect)

Question 8

Protein C

half-life

activated by what

Answer 8

• 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

Question 9

Protein C exerts irreversible proteolytic inactivation of what 2 compounds?

Answer 9

• Va
• VIIIa

Question 10

Protein C

cofactors

Answer 10

• PS, Phospholipids, V, HDL, glycosphingolipids

Question 11

APc is inactivated by what?

Answer 11

• protein C inhibitor (PAI-3)
  
  • alpha₁-antitrypsin
  • alpha₂-macroglobulin

Question 12

Proetin S

serves as a co-factor for who?

possesse what unique attribute

Answer 12

• co-factor for APC
• possesses APC independent anticoagulant activity
  
  • direct & irreversible binding to Va
  • competition with Xa

Question 13

TM

Thrombomodulin

Answer 13

non-enzymatic cofactor that accelerates PC activation by IIa

Question 14

TM-bound IIa

Answer 14

• loses its ability to cleave/clot fibrinogen and/or activate platelets
• TM-bound 2a is inactivated by protease inhibitors more easily than free 2a

Question 15

EPCR

(endothelial protein C receptor)

Answer 15

• enhances the rate of PC activation by 2a/TM (by 5-fold)

Question 16

Fibrin(ogen) degradation products

Answer 16

• d-Dimers levels: an indirect measure of coagulation activation in the clinic,
• helpful in diagnosiing DIC

Question 17

tPA (tissue-type plasminogen activator)

Answer 17

• a major endogenous PA activator,
• glycoprotein secreted mainly by endothelial cells
• its assmebly with plasminogen is fibrin dependent

Question 18

12a-Kallikrein-HMWK system:

Answer 18

• the second major endogenous PA activator

Question 19

u-PA (urokinase type PA)

Answer 19

• 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

Question 20

streptokinase

Answer 20

• an exogenous PA activator, product of hemolytic streptococci
  *

Question 21

Activation receptors

u-PAR

Answer 21

• expressed on many cell types including endothelial cells
• bound u-PA maintains its activation capability

Question 22

Activation

Annexin 2

Answer 22

• possesses binding affinity for plasminogen and t-PA (but not u-PA)

Question 23

Name the 3 general inhibitors of Fibrinolysis

Answer 23

• plasmin inhibitors
• plasminogen activator inhibitors
• Clearance receptors

Question 24

plasmin inhibitors

Answer 24

inhibitor of fibrinolysis

• serpin: alpha2-plasmin inhibitor
• non-serpin: alpha2-macroglobulin
• Nexin: broad specificity protease

Question 25

Clearance receptors

Answer 25

inhibitors of fibrinolysis * **LRP**, mannose receptors play a major role in the clearance of 't-PA-PAI-1' complex

Question 26

TAFI Thrombin-activatable fibrinolysis inhibitor * what is it * actiavted by what * moa

Answer 26

* **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*

Question 27

Name 4 disease that are hereditary resistance to APC

Answer 27

* Factor V leiden (R506Q) * Factor V cambridge (R306T) * Factor V hong kong (R306C) * Primary pulmonary embolism (less freq)

Question 28

prothrombin G202010A gene alteration * MOA * clincial manifestaion * having _ _ increased likelihood of this disease

Answer 28

* _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

Question 29

Protein C def * Type I * Type II * clinical features

Answer 29

* **Type I:** low levels and activity * **Type II:** normal levels but altered/decreased activity * clinical features: _ superfical/deep venous thrombosis,_ unusal sites (cerebreal, mesentery)

Question 30

Protein S * Type I * Type II * Type III * clincal manifestations

Answer 30

* **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)

Question 31

Antithrombin def * Type I * Type II a,b,c * most common symptom

Answer 31

* **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.

Question 32

most common symptom of antithrombin def

Answer 32

* venous thrombosis of the lower extremities * at early agepeaking at the 2nd decade of life