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Boards: Coag Transfusion > Thrombin Physiology Pathophysiology. Licari and Kovacic. 2009. JVECC > Flashcards

Thrombin Physiology Pathophysiology. Licari and Kovacic. 2009. JVECC Flashcards

1
Q

What are the parts of the prothrombinase complex?

A
  • FVa
  • FXa
  • Calcium
  • phospholipids (e.g., from platelets or other cells)
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2
Q

List 6 Vitamin K dependent factors

A
  • II, VII, IX, X
  • Protein C and S
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3
Q

What part of the Vitamin-K dependent factors needs Vitamin K for its production

domain

A

The Gla domain (NH2-terminal domain of gamma-carboxyglutamic acid) is formed from glutamic acid in the presence of vitamin K-dependent carboxylase

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4
Q

How does Vitamin K antagonism affect Thrombin and Prothrombin specifically?

A

Gla domain needed for binding to phospholipid cell membranes –> part of prothrombinase complex –> inhibits coagulation

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5
Q

Thrombin has an A- and B-chain which one of these has reported binding sites important for coagulation?

A

B-chain

A-chain has no documented function

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6
Q

What are the 4 functional binding sites of thrombin?

A
  • Sodium binding site
  • Active site
  • Exosite I
  • Exosite II
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7
Q

What is the function of the thrombin Na binding site?

A

determines whether thrombin acts pro- or anticoagulant
Na ion bound -> favor coagulation
Absence of Na ion -> primarily anticoagulant activity

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8
Q

What is the main function of the Active Site of thrombin?

A
  • Principal binding site of antithrombin and Protein C
  • binds fibrinogen together with Exosite I
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9
Q

What is the main function of Exosite I of thrombin?

A
  • Binds Fibrinogen together with the Active Site
  • binding site for thrombomodulin
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10
Q

What is the main function of Exosite II of thrombin?

A

binding site for heparin -> low molecular weight heparin cannot bind well here

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11
Q

What initiates the coagulation “cascade”?

A

endothelial damage -> TF expressed and contacts circulating FVII

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12
Q

Explain the “extrinsic” and “common” pathway

A

TF and FVII interact -> FVIIa -> FX to FXa -> FV to FVa -> prothrombin to thrombin

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13
Q

What is an intermediate form between prothrombin and thrombin?

A

meizothrombin

  • local adrenergic receptor activity -> vasoconstriction
  • activation of platelets
  • fibrinogen cleavage
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14
Q

Explain the thrombin burst

A
  • initially small amounts of thrombin are produced via the TF (extrinsic) pathway
  • thrombin activates platelets and VIIIa is released
  • thrombin causes XI to XIa activation
  • initiated more FXa and FVa activation
  • FVa + FXa + phospholipids + Ca = prothrombinase complex -> thrombin burst
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15
Q

What binding sites of thrombin does fibrinogen bind to?

A

Active site and exosite I

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16
Q

What is factor XIIIa?

A

fibrin-stabiliing factor
activated by thrombin
forms bonds between fibrin glutamate and lysine residue -> cross-linking of the clot

17
Q

Why does FXII deficiency rarely cause clinical bleeding?

A

with thrombin activating FXI, FXIIa is not needed for this activation
thrombin bypasses FXII

18
Q

What is TFPI?

A

Tissue factor pathway inhibitor -> inhibits TF-FVIIa-Ca2+ complex

19
Q

What factor are hemophilia B patients deficient in?

A

FIX

20
Q

What binding site of thrombin does thrombomodulin bind to?

A

Exosite I

21
Q

How does the Sodium binding site affect thrombomodulin activity?

A

affinity of thrombomodulin to exosite I decreases if Na ion bound at Sodium binding site
i.e., Na ion presence procoagulant

22
Q

What is TAFI, how is it activated, and how does it work?

A

thrombin activatable fibrinolysis inhibitor (TAFI)
* activated by thrombomodulin-thrombin complex
* removes terminal lysine residue of fibrin that normally facilitates binding of plasminogen and TPA -> less plasmin -> less fibrinoysis

23
Q

How is Protein C activated?

A

PC binds to endothelial PC receptor (EPCR) -> interacts with Active Site of thrombin-thrombomodulin complex -> APC

24
Q

What is APC’s cofactor?

A

Protein S

25
Q

What factors does APC inactivate?

A
  • inactivates FVa and FVIIIA
  • inactivates PAI-1

i.e., APC is anticoagulant and profibrinolytic

26
Q

What factors does antithrombin inactivate?

A

FIIa (thrombin)
FXa and FIXa

27
Q

How can APC and AT potentiate each other?

A

APC inactivates FVa and FVIIIa
AT inactivates FIIa, FXa and FIXa
when FXa-FVa and FIXa-FVIIIa complexes form these are more resistant to AT inactivation
APC inactivation reduces these complex formation due to less substrate

28
Q

What receptors does thrombin interact with?

A

protease activated receptors (PARs)
= G-protein coupled receptors
* highly expressed on platelets
* PAR-1, PAR-3, and PAR-4

29
Q

How does thrombin stimulate angiogenesis?

A

thrombin upregulates VEGF (vascular endothelial growth factor) -> initiates angiogenesis

30
Q

By what mechanisms can thrombin cause vasodilation?

A
  • sitmulates nitric oxide release
  • stimulates histamin and serotonin release
  • simulates PGI2 release
31
Q

Explain how cytokines (e.g., TNF-alpha) may have an procoagulant effect

A

reduces EPCR activation -> decreases APC -> more FVa and FVIIIa -> more thrombin generated
more FVa-FXa and FVIIIa-FIXa complex formation -> more resistance to AT

32
Q

What is the most important platelet activator?

A

thrombin

via PAR-1 and PAR-4 receptors

33
Q

How doe FDPs affect coagulation in DIC

A

accumulation of FDPs in plasma -> compete with fibrinogen for thrombin exosite I binding site -> less fibrin formation -> less clotting

34
Q

Explain the mechanisms by which unfractionated heparin works as an antithrombotic

A
  • AT rate of thrombin inactivation low -> heparin induces** conformational change of AT** -> irreversibly binds the Active Site of thrombin
  • heparin binds to the Exosite II of thrombin
  • -> forming AT-thrombin-heparin complex -> increaes rate of thrombin inactivation by thousan fold
35
Q

What is the difference between unfractionated and low-molecular-weight heparin?

A

unfractionated 3,000-30,000 Da
LMWH 1,000-10,000 Da
* LMWH can cause conformational change of AT and significantly increase FXa inhibition, but
* cannot hold Exosite II binding site as well to maintain AT-thrombin-heparin complex -> less thrombin inhibition

longer half-life of LMWH and more predictable repsonse

Boards: Coag Transfusion (13 decks)

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