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MBBS II HIS > L27- Biochemistry of the blood coagulation system > Flashcards

L27- Biochemistry of the blood coagulation system Flashcards

1
Q

What are the cellular and non-cellular components of blood clot?

A

Platelet = cellular

Fibrin = non-cellular

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2
Q

What are the molecular species involved in coagulation?

A
  1. Proteins - Enzymes = coagulation factor
  2. Co-factors
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3
Q

Describe the structure of coagulation factors and their functional sections.

A

S-S region = stabilize in blood

Gla domains *** = enable localized coagulation at site of injury on membrane surfaces ***

Catalytic domain = serine-dependent proteases = cleave Arg in peptide bonds for activation (i.e. Activated F-12a cleaves F-11 to activate it)

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4
Q

List all the Factors that act as enzymes and co-factors?

A

Enzymes: Factor 7,9,10

Co-factors: Factor 5, 8

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5
Q

Which structural domain of coagulation factor allows localized clotting?

A

Gla domain **

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6
Q

List the 2 pathways for formation of blood clot?

A
  1. Humoral pathway
  2. Cellular pathway
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7
Q

Describe the humoral pathway in blood clot formation.

A
  1. Activate extrinsic, intrinsic coagulation pathways (can be caused by activated platelets)
  2. Convert prothrombin to thrombin (can cause activation of platelets)
  3. Fibrinogen polymerizes to fibrin
  4. Linear fibrin cross-link
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8
Q

What controls the rate of blood clot in the humoral pathway?

A
  1. Factor 13 increase cross-linking of linear fibrin into meshwork >> more clot
  2. TAIF: thrombin activated inhibitor of fibrinolysis: Inhibit fibrolysis and slow degradation of clot
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9
Q

Describe the cellular pathway in blood clot formation

A

Blood vessel injury

>> Activation of platelets: Activated by thrombin formed in humoral pathway; Can activate coagulation pathways in humoral pathway

>> Blod clot

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10
Q

Describe the intrinsic pathway of coagulation

A
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11
Q

What are the 2 essential components for extrinsic pathway in coagulation?

A
  1. Tissue factor
  2. Factor 7
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12
Q

Location of tissue factor? Which cells express it? How does it trigger the extrinsic pathway to start coagulation?

A
  • Transmembrane protein at tissue adventitia
  • Expressed in most cells except resting endothelial cell
  • Exposed to intravascular space after vascular injury (no proteolytic activation needed)
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13
Q

Structure of Factor 7? What activates it?

A
  1. Single chain zymogen
  2. Has low intrinsic enzymic activity
  3. Highly active when bound to tissue factor
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14
Q

Describe the extrinsic pathway in coagulation?

A

Factor 7 >> 7a through unknown protease

Factor 7a bind to extracellular domain of tissue factor after vascular injury >> TF/Factor 7a complex >> Activate Factor 9,10 >> Activate prothrombin >> Thrombin cleaves fibrinogen >> Fibrin polymer

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15
Q

List all the factors involved in the intrinsic pathway?

A

Factor 12,11,9,10 = coagulation factors

Factor 5,8 = co-factors

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16
Q

List all the factors involved in the extrinsic pathway?

A

Factor 7, Tissue factor

Factor 9,10

Factor 5,8 = co-factors

17
Q

Describe the initiation phase of coagulation?

A
  1. Factor 10 converted to 10a by TF/Factor 7a complex, Inhibited by tissue factor pathway inhibitor (TFPI)
  2. Small amount of factor 10a made
  3. Factor 10a turn Factor 9 to 9a, stimulated by TF/ Factor 7a process
  4. More factor 9a = catalyze more factor 10 to 10a >> positive feedback
18
Q

Describe how blood clot formation is self-sustained once initiated?

A

Factor 9a formed take over the activation of Factor 10

No longer require TF/Factor 7a which is rate limiting

19
Q

Lack of which coagulation factors cause Haemophilia?

A
  • Lack of Factor 9: Haemophilia B
  • Lack of Factor 8: Haemophilia A
20
Q

Lack of which factor results in spontaneous bleeding?

21
Q

Factor 12 deficiency causes clotting defects. T or F?

22
Q

Define how thrombin forms a positive feedback loop in the intrinsic coagulation pathway?

A
  1. Stimulate Factor 8 to Factor 8a
  2. Stimulat Factor 5 to Factor 5a
  3. Stimulate Factor 11 to factor 11a
23
Q

Describe how platelet becomes activated?

A

Vascular injury cause exposure of ECM into intravascular space:

Resting Plt activated by exposed Collagen and VWF at vascular injury site

24
Q

List 4 intracellular processes in activated platelet to prepare for adhesion.

A

Release reactions: coagulation factors, ADP

Membrane vesiculation = increase surface area for adhesion

Express Prostaglandins (TrxA2), Thromboxane A2 = vasoconstriction

Floppase redistribute phospholipids to form coagulation complex ***

25
Describe how activated platelets prepare for formation of coagulation complex? (think cell membrane changes)
Floppase redistributes phospholipid molecules on plasma membrane of platelets \>\> flipping phosphatidylserine (PS) from inner to outer surface \>\> form coagulation complex with coagulation factors
26
Describe the 2 ways of anchoring coagulation factor to Platelet membranes?
1. Coagulation complex formed by Gla domain of coagulation factor + Ca2+ + Phosphatidylserine (PS) 2. Hydrophobic interaction between membrane and Gla domain on coagulation factor
27
Describe the events that occur on Fibroblast surface to increase thrombin concentration in platelet
Tissue factor and Factor 7a catalyze: 1) Factor 10 to 10a\>\> 10a turn 9 to 9a 2) Factor 5 to 5a 5a and 10a increase catalysis of Prothrombin to thrombin Thrombin diffuse to platelet surface
28
Describe the coagulation reactions at platelet surface?
Thrombin diffuse from fibroblast, catalyze: Factor 5 to 5a Factor 8 to 8a Factor 11 to 11a
29
Describe the coagulation reactions in activated platelet surface?
Adhesion to collagen in ECM of damaged endothelium: - Factor 11a turns 9 to 9a - Factor 9a + co-factor Factor 8 turns Factor 10 to 10a - Factor 10a + co-factor 5 turns prothrombin to thrombin
30
List the 3 pathways to control coagulation.
1. Antithrombin-III (serpin) pathway 2. Thrombomodulin and Protein C pathway 3. Prostaglandin I2 pathway
31
Describe the Antithrombin-III pathway to limit coagulation
Antithrombin-III (= serpin) + heparin (expressed on surface of endothelial cells) complex with thrombin (and Factor Xa) \>\> no activity (inhibited)
32
Describe the thrombomodulin - Protein C pathway to limit coagulation. (2)
1. Thrombin bind to thrombomodulin on endothelial surface \>\> Activates protein C --[protein S]--\> Directly cleave membrane bound Factor 5a and 8a \>\> No activity 2. Thrombin bind to thrombomodulin on endothelium \>\> Activate protein C \>\> turn Factor 5 to 5ac\* (anticoagulant Factor 5) Protein C + Protein S + Factor 5ac complex on endothelium and inactivate Factor 8a
33
Describe the Prostaglandin I2 pathway to limit coagulation?
Endothelial cells produce prostaglandin I2 \>\> Inhibit platelet response \>\> Coagulation reactions continues within the clot until exhaustion of factors

MBBS II HIS (30 decks)

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