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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?

A

Factor 11

21
Q

Factor 12 deficiency causes clotting defects. T or F?

A

False

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
Q

Describe how activated platelets prepare for formation of coagulation complex? (think cell membrane changes)

A

Floppase redistributes phospholipid molecules on plasma membrane of platelets

>> flipping phosphatidylserine (PS) from inner to outer surface

>> form coagulation complex with coagulation factors

26
Q

Describe the 2 ways of anchoring coagulation factor to Platelet membranes?

A
  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
Q

Describe the events that occur on Fibroblast surface to increase thrombin concentration in platelet

A

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
Q

Describe the coagulation reactions at platelet surface?

A

Thrombin diffuse from fibroblast, catalyze:

Factor 5 to 5a

Factor 8 to 8a

Factor 11 to 11a

29
Q

Describe the coagulation reactions in activated platelet surface?

A

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
Q

List the 3 pathways to control coagulation.

A
  1. Antithrombin-III (serpin) pathway
  2. Thrombomodulin and Protein C pathway
  3. Prostaglandin I2 pathway
31
Q

Describe the Antithrombin-III pathway to limit coagulation

A

Antithrombin-III (= serpin) + heparin (expressed on surface of endothelial cells) complex with thrombin (and Factor Xa)

>> no activity (inhibited)

32
Q

Describe the thrombomodulin - Protein C pathway to limit coagulation. (2)

A
  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
Q

Describe the Prostaglandin I2 pathway to limit coagulation?

A

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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