Haemostasis stuff

Question 1

Haemostasis

Answer 1

• The cessation/stopping of bleeding (Normal response)
• General process:
  1) Injury, vessel spasm (Vasoconstriction) + collagen is exposed
  2) Platelet Plug Formation
  3) Coagulation
  4) Clot retraction
  5) Fibrinolysis

Question 2

Haemorrhage

Answer 2

The excessive flow of blood (Pathogenic response)

Question 3

Blood vessel anatomy

Answer 3

• Tunica intima = The innermost layer of the blood vessel, made up of 1 cell thick endothelial cells
• Tunica media = Where smooth muscle resides
• Tunica externa = Outermost tunica layer
• Arteries + Veins contain all 3, whereas the capillaries only have tunica intima to allow gaseous exchange pathway

Question 4

Vessel Spasms

Answer 4

• Also known as vasoconstriction
• Direct smooth muscle cell damage triggers vasoconstriction, triggering pain receptors too
• Vasoconstriction helps slow down the leak of blood out of the wound

Question 5

Platelets active vs dormant state

Answer 5

• At rest, platelets have a discoid shape, but develop pseudopodia when activated, which can enable it to form 2 forms:
  + Filopedia
  + Followed by lamelliopedia, allowing it cover the wound

Question 6

Platelet agonists

Answer 6

• Each agonist has a different degree of “strength” to activate the platelets
• The stronger the platelet agonist, the more likely platelet activation will happen and stronger the response
• Strong agonists: Collagen, Thrombin
• Intermediate agonists: Thromboxane A2
• Weak: ADP, Platelet Activating Factor, Adrenaline, Vasopressin, Serotonin

Question 7

Platelet Plug Formation (PPF)

Answer 7

• 4 steps
  1) Adhesion
  2) Activation
  3) Secretion
  4) Aggregation

Question 8

Platelet Plug Formation: Adhesion

Answer 8

• First step of PPF
• Happens when collagen fibres become exposed and the Von WIllebrand Factor (VWF) binds to the collagen
  + VWF is a plasma protein, just like any other plasma protein flows freely around the body
• VWF binding to the collagen then allows it to bind to the platelet via the GlycoproteinIb(GPIb)-V-IX complex, slowing down the platetlet’s movement so it rolls on the surface of the collagen

Question 9

Platelet Plug Formation: Activation (Some Secretion + Aggregation)

Answer 9

• Second step of PPF
• As the platelet rolls, its other receptors also come into contact with the collagen, including GPVI (GP6)
• When GPVI touches collagen, it triggers a signalling cascade inside the platelet, leading to the release of Ca from its stores, increasing Ca concetration in the platelets, which has 3 effects:
  + Shape morphing: Discoid -> lamellipodia
  + Degranulation of alpha-granules + dense granules to recruit other nearby platelets or have an autocrine effect on the secreting platelet (+tive feedback for both outcomes)
  + Aggregation

Question 10

Platelet Plug Formation: Secretion

Answer 10

• Third step of PPF
• Dense granules contents:
  + ADP
  + Serotonin
• Alpha-granules contents
  + Fibrinogen
  + VWF
• Cytoplasmic Thromboxane A2 also secreted
• These all contribute to the +tive feedback loop

Question 11

Platelet Plug Formation: Aggregation

Answer 11

• Fourth step of PPF
• The buildup of Ca in the platelet changes the shape of alpha2b/beta3 receptors on platelet surface
  + Alpha2b/beta3 are an example of integrin, receptors that have a low affinity (inactive) shape along with a high affinity (active) shape, which when active binds to fibrinogen (respective ligand)
• Fibrinogen binds to 2 alpha2b/beta3 on 2 separate platelets, cross-linking them together, causing aggregation
• Secretion of fibrinogen means more cross-links can take place

Question 12

Negative regulation of platelets

Answer 12

• Majority of the time, the body is actively silencing platelets when they are not needed
• This is done by Prostacyclina nd Nitric Oxide (NO) secreted by healthy endothelial cells
• These chemicals are released into the bloodstream as platelets pass, keeping them inactive
• If endothelium is damanged, platelets are more likely to become active, increasing risk of thrombosis

Question 13

Coagulation

Answer 13

• The process in which the fluid blood is converted into a gelatinous clot
• Helps convert the platelet plug structure into a more stable clot, formation of the scab caused by clot being exposed to air, causing it to dry out

Question 14

Fibrin

Answer 14

• A polymer protein made up of fibrinogen monomer units
• Fibrinogen monmer can bind to alpha2b/beta3 receptors on 2 different platlets to aggregate the platelets
• To form fibrin, thrombin (preotease) catalyses the conversion of fibrinogen into fibrin
  + Cuts out fibrinopeptides, creating a site for monomers to bind together

Question 15

Thrombin

Answer 15

• Protease that catalyses fibrinogen conversion
• Circulates in precursor form (Prothrombin) in the plasma
• Can also trigger platelet activation
• To become active, prothrombin is cleaved to generate thrombin via intrinsic or extrinisc pathway
• Difference between intrinsic + extrinsic pathway is that the extrinsic pathway requires endothelial cells to release tissue factor after injury

Question 16

Intrinsic pathway of Thrombin

Answer 16

• Stimulated on contact between blood + collagen/charged surfaces
  1) Platelets also activated by exposed collagen, causing the platelets to release phsopholipids to create a charged surface for the intrinsic pathway cascade to take place

Question 17

Extrinsic pathway of Thrombin

Answer 17

• Tissue stimulation by thromboplastin tissue (Example of tissue factor + tissue protein)
  1) Damaged tissue releases thromboplastin tissue to trigger extrinsic cascade

Question 18

Clotting/Coagulation Factors

Answer 18

• Mostly proteins
• Generally found as inactive enzymes/cofactors in the plasma
• Helps regulate the conversion of prothrombin to thrombin
• Most are produced by the liver
• No factor 6 due to it being the activated form of factor 5
• Numbers represent the order that they were discovered in

Question 19

Final Common Pathway

Answer 19

Whether it is intrinsic or extrinisic pathway, they eventually both lead to the common pathway

Question 20

Coagulation Factor 1: Fibrinogen

Answer 20

Function: Converted to fibrin
Pathway: Common pathway

Question 21

Coagulation Factor 2: Prothrombin

Answer 21

Function: Enzyme
Pathway: Common

Question 22

Coagulation Factor 3: Tissue thromboplastin/factor

Answer 22

Function: Cofactor
Pathway: Extrinsic

Question 23

Coagulation Factor 4: Ca2+ ions

Answer 23

Function: Cofactor
Pathway: Common, Extrinsic, Intrinsic

Question 24

Coagulation Factor 5: Praccelerin

Answer 24

Function: Cofactor
Pathway: Common

Question 25

Coagulation Factor 7: Proconvertin

Answer 25

Function: Enzyme Pathway: Extrinsic

Question 26

Coagulation Factor 8: Antihaemophilic Factor

Answer 26

Function: Cofactor Pathway: Intrinsic

Question 27

Coagulation Factor 9: Plasma Thromboplastin Component/Xmas Factor

Answer 27

Function: Enzyme Pathway: Intrinsic

Question 28

Coagulation Factor 10: Stuart-Prower Factor

Answer 28

Function: Enzyme Pathway: Common

Question 29

Coagulation Factor 11: Plasma Thromboplastin Antecendent

Answer 29

Function: Enzyme Pathway: Intrinsic

Question 30

Coagulation Factor 12: Hageman Factor

Answer 30

Function: Enzyme Pathway: Intrinsic

Question 31

Coagulation Factor 13: Fibrin Stabilising Factor

Answer 31

Function: Enzyme Pathway: Common

Question 32

Intrinsic Pathway Process

Answer 32

1) Factor 12 activated by exposed collagen, turning into Factor 12a 2) Factor 12a activated Factor 11 into Factor 11a, which works with Ca2+ to activate Factor 9 into Factor 9a 3) Factor 9a with Ca2+ + Factor8a on platelet surface activate Factor 10 into Factor 10a 4) Factor 10a then goes on with Ca2+ along with Factor 5a, then continuing into Common Pathway

Question 33

Extrinisc Pathway Process

Answer 33

1) Damaged tissue releases tissue factor 2) Tissue factor activates Factor 7 into 7a:Tissue Factor (Complex) 3) Factor 7a:Tissue Factor with Ca2+ cofactor activates Factor 10 into Factor 10a, which then goes into the final common pathway along with Ca2+ + Factor 5a on platelet surface

Question 34

Common Pathway Process

Answer 34

1) Factor 10a converts prothrombin into thrombin, this in turn activates Factor 13 into Factor 13a 2) Thrombin also converts fibrinogen into fibrin + activate Factor 5 + Factor 13 into 5a + 13a 3) Factor 13a then stabilises the fibrin, which then goes on to form a clot

Question 35

Positive + Negative Feedback of Coagulation Cascade

Answer 35

Positive feedback (Promotes enhanced thrombin productions): Ca2+ cofactor, Factor 13a + platelet surface, Factor 5a + platelet surface Negative feedback: Antithrombin 3 inactivates Thrombin, Factor 10a, Factor 9a + 11a, Plasminogen (acts on fibrin)