Lecture 13: Physiology of Coagulation

Question 1

What is Hemostasis?

Answer 1

physiological process of

• keeping blood in liquid state in the vasculature
• prevents blood loss through clotting

Question 2

what are the 4 main hemostatic events upon tissue injury?

Answer 2

1. vasoconstriction: neural & platelet reinforced
2. platelet activation: Adhesion, aggregation
3. coagulation: blood clot, thrombin generation, fibrin polymerisation
4. fibrinolysis - blood clot dissociation

Question 3

why do we need to maintain blood flow?

Answer 3

regulation of pH

transport - O2, CO2, waste, nutrients

Question 4

what is the purpose of vascular constriction and how is it achieved?

Answer 4

• limit blood flow
  inherent vascular response to injury
  release of activators by platelets
  sympathetically induced

Question 5

what are 4 significant histological features of platelets/

Answer 5

• shed from megakaryocytic
• lack nucleus
• store secretory product in granule
• high concentration of actin and myosin - high contraction, want platelets to contract and solidify plug

Question 6

how are platelets activated?

Answer 6

release of secretory factors

Question 7

how do platelets adhere to each other?

Answer 7

binding through expression of von Willebrand factor

Question 8

what are some platelet secretary granules?

Answer 8

• serotonin - vasoconstriction
• growth factor - help stem tissue repair
• factor 5 and 13 - produced at side of of injury (classic coag pathway )
• thromboxane, ADP, help prevent the clot spread

Question 9

what is vWF ?

Answer 9

multimeric, 8 subunit receptor expressed on platelets
sub endothelial collagen binds
high avidity

Question 10

what are the two pathways of platelet aggregation?

Answer 10

1. in response to collagen, vWF and tissue factor when there is injury to endothelial lining
2. ADP, thromboxane, 5HT

Question 11

what is the end point of platelet aggregation?

Answer 11

increase in cystolic calcium which induces platelet activation / aggregation
externalisation of glycoprotein receptors cause fibrin bands to bind to different platelets

aspirin interferes with conversion of AA to TXA2 and inhibits release of cystolic calcium and therefore platelet aggregation

Question 12

what limits platelet aggregation?

Answer 12

normal epithelium produces prostacyclin and NO
inhibits platelet aggregation
–> therefore no platelets on healthy tissue and ending up in potential thrombis

Question 13

what is the platelet plug?

Answer 13

physically seals endothelial injury

• actin myosin contracts which compacts and strengthens plug
• release chemicals such as serotonin
• other chemicals enhance coagulation

Question 14

what is coagulation

Answer 14

transformation of liquid to solid gel
clot formation provides strength and support to platelet plug
ultimately results in conversion of fibrin from fibrinogen by thrombin
= formation of mesh link that traps blood components

Question 15

what are the three coagulation pathways

Answer 15

intrinsic - everything you need in blood
extrinsic - activated by factors outside of blood
common - shared end pathway

Question 16

what is the end of all coagulation pathways

Answer 16

cleavage of fibrinogen to fibrin by thromboxane and cross linking with transglutaminase = strength

Question 17

how do clotting factors concentrate on activated platelets?

Answer 17

• expression of negatively charged phospholipids on activated platelets
• attachment of calcium ions to surface
  clotting factors attach to calcium
  amino terminal domains contain gamma carboxyl glutamate residues

Question 18

what occurs during the intrinsic pathway?

Answer 18

within a damaged blood vessel - all elements are within blood
7 steps set off by factor 10
activated by -ve charged surface eg/ collagen
occurs simultaneously with platelet plug formation
platlets secrete PF3: essential for clotting cascade and enhance platelet aggregation

Question 19

what is phospholipid F3?

Answer 19

expressed by activated platelets
surface phospholipid
acceleration of coagulation cascades - promotes platelet recruitment, aggregation, fibrin formation

Question 20

what is the extrinsic pathway?

Answer 20

x4 steps - incl x3 of the common pathway
requires contact with tissue factors
injured tissue release a protein complex directly activates factor 10

Question 21

what is thrombin?

Answer 21

generated from pro-thrombinase complex
Xa, II and Va bind calcium to anionic phospholipid on platelet membrane
calcium binding is mediated by Gla domains, binds gamma carboxyglutamate

Question 22

what are the actions of thrombin?

Answer 22

a pro coagulent - cleaves fibrinogen to fibrin, activates clotting factors 5, 8, 11 and 13.
stimulate platelet activation

an anti-coagulent - activates protein C, which inactivates clotting factors 5a and 8a

Question 23

explain the cross linking of fibrin

Answer 23

initial soft plug characterised by H bonding
covalent x links of fibrin add strength
mediated by transglutaminase factor 12a

Question 24

what limits clot formation at site of injury?

Answer 24

clots must rapidly form but be confined to area of injury
labile clotting factors - diluted by blood flow, removed by liver, anticoag mechanisms: tissue factor pathway inhibitor, thrombomodulin, anti thrombin II

Question 25

what is antithrombin II

Answer 25

inactivates thrombin by forming complex with it - irreversible
also blocks other factors, 11a, 9a and 10a
enhanced by heparin

Question 26

what is thrombomodulin?

Answer 26

forms complex with thrombin
thrombomodulin and calcium act as co-factors for thrombin activation of protein C
protein C and S inactivate factors 5a and 7a through proteolytic cleavage

Question 27

what are 6 anticlotting roles of EC’s?

Answer 27

1. normally provide intact barrier
2. synth and release PGI2 and NO
3. secrete tissue factor pathway inhibitor
4. bind thrombin which activates protein C
5. display heparin molecule on surface
6. secrete tissue plasminogen activator

Question 28

what is fibrinolysis?

Answer 28

plasminogen = inactive zymogen of plasmin
plasmin degrades fibrin into peptides dissolving blood clot
plasminogen activated by tissue plasminogen activator only when bound to fibrin
- promotes its own breakdown

early on = not much fibrin = not much plasmin so you get more thrombin
later = more fibrin = more plasmin = more breakdown as theres a good change endothelial cells underneath are repaired.

Question 29

in short what occurs to stop bleeding:

Answer 29

1. injury damages vascular endothelium and exposes sub endothelial collagen
2. vWF cements platlets to collagen to form cellular plus
3. fibrin deposits on platelet plug and later contracts by covalent cross linking
4. plasmin digests fibrin clot and endothelium regenerates