Flashcards in Lecture 13: Physiology of Coagulation Deck (29):
What is Hemostasis?
physiological process of
- keeping blood in liquid state in the vasculature
- prevents blood loss through clotting
what are the 4 main hemostatic events upon tissue injury?
1. vasoconstriction: neural & platelet reinforced
2. platelet activation: Adhesion, aggregation
3. coagulation: blood clot, thrombin generation, fibrin polymerisation
4. fibrinolysis - blood clot dissociation
why do we need to maintain blood flow?
regulation of pH
transport - O2, CO2, waste, nutrients
what is the purpose of vascular constriction and how is it achieved?
- limit blood flow
inherent vascular response to injury
release of activators by platelets
what are 4 significant histological features of platelets/
- 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
how are platelets activated?
release of secretory factors
how do platelets adhere to each other?
binding through expression of von Willebrand factor
what are some platelet secretary granules?
- 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
what is vWF ?
multimeric, 8 subunit receptor expressed on platelets
sub endothelial collagen binds
what are the two pathways of platelet aggregation?
1. in response to collagen, vWF and tissue factor when there is injury to endothelial lining
2. ADP, thromboxane, 5HT
what is the end point of platelet aggregation?
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
what limits platelet aggregation?
normal epithelium produces prostacyclin and NO
inhibits platelet aggregation
--> therefore no platelets on healthy tissue and ending up in potential thrombis
what is the platelet plug?
physically seals endothelial injury
- actin myosin contracts which compacts and strengthens plug
- release chemicals such as serotonin
- other chemicals enhance coagulation
what is coagulation
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
what are the three coagulation pathways
intrinsic - everything you need in blood
extrinsic - activated by factors outside of blood
common - shared end pathway
what is the end of all coagulation pathways
cleavage of fibrinogen to fibrin by thromboxane and cross linking with transglutaminase = strength
how do clotting factors concentrate on activated platelets?
- 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
what occurs during the intrinsic pathway?
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
what is phospholipid F3?
expressed by activated platelets
acceleration of coagulation cascades - promotes platelet recruitment, aggregation, fibrin formation
what is the extrinsic pathway?
x4 steps - incl x3 of the common pathway
requires contact with tissue factors
injured tissue release a protein complex directly activates factor 10
what is thrombin?
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
what are the actions of thrombin?
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
explain the cross linking of fibrin
initial soft plug characterised by H bonding
covalent x links of fibrin add strength
mediated by transglutaminase factor 12a
what limits clot formation at site of injury?
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
what is antithrombin II
inactivates thrombin by forming complex with it - irreversible
also blocks other factors, 11a, 9a and 10a
enhanced by heparin
what is thrombomodulin?
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
what are 6 anticlotting roles of EC's?
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
what is fibrinolysis?
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.