Blood Clotting Flashcards
What is hemostasis?
Hemostasis – maintaining volume of blood
What is the normal state of the blood vessel wall?
Anti-thrombogenic
What happens after blood vessel is damaged? (brief)
Vessel damage exposes underlying tissue – platelets can adhere and are activated Activated platelets release factors to activate other platelets that adhere to the wound Coagulation factors are activated Fibrinogen is converted to fibrin – assembles meshlike structure to support the clot
How is blood clotting speed ensured?
Factors are always in blood, but inactive
What are platelets?
Fragments of cells in
the blood (made by
megakaryocytes in bone
marrow)
What do platelets do?
Vessel damage -> platelet
activation – adhere and plug hole,
release factors to promote clotting
What is the normal state of platelets?
Platelet adhesion is regulated – normal is “non-sticky” and activated is
“sticky”
How are platelets activated?
Activated platelets release ADP and produce thromboxane A2
to activate
more platelets
How does aspirin prevent clotting?
Inhibit enzymes involved in synthesis of thromboxane A2 from arachidonic acid (via prostaglandin)
What is the descriptive name of factor I? What is its function?
fibrinogen
forms fibrin
What is the descriptive name of factor II? What is its function?
prothrombin
serine protease
What is the descriptive name of factor III? What is its function?
tissue factor
receptor/co-factor
What is the descriptive name of factor IV? What is its function?
Ca2+
cofactor
Which factors are serine proteases?
II, VII, IX, X, XI, XII, pre-kallikrein
What is the function of factor XIII?
Ca2+ dependent transglutaminase
What is the function of factors IV, V, VIII, HMW kininogen?
cofactor
How many factors are there?
15
Factors I - XIII, pre-kallikrein, and HMW kininogen
What name change occurs when a factor is activated?
When clotting factors are activated, their name
changes – e.g. X becomes Xa
What are the steps in the extrinsic pathway cascade?
1) VII is activated to VIIa (catalyzed by III [tissue factor], phospholipase, and Ca2+)
2) VIIa catalyzes activation of X -> Xa
What are the steps in the intrinsic pathway?
1) In damaged tissue, pre-kallikrein converted to kallikrein
2) kallikrein catalyzes conversion of XII to XIIa
3) XIIa catalyzes conversion of XI to XIa
4) XIa catalyzes conversion of IX to IXa
5) IXa combines with VIIIa, and then catalyzes the conversion of X -> Xa
What is the common product of the extrinsic and intrinsic pathways?
Factor Xa
What are the steps in the common pathway?
1) Factor V is activated to Va
2) Va and Xa combine to activate II to IIa (prothrombin to thrombin)
3a) Thrombin (IIa) catalyzes activation of I (fibrinogen) to Ia (fibrin)
3b) Thrombin cleaves zymogens in intrinsic and extrinsic pathways
3c) Thrombin catalyzes activation of XIII to XIIIa
4) Fibrin (Ia) causes formation of a crosslinked clot
What is the purpose of the factor cascade?
Signal amplification
What is carboxylation? What amino acid does it commonly occur on in the context of clotting?
Posttranslational addition of carboxyl group
Often on Glu
Why is carboxylation important for clotting?
Factors VII, IX, and X require Ca2+
Carboxylation allows these factors to interact with Ca2+
Why is vitamin K important for clotting?
Necessary for carboxylation of Glu to Gla
1) Glu + vitK -> Gla + vitK-epoxide (via vitK carboxylase)
2) VitK must be regenerated, so…
vitK-epoxide -> vitK (via vit K reductases)
How does warfarin prevent clotting?
Inhibits vitK reductases, preventing regeneration of vitK
How is fibrin produced? What does it do? What is its structure?
Fibrinogen – hexamer – 2Aa, 2Bb and 2g chains -soluble
Thrombin cleaves fibrinogen to fibrin – removes
small peptides from the a and b chains – fibrin
molecules can now polymerize
Which factor crosslinks fibrin?
XIIIa
What is factor XIIIa? How does it work?
Transglutaminase
Crosslinks by forming isopeptide bond
between lysine and glutamine residues
What causes hemophilia?
Deficiency of clotting factors?
What are the 2 main types of hemophilia?
in US 80% have defective VIII – X-linked
in US 20% have defective IX
What causes Glanzman’s thrombasthenia?
Platelet defect or deficiency
What are the steps in turning off clotting?
Called anti-coagulation phase
1. Diffusion of factors away from wound
2. Protein C – a protease that degrades Va
and VIIIa
• Activated by thrombin
3. Serpins – serine protease inhibitors
• Antithrombin III (AT3) – in blood – inhibits thrombin and
other clotting factors – heparin dramatically enhances
inhibition of thrombin and Xa
How are blood clots removed?
Fibrinolysis
1. Plasmin – protease that degrades fibrin
2. Plasminogen – inactive precursor to plasmin
– binds to fibrin (in the clot)
3. Plasminogen – activated by protease – tissue
plasminogen activator (tPA)
4. tPA released from vessel wall
