Blood Coagulation Flashcards
What is the intrinsic pathway?
Activates the clotting cascade by contact with an abnormal surface, relies entirely on substances circulating within the blood
What is the extrinsic pathway?
Activates the clotting cascade by substances released from damaged tissue
What is released from damaged tissue and what is its role?
Factor III (Tissue factor
Cofactor for Factor VII, required for its activity
What is the pathway and function of Factor VII?
Extrinsic pathway
Cleaves Factor X to Xa in the presence of tissue factor (III) and calcium.
What is the pathway and role of HMWK?
Intrinsic pathway.
Cofactor for the activation of Kallikerin and Factor XII
What is the pathway and function for Kallikrein?
Intrinsic.
Activates Factor XII
What is the pathway and function for Factor XII?
Intrinsic.
Activates other XII molecules and prekallikrein (positive feedback)
Also cleaves Factor XI to XIa
What is the pathway and function of Factor XI?
Intrinsic.
Once activated, XIa cleaves Factor IX to IXa
What is the pathway and functions of Factor IXa?
Intrinsic
Activates its protein cofactor, Factor VIII to VIIIa
Forms a complex with VIIIa, and in the presence of calcium and phospholipid, cleaves Factor X to Xa
What is the pathway and function of Factor VIII?
Intrinsic
Once activated, Cofactor for Factor IXa
Activated by Factor IXa and thrombin (IIa)
What is the pathway and function of Factor X?
Common.
Xa forms a complex with phospholipid, calcium, and cofactor Factor V
This complex cleaves prothrombin (II) to thrombin (IIa)
What are the functions of Thrombin
- Cleave fibrinogen to fibrin
- Feeds back to activate VIII and V
- Activates XIII, which crosslinks fibrin strands
- Activates Protein C, inactivates V and VIII
What is Protein C and what is its function?
Protein C is a protease activated by thrombin that inactivates V and VIII
What intrinsic factors can activate VII?
XII
IX
X
What is the structure of fibrinogen?
Large complex of 6 proteins (Aa)2(BB)2(y)2
Globular domain at each end, joined by rod-like sections that meet at a globular central domain
What is the role of the negatively charged amino acids in the A and B peptides?
Keep the fibrinogen molecules apart.
Make them more soluble
What is factor XIII and how does it function?
A transglutaminase that crosslinks glutamine and lysine side-chains in adjacent monomers
What are the three roles of platelets in coagulation?
Physical blockage via aggregation
Contribution of phospholipid surface for CF activation
Contribution of clotting and accessory factors
What happens as a result of platelet aggregation?
Release of CFs, adenine, serotonin, and growth factors
Flipping of phosphotidylserine to the surface to provide a binding site for CFs
What Clotting factors do platelets release upon activation?
V
XI
XIII
Fibrinogen
Von Willebrand factor
HMWK
What are the functions of von Willebrand factor?
Link between platelet surface glycoprotein and ECM
Carrier for VIII
What four factors limit the clotting activity to the area of damage?
- Factor concentrations diluted by blood flow
- active factors removed from circulation by liver
- Proteases degrade factors
- Specific plasma inhibitors of clotting factors (AT3)
What is antithrombin 3 and what are its functions?
Serine protease inhibitor (Serpin)
Strongly inhibits thrombin by forming an irreversible complex with it
Inhibits XII, XI, IX, X
What is responsible for dissolving clots?
Plasminogen bound to fibrin strands is activated at the right time by tissue plasminogen activator (TPA)
Plasmin cleaves fibrin into small peptides, dissolving the clot
How are the proteases in the clotting cascade related to each other?
All are serine proteases
Have the same critical active site residues (His, Ser, Asp)
What is common between the three contact phase proteases (Kallikrien, XII, and XI)?
All have a portion allowing them to bind to negatively charged surfaces
What is common between the four proteases that require Ca and a phospholipid?
Have a special N-terminal domain containing a large number of Glu residues (called the Gla domain)
What is significant about the Gla domain?
Glu residues have been modified to contain an extra carboxyl group in their side chains (y-carboxyglutamate) (Gla)
What is required for the modification of Glu to Gla?
Vitamin K
This reaction requires a Vitamin K-dependent enzyme.
**Not required for activity, required to properly localize factors to substrate
What is the genetic defect in Hemophilia A?
Factor VIII deficiency, x-linked recessive
What is the genetic defect in Hemophilia B?
Factor IX deficiency, x-linked recessive
What was the traditional treatment for hemophilia and its drawbacks?
Administration of purified clotting factor
Expensive
Risk of blood-borne pathogens
What are current treatments for hemophilia?
A wide variety of recombinant proteins like factors VIII, IX, and VII
Aspirin
Inhibits platelet aggregation
Clopidogrel
Inhibits platelet aggregation
Coumadin
Inhibits factors associated with Vitamin K dependent enzymes
II, IX, X, XII
Dabigatran
Competitive inhibitor of thrombin
Rivaroxaban
Inhibits X
