Goueli- Biochemistry of Coagulation Flashcards
What is hemostasis?
Physiological blood clotting in response to injury or vascular leak
What is thrombosis?
Patholgoic blood clotting
What is hemorrhage?
Pathologic bleeding
What are the 4 phases of hemostasis?
- Vascular constriction- limits flow of blood to area of injury
- Platelets aggregate at site of injury forming loose platelet plug
- Fibrin mesh form and entraps the plug
- Clot is dissolved in order for normal blood flow to resume
What are the three types of granules platelets contain?
Electron dense granules
alpha granule
lysosomal granules
What is a normal platelet level?
150–450,000
Platelet level <10,000
increased risk of spontaneous hemorrhage
platelet level <50,000
INcreased difficulty clotting if you’re already bleeding
What is the ideal platlet count for procedures?
For neurosurgical procedures?
50,000
above 100,000
What are the fundamental mechanisms involved in platelet function during blood coagulation
Adhesion
aggregation
secretion
How does primary homeostasis (adhesion) occur?
Platelets adhere to exposed collage at injured site–> release contents of granules–> aggregate
What mediates the adhesion of platelets to collagen exposed on endothelial cell surfaces?
vW
What Gp binds directly to exposed collagen?
GpVI
What does vWF do?
Acts as a bridge between a specific glycoprotein complex on the surface of platelets and collagen fibrils
Where is vWF produced and stored?
alpha-granules
What does vWF bind to at the site of injury?
- subnedothelial collagen 2. glycoprotein IB on the platelet surface
- Factor 8
What happens in vWF def?
Reduced levels of Factor 8
What happens in Gp1B def?
Bernard Soulier syndrome
Qualitative defect in platelet–> protein can’t bind to vWF
tx–give someone else’s platelets
Schistocytes in a blood smear is a sign of….
microangiopathic hemolytic anemia
What are the two most important hallmarks of TPP?
Profound thrombocytopenia
Microangiopathic hemolytic anemia (red cell fragmentation)
TPP is d/t a def in…
ADAMTS13
Def is acquired OR hereditatory
What happens when a platelet binds to collagen?
It causes the platelet to change shape from a flat disc to a spherical cell–>
exposes Gp complex binding sites to fibrinogen and vWF
The binding of platelets leads to the release of arachidonic acid. What does arachidonic acid do?
Leads to an increase in the production and release of TXA2.
What is TXA2?
Potent vasoconstrictor
Induces platelet aggregation
What does fibrinogen do?
Circulates in the blood
Binding of fibrinogen allows platelets to adhere to one another–> soft clot
What are the two pathways that lead to the formation of a fibrin clot and what do they do?
Intrinsic and extrinsic
converge on a common pathway that promotes clot formation
Where are most coagulation factors synthesized?
the liver
How do you generate fibrin?
By promoting thrombin activity
What happens in the extrinsic pathway?
factors 9a and 10a assemble w/ cofactors (8a and 10a) on the surface of the aggregated platelet–>
generation of large amounts of 10-a and thrombin (IIa)–>
conversion of fibrinogen to fibrin
What activates the extrinsic pathway? the intrinsic?
It responds to release of TF
Hyperlipidemic states or bacterial infiltration
The intrinsic pathway requires what clotting factors? It ultimately leads to….
Factors 8,9,10,11,12
Converstion of factor 10 to 10a
What is factor 8a?
A cofactor in the clotting cascade that is activated by thrombin
What occurs in the common pathway?
Factor 5 a binds to specific receptors on surfaces of activated platelets and forms complex w/ prothrombin and factor 10a.
Factor 10a converts prothrombin to thrombin
What regulates thrombin?
Thrombin inhibitors!
What are the thrombin inhibitors?
Antithrombin III (can also inhibit factors 9,10, 11, 12
What potentiates the activity of thrombin?
heparin
What does thrombin do to Protein S and C?
Thrombin forms a complex w/ another protein to convert protein C to protein Ca. Protein S and APC degrade factors 5a and 8a and decrease thrombin production.
Proteins C and S put the breaks on coagulation
What is fibrinolysis?
Degradation of fibrin in a clot by plasmin
What factors require Vit K gamma carboxylation for optimal function?
Factors 2,7,9,10, C and S
**takes place in the hepatocyte before release of the clotting factor
What happens if you’re def in vit K?
you’ll have an issue w/ clotting/bleeding
What is warfarin?
Anticoagulant
Has structure resembling vit K
What does warfarin do?
Competes w/ fvit K preventing gamma carboxylation of glutamate residues in Factors 2,7,9,10, C adn S
What happens to the noncarboxylated blood clotting precursors?
They increase in both blood and plasma but can’t promote blood coagulation because they can’t bind Ca and therefore can’t bind to the phospholipid membrane for activation
What else does warfarin block?
Proteins S and C–so you can’t turn down coagulation
*primary reason why there needs to be a “bridge w/ heparin”
How do heparins work?
Anticoagulant
They bind to and activate ATIII which leads to thrombin inactivation
Also block activity of factors 8a, 9a, 10a
