Biochemistry of Coagulation Flashcards
What does aspirin do to platelets?
It irreversibly inhibits their cyclooxygenase - so it irreversibly inhibits them
What are the 4 phasea of hemostasis?
- vascular constriction limits flow of blood to injury
- platelets activate and aggregate to form temporary loose platelet plug
- a fibrin mesh (clot) forms and entraps the plus
- clot is dissolved in order for normal blood flow to resume after tissue repair
What molecules i primarily responsible for stimulatin gplatelet clumping?
fibrinogen
What do platelets release when they are activated?
ADP and TXA2 - they both activate additional platelets
and other proteins important for the coagulation cascade
Although normal platelet count is 150,000 to 450,000, how many do we actually need before we have trouble clotting?
50,000 (below that and we’ll have issues with stopping bleeding, below 10,000 and we’ll have issues with spontaneous bleeding)
What do platelets adhere to in the area of injury?
exposed collagen on the subednothelial layer
What factor mediates the adhesion of platelets to collagen?
vonWillebrand factor
and GpIX-GpV and GpVI
Specifically, how does vWF work?
It acts as a bridge between the collagen fibrils on the subendothelial layer and the glycoprotein IB (GpIX-GpV) on the surface of the platelet
What enzyme is usually lacking in thrombotic thromobocytopenic purpura? What does it usually do?
ADAMTS13 - which usually cleaves vWF aggregates
If they’re not broken down, they block up the vessels and cause a microangiopathic hemolytic anemia
What’s the pentad of symptoms in TTP? Do they need all of them for a diagnosis?
microangiopathic hemolytic anemia, thrombocytopenia, fevers, renal failure, and neurologic deficits
They don’t need all of them - only RBC fragmentation and thrombocytopenia
What’s the treatment for TTP?
early plasmapheresis
and Rituxan
When ADP binds to new platelets, what does it do?
It leads to further unmasking of GpIIb-IIIa binding sites for additional platelet aggregation
Also indices swelling of activated platelets, promoting platelet/platelet contact and adherence
How does platelet adherence lead to production of the vasoconstrictor TXA2?
It leads to activatin of pohospholipase A2 which hydrolyzes membrane phospholipids to liverate arachidonic acid, which is then broken down to TXA2 by cyclooxygenase
GpIIb-GpIIIa acts as a receptor fo vWF and what else?
fibrinogen
What cleaves fibinrogen to produce fibrin monmers that polymerize with platelets to form the soft clot
thrombin
Where are clotting factors synthesized?
liver
There are two pathways in clotting cascades: intrinsic and extrinsic. Where do they converg?
they both converge on factor 10 to ocnvert to 10a
What does factor Xa do>
converts prothrombin (factor 2) to thrombin (factor 2a),
Again, what does thrombin do?
It cleaves fibrinogen into fibrin monomers that cross link to form clot
What factor is needed for cross-linking of fibrin polymers?
activated factor XIII
What’s the most important thrombin inhibitor?
antithrombin III
What drug potentiates the activity of antithrombin III?
heparin - it alters it’s structure slightly so it can bind thrombin more readily
Activated protein C with it’s necessary cofactor protein S do what to put the breaks on coagulation?
They degrade factors Va and VIIIa via proteolysis so you decrease thrombin production
What serine protease is largely responsible to degrading fibrin?
plasmin (formed from plasminogen)
What are two endogenous plasminogen activators?
tPA (from vascular endothelial cells)
single-chain urokinase
What vitamin is vital for the coagulation cascade?
vitamin K - used as a cofactor
What drugs works as a vitamin K antagonist to reduce activation of factors 2, 7, 9, and 10?
warfarin (coumadin)
What does warfarin block specifically
the vitamin K reductase enzymes used to regenerate active vitamin K
What are the factors not able to do if not gamma-carboxylated?
they can’t bind the necessary calcium nor form complexes
What other proteins are blocked by warfarin, which is why you need to “bridge with heparin”. What does this mean for clotting?
protein S and C
this means that warfarin will actually make you clot initially
What drug can cause thrombocytopenia by triggering an autoimmune prothrombotic disorder?
heparin - you get IgG antibodies that cause platelet activation
