WK07L1 - Hemostasis III (Ben) Flashcards
What membrane-bound molecule does the action of the protein C-dependent anticoagulant pathway depend on?
And what determines the availability of this molecule?
Why?
Thrombomodulin
- the location within the cardiovascular system determines TM availability
- vessel perimeters vary in different locations and since TM is found on endothelial surfaces, the local amount of TM is directly correlated to vessel perimeter
What determines the local amount of factors on which thrombomodulin can act?
Cross sectional area of blood vessels determines local amount of thrombin (the main target of TM)
Considering dependence of TM amount on vessel perimeter and thrombin amount on vessel cross-sectional area…
Where is relative thrombomodulin activity the highest?
What does this mean for hemostasis in these areas?
In smaller vessels
- so capillaries have the highest anti-coagulant power
(Because cross sectional area is relative to the square of vessel radius… so even small increases in radius mean large increases in the amount of thrombin on which TM must act in order to inhibit coagulation.)
What characteristic of blood flow has an effect on the differences in thrombotic actions throughout different parts of the circulation?
What parameter and unit can be used to indicate this blood flow characteristic?
(Think of movement, as opposed to the more static characteristics of blood amount related to vessel cross-sectional area and endothelial surface amount as related to vessel perimeter.
Shear forces affect thrombotic activity.
Shear rate is a parameter which describes the difference of flow rates per unit distance (ΔV/Δr) with a unit of 1/s.
Where is shear rate the highest in the vascular system?
What happens to shear rate if a stenosis occurs?
In the capillaries
Any narrowing of a vessel, as seen in stenosis, results in an increase in shear rate.
What is the effect of increased shear rate on thrombin activity?
Increased shear rate decreases thrombin activity
(figure shows thrombin conc. across cross section of a vessel at different shear rates)
Describe the two-step activation of thrombin resulting in an important, catalytically active intermediate.
- Factor Xa cleaves prothrombin (@ R320)
- Resulting intermediate meizothrombin is active (but with diff. substrate specificity)
- Factor Xa then cleaves meizothrombin (@R271), removing prothrombin fragment 1,2 to give thrombin
What is the difference in activity between thrombin and meizothrombin?
Meizothrombin is a much less efficient activator of clotting factors, but…
has almost equal activity to thrombin on thrombomodulin + protein C and can thus be considered an anti-coagulant intermediate in the activation of thrombin.
Considering the two-step activation of prothrombin and the anti-coagulant action of meizothrombin…
why does increased shear rate result in decreased thrombin activity?
And what does this mean for thrombin activity in different parts of the circulation?
With slow flow/low shear rate, meizothrombin can remain in complex with prothrombinase and complete its conversion to thrombin.
With higher shear rates, more meizothrombin is moved away from the complex and can activate the thrombomodulin-protein C anticoagulant pathway.
This means that in veins thrombin activity is higher (due to lower shear rates).
How are the effects of antithrombin different in different parts of the circulation?
Meizothrombin is not sensitive to inactivation by antithrombin, so…
in vessels with higher shear rate and thus more meizothrombin, antithrombin does not have as much thrombin substrate.
What are the 3 main types of hemophilia and the causes of each?
What is their relative frequency?
- Hemophilia A - Factor VIII deficiency (most common)
- Hemophilia B - Factor IX deficiency (less common)
- Hemophilia C - Factor XI deficiency (least common)
Hemophilias A, B and C are not fatal.
Why?
Because they are mainly intrinsic pathway factors and the extrinsic pathway (tissue factor-dependent) is the most important hemostatic pathway.
Factors VIII, IX and XI that are deficient in these hemophilic conditions do take part in positive feedback loops of the extrinsic pathway, but are not essential for its functioning, so patient’s will have bleeding, but not a fatal amount.
What are some common thrombophilic conditions?
(6 of them, listed in order of frequency, probably not so important for the midterm)
- Factor V Leiden - un-inactivatable factor V (8-15% of population)
- High FVIII
- High FII
- Low Protein C
- Low Protein S
- Low Antithrombin (2/10,000 people)
This graph shows thrombin concentrations in health subjects (blue) and hemophilic patients (orange) over time.
The arrows under the x-axis show the times at which enough thrombin is formed to create a visible clot.
If hemophilic patients can form these visible clots, why do they still have bleeding issues?
The main difference between healthy and hemophilic patients is the peak thrombin concentrations reached in later stages of clot formation.
These higher concentrations are necessary for activation of factor XIII which performs covalent stabilization of clots, without which the clots are prone to dissolution by shear forces.
What are the 2 main types of indirect thrombin inhibitors?
- Heparin + heparin derivatives (low molecular weight heparin, fondaparinux)
- Vitamin K antagonists (VKAs)
