L 39 Flashcards
The balance of blood fluidity is between these 2 things….
Haemostasis (clotting) and bleeding
Things that favour the haemostasis x5
- Turbulent of static blood flow
- Venous thromboembolism
- Reduced natural anticoagulation or fibrinolysis
- Atrial fibrillation
- Post-trauma
Things that favour bleeding x4
- Vascular damage
- Haemophilia
- Thrombocytopenia
- Anticoagulation and anti-platelet drugs
Thrombocytopenia meaning?
Reduced activity/number of platelets
Haemophilia meaning?
Reduced ability to make blood clots.
In some pathologies, the balance is tipped towards…. We can counter-balance the system using…. therapy. This makes the scale ….
In some pathologies, the balance is tipped towards hypercoagulability. We can counterbalance the system using anticoagulant therapy.
This makes the scale tip slightly towards blood flow/bleeding.
Thrombus definition + composition?
A blood clot that completely or partially occludes a blood vessel. It is composed of platelets, fibrin, clotting factors
Haemostasis definition?
Clot formation as a normal response to injury
Thrombosis definition?
A pathological clot formed in the absence of an injury (e.g haemostasis in the wrong place/somewhere it is not meant to)
Coagulation definition?
The physiological process that leads to clot formation
Thromboembolism definition?
Example of something that can cause a thromboembolism?
Obstruction of a blood vessel caused by a blood clot that has become dislodged from another site.
Atrial fibrillation can cause a clot to form in the atria, which can potentially move into the brain.
Coagulation/clotting cascade uses and limitations?
Uses: useful for describing in vitro coagulation (e.g prothrombin time, aPTT)
Limitations: limited for understanding in vivo coagulation
What is the end product of the coagulation cascade?
A fibrin mesh
Is the coagulation cascade aptly named?
No, as it is not a one way system. It feeds backwards and forwards on itself, and within the different pathways/stages.
4x stages of the coagulation pathway (extrinsic)
1a. Initiation (platelet activation)
1b. Initiation (activation of factors X and IX)
2. Amplification (of Xa/2a, causing a burst of activated thrombin)
3. Propagation (formation of the fibrin clot)
What is the intrinsic pathway?
How does it differ from the extrinsic pathway?
A coagulation pathway that is activated by trauma inside the vascular system (e.g in a blood vessel) rather than external damage (e.g a cut)
It is slower than the extrinsic pathway
What is the target of Vitamin K antagonists?
+ an example
Vitamin K epoxide reductase - VKOR (in the VitK cycle in the liver)
e.g Warfarin
What is the target of heparins? + 3x examples of heparins/related drugs
Antithrombin
- Unfractionated heparin
- Low molecular weight heparin
- Fondaparinux (hospital only)
What is the target of NOACs?
What does NOAC stand for?
What are 2 examples of NOACs?
The target of NOACs: Thrombin, Factor Xa
NOAC = Novel oral anticoagulants
e.g dabigatran, rivaroxaban
How was warfarin discovered?
The chemical compound of coumarins was discovered to have anticoagulant properties when hay became mouldy. It was fed to cows and they kept bleeding.
This compound is the basis for warfarin.
When was warfarin first available for human use?
1952
Pharmacokinetics of warfarin: x3
- Racemic mixture of R- and S- wafarin
- Highly protein bound and well absorbed
- Hepatically metabolised with a low clearance
PK differences between S and R warfarin
- S warfarin = CYP2C9 and t0.5 of ~24hours. 3-5x more potent than R-warfarin.
- R warfarin = CYP3A4, 1A2 and 2C19. t0.5 = ~36 hours
MoA of warfarin
By inhibiting VKOR, warfarin reduces the production of clotting factors II, VII, IX, and X
What does VKOR do?
What is the impact of inhibiting this?
It catalyses the reaction of Vitamin K into Vitamin K epoxide and back.
Vitamin K is a cofactor in the clotting factor formation, therefore inhibiting this will produce less clotting factors.
What is the half-life of S-warfarin?
Therefore how long would it take to reach steady-state?
Half life = ~24hours
Steady state = 5x half lives = 5 days (120 hours)
Why does the INR clotting rate take longer to reach steady state than warfarin does to reach steady state?
Thrombin is a clotting factor (factor IIa) that has a reduced production from warfarin.
The t0.5 of thrombin is ~60 hours (not 24hours like S-warfarin)
Therefore, 5x 60 hours = ~10 days to reach steady state, which is shown through INR testing.
What does an INR value of 1 represent?
The length of time taken for your blood to clot is ‘normal’
below 1.1 = normal. Those with a high clotting risk on blood thinners will have higher values
What is the significance of INR taking longer to show steady state?
Monitoring!
Don’t increase the dose until at least the 8-10 day mark because the steady state hasn’t been reached yet - will potentially overdose patient/dangerously increase bleeding risk.
The time course of INR change is determined by … not ….
The time course of INR change is determined by clotting factor turnover, not warfarin plasma concentrations.
What is unfractionated heparin?
Where is it naturally found?
What is meant by unfractionated?
A large polymer with alternating disaccharide units of variable lengths. It is found naturally in mast cells.
Unfractionated: different chain length therefore different molecular weights.
What is the average molecular weight of UFH?
~15kDa
How is UFH given?
What is its half life?
Is there an antidote?
Given intravenously and subcutaneously
Short half life of ~ 1 hour
Antidote/reversal agent: protamine sulphate.
What is the MoA of unfractionated heparin?
When UFH binds to antithrombin III, it induces a conformational change to enhance the binding of ATIII to activated clotting factors (e.g Xa). This inhibits coagulation.
Long UFH molecules bind both … to inhibit …
Long UFH molecules bind both antithrombin and factor IIa to inhibit IIa.
Antithrombin is a natural ….. of ….
Antithrombin is a natural inhibitor of coagulation.
Low molecular weight heparins clearance
Is it reversible?
Mainly renally cleared (dose adjustment in renal impairment)
Effects can be PARTIALLY reversed by giving protamine sulphate.
Does UFH or LMWH have a better bioavailability when given subcutaneously?
Does UFH or LMWH have a longer half life overall?
LMWH has a more reliable bioavailability when given subcutaneously
LMWH has a longer half life than unfractionated heparin overall.
What is the t0.5 of enoxaparin?
~5 hours
MoA of LMWH
binds to antithrombin III-> LMWH-antithrombin III complex then inhibits:
- factor Xa
- less of an effect on thrombin (2a)
- *less likely to cause HIT
What is HIT?
Heparin induced thrombocytopenia
Heparin: Route Bioavailability (SC) Elimination T0.5 Monitoring
Route: IV/SC Bioavailability (SC): ~30%, variable Elimination: Complex t0.5: 1-2 hours Monitoring: required (aPTT) due to risk of bleeding.
LMWH: Route Bioavailability (SC) Elimination t0.5 Monitoring?
Route: SC Bioavailability (SC): >90% (predictable) Elimination: Renal, predictable t0.5: 4-6 hours Monitoring: Not usually required (antiXa assay) Examples of NOACs Dabigatran etexilate Rivaroxaban Dabigatran etexilate: MoA
Prodrug or immediate acting? Oral bioavailability % and Clearance?
t0.5 and daily dosing
MoA: competitive and reversible inhibition of free and clot bound thrombin
Prodrug. Dabigatran is the active compound.
Oral bioavail = 7%
80% renal clearance, 20% glucuronidation
t0.5 = ~12 hours, bd dosing.
Rivaroxaban: MoA: Oral bioavail:Clearance:
t0.5 and daily dosing:
MoA: Competitive and reversible inhibition of free and clot bound Xa
Oral bioavail: Good >80%
Clearance: 35% renal, 65% CYP3A4 metabolised
t0.5: 7-10 hours, od dosing
The physiological response to ALL anticoagulants is….?
Prolonged clotting time.
Give 3 examples of how clotting time/coagulation screening is measured
Prothrombin time and INR
Activated partial thromboplastin time (aPTT)
Anti Xa (not commonly available)
What does INR stand for?
What does an INR of 3 mean?
International Normalized Ratio.
(1.0 is normal and is an indication of bleeding time)
INR 3 = blood takes 3x as long to clot.
Not all …. will detect a change in …. equally when anticoagulants are given (it depends on the …..)?
Whether newer agents (….) require monitoring with coagulation screening is …… Therefore …. and …. are …… via INR?
Not all coagulation screens will detect a change in clotting time equally when anticoagulants are given (it depends on the drugs mechanism).
Whether newer agents (NOACs) require monitoring with coagulation screening is controversial. Therefore dabigatran and rivaroxaban are not routinely monitored via INR.
What is prothrombin time (PT)?
What is a normal PT time?
The time (seconds) it takes for plasma to clot in a test tube (in vitro). Is used to measure anticoagulant response. Normal time = 12-15 seconds
Is there any variability in PT?
Yes, the labs have to calculate it based on a ratio. This is not clinically useful, therefore we use INR as a correction.
What is INR?
A “correction” of the PT ratio.
INR = (Patient’s PT/mean normal PT) ^ISI
with ISI meaning international sensitive index (comparing to a standardised reagent with a known sensitivity to anticoagulants.
INR control?
- importance
- usual target range
- Is a tight therapeutic range true for all anticoagulants?
Importance: to balance the risk of bleeding with the risk of non-response (e.g stroke) therefore a small therapeutic window exists.
Usual target range: 2-3.5
The tight therapeutic range for anticoagulation is true for all anticoagulants (but is not always measurable with coag screening)
What does aPTT stand for? What does this mean? What is this primarily used for? What is the normal range? Target range?
Activated partial thromboplastin time
Time to clot in a test tube using different activators.
Primarily used to monitor unfractionated heparin therapy
Normal range: 25-40 seconds
Target range: 1.5-2.5x the control value.
What is an anti-factor Xa assay?
Is it widely available?
A proposed way to monitor LMWHs
Not widely available
Major determinants of warfarin dose requirements:
Age Body size Genetic differences (e.g CYP2C9, VKORC1) Drug interactions Vitamin K status
What are 2 importance enzyme polymorphisms to warfarin and why?
- CYP2C9: involved in S-warfarin metabolism. Poor metabolisers require much lower doses (e.g 1mg/day rather than 4-6mg/day)
- VKOR: involved in warfarin binding at the site of action (different amounts of VKOR gives a 2 fold range of potential doses)
How many potential drug interactions with warfarin are there?
Why do we need to be aware of these interactions?
Potentially >120 drugs
Potential toxicities and especially as warfarin has a narrow therapeutic window
Examples of enzymes that when inhibited or induced, can alter the efficacy of warfarin
CYP2C9, CYP3A4, CYP1A2, other CYPs
What happens when a drug inhibits a CYP enzyme? (e.g CYP2C9?)
Drugs that inhibit CYP2C9 activity will increase the plasma concentrations of certain medications and sometimes adverse outcomes will occur.
e.g: Any drug that inhibits CYP2C9, will almost certainly increase the hypoprothrombinemic response to warfarin.
What happens when a drug induces a CYP enzyme?
CYP enzyme inducers increase the rate of hepatic metabolism and decrease serum concentrations of other drugs also metabolised by the same hepatic isoenzyme.
Vitamin K is normally found/consumed by…
Vitamin K deficiency causes…
Normal Vitamin K intake
What impact would occasional consumption of vitamin K rich food have on warfarin patients? What patients do you need to be careful of (in terms of VitK and warfarin?)
Vitamin K is normally found in plants and consumed via diet.
Vitamin K deficiency causes bleeding
Normal Vitamin K intake is 100 micrograms
What impact would occasional consumption of vitamin K rich food have on warfarin patients?
Unlikely to be important
What patients do you need to be careful of (in terms of VitK and warfarin?)
Caution with vitamin K deplete patients e.g elderly, malnourished.
Tbh, dose variability between patients can generally be put down to… x3
- Demographic differences (body size, age etc)
- Genetic differences
- Adherence
