Transcript Slide 1

Aspirin Resistance
Issa Majed Ghanma MD.
Platelets Function
- Platelets play an important role in homeostasis.
- they bind to collagen and to each other forming a
barrier to blood loss at the site of injury.
Cont. Platelets
Function
they accelerate the rate of activation of
coagulation proteins and release granules that
promote further platelet activation and healing.
Cont. Platelet Function
- There are many important platelets
agonists:
1- thrombin
2- thromboxane A2
3- ADP
Antiplatelet Agents
Several antiplatelet agents are available that work at
different sites of platelet activation:
1- Aspirin.
2- Clopidogrel .
3- dipyridamole .
4- thrombin inhibitors (bivalirudin, lepirudin).
5- IIb / IIIa receptor blockers.
The History of Aspirin
- Salicylates have been used to treat pain and
inflammation associated with rheumatism.
- Industrial production of salicylic acid started in
1859, however early preparation were associated
with side effects, such as unpleasant taste and
dyspepsia.
- Felix Hoffman of Friedrich Bayer & Co.
developed a stable and better-tolerated form of the
drug (acetylsalicylic acid).
Cont. Aspirin History
1950… Reports linked aspirin use
with prolongation of bleeding time.
1970… Aspirin demonstrated to be
a potent inhibitor of prostaglandin
synthesis.
Later … It was confirmed that
aspirin acetylates serine 529 in the
active site of the cyclooxygenase-1
enzyme
(prostaglandin H2 synthase-1),
permanently deactivating it and
preventing thromboxane A2 platelet
activation.
These observations paved the way
for the clinical investigation of
aspirin's antiplatelet effects in
preventing thrombotic events, such
as ischemic strokes and acute
myocardial infarction.
Mechanism Of Action Of
Aspirin
Aspirin inhibit the cyclooxygenase
(COX) activity of prostaglandin
(PG), which in turn blocks the
metabolism of arachidonic acid to
cyclic prostanoids such as
thromboxane A2 (TXA2).
Aspirin
Membrane Phospholipids
(Phospholipase A)
Platelet COX-1
Arachidonic Acid
inhibition
(COX-1/PGH-Synthase)
Prostaglandin G2
(HOX/PGH-Synthase)
Prostaglandin H2
(PGH-Synthase)
TXA2
- Increased platelet aggregation.
- Vasoconstriction.
Pharmacokinetics Of
Aspirin
-Aspirin is rapidly absorbed from the gastrointestinal
tract and peak plasma concentration are achieved in
30 to 40 minutes.
-Significant platelet inhibition is noted within 60
minute of ingestion and a single dose of 100mg of
aspirin can completely block TXA2 production for
the life of the platelet in most individual.
Cont. Pharmacokinetics
Of Aspirin
-The plasma half-life of aspirin is only
20 minutes but the irreversible nature
function makes once-daily dosing
sufficient to maintain its antithrombotic
benefit.
Aspirin Efficacy
- Aspirin plays an important role in primary and
secondary prevention of vascular events.
- Aspirin is very effective therapy for patients
suffering an acute M.I, as demonstrated by (ISIS-2)
trial in which aspirin administration reduced
mortality by 23%, a comparable effect to
thrombolytic therapy.
People still have events while on
ASA!!!
Do all patients respond in the
same way?
Definition(s) of “APT Resistance?”
The fact that some patients may experience
recurrent vascular events despite the use of APT
should be properly defined as “treatment failure”
rather than “APT resistance” (multiple pathways
mediate thrombotic events).
APT Resistance/Non-responsiveness=failure to
inhibit the target
APT Resistance/Non-responsiveness≠clinical
failure
Antiplatelet Drug
Resistance
1- What do we know about it ?
2- How do we define it ?
3- What do we do about it ?
Aspirin Resistance
- Clinical observation of aspirin's inability to protect
individuals from thrombotic complications.
- Laboratory phenomenon of absence of aspirin's
effect on one or more tests of platelets function.
Aspirin Resistance
No… formal diagnostic criteria…but
aspirin resistance generally describes the
failure of aspirin to produce an expected
biological response or the failure of
aspirin to prevent atherothrombotic
events.
Aspirin resistance has been reported to
occur in 5% to 45% of the general
population.
Cont. Aspirin Resistance
The exact prevalence of aspirin
resistance remains uncertain… but
Measurement of platelet aggregation,
platelet activation, and bleeding time
have all confirmed variability in patient's
anti-thrombotic responses to aspirin
therapy.
Platelet Function Tests
. Platelet aggregation
Light transmittance aggregometry (LTA)←gold standard
impedance platelet aggregation
. Flow Cytometry
GPIIb/IIIa receptors activation
P-selectin expression
Monocyte-platelet aggregates
Vasodilator-associated stimulated phosphoprotein (VASP)
. Point-of-care
Ultegra rapid platelet function analyzer (Verify Now)
Thromboelastagraph (TEG)
Platelet works
Cone and platel(let) analyzer (IMPACT)
.Genetic testing
Potential mechanisms
/causes of aspirin resistance
Although the mechanism for aspirin
resistance remains uncertain, it is likely due to
a combination of clinical, biological, and
genetic properties affecting platelet function.
Aspirin Resistance Patient
Management
- Educate patients on importance of compliance
- Eliminate interfering substances (ibuprofen)
- Increase aspirin dose(?) (….increasing the dose of
aspirin does not enhance COX-1 inhibition)
- Use other anti-platelet medications (e.g.
clopidogrel) (?) (….no scientific evidence that
switching to alternative treatment strategies
improves outcomes).
Main points
1-Aspirin is effective antiplatelet agent with proven
benefit in the prevention of atherothrombotic
complications of cardiovascular; however, the
absolute risk of recurrent vascular events among
patients taking aspirin relatively high.
2-Although formal diagnostic criteria are lacking,
aspirin resistance generally describes the failure of
aspirin to produce an expected biological response
(ie, platelet inhibition) or to prevent
atherothrombotic events
3-Aspirin resistance has been estimated to exist in
anywhere from 5% to 45% of the population,
representing a phenomenon of possible clinical
significance.
4-Traditionally, platelet aggregation has been
measured in platelet-rich plasma using an optical
aggregometer. Other effective means of analizing
platelet function include the platelet function
analyzer (PFA)-100 and the rapid platelet function
assay (RPFA).
Conclusions
- Variability in individual responsiveness to antiplatelet agents
is an emerging clinical problem: poor responsiveness has
been associated with an increased risk of ischemic events,
including stent thrombosis.
- WHAT and HOW to measure antiplatelet drug
responsiveness still needs to be fully defined.
- WHAT do we do with the results coming from the “test
tube”? (No demonstration of an association with clinical
events conditioning cost-effective changes in treatment).
- responsiveness to antiplatelet therapy should be evaluated
for mainly investigation purposes!!!
Thank You
Aspirin Resistance:
Relative Risk Of Different events
Events
risk
M.I or UAP
Stroke or TIA
Relative
3.8
4.1