Basic Science applied to medicine

1. There is no belief, however foolish, that will not gather its faithful adherents who will defend it to
the death.
-Isaac Asimov
INTRODUCTION
Analgesic, antipyretic, and antiplatelet properties
Commonly used for the primary and secondary prevention of cardiovascular disease (CVD)
Reduce nonfatal CVD events by approximately 25%
Reduce fatal events by approximately 15%
DEFINITIONS
● Treatment failure
○ Occurrence of occlusive CVD events ​despite​ regular intake of aspirin at
recommended doses
○ Treatment failure during single antiplatelet therapy is not synonymous with
antiplatelet resistance.
● Aspirin resistance or nonresponsiveness
○ Laboratory phenomenon
○ Based on laboratory technique that detects the activity of the target receptor
before and after administration of the specific antiplatelet agent.
○ Persistent presence of platelet cyclooxygenase (COX)-1 activity after treatment
with aspirin
○ Only meaningful when it is significantly associated with clinical outcomes.
TYPES
1. Type I resistance
a. No inhibition of thromboxane synthesis or collagen induced platelet aggregation
with oral aspirin intake for 5 days.
b. In vitro show remarkable change in parameters
c. Called as pharmacokinetic type resistance
2. Type II resistance
a. Platelet functions altered by the oral intake of aspirin + In vitro
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by Dr. Eashan Srivastava

2. There is no belief, however foolish, that will not gather its faithful adherents who will defend it to
the death.
-Isaac Asimov
b. The mechanism is unclear, but ? genetic
c. Called as pharmacodynamic type resistance
3. Type III resistance (pseudoresistance)
a. Oral treatment resulted in the inhibition of thromboxane synthesis
b. Not accompanied by the expected inhibition of platelet aggregation in response to
collagen.
c. May be due to increased sensitivity of platelets to collagen.
EPIDEMIOLOGY
Various studies done
Prevalence about 5 - 15%
Significantly higher rate of death, myocardial infarction (MI), or stroke
POTENTIAL CAUSES
● Genetic variability
○ Number of single nucleotide polymorphisms (SNPs) associated
○ None causative/definitive
● Adherence issues
○ Likely the most common cause
● Use of enteric-coated aspirin
○ To prevent or reduce gastrointestinal toxicity
○ May result in an insufficient antithrombotic effect, especially in the acute setting
● Use of proton pump inhibitors
○ Interferes with aspirin function
● Other possible mechanisms
○ Aspirin nonresponders may have more advanced atherosclerosis as well as more
macrophages in the atherosclerotic plaques, which may produce thromboxane A2
via cyclooxygenase (COX)-2 even in the presence of aspirin
- Created with love
by Dr. Eashan Srivastava

3. There is no belief, however foolish, that will not gather its faithful adherents who will defend it to
the death.
-Isaac Asimov
○ Polymorphisms in the COX-1 gene​ - Intrinsic platelet mechanism that allows
thromboxane production despite the presence of aspirin.
○ Underdosing (eg, increased body weight)
○ Poor absorption of aspirin
○ Increased platelet turnover or activation may also be a factor in aspirin
nonresponse example, twice-daily dosing of low-dose aspirin may be more
effective than once-daily dosing in essential thrombocythemia because of
enhanced platelet turnover
CLINICAL MANIFESTATIONS
May experience no clinical events or, at worst, an acute thrombotic event.
LABORATORY TESTING
Arachidonic acid-induced platelet activation/aggregation
● Ex vivo
● Demonstrated via the ability of aspirin to markedly inhibit arachidonic acid-induced
platelet activation and aggregation
● Defined as ≥20 percent platelet aggregation when using 0.5 to 1.6 mg/mL
arachidonic acid as the agonist
Other ex vivo tests of platelet function
● Inhibition of ex vivo platelet function by aspirin, as measured by platelet aggregation
responses to
○ ADP- <40 % inhibition by three weeks
○ Collagen- < 50 % inhibition by three weeks
○ Epinephrine
● Clinical relevance is unclear
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by Dr. Eashan Srivastava

4. There is no belief, however foolish, that will not gather its faithful adherents who will defend it to
the death.
-Isaac Asimov
● Aspirin Reaction Unit score of ≥550 units
● Serum thromboxane B2 levels – 99+ percent reduction at one week
● UTXB2 levels – 66 percent reduction at one week
● VerifyNow ​Aspirin​ assay – 30 to 35 percent inhibition over the entire eight-week period
DRAWBACKS OF Ix
● Correlate poorly with one another
● Variability has been shown in normal volunteers as well as in patients
● Aggregometry after 5 to 20 microM adenosine diphosphate – 10 to 52 percent
- Created with love
by Dr. Eashan Srivastava

5. There is no belief, however foolish, that will not gather its faithful adherents who will defend it to
the death.
-Isaac Asimov
- Created with love
by Dr. Eashan Srivastava

6. There is no belief, however foolish, that will not gather its faithful adherents who will defend it to
the death.
-Isaac Asimov
SCREENING
Not recommended
MANAGEMENT
Usually, it is not possible to identify the cause of treatment failure
All patients should be evaluated for nonadherence
Using a non-enteric extended-release formulation of aspirin
Increasing the aspirin dose
Adding another antiplatelet agent
Omega-3 fatty acids -Fish oil
- Created with love
by Dr. Eashan Srivastava