Term
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Definition
Thrombosis: clot formation in arterial/venous
vessels
• Arterialàacute coronary syndrome (ACS), myocardial
infarction (MI), ischemic stroke
o Arterial circulation: oxygen rich, high shear stress due to rapid
flow
• Venousàdeep vein thrombosis (DVT), pulmonary
embolism (PE)
o Venous circulation: capacitance system, oxygen poor, low shear
stress
• All blood clots can cause major morbidity and mortality
o Therapy selection depends on acuity, clot composition/location |
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Term
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Definition
• Associated with atherosclerotic plaque rupture
• Exposed vessel collagen à platelet cascade
• Rich in platelets because of high shear in arteries o “White” clots |
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Term
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Definition
• Associated with surgery, critical illness, hemostasis
• Rarely form at site of vascular injury
• Rich in fibrin cross-linkages, trapped red blood cells o “Red” clots |
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Term
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Definition
Platelet Cascade
1. Adhesion
o Coronary atherosclerotic plaque ruptures
o Subendothelial matrix of vessel wall exposed
o Circulating von Willebrand factor (vWF) bind to collagen o Platelets slow, tumble, and tether along vessel wall
Platelet Cascade (cont.)
2. Activation
o Collagen complexes with von Willebrand factor (vWF)
o Binds to glycoprotein Ib/V/IX receptors on platelet surface o Platelets degranulate, releasing aggregation factors:
§ Adenosine diphosphate (ADP) § Platelet factors 3 and 4
§ Thromboxane A2
§ Epinephrine
§ Serotonin
Platelet Cascade (cont.) 3. Aggregation
o ADP binds P2Y12 receptors on platelet surface
o Induces conformational change, forms “sticky arms”
o Glycoprotein IIb/IIIa (GPIIb/IIIa) bind fibrinogen
o GPIIb/IIIa-fibrinogen linkages aggregate adjacent platelets
§ Final common pathway in platelet cascade |
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Term
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Definition
Nomenclature for any drug opposing hemostasis
• Anticoagulants (heparin, warfarin, apixaban, etc.) o Disrupt coagulation cascade
o Prevent venous thrombosis
• Antiplatelets (aspirin, clopidogrel, tirofiban, etc.) o Inhibit platelet adhesion/aggregation
o Prevent arterial thrombosis
• Fibrinolytics (alteplase)
o Promote lysis of fibrin linkages o Dissolve formed thrombus |
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Term
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Definition
• COX-1 inhibitors
o Aspirin (Bayer®)
• ADP inhibitors / P2Y12 antagonists
o Ticlodipine (Ticlid®), clopidogrel (Plavix®), prasugrel (Effient®), ticagrelor (Brilinta®), cangrelor (Kengreal®)
• GP IIb/IIIa receptor antagonists
o Abxicimab (ReoPro®), eptifibatide (Integrilin®), tirofiban (Aggrastat®) |
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Term
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Definition
| Now looking at where COX-1 inhibitors fit on the overall disruption of formed thrombus, you can see that they're actually really involved in the platelet activation step. Inhibiting COX-1, which is characteristic of aspirin, prevents the formation of thromboxane A2, and that's one of the platelet activation signals that is used to then go on and recruit nearby platelets. You can see where it fits with the mechanism of other antiplatelets, anticoagulants, and fibrinolytics in this overall scheme pictured here. |
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Term
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Definition
• Aspirin (Bayer®)
• Aspirin Chewable (Disprin®)
• Aspirin Enteric Coated (Ecotrin®) |
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Term
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Definition
Mechanism of Action
• Nonsteroidal anti-inflammatory drug (NSAID)
o Analgesic, antipyretic, and anti-inflammatory effects
• Inhibits cyclooxygenase-1 (COX-1) enzyme
o Irreversibly acetylates serine residue near active site
o Reduces prostaglandin synthesis for life of platelet (7–10 days)
§ COX-1: thromboxane A2 à vasoconstrictor, induces platelet aggregation
‒ Inactivation achieved with aspirin 100 mg
§ COX-2: prostacyclin à vasodilator, inhibits platelet aggregation
‒ Maximum inhibition achieved with aspirin 1,000 mg |
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Term
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Definition
Let's look a little bit closer at the actual COX-1 enzyme active site. You can see that arachidonic acid is normally one of the byproducts that's then converted downstream to thromboxane A2. However, when aspirin is circulating in the plasma, it penetrates platelets and blocks that serine residue.
Because it covalently modifies that particular residue, arachidonic acid cannot be formed. For the life of the platelet aspirin's acetyl group, it blocks any kind of products from working on COX-1 while aspirin is active. So for seven days, the platelet that aspirin binds to is going to be completely inactivated by virtue of blocking the active site. |
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Term
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Definition
Now, in the presence of other nonselective COX inhibitors like ibuprofen, another common over-the-counter, non-steroidal anti-inflammatory drug, aspirin's not able to do its job very well. So in COX-1, that active site is competitively blocked by the ibuprofen. In the presence of ibuprofen, jumping on and off that active site, aspirin can't covalently modify the enzyme, so aspirin actually works to block aspirin from doing its normal job.
This can actually mean aspirin is not going to have the same cardioprotective effects that it's normally characteristic of. So in the presence of ibuprofen, aspirin actually doesn't do very much cardioprotection at all and can then have more off-target effects like gastrointestinal upset. It's important to not combine the use of these medications. And in fact, guidelines suggest not using them together at all. |
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Term
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Definition
Now let's review a little bit about the aspirin dose and how that correlates to its selectivity for COX-1 or COX-2. Now I mentioned COX-1 is the cardioprotective inhibitor. We like when aspirin's inhibiting that. And as you can see from this graph that has aspirin dose on the x-axis, you only need about 100 milligrams to completely inactivate COX-1.
So that's 100% inactivation of COX-1 activity with just 100 milligrams. At about 1 gram, you achieve peak inactivation of COX-2. No matter how higher the dose goes, COX-2 is not expressed enough to actually get 100% inactivation, leaving a lot of room for off-target effects.
So it's important that when we're using aspirin for cardioprotective effects, the dose should not exceed 100 milligrams. And if we're using aspirin for anti-inflammatory purposes, a process that COX-2 is more closely involved in, it's understandable that we may need doses greater than 100 milligrams. But we know that by doing that, we also increase the risk of side effects. |
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Term
| cox1 inhibitor approved uses |
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Definition
• Pain
• Fever
• Inflammation
• Rheumatoid disease
• Coronary artery disease
• Acute coronary syndrome
• Stroke/transient ischemic attack
• Prevention of cardiovascular disease
• Chemoprevention of colorectal cancer |
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Term
has ADE:
• Central nervous system: Reye’s syndrome (pediatric)
• Dermatologic: skin rash, urticaria
• Gastrointestinal: erosive gastritis, peptic ulcers (6–31%) o Buffered or enteric-coated formulations do not eliminate GI side effects
• Hematologic: major bleeding (1–3%), thrombocytopenia
• Immunologic: anaphylaxis
• Respiratory: aspirin-sensitive asthma à nasal polyps,
rhinitis |
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Definition
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Term
| cox-1 inhibitors contraindications |
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Definition
• Hypersensitivity to salicylates
o Aspirin desensitization may be warranted (risk vs. benefit) |
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Term
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Definition
| As we mentioned in an earlier module, adenosine diphosphate is an activator of platelet aggregation. It's one of the earlier signals for the sticky arms to platelets to form in recruiting its neighbors. So if we can block this step with a medication like clopidogrel, we can prevent platelets from sticking together. This is very useful for the treatment of acute coronary syndrome where we know a patient has had a blood clot form in their coronary arteries. Therefore, clopidogrel and other P2Y12 inhibitors are a mainstay of therapy for these folks. |
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Term
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Definition
• Clopidogrel (Plavix®)
• Prasugrel (Effient®)
• Ticagrelor (Brilinta®)
• Cangrelor (Kangreal®) |
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Term
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Definition
• Antagonize P2Y12 receptor to prevent ADP-induced platelet aggregation
o Irreversible inhibitors: thienopyridines § Clopidogrel
§ Prasugrel
o Reversible inhibitors: cyclopentyltriazolopyrimidines
§ Ticagrelor § Cangrelor |
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Term
| P2Y12 Inhibitors approved clinical uses |
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Definition
• Adjunctivetherapyforprimarypercutaneous coronary intervention (PPCI) with stent implantation
• Strokepreventioninatrialfibrillationwhen anticoagulation not viable
• Acutecoronarysyndrome
• Peripheralarterydisease |
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Term
has ADE:
• Cardiac:ventricularpause |
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Definition
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Term
has ADE:
• Dermatologic:pruritus,rash |
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Definition
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Term
has ADE:
• Hematologic:bleeding |
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Definition
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Term
has ADE:
• Metabolic:increaseduricacid |
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Definition
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Term
has ADE:
• Respiratory:dyspnea |
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Definition
(14%ticagrelor,5%prasugrel)
o Adenosine-related, reversible P2Y12 inhibitor effect |
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Term
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Definition
| Now these off-target effects are thought to be due to the chemical similarity between these, emphasizing that pharmacology can have a lot of emphasis on how the medication works to benefit patients, but also how it can work to have off-target side effects that we maybe didn't want the patient to experience. Dyspnea is the most common, and that's because that conduction blockade thought to be due to the adenosine chemical component. Again, the uric acid level can be an issue, but the mainstay tend to happen to be bleeding, and that cannot be emphasized enough with the whole P2Y12 inhibitor class. |
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Term
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Definition
The side effects of these class of medications are namely bleeding. However, because ticagrelor is a PT, or another class that's reversible and chemically looks a lot like its adenosine cousin, it has a lot of off-target effects that many of the other P2Y12 inhibitors do not have. Some of them can be cardiac in nature, like ventricular pause. And some of them can also be metabolic, such as increased uric acid levels, because adenosine looks a lot like a uric acid building block, so it actually is thought to maybe to be a laboratory artifact and not a true increase in uric acid levels.
Because ticagrelor looks like adenosine and adenosine can stop conduction from the AV node across the heart and to the ventricles, dyspnea it can be a common side effect, or shortness of breath. These are all thought to typically be adenosine related. And if we look closer at the chemical structures of adenosine and ticagrelor, we can see that they're very, very similar. |
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Term
P2Y12 Inhibitors
Contraindications |
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Definition
• Activepathologicalbleeding(pepticulcerbleed, etc.)
• Priorstrokeortransientischemicattack (prasugrel)
• Hypersensitivity to specific P2Y12 inhibitor
• Priorintracranialhemorrhage(ticagrelor)
• Aspirindoses>100mgdaily(ticagrelor)
o North American paradox |
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Term
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Definition
Now let's review a little bit about the pharmacokinetic differences between these medications. Clopidogrel is a key component of a prodrug. It needs to actually be activated twice before it can reach the platelet receptor. It needs to be first metabolized through CYP2C19, and then again through CYP2C19, as well as 2C9 in order to reach its 2-oxo-clopidogrel active component. And it's important to understand that it's really the active component that's doing all the pharmacologic work at the ADP receptor site. So if we don't have an intact liver to help assist in this metabolic conversion from prodrug to active drug, we're not going to see the beneficial cardiac effects of this medication.
Prasugrel is also a prodrug, but this one is converted by plasma esterases, and then through CYP3A4 in order to get to its active component. It's important to know that prasugrel's higher degree of potency compared to clopidogrel can make up for a lot of the prodrug effects that may be associated with side effects. Ticagrelor is vastly different from both prasugrel and clopidogrel, because it is not a prodrug. It is directly active and ready to perform pharmacologic work at the ADP receptor site as soon as it's absorbed. This is one of the reasons why we think ticagrelor may be slightly more effective than both prasugrel and clopidogrel. |
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Term
P2Y12 Inhibitors
Pharmacokinetics/Pharmacodynamics |
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Definition
• Clopidogrel resistance
o Requires two-step activation via cytochrome P450 2C19 (CYP2C19)
o High genetic variability: loss-of-function allele (CYP2C19*2)
§ Caucasian 25%, African American 30%, Asian 50% • VerifyNow® P2Y12 test
o Point-of-care platelet function assay
o Identifies high-platelet reactivity patients
o Did not improve efficacy (GRAVITAS trial) § Despite receiving double clopidogrel dose |
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Term
P2Y12 Inhibitors
Drug-Drug Interactions |
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Definition
• FDA warning: avoid clopidogrel with proton pump inhibitors o Omeprazole (Prilosec®) potently inhibits CYP2C19
o Decreases production of active metabolite
o Reduced platelet inhibition may increase cardiovascular risk
• Clinical relevance of interaction challenged (COGENT trial) o Clopidogrel + omeprazole vs. clopidogrel
o No difference in efficacy outcomes
o Reduced gastrointestinal bleeding |
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Term
has ADE:
Any bleed (8%), pruritus, rash
-prodrug, onset/peak 2 hr 6hr |
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Definition
| Clopidogrel (Plavix®) - P2Y12 inhibitor |
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Term
has ADE:
Any bleed (14%)
-prodrug onset/peak 30 min/4 hrs |
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Definition
| Prasugrel (Effient®)- P2Y12 inhibitor |
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Term
has ADE:
Any bleed (10%), dyspnea during initial 1–2 weeks (14%), ventricular pause (2-6%), hyperuricemia (22%)
-immediate onset/peak 30min/2hrs |
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Definition
| Ticagrelor (Brilinta®)- P2Y12 inhibitor |
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Term
P2Y12 Inhibitors
Monitoring |
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Definition
• Genotyping of CYP2C19 loss-of-function alleles
• Platelet function testing to determine reactivity
• Periodic complete blood count
• Symptoms of dyspnea
• Signs of bleeding
• Uric acid levels
• Adherence
o Prior-authorization requirement o Insurance coverage
o Copay affordability |
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Term
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Definition
| Intravenous antithrombotics are the class of blood thinners that are only available in IV form. The first that we'll talk about are the glycoprotein IIb/IIIa inhibitors-- tirofiban, eptifibatide, and abciximab. These medications are only available in IV form because they are so potent that they need to be administered under a very controlled setting. They inhibit the final common pathway of platelet aggregation by blocking the GpIIb/IIIa linkages with fibrinogen. Blocking these cross-links unravels an entire platelet thrombus, so it provides a very high degree of platelet inhibition, but also a very high risk of bleeding. |
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Term
| GPIIb/IIIa Inhibitors agents |
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Definition
• Abciximab (ReoPro®)
• Eptifibatide (Integrilin®)
• Tirofiban (Aggrastat®) |
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Term
GPIIb/IIIa Inhibitors
Mechanism of Action |
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Definition
• Antagonize GPIIb/IIIa receptors to prevent the final-common pathway in platelet aggregation
o Irreversible “biologic” inhibitor § Monoclonal antibody: abciximab
o Reversible “small molecular” inhibitors § Nonpeptide: tirofiban
§ Peptide based: eptifibatide
– Derived from viper and rattlesnake venom |
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Term
GPIIb/IIIa Inhibitors
Approved Clinical Uses |
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Definition
• Adjunctive therapy for PPCI in ACS
o Provides rapid platelet inhibition
o Bridge until oral P2Y12 agent active
§ Commonly only needed for STEMI
- Anterior wall myocardial infarction
- Large culprit vessel thrombus burden |
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Term
GPIIb/IIIa Inhibitors
Pharmacokinetics/Pharmacodynamics |
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Definition
• Abciximab: fab fragment of chimeric human-murine antibody
o Biologic half-life prolongs antiplatelet effects up to 72 hours
§ Platelet function may remain abnormal up to 7 days postinfusion
• Eptifibatide, tirofiban: newer, “small molecule” inhibitors
o Shorter half-life (~2.5 hours), limits duration of platelet effects
§ Platelet function restored 4–8 hours after discontinuation - Similar efficacy to abciximab
- More favorable side-effect profile |
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Term
Has ADE:
• Hematologic: thrombocytopenia, bleeding (1–14%)
• Immunologic: hypersensitivity, antibody formulation |
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Definition
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Term
| GPIIb/IIIa Inhibitors contraindications |
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Definition
• Thrombocytopenia (platelets <100,000 cells/uL)
• Hypersensitivity to specific GP IIb/IIIa inhibitor
• Active or recent clinically significant bleed
• Recent major surgery within 6 weeks |
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Term
GPIIb/IIIa Inhibitors
Monitoring |
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Definition
• Platelet count:
o Baseline, 6 hours after infusion start, then daily o Persistent thrombocytopenia à hold infusion
• Hemoglobin/hematocrit
• Signs of bleeding
o Particularly at vascular access site
• Serum creatinine
o Renal dose adjustment for small molecular inhibitors |
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Term
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Definition
| Fibrinolytics are the next class of intravenous antiplatelets, and they are by far the highest risk for bleed because they directly act on the fibrin linkages through enzymatic breakdown. This is the final step in all thrombus formation, that that fibrin linkage wraps the entire thrombus. This applies to both red and white clots, which is why fibrinolytics are thought to confer the highest risk of bleed of all intravenous antithrombotic agents. |
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Term
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Definition
-Recombinant human tPA
o Alteplase (Activase®; Cathflo®), Tenecteplase (TNKase®)
• Urinary-type plasminogen activator o Urokinase (Abbokinase®)
• Antistreplase
o Streptokinase (Streptase®) |
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Term
Fibrinolytics
Mechanism of Action |
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Definition
| • Binds exposed fibrin, converts entrapped plasminogen to plasmin, helping degrade existing thrombus |
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Term
Fibrinolytics
Approved Clinical Uses |
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Definition
• Acute massive or submassive pulmonary embolism
• ST-segment elevation myocardial infarction (STEMI)
• Acute ischemic stroke |
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Term
Has ADE:
• Hematologic: bleeding (7–15%), bruising, anemia
• Immunologic: hypersensitivity |
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Definition
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Term
Fibrinolytics
Contraindications |
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Definition
• Elevated blood pressure
(SBP >185 mm Hg / DBP >110 mm Hg)
• Intracranial neoplasm, arteriovenous malformation, or aneurysm
• Significant head trauma or prior stroke in previous 3 months
• History of previous intracranial hemorrhage
• Recent intracranial or intraspinal surgery
• Subarachnoid hemorrhage
• Active internal bleeding
• Anticoagulant use |
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Term
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Definition
• Frequent neurologic assessments during and after treatment
• Head computed tomography (CT) scan
• Complete blood count
• Electrocardiogram
• Signs of bleeding
• Blood pressure
• Coagulation tests
o Activated partial-thromboplastic time (aPTT)
o Prothrombin time (PT) / international normalized ratio (INR) |
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Term
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Definition
• Antiplatelets, anticoagulants, and fibrinolytics are all unique yet high-risk antithrombotic agents used for a variety of indications
• Aspirin is a versatile antiplatelet agent with diminished cardiovascular utility and higher adverse effects with larger doses
• Clopidogrel inferiority, resistance, and drug interactions have made ticagrelor the preferred P2Y12 inhibitor for ACS management
• Newer, rapid-acting, and more potent oral P2Y12 inhibitors have displaced GPIIb/IIIa antagonists to a limited clinical role in STEMI
• Fibrinolytics are a mainstay for acute ischemic stroke and massive PE, but no longer used for ACS due to advent of PCI |
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Term
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Definition
o Prolonged oozing >15 minutes, reddish or pink-tinged urine, dark or tarry stool, and coffee-ground emesis
§ Multiple antithrombotic agents or higher doses increase bleed risk
- Lowest effective dose for minimum duration |
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Term
| • Allergic reaction signs |
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Definition
o Itching, hives, flush, fever, dyspnea, bronchospasm, hypotension
§ Aspirin may worsen asthma; not true allergy
§ Clopidogrel may rash; alternative P2Y12 preferred |
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Term
| Over-the-Counter Considerations |
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Definition
o Avoid NSAIDs while on aspirin, dual, or triple therapy § Acetaminophen preferred if pain, swelling, or fever
- No clinical anti-inflammatory or COX-1/COX-2 interaction
o Many proton pump inhibitors available without a prescription
§ Avoid omeprazole/esomeprazole with clopidogrel when possible
§ Consider histamine-2 receptor antagonist (famotidine, etc.) instead |
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Term
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Definition
o Full (>80%) adherence to guideline-directed medical therapy
§ 27% fewer cardiovascular deaths, heart attacks, strokes, and hospitalizations |
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