Medicine and surgery
Antiplatelet medications exam links
Content Reviewers:Yifan Xiao, MD, James Schurr, PharmD, Justin Ling, MD, MS
Contributors:Sam Gillespie, BSc, Robyn Hughes, MScBMC, Elizabeth Nixon-Shapiro, MSMI, CMI, Sean Watts, MD
Antiplatelet medications prevent blood clot formation during hemostasis, where hemo means blood, and stasis means to halt or stop.
Hemostasis is divided into primary hemostasis, where circulating cell fragments called platelets form a plug at the site of an injured blood vessel, and secondary hemostasis, which involves multiple coagulation factors working together to form a fibrin mesh to stabilize the platelet plug.
Antiplatelet medications inhibit the steps of primary hemostasis to prevent the platelet plug from forming.
Primary hemostasis can be further divided into five steps: endothelial injury, exposure, adhesion, activation, and aggregation.
Endothelial injury is when the innermost layer of the artery, called the endothelium, gets damaged.
The second step is exposure, where the damaged endothelium exposes the underlying collagen.
The underlying collagen and endothelial cells then release a protein called Von Willebrand's factor, or vWF, that binds to this collagen.
The third step is adhesion where circulating platelets bind to the vWF via a surface protein called GPIB. The fourth step is activation, where platelets become active after binding to vWF.
First, the platelet changes shape and its membrane forms tentacle-like arms allowing it to grab onto other platelets.
Second, platelets release more vWF, as well as serotonin, a tiny molecule that attracts more platelets to the area.
Third, the platelets also release adenosine diphosphate or ADP, and thromboxane A2, or TXA2. These two molecules can activate other platelets that haven’t bound to vWF.
ADP and TXA2 also cause platelets to express new surface proteins called GPIIb/IIIa, which is needed for the fifth step, aggregation.
Now each platelet has multiple GPIIb/IIIa receptors that can bind to circulating proteins called fibrinogen. When two platelets attach to the same fibrinogen protein, they are linked together.
This allows platelets to rapidly aggregate at the site of injury, and form a large platelet plug that can stop the bleeding. Now, antiplatelet medications interfere at different steps during this process.
Aspirin, the NSAID or non-steroidal anti-inflammatory drug, has antiplatelet effects by blocking the synthesis of thromboxane A2, which activates platelets.
Aspirin accomplishes this by irreversibly inhibiting the activity of cyclooxygenase enzymes, abbreviated COX-1 and COX-2, via acetylation.
This is where an acetyl group made up of two carbons, three hydrogens, and an oxygen is permanently attached to the enzyme.
When COX-1 and COX-2 get inhibited, thromboxane A2, which is a downstream product of the cyclooxygenase pathway can no longer be produced.
Aspirin, as an antiplatelet medication, gets used in a low dose form of 75-325 milligrams in several clinical situations to prevent clots from worsening.
325 milligram aspirin tablets are used for the treatment of acute strokes and myocardial infarctions, or heart attacks.
Low doses of aspirin in the form of 81 mg tablets also gets used for the prophylaxis or prevention of future heart attacks in high risk individuals.
Aspirin, when used as an antiplatelet in low dose formulations, carries the risk of developing gastric ulcers, as well as bleeding. Aspirin can also cause allergic reactions at low doses.
Patients with aspirin allergy can develop bronchoconstriction, or narrowing of the airways, causing shortness of breath and wheezing. Like thromboxane A2, ADP is also a potent platelet activator.
So the ADP receptor inhibitors like clopidogrel, prasugrel, ticlopidine, cangrelor, and ticagrelor also interfere with platelet function.
Ticlopidine, clopidogrel, and prasugrel are first metabolized by the liver, and their active metabolites bind irreversibly to the platelet P2Y12 ADP receptor, and prevent ADP from binding.
Without ADP, the platelets will not express GPIIb/IIIa on their surface and thus, will not aggregate together. Ticagrelor doesn’t need to be activated by the liver since it’s not a prodrug.
Ticagrelor binds reversibly and in a non-competitive manner--meaning it binds to the receptor in an area outside of the active site where ADP normally binds. This decreases the receptors affinity for ADP, leading to decreased platelet activation.
The ADP receptor inhibitors are used in combination with aspirin for the treatment of acute coronary syndrome, which is a spectrum of symptoms that arise when there is limited blood flow to the heart.
They are also effective for preventing ischemic strokes and myocardial infarctions in people with atherosclerosis, and can be used inplace of aspirin if the person has an aspirin allergy. In fact, clopidogrel is considered equally effective as aspirin.
Additionally, the medication clopidogrel has been used in combination with aspirin as a pretreatment to prevent clots from forming for people undergoing coronary stenting.
This is a procedure where blocked vessels in the heart are kept open using a tube shaped device.
In terms of toxicity, the ADP receptor inhibitors increase the risk of bleeding like other antiplatelet medications, but they can also cause a condition called thrombotic thrombocytopenic purpura, where microthrombi form in small blood vessels, causing ischemic damage to various organs.
The platelets also get depleted in the process, which leads to bleeding under the skin, forming purple bruises called purpura.
The medication ticlopidine, is rarely used now, because it can cause a very serious condition called neutropenia, or low levels of a type of immune cell called neutrophils, and increases the risk of serious infections.
The phosphodiesterase inhibitors cilostazol and dipyridamole also work by interfering with platelet aggregation. They inhibit an enzyme called phosphodiesterase III inside of platelets.
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