Back To Search Results

Antiplatelet Drug Toxicity

Editor: Brandon K. Wills Updated: 6/12/2023 8:05:01 PM


As the prevalence of cardiovascular disease (CVD) escalates worldwide, so does the use of antiplatelet medications in its management.[1] These agents are used to decrease major adverse events due to acute coronary syndromes, peripheral vascular disease, and stroke.[2] Despite a variety of pharmacologic actions, all antiplatelet drugs inhibit platelet activation and aggregation, lowering atherothrombotic related events.[1][3] Given the relatively narrow pharmacologic actions of antiplatelet drugs, toxicity primarily confines itself to an increased risk of hemorrhage. When compared to individuals not taking antiplatelet medications, patients on an antiplatelet agent have a 1.5 times greater risk of bleeding, and this increases when taking additional antiplatelet agents.[2] The toxicity of salicylates is complex. As such, a separate monograph specifically devoted to salicylate toxicity is available.[4] Salicylates are only briefly mentioned here, primarily in comparing various mechanisms of antiplatelet drugs.


Register For Free And Read The Full Article
Get the answers you need instantly with the StatPearls Clinical Decision Support tool. StatPearls spent the last decade developing the largest and most updated Point-of Care resource ever developed. Earn CME/CE by searching and reading articles.
  • Dropdown arrow Search engine and full access to all medical articles
  • Dropdown arrow 10 free questions in your specialty
  • Dropdown arrow Free CME/CE Activities
  • Dropdown arrow Free daily question in your email
  • Dropdown arrow Save favorite articles to your dashboard
  • Dropdown arrow Emails offering discounts

Learn more about a Subscription to StatPearls Point-of-Care


Antiplatelet drug toxicity can be the result of either therapeutic dosing or overdose. Adverse drug effects from therapeutic dosing or overdose can result in hemorrhage. A summary of 2017 National Poison Center data reported 2,831 cases of antiplatelet drug exposures with 972 being unintentional and 48 intentional.[5] With an overdose of antiplatelet drugs, there are no other significant organ system effects that are impacted but an exaggerated antiplatelet effect may cause a variety of bleeding disorders.


There were 2831 cases of antiplatelet exposures reported to United States poison centers in 2017. The majority of exposures were unintentional and occurred in individuals less than 20 years of age. Of these cases, 198 sought care in a medical facility, with 16 moderate outcomes, five major outcomes, and no deaths reported.[5] An overdose of antiplatelet medications increases the risk of significant hemorrhage, although the risk is lower than for anticoagulants.[6]


Under physiological conditions, platelets are activated by a series of intracellular signals when vascular endothelium is damaged. Underlying collagen interacts with tissue factor (TF) to trigger the clotting cascade, activating thrombin, which contributes to platelet adhesion at the injury site. Simultaneously, collagen also binds von Willebrand factor (vWF) to activate platelets via glycoprotein (GP) Ia/IIa and GP IV receptors. Mediators including thromboxane A2, adenosine diphosphate (ADP), thromboxane A2 (TXA2), and cAMP activate platelets, and activation of GPIIb/IIIa receptors promote platelet aggregation.[1] While the final common pathway is platelet inhibition, there are several different mechanisms that antiplatelet agents can utilize.

The most widely used antiplatelet drugs are cyclooxygenase (COX) inhibitors, such as aspirin. This class irreversibly inhibits COX-1 preventing TXA2, which is essential for platelet aggregation.[3] Oral low dose aspirin is given preventatively for ischemic stroke and cardiovascular events.[7]

Clopidogrel and prasugrel are prodrugs that irreversibly block P2Y12 receptors on platelets after undergoing conversion to their respective active metabolites.[3] Ticagrelor directly but reversibly binds the P2Y12 receptor.[8] By both mechanisms, ADP-mediated aggregation becomes inhibited.[3]

Abciximab and eptifibatide are GP IIb/IIIa inhibitors that elicit their effects by blocking the GPIIb/IIIa receptors on the platelet surface to prevent aggregation.[3]

Phosphodiesterase inhibitors such as cilostazol and dipyridamole exert their antiplatelet effects by increasing cAMP levels in platelets. As cAMP levels rise inside the platelets, TXA2 levels decrease, effectively hindering aggregation abilities.[3][7] Dipyridamole is also thought to inhibit the reuptake of adenosine, which would amplify the effect on cAMP levels.[2]


Detailed information on the toxicokinetics for these agents is limited. Detailed pharmacokinetics for aspirin is covered in the salicylate chapter. Briefly, gastrointestinal aspirin absorption is variable and depends on the dose, tablet formulation, and rate of gastric emptying.[9] Aspirin gets hydrolyzed into salicylic acid utilizing two hepatic pathways: glucuronide formation and conjugation with glycine.[10] Salicylic acid’s serum half-life is directly proportional to dosing.[10]  Aspirin is renally eliminated and follows mixed elimination kinetics depending on the salicylate concentration. Other factors influencing elimination are urine pH, presence of organic acids, and urine flow rate.[10]

The P2Y12 receptor inhibitors, (clopidogrel, prasugrel, and ticagrelor), are rapidly absorbed by the gastrointestinal tract with a bioavailability of approximately 50%, 79%, 78% respectively.[11][12] Prasugrel’s absorption gets delayed when taken with food.[12] All three agents are 98% to 99% protein-bound and have a large volume of distribution.[8][12]  The P2Y12 receptor inhibitors undergo hepatic metabolization by the CYP enzymes.[11][12][13] Clopidogrel is a prodrug metabolized by CYP2B6, CYP2C19, CYP3A4, and CYP3A5 into its active thiol metabolite.[11][14] Prasugrel is also a prodrug, metabolized by CYP3A4 and CYP2B6 to form its active metabolite.[12] Final clearance of clopidogrel and prasugrel occurs via renal and fecal elimination.[11][12] Ticagrelor gets eliminated by biliary excretion.[8]

Orally dosed dipyridamole has variable absorption and is 99% protein bound with a half-life of approximately 12 hours.[15][16] It converts to the monoglucuronide form by hepatic biotransformation and gets cleared by biliary and fecal excretion.[15]

Cilostazol also has decreased absorption when administered orally; however, the reason for these low rates stems from its limited solubility.[17] Its extensive distribution and low first-pass metabolism are indicated by low plasma clearance and high Vd (volume of distribution) values.[17] Analogous to the antiplatelet medications discussed previously, cilostazol also undergoes hepatic metabolization via CYP enzymes into two main metabolites: 3,4-dehydrocilostazol and 4'-trans-hydroxycilostazol.[14] Considering no unchanged drug is detected in urine, the elimination of cilostazol is thought to be almost entirely metabolism-based.[17]

Abciximab and eptifibatide are parenteral antiplatelet drugs with very low volumes of distribution.[18] Abciximab has a plasma half-life of 20 minutes. However, antiplatelet effects can persist up to 48 hours after drug cessation.[19] Eptifibatide has a plasma half-life of two hours, but the duration of antiplatelet effects is similar to abciximab. Eptifibatide undergoes mostly renal clearance.[18]

History and Physical

For any suspected antiplatelet toxicity, thorough exposure history and physical exam will aid decision-making for subsequent laboratory investigations and treatment.[20] Focused questions may include how much medication the patient took, route of administration, co-ingestants, and intent. Since hemorrhage is of primary concern in antiplatelet toxicity, a review of systems focusing on bleeding presentations is reasonable. The history should also include a medication review to determine any potential interactions or synergy that may compound the bleeding risk with antiplatelet drugs. If overt bleeding is present, further characterization should be done by determining the onset, duration, and location.[20] Furthermore, a clinical assessment for these patients should include vital signs and identification of any platelet dysfunction manifestations such as subconjunctival hemorrhage, ecchymosis, petechiae, epistaxis, gingival bleeding, hematuria, or gastrointestinal bleeding.[20] An abnormal neurologic exam may be an indication of intracranial hemorrhage.


Monitoring platelet function for therapeutic monitoring of an antiplatelet regimen or after an overdose is difficult. Bleeding time reflects platelet function but has significant limitations.[21] A newer assay, light transmittance aggregometry, is not widely available and also has disadvantages.[21] Thromboelastography (TEG), an increasingly popular assay of global hemostatic function, has conflicting data on the utility of TEG in patients on antiplatelet drugs.[22][23]

For patients presenting with bleeding, laboratory studies can include a complete blood count for determining both platelet count and total hemoglobin.[20] Bleeding time and platelet function analysis (PFA-100) will highlight functional abnormalities while a peripheral blood smear identifies any morphological abnormalities.[20] Additional tests that may be useful in the setting of serious hemorrhage include prothrombin time (PT), activated partial thrombin time (APTT), and cross-match of packed red blood cells.

Treatment / Management

Currently, there no specific antidotes for any antiplatelet medications discussed above, and reversal guidelines are not universal. Activated charcoal can be considered if the patient can safely take oral liquids, and the patient arrives early post-ingestion, typically within the first 1 to 2 hours. Initial treatment should focus on local hemorrhage control. Gastrointestinal hemorrhage, if proximal or distal, may be amenable to endoscopic evaluation and treatment. Management for patients presenting with severe bleeding associated with antiplatelet medications may include platelet transfusions and desmopressin. However, there is no robust data to support desmopressin.[2][7] Desmopressin exerts its effect by increasing levels of factor VIII and Von Willebrand factor to induce platelet aggregation via GPllb/IIIa, interactions that are mechanistically distinct from antiplatelet drugs.[2] Resuscitation with blood products, including packed red blood cells and platelets may be necessary for severe hemorrhage. If there is associated coagulopathy from severe hemorrhage, plasma may also be required. For GPIIb/IIIa inhibitors, discontinuation of infusion will result in normalization of platelet function within 48 to 72 hours for abciximab and 4 to 8 hours for eptifibatide and tirofiban.[7]

Differential Diagnosis

The clinical presentation for patients on antiplatelet therapy will be bleeding complications. The differential diagnosis will differ depending on the source of bleeding. Gastrointestinal, genitourinary, intracranial, or other types of bleeding will each have distinct differential diagnoses. It is reasonable, therefore, to consider antiplatelet drug toxicity and perform medication reconciliation for all patients presenting with bleeding-related complaints.


Prognosis will vary depending on the location and severity of the bleeding. The natural history of antithrombotic exposure is generally benign. Nevertheless, serious bleeding complications and death can occur. National Poison Data System data from 2017 revealed five major outcomes and zero deaths from 2831 exposures.[5] Another poison center study of antiplatelet overdoses reported 322 acute overdoses with 16 cases of hemorrhage that included two deaths.[6] Patients suffering from an intracranial hemorrhage while on antiplatelet or anticoagulant medications have significantly worse outcomes than those who are not.[24]


Hemorrhagic complications could include:

  • Intracranial hemorrhage
  • Gastrointestinal hemorrhage
  • Retroperitoneal bleeding
  • Hemorrhagic shock


The clinician or patient can obtain a consultation with a medical toxicologist and/or regional poison center in the United States by calling (800) 222-1222.

Deterrence and Patient Education

Patients that are prescribed antiplatelet medications should be educated on the risk of bleeding related to these medications. They should also be encouraged to keep these medications in a safe place where young children cannot access them. Patients on these medications are encouraged to call their regional poison center should they have questions or concerns regarding possible toxicity.

Enhancing Healthcare Team Outcomes

As the population continues to age, there will likely be an increasing prevalence of antiplatelet drug use. Most exposures will not have severe symptoms and not require a lot of healthcare resources. Others can have devastating complications requiring interprofessional care. Additionally, the healthcare team should ascertain whether the exposure was intentional or unintentional, which may lead to involvement in mental health services. 

The majority of patients will present with bleeding ranging from mild to severe, and clinicians in the emergency department need to be aware that there is no specific antidote to any of these agents. Thus, supportive care is necessary. The clinician should consult with a hematologist and poison control on the management of patients with moderate to severe bleeding. Some patients may need to be admitted and managed with transfusion of blood products. The pharmacist should thoroughly educate patients about the adverse effect profile and when to seek medical help. Prevention of and early intervention in cases of antiplatelet agent toxicity are crucial. The pharmacist can play a critical role by monitoring doses and verifying that there are no drug-drug interactions that can enhance antiplatelet activity beyond the therapeutic level. Nursing will help assess therapy effectiveness and watch for adverse events; they may be the first to have the opportunity to notice something is amiss. Specialty trained nurses in emergency medicine and critical care will be responsible for monitoring patients. Cardiovascular specialty nurses play a role in patient education of the patient and family. In both instances, immediate consultation with the managing clinician is important to make necessary changes to the treatment regimen or initiate other interventions.

The interprofessional team should communicate with other members if there is a dose change/frequency of use of the antiplatelet medication. Only through open communication can the morbidity of these agents be reduced. [Level 5]



Smith TJ, Johnson JL, Habtewold A, Burmeister MA. Cardiovascular Risk Reduction: A Pharmacotherapeutic Update for Antiplatelet Medications. Critical care nursing clinics of North America. 2019 Mar:31(1):15-30. doi: 10.1016/j.cnc.2018.11.001. Epub 2018 Dec 21     [PubMed PMID: 30736932]


Raimondi P, Hylek EM, Aronis KN. Reversal Agents for Oral Antiplatelet and Anticoagulant Treatment During Bleeding Events: Current Strategies. Current pharmaceutical design. 2017:23(9):1406-1423. doi: 10.2174/1381612822666161205110843. Epub     [PubMed PMID: 27917717]


Iqbal AM, Lopez RA, Hai O. Antiplatelet Medications. StatPearls. 2023 Jan:():     [PubMed PMID: 30725747]


Runde TJ, Nappe TM. Salicylates Toxicity. StatPearls. 2023 Jan:():     [PubMed PMID: 29763054]


Gummin DD, Mowry JB, Spyker DA, Brooks DE, Osterthaler KM, Banner W. 2017 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 35th Annual Report. Clinical toxicology (Philadelphia, Pa.). 2018 Dec:56(12):1213-1415. doi: 10.1080/15563650.2018.1533727. Epub 2018 Dec 21     [PubMed PMID: 30576252]


Levine M, Beuhler MC, Pizon A, Cantrel FL, Spyres MB, LoVecchio F, Skolnik AB, Brooks DE. Assessing Bleeding Risk in Patients With Intentional Overdoses of Novel Antiplatelet and Anticoagulant Medications. Annals of emergency medicine. 2018 Mar:71(3):273-278. doi: 10.1016/j.annemergmed.2017.08.046. Epub 2017 Oct 9     [PubMed PMID: 29032872]


Dornbos D 3rd, Nimjee SM. Reversal of Systemic Anticoagulants and Antiplatelet Therapeutics. Neurosurgery clinics of North America. 2018 Oct:29(4):537-545. doi: 10.1016/ Epub     [PubMed PMID: 30223966]


Teng R, Butler K. Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y(12) receptor antagonist, in healthy subjects. European journal of clinical pharmacology. 2010 May:66(5):487-96. doi: 10.1007/s00228-009-0778-5. Epub 2010 Jan 21     [PubMed PMID: 20091161]

Level 1 (high-level) evidence


Levy G. Clinical pharmacokinetics of aspirin. Pediatrics. 1978 Nov:62(5 Pt 2 Suppl):867-72     [PubMed PMID: 724339]


Needs CJ, Brooks PM. Clinical pharmacokinetics of the salicylates. Clinical pharmacokinetics. 1985 Mar-Apr:10(2):164-77     [PubMed PMID: 3888490]


Mehta SR, Tanguay JF, Eikelboom JW, Jolly SS, Joyner CD, Granger CB, Faxon DP, Rupprecht HJ, Budaj A, Avezum A, Widimsky P, Steg PG, Bassand JP, Montalescot G, Macaya C, Di Pasquale G, Niemela K, Ajani AE, White HD, Chrolavicius S, Gao P, Fox KA, Yusuf S, CURRENT-OASIS 7 trial investigators. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet (London, England). 2010 Oct 9:376(9748):1233-43. doi: 10.1016/S0140-6736(10)61088-4. Epub     [PubMed PMID: 20817281]

Level 1 (high-level) evidence


Teng R, Maya J. Absolute bioavailability and regional absorption of ticagrelor in healthy volunteers. Journal of drug assessment. 2014:3(1):43-50. doi: 10.3109/21556660.2014.946604. Epub 2014 Aug 12     [PubMed PMID: 27536453]


Zhang YJ, Li MP, Tang J, Chen XP. Pharmacokinetic and Pharmacodynamic Responses to Clopidogrel: Evidences and Perspectives. International journal of environmental research and public health. 2017 Mar 14:14(3):. doi: 10.3390/ijerph14030301. Epub 2017 Mar 14     [PubMed PMID: 28335443]

Level 3 (low-level) evidence


Kim HS, Lim Y, Oh M, Ghim JL, Kim EY, Kim DH, Shin JG. The pharmacokinetic and pharmacodynamic interaction of clopidogrel and cilostazol in relation to CYP2C19 and CYP3A5 genotypes. British journal of clinical pharmacology. 2016 Feb:81(2):301-12. doi: 10.1111/bcp.12794. Epub 2015 Dec 28     [PubMed PMID: 26426352]


Nielsen-Kudsk F, Pedersen AK. Pharmacokinetics of dipyridamole. Acta pharmacologica et toxicologica. 1979 May:44(5):391-9     [PubMed PMID: 474151]


Bjornsson TD, Mahony C. Clinical pharmacokinetics of dipyridamole. Thrombosis research. Supplement. 1983:4():93-104     [PubMed PMID: 6579711]


Bramer SL, Forbes WP, Mallikaarjun S. Cilostazol pharmacokinetics after single and multiple oral doses in healthy males and patients with intermittent claudication resulting from peripheral arterial disease. Clinical pharmacokinetics. 1999:37 Suppl 2():1-11     [PubMed PMID: 10702882]

Level 1 (high-level) evidence


Schrör K, Weber AA. Comparative pharmacology of GP IIb/IIIa antagonists. Journal of thrombosis and thrombolysis. 2003 Apr:15(2):71-80     [PubMed PMID: 14618072]

Level 2 (mid-level) evidence


Sukul D, Seth M, Schreiber T, Hanzel G, Khandelwal A, Cannon LA, Lalonde TA, Gurm HS. The comparative safety of abciximab versus eptifibatide in patients on dialysis undergoing percutaneous coronary intervention: Insights from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2). Journal of interventional cardiology. 2017 Aug:30(4):291-300. doi: 10.1111/joic.12388. Epub 2017 May 22     [PubMed PMID: 28543770]

Level 2 (mid-level) evidence


Bashawri LA, Ahmed MA. The approach to a patient with a bleeding disorder: for the primary care physician. Journal of family & community medicine. 2007 May:14(2):53-8     [PubMed PMID: 23012146]


Orme R, Judge HM, Storey RF. Monitoring Antiplatelet Therapy. Seminars in thrombosis and hemostasis. 2017 Apr:43(3):311-319. doi: 10.1055/s-0036-1597298. Epub 2017 Mar 6     [PubMed PMID: 28264200]


Zhou H, Chen L, He H. Intraoperative and postoperative effects of TEG-guided platelet transfusion on antiplatelet drug-related intracerebral hemorrhage patients. Experimental and therapeutic medicine. 2019 Mar:17(3):2263-2267. doi: 10.3892/etm.2019.7169. Epub 2019 Jan 14     [PubMed PMID: 30783485]


Lam H, Katyal N, Parker C, Natteru P, Nattanamai P, Newey CR, Kraus CK. Thromboelastography With Platelet Mapping is Not an Effective Measure of Platelet Inhibition in Patients With Spontaneous Intracerebral Hemorrhage on Antiplatelet Therapy. Cureus. 2018 Apr 22:10(4):e2515. doi: 10.7759/cureus.2515. Epub 2018 Apr 22     [PubMed PMID: 29942718]


Romem R, Tanne D, Geva D, Einhorn-Cohen M, Shlomo N, Bar-Yehuda S, Harnof S. Antithrombotic Treatment Prior to Intracerebral Hemorrhage: Analysis in the National Acute Stroke Israeli Registry. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association. 2018 Nov:27(11):3380-3386. doi: 10.1016/j.jstrokecerebrovasdis.2018.07.040. Epub 2018 Sep 9     [PubMed PMID: 30205997]