Antiplatelet Drug Toxicity

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 followed mixed elimination kinetics depending on the salicylate concentration.  Other factors influencing elimination is 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 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, elimination of cilostazol is thought to be almost entirely metabolism-based.[17]

Abciximab and eptifibatide are parentally 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]

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 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 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.

Currently, there no specific exists antidote 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 are no robust data to support desmopressin.[7][2] 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]

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 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.

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 physician 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 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 physician is necessary 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 V]