Antiplatelet Drug Toxicity

Etiology

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.

Epidemiology

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]

Pathophysiology

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]

Toxicokinetics

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.

Evaluation

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

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]

Complications

Hemorrhagic complications could include:

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