Continuing Education Activity

Aminocaproic acid, an antifibrinolytic agent, is a medication used to manage and treat acute bleeding disorders. This activity outlines the indications, mechanism of action, and contraindications for aminocaproic acid as a valuable agent in managing hyperfibrinolysis-induced hemorrhage. This activity will also highlight other key factors, including the adverse event profile, off-label indications, dosing, and monitoring, pertinent for the healthcare team members in the management of patients with acute hyperfibrinolysis-induced hemorrhage and related conditions.

Objectives:

• Identify the mechanism of action of aminocaproic acid.
• Describe the adverse effects of aminocaproic acid.
• Summarize appropriate monitoring parameters for aminocaproic acid-induced toxicity.
• Review interprofessional team strategies for improving care coordination and communication to advance aminocaproic acid use and improve its outcomes.

Indications

Aminocaproic acid has received approval from the Food and Drug Administration (FDA) for the therapeutic management of acute hemorrhages caused by elevated fibrinolytic activity leading to surgical complications after cardiac surgery, hematological disorders, hepatic cirrhosis, and neoplastic disease. Indications also include the treatment of surgical and non-surgical hematuria.[1][2]

Aminocaproic acid has been used off-label for the following indications[3]:

• Prevention of dental bleeding after dental procedures in patients with hemophilia A
• Intracranial rebleeding prophylaxis after recent aneurysmal subarachnoid hemorrhage
• Prophylaxis of secondary ocular bleeding in the setting of traumatic hyphema
• Angioedema prophylaxis in patients with hereditary angioedema
• Surgical bleeding prophylaxis for a cardiopulmonary bypass as monotherapy or in combination with desmopressin

Mechanism of Action

Aminocaproic acid is a lysine analog that binds competitively to plasminogen, blocking plasminogen from binding to fibrin and the subsequent conversion to plasmin. This activity subsequently results in the inhibition of fibrin degradation (fibrinolysis).[4][5]

Administration

For the management of acute bleeding caused by hyperfibrinolysis, the recommended oral dosage is 5 g the first hour, followed by 1 to 1.25 g/hour for 8 hours or until bleeding is under control. The intravenous dosage is 4 to 5 g over 1 hour, followed by 1 g/hour continuous infusion in 50 mL of diluent for 8 hours or until achieving bleeding control. It is recommended to dilute the initial intravenous dose (4 to 5 g of aminocaproic acid) in 250 mL of 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection. Rapid infusion of the undiluted drug is not recommended and may result in hypotension, bradycardia, and/or arrhythmia. The maximum daily dose for both oral and intravenous formulations is 30 g.[6]

Aminocaproic acid given by mouth is rapidly absorbed, almost entirely from the gastrointestinal tract. After the oral administration of 100 mg/kg of aminocaproic acid, the peak plasma drug concentration is 0.3 mg/mL, about 2 to 3 hours after ingestion. At 4 hours, it decreased to a concentration of 0.16 mg/mL. Approximately 10% of the administered oral dose is excreted in the urine within an hour, and excretion of 25% of the given dose occurs within 3 hours. The 24-hour urinary recovery following oral administration is 64%.[6]

Intravenous administration of 10 g or 100 mg/kg of aminocaproic acid produces an initial serum concentration of about 1.5 mg/mL, which falls to 0.035 mg/mL within 3 to 4 hours. The biological half-life of aminocaproic acid is approximately 77 minutes. According to reports, about 70% of the dose given intravenously was excreted in the urine within 24 hours.[6]

Adverse Effects

Aminocaproic acid is generally well-tolerated. Reported adverse effects include malaise, myalgias, renal impairment, seizures, hypotension, bradycardia, thrombosis, edemas, and injection site reactions.[7][8][9] Aminocaproic acid, though less often, may also cause gastrointestinal symptoms, including nausea and diarrhea. There are also reports of nasal congestion and conjunctival suffusion.[6]

Contraindications

Aminocaproic acid use is contraindicated in the following cases:

• Active intravascular clotting
• Disseminated intravascular coagulation (DIC)

Aminocaproic acid may be used in these scenarios if with concurrent heparin administration.

Clinicians can apply the following tests to differentiate between DIC and primary fibrinolysis:

• Platelet count is normally decreased in DIC but is usually normal in primary fibrinolysis.
• Euglobulin clot lysis is normal in DIC; however, it is abnormal in primary fibrinolysis.
• Protamine para-coagulation test is positive with DIC; however, it is negative with primary fibrinolysis

Monitoring

Monitoring parameters serum creatinine, blood urea nitrogen, creatine phosphokinase, and coagulation tests.[7]

Multiple methods are possible to assess fibrinolysis; however, there is no “gold standard” test. Point-of-care testing with whole blood is beneficial in the perioperative setting as it evaluates plasma and cellular contents. The most widely utilized tools for assessing fibrinolysis in the perioperative setting are thromboelastography (TEG), which uses several activators to measure viscoelastic changes in whole blood.[10]

Toxicity

Aminocaproic acid is of low acute toxicity. Research has found no fetal abnormalities in teratogenic in-vitro studies given aminocaproic acid doses up to 5000 mcg/kg/day. Retinal changes have been reports in dogs after receiving aminocaproic acid by mouth over one year in doses approximately seven-fold higher than the maximum recommended in-vivo dose.[6]

A significant concern is whether treatment with aminocaproic acid predisposes patients to thrombosis and intravascular coagulation. There are isolated reports of arterial or venous thrombosis, but there is underlying thrombotic comorbidity present in each case.[6]

There is no available antidote for use in the setting of aminocaproic acid toxicity. There are case reports that have described the use of tissue plasminogen activator for suspected antifibrinolytic-induced intraoperative thromboembolic events.[11]

Enhancing Healthcare Team Outcomes

Fibrinolysis serves as a physiologic component of hemostasis functioning to limit clot formation. The critical event for clot formation is fibrin formation following vascular injury, tissue factor binding to factor VIIa, and activation of the X-ase complex for hemostatic activation and thrombin generation. Thrombin stimulates the endothelial release of tissue plasminogen activator and increases vascular flow, kinins, and other factors that will release tissue plasminogen activator. Plasmin release follows the formation of a plasminogen-tissue plasminogen activator complex that assembles on fibrin and binds to lysine sites on fibrin clot. Once assembled, tissue plasminogen activator cleaves plasminogen to its active form plasmin. Other mechanisms can also generate plasmin, including urokinase, contact activation, and kallikrein mediated protease activation. Fibrinolysis is inhibited by plasminogen activator inhibitors (plasminogen activator inhibitor 1 and 2) and by thrombin binding to thrombomodulin to release and activate thrombin-activatable fibrinolysis inhibitor.[10] [Level 5]

After tissue injury associated with trauma and surgery, ischemia and reperfusion, or blood interaction with large nonendothelial surfaces, excessive fibrinolysis may contribute to bleeding, coagulopathies, and inflammatory responses. As a result, growing data have reported the efficacy of antifibrinolytic agents to reduce bleeding, blood transfusions, and adverse clinical outcomes. Aminocaproic acid, an antifibrinolytic agent, is one of the medications used to treat acute bleeding disorders.[10] [Level 5]

Managing life-threatening hemorrhagic events requires an interprofessional team of healthcare professionals that includes a nurse, laboratory technologists, pharmacists, and several physicians in different specialties. Without proper management, the morbidity and mortality from massive bleeding are high. It has inevitable consequences in the perioperative period, including re-operation, increased transfusion requirements, and multiorgan dysfunction.[2] [Level 1]

Prophylactic use of the synthetic lysine-analog antifibrinolytic agent, aminocaproic acid, has been the primary pharmacologic approach to blood conservation in cardiac surgery since the removal of aprotinin from clinical use.[12] [Level 1] In the 2011 Update to The Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists Blood Conservation Clinical Practice Guidelines, antifibrinolytic agents were a strong recommendation as a part of the blood conservation approach.[13] [Level 5] Aminocaproic acid reduces bleeding and chest tube drainage output in cardiac surgical patients and is associated with a well-tolerated side effect profile.