Antifibrinolytics in Cardiac Surgery

Introduction

• Fibrinolysis is a process by which a fibrin blood clot is broken down by plasmin into fibrin degradation products. Primary fibrinolysis occurs naturally to prevent the propagation of a clot and restore the patency of a blood vessel. Secondary fibrinolysis is abnormal clot breakdown secondary to medication, pathology, or other factors.
• Major blood loss during cardiac surgery is associated with high transfusion requirements, increased rates of operative re-exploration, and increased mortality. Other associated complications include an increased risk of infection, arrhythmias, and a longer hospital stay.^1,2
• Please see the OA summary on antifibrinolytics, which focuses on the use of antifibrinolytics in cardiac surgery, for more details. Link

Fibrinolysis

• Fibrinolysis occurs by several CPB-related mechanisms during cardiac surgery:²
  • Contact of blood with the CPB circuit leads to increased expression of tissue factor, activation of factor VII, and the extrinsic pathway of the coagulation cascade, resulting in thrombin generation.
  • Thrombin allows for the conversion of fibrinogen to fibrin.
    • During CPB, total fibrin concentrations decrease due to heparinization, but soluble fibrin concentrations increase. Soluble fibrin is an intermediate form of fibrin that is non-hemostatic.
  • Conversion of plasminogen to plasmin, which breaks down fibrin clots
  • Consumption of fibrinogen
  • Inflammatory response
• Antifibrinolytic agents have been shown to reduce perioperative blood loss, transfusion requirements, and the need for re-exploration. Because of this, they are routinely used in cardiac surgery.³

Antifibrinolytic Agents

Aprotinin

• Serine protease inhibitor that inhibits plasmin, kallikrein, thrombin, and other inflammatory mediators
• Has antifibrinolytic and anti-inflammatory effects
• No longer available in the US due to concerns for renal toxicity and increased mortality (BART trial)³

EACA, Amicar

• Synthetic lysine analog
• Mechanism: binds to plasminogen and prevents conversion of plasminogen to plasmin by tissue plasminogen activator (tPA) → stabilizes fibrin clot
• Pharmacokinetics:
  • Large volume of distribution
  • Does not cross the blood-brain barrier (BBB) and is safe in patients with seizure disorder
  • Renally cleared
• Dosing:
  • Typically started after induction of anesthesia and before initiation of CPB.
  • Loading dose: 5-10 g
  • Infusion dose: 1 g/hr
  • Note: Institutional dosing protocols may vary.
• Potential adverse effects:
  • Thrombotic events
    • Avoid in patients with hypercoagulable conditions, patients undergoing vascular anastomosis, patients with disseminated intravascular coagulation, and patients with fibrinolytic shutdown
  • Hypotension (if given too quickly)
  • Renal dysfunction – reduce dose in patients with renal impairment
  • Nausea/vomiting
  • Myopathy if used for prolonged periods

TXA

• Synthetic lysine analog
• 6-10 times more potent than EACA due to increased affinity for plasminogen
• Mechanism: binds to plasminogen and prevents conversion of plasminogen to plasmin by tPA → stabilizes fibrin clot
• Pharmacokinetics:
  • 100% bioavailable when given intravenously (IV), but also available for oral and topical administration
  • Low volume of distribution
  • Crosses BBB and is associated with increased risk of seizures
  • Renally cleared
  • Rapid onset
  • Half-life is ~80 minutes
• Dosing:⁴
  • Typically started after induction of anesthesia and before initiation of CPB.
  • Loading dose: 10-30 mg/kg IV TXA
  • Infusion dose: 1-16 mg/kg/hr throughout CPB until skin closure
  • NOTE: Institutional dosing protocols may vary.
• Potential adverse effects:⁵
  • Seizures (associated with higher doses) via GABA/glycine receptor inhibition
    • Avoid in patients with a known history of seizure disorder
  • Thrombotic events
    • Avoid in patients with hypercoagulable conditions, patients undergoing vascular anastomosis, patients with DIC, and patients with fibrinolytic shutdown
  • Hypotension (if given too quickly)
  • Renal dysfunction – reduce dose in patients with renal impairment