Description

• The 2 antifibrinolytic agents in current clinical use – epsilon-aminocaproic acid (EACA) tranexamic acid (TA) – are synthetic lysine analogs that are similar in mechanism of action, molecular weight, metabolism, clinical effects.
• Clinical uses include prophylaxis /or adjunctive therapy for the prevention of perioperative bleeding in a variety of patients surgeries:
  • Cardiac surgery requiring cardiopulmonary bypass (CPB)
  • Liver transplantation or resection
  • Orthopedic procedures (e.g., revision joints, spinal surgery)

Physiology Principles

• Mechanism regulation of fibrinolysis: The normal fibrinolytic response is a complex physiologic reaction that prevents excessive intravascular hemostasis at the site of a vascular injury.
  • Vascular injury results in the activation of pro-coagulant pathways that culminate in the formation of fibrin clot at the site of vascular injury.
  • Intravascular fibrin thrombin initiate the normal fibrinolytic response.
• Tissue plasminogen activator (tPA) plasminogen are serine proteases in endothelial cells that are released at the site of vascular injury. They bind to positively charged lysine residues on the fibrin molecule.
  • tPA plasminogen bind to fibrin which then converts plasminogen to plasmin.
  • Plasmin directly cleaves fibrin clot, resulting in fibrin degradation clot breakdown.
  • Regulation of fibrinolysis occurs via multiple local systemic mechanisms. A delicate balance between competing pro-coagulant anti-coagulant systems occurs during normal intravascular homeostasis.
• Mechanism of action of lysine analogs:
  • EACA TA share a common mechanism of action by reversibly inhibiting the binding of plasminogen to charged lysine sites on the surface of fibrin molecules, thus preventing the conversion of plasminogen to plasmin.
  • Unlike the serine protease inhibitor aprotinin, lysine analogs do not directly inhibit the actions of plasmin.
  • The potency of TA is approximately 10 times higher than EACA.
  • Plasma half-life of both drugs is approximately 2 hours, excretion is primarily via renal mechanisms. 95% of the drug is excreted unchanged in the urine.

Physiology/Pathophysiology

• Excessive systemic fibrinolysis may be stimulated by:
  • Disease states: Sepsis, massive trauma
  • Major surgery: Cardiac surgery with CPB, liver transplantation, major orthopedic surgery
• Consumptive coagulopathy is defined by the presence of the simultaneous generation of both thrombin plasmin, which results in the potential for severe diffuse bleeding.
• Systemic fibrinolysis may be detected clinically by the observation of excessive bleeding at sites of tissue injury:
  • Surgical wounds
  • Intravascular catheters
  • Invasive devices such as Foley catheters
• Laboratory abnormalities reflecting the degradation of fibrin clot may assist in the diagnosis of fibrinolysis. They include:
  • Increased levels of fibrin split products
  • Increased D-dimer
  • Decreased levels of fibrinogen
  • Increased levels activity of tPA
  • Characteristic abnormalities on thromboelastogram
• Side effects of antifibrinolytics:
  • Renal:
    • EACA has been shown to exhibit a range of nephrotoxicity (acute tubular necrosis, myoglobin-induced renal failure, glomerular capillary thrombosis) in patients following prolonged use /or receiving high doses. Cardiac surgical patients with normal renal function who receive moderate dosing protocols do not demonstrate significant renal effects.
    • Both drugs should be avoided in patients with severe renal dysfunction.
  • Central nervous system:
    • Lysine analogs cross the blood–brain barrier have the potential to cause neuronal hyperexcitability.
    • TA has been associated with a higher level of seizure activity in cardiac surgical patients compared to aprotinin.
  • Immunologic:
    • Lysine analogs have low molecular weights, making them less antigenic than larger molecules associated with anaphylaxis, such as aprotinin.
  • Prothrombosis:
    • In non-heparinized surgical patients, co-administration of antifibrinolytics poses a potential concern for prothrombotic complications.
    • Studies in cardiac liver transplant surgery patients have not shown an increase in the rate of thrombotic complications in patients receiving antifibrinolytics (myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism, or liver graft vascular thrombosis) (1,2).

Perioperative Relevance

• Antifibrinolytic therapy has been mainly used to control the consumptive coagulopathy that can occur during cardiac surgery with CPB, liver transplantation, major orthopedic surgery.
• Cardiac surgery with CPB: Application of all extracorporeal circulation devices, including CPB, results in the continuous systemic generation of thrombin. Despite the use of heparin to prevent massive intravascular coagulation, thrombin generation continues throughout CPB. TPA release, stimulated by circulating thrombin, increases throughout the duration of CPP remains elevated for many hours after (accompanied by accelerated fibrinolysis). Prophylactic antifibrinolytic therapy is regularly used to decrease CPB-associated fibrinolysis.
  • Multiple studies have demonstrated decreased postoperative transfusion, decreased risk of re-exploration, reduced plasma markers of fibrinolysis compared to placebo. Additionally, no increase in acute coronary artery thrombosis has been shown to occur. TA has been studied more intensively than EACA in cardiac surgery (1,3,4).
  • TA may be administered in low- or high-dose regimens. Low-dose TA: 10 mg/kg loading dose, 1 mg/kg/hr infusion. High-dose TA: 50–150 mg/kg loading dose, 1 mg/kg/hr infusion.
  • EACA dosages: 5–10 g loading dose prior to incision, 1 g/hr infusion. The maximum safe total dosages of EACA have been described between 30 90 g.
  • Abnormal renal function requires lower doses.
  • Some experts recommend the continuation of antifibrinolytic therapy for up to 12 hours following CPB, although common practice is to discontinue treatment upon completion of surgery (5).
  • Topical TA administered in the wound at surgical closure has been shown to reduce postoperative blood drainage (5).
• Orthotopic liver transplantation (OLT): Enhanced fibrinolysis is common with OLT, especially during the anhepatic early post-anhepatic phases of the procedure. Increased tPA activity decreased fibrinolytic inhibitor activity regularly occur during OLT. Fibrinolysis contributes to blood loss transfusion requirements during OLT. Serial laboratory coagulation testing (thromboelastography, fibrinogen, D-dimer, fibrin degradation products) is routinely employed to assist in the diagnosis of excessive fibrinolysis during OLT.
  • Clinical use of antifibrinolytics in OLT varies by practice: Prophylactic infusion selective bolus rescue dosing have been described.
  • Both TA EACA have been used clinically in OLT for many years, although TA has been studied more extensively (2).
  • TA has not been shown to increase the incidence of postoperative deep vein thrombosis or pulmonary embolism (3,6).
  • EACA: A single 1 g dose has been shown to be effective in normalizing fibrinolytic abnormalities on thromboelastography. However, it has not definitively been shown to impact transfusion requirements during OLT (2).
  • TA has been shown to decrease blood loss reduce transfusion requirements in prospective studies during OLT (2,3).
  • Significant preoperative renal dysfunction poses an increased risk for the exacerbation of acute kidney injury by antifibrinolytics.
  • Thromboembolic complications are a rare but devastating intraoperative complication during OLT; there are concerns regarding the pro-thrombotic potential of antifibrinolytics in this setting. However, antifibrinolytic therapy has never been determined as a definitive cause of thromboembolic complications in this patient population. Antifibrinolytic therapy should be withheld in OLT patients with a known pre-existing hypercoagulable state (2).
• Orthopedic surgery: Antifibrinolytic therapy has been employed in a variety of major orthopedic procedures with a risk of significant blood loss, including adult pediatric scoliosis spine surgery revision joints. Major prolonged orthopedic surgery may result in significant bone tissue trauma that can stimulate fibrinolysis. The use of a lower extremity tourniquet, as in total knee arthroplasty, may be associated with enhanced fibrinolysis.
  • Total knee arthroplasty: Studies have demonstrated that TA use decreases blood loss transfusion requirements (3,6).
  • Pediatric scoliosis: TA has also been shown to decrease intraoperative blood loss.
  • A variety of regimens, including preoperative postoperative oral IV dosing, have been described.
• Future directions in antifibrinolytic therapy:
  • Fibrinogen levels: Effective antifibrinolytic therapy requires maintenance of adequate levels of fibrinogen. Low fibrinogen levels are associated with significant post-CPB bleeding in cardiac surgery. Cryoprecipitate transfusion has been the stard treatment for increasing fibrinogen levels. Newly developed factor concentrates, including virus-inactivated purified fibrinogen, may be an alternative to cryoprecipitate fresh frozen plasma for the treatment of hypofibrinogenemia (7).
  • Aprotinin: Following the withdrawal of aprotinin in 2007, antifibrinolytic therapy has been limited to the use of the lysine analogs.
  • CU-2010—a synthetic protease inhibitor with properties similar to aprotinin—has recently been described as a new antifibrinolytic agent; however, further clinical studies are required (8).

• Pulmonary Embolism
• Cardiopulmonary Bypass
• D-Dimer
• Fibrinogen

Christopher Wray , MD