Role of Tranexamic Acid in Patients Undergoing Non-cardiac Surgery

What Is an Antifibrinolytic Agent?

Antifibrinolytic agents are chemicals used to prevent fibrinolysis. Fibrinolysis is a normal body process that dissolves naturally occurring blood clots. However, during major surgical procedures, the same fibrinolysis that was necessary for healthy circulation will become a pathological mechanism leading to excessive bleeding and inflammatory responses.

Tranexamic acid, which is an antifibrinolytic drug, prevents and treats excessive bleeding during the perioperative period.

What Is Fibrinolysis?

Hemostasis (a mechanism that stops bleeding) is a balanced combination of clotting and fibrinolysis. When a physical trauma happens, the blood vessels surrounding the injured soft tissue also get affected. The body heals these vascular injuries through a process called clotting. If clotting does not happen, the blood will seep from the blood vessels leading to serious life-threatening conditions.

During clotting, a few specific enzymes get activated, which initiate clot formation. The blood clot is made up of platelets in a meshwork of protein strands called fibrin. This is a regulated procedure because if left unattended, the enzymes will continue clotting, ultimately leading to ischemia (reduced or restricted blood flow).

Regulation of clotting is made by fibrinolysis; during this process, a new set of enzymes will activate a protein called plasmin which will dissolve the excess fibrin formed during clotting. Fibrinolysis is also a regulated procedure involving complex interactions and feedback mechanisms.

How Does Tranexamic Acid (TXA) Prevent Excess Bleeding?

• Tranexamic acid is the synthetic analog of a naturally occurring amino acid called lysine. It inhibits the formation of plasmin (which is essential to dissolve the fibrin clot during fibrinolysis) by binding itself to the enzymes responsible for activating plasmin.

• TXA also has anti-inflammatory properties (by inhibiting the activation of immune cells monocytes and neutrophils), through which it can reduce pain, swelling, and other symptoms.

• During major surgeries and emergency procedures, there will be excessive loss of blood, leading to hypoperfusion (reduced amount of blood flow) and hypoxia (reduced oxygen supply). This drives the balance of hemostasis towards hyperfibrinolysis, which will constantly dissolve the much-needed blood clot leading to more bleeding and subsequent coagulopathy.

• The excess intraoperative bleeding will increase the operative risk and the consequent reduction in intraoperative visualization, which will hinder the surgical progress, prolong surgery, reduce success rates, and in some cases, even prevent the surgeon from completing the procedure.

• To prevent this, the surgeon will administer tranexamic acid (an antifibrinolytic agent) either intravenously, orally, or topically (less often) to prevent excess bleeding.

What Are the Uses of TXA?

TXA is indicated during the perioperative and intraoperative period of major, minor surgeries and emergency procedures to prevent excess loss of blood. Some of the procedures are mentioned below-

• Off-label Intravenous TXA For Emergency Surgeries- Some health conditions have bleeding as one of the associated symptoms; it can only be repaired through surgery, during which the surgeon will prescribe TXA. A few medical conditions with symptomatic bleeding are-

1. Hereditary Angioneurotic edema- It is an inherited disorder that causes acute episodes of rapid non-pitting swelling (due to perfusion of blood) in the face, periorbital skin, lips, pharynx (food pipe), larynx (windpipe), tongue, and occasionally the gastrointestinal tract. These episodes become problematic when the swelling obstructs the airway; in severe cases, the airway integrity may be lost, leading to death. Severe episodes of angioneurotic edema will need intubation to maintain a patent airway. It is resistant to antihistamines, corticosteroids, and epinephrine which are the usual drugs of choice for histaminergic angioedema. Intravenous TXA is used as a front-line emergency therapy to reverse episodes of angioneurotic edema.
2. Upper Gastrointestinal Bleeding- Upper gastrointestinal bleeding is a common reason for emergency hospital administration and a common complication in hospitalized patients. Patients with acute upper gastrointestinal bleeding should undergo endoscopy within 24 hours to prevent life-threatening conditions. Prior to the procedure, patients are given intravenous TXA to achieve hemostasis, thereby stabilizing the patient until the endoscopy is complete.
3. Postpartum Hemorrhage- TXA reduces morbidity and mortality in women with postpartum hemorrhage if given immediately after the onset of bleeding.
4. Non-traumatic Subarachnoid Hemorrhage- Subarachnoid hemorrhage is bleeding in the space between the brain and its surrounding membranes due to a ruptured aneurysm. Research has shown a reduction in rebleeding and mortality with the use of TXA while treating patients with subarachnoid hemorrhage. Intravenous TXA of one gram during diagnosis and then one gram for every six hours as part of the treatment is given till the occlusion of the aneurysm.

• Off-label Intravenous Uses of TXA In Surgical Operations to Reduce Blood Loss- A few elective and planned surgical procedures require TXA to prevent unnecessary bleeding during the course of the surgery; they are-

1. Elective Cesarean- Women who undergo elective cesarean are given intravenous TXA to reduce blood loss and prevent the thromboembolic events that follow with blood loss. One gram of intravenous TXA over five minutes should be given at least ten minutes before the skin incision.
2. Total Knee Arthroplasty- Intravenous TXA during total knee arthroplasty reduces loss of blood and the need for blood transfusion. The recommended dose is 10 mg/kg to 15 mg/kg over ten minutes through IV just before the deflation of the first tourniquet and three hours after the first dose.
3. Orthognathic Surgery- Patients undergoing bi-maxillary osteotomy are given intravenous TXA to reduce blood loss during the surgery. Bi-maxillary osteotomy is a surgical procedure done when it is not possible to correct the teeth and the bite with orthodontics alone. The maxillofacial area is a blood-rich area, so bleeding is expected in most orthognathic surgeries, which will have a negative impact on the quality of the surgery.
4. Transurethral Retrograde Prostatectomy (TURP)- Patients undergoing TURP, when administered with TXA, have less hemoglobin loss per gram of resected prostate.
5. Spinal Surgery: Significant reduction in blood loss with intravenous TXA is seen in patients undergoing multi-level posterior spinal segmental instrumented fusion. The administered dose is 2 grams over twenty minutes just before the incision, followed by 100 mg for every hour of the surgery, which is also continued for five hours post-surgery.

• Off-label Oral TXA- The following are a few minor surgical procedures that benefit from prophylactic oral TXA-

1. Post-procedural After Cervical Conization- Cervical conization is a surgical procedure used to diagnose and treat cervical dysplasia or very early cervical cancer. Patients undergoing this procedure experience reduced blood loss with an oral TXA regime or if given prophylactically prior to the procedure.
2. Transurethral Retrograde Prostatectomy- Short-term oral TXA, when given three times daily after the first day of the operation or prior to the procedure, reduces blood loss during TURP.
3. Tooth Extraction in Patients on Oral Anticoagulants- Anticoagulants are medications that are prescribed to patients with a previous history of heart attack and stroke. They prevent the formation of stroke-inducing blood clots in the blood vessels. When patients on these drugs undergo minor surgeries like tooth extraction, the associated bleeding that ensues during and after surgery will not clot because of the anticoagulant medication they are on for their previous heart conditions. To prevent this, after obtaining complete medical history, the surgeon will prescribe a two-day TXA regime to prevent postoperative blood loss.
4. Total Unilateral Hip Replacement Surgery- Patients undergoing unilateral hip replacement often receive blood transfusion due to the excess loss of blood during the procedure. Intra-auricular (inside of the hip joint) TXA injection of 15 mg/kg at the time of skin incision followed up by the same dose after three hours is given to these patients to prevent excess bleeding.

The procedures are mentioned as off-label because the FDA (food and drug administration) has officially approved TXA for heavy menstrual bleeding and as short-term prevention in patients with hemophilia.

Contrary to the FDA’s indications, surgeons use intravenous TXA to prevent severe bleeding in patients who will otherwise need massive transfusion protocols (MTP). TXA should be administered within three hours of the onset of hemorrhage in adult patients with a systolic blood pressure of less than 90 mmHg and a heart rate of more than 110 beats per min. This has been shown to reduce mortality, especially in the ones needing MTP.

What Are the Adverse Effects of TXA?

A few studies have shown that patients who receive TXA have a three-fold higher risk of developing postoperative thrombotic effects (stroke symptoms). However, there is not enough evidence to support this statement. As with any medication, TXA has its side effects and is administered only when the benefits outweigh the complications.

Some of the complications of TXA are-

• Seizures.

• Headaches and backaches.

• Abdominal pain.

• Nausea and vomiting.

• Diarrhea and fatigue.

• Deep vein thrombosis (where a blood clot will form in one or more of the deep veins in the body).

• Anaphylaxis is a potentially life-threatening allergic reaction.

• Impaired color vision and other visual disturbances.

Conclusion:

Even though the FDA has approved TXA for only two conditions, it is a well-researched drug with the potential to reduce the relative risk of death due to excess bleeding. Administering TXA depends on the clinician's choice, and if decided to do so should be communicated to the interprofessional team to ensure that it is given between one to three hours of the perioperative period to improve the chances of survival.