What Are the Risks of Fibrinolytic Therapy?

The process of fibrin formed during blood coagulation is decomposed and liquefied, which is called fibrinolysis [phenomenon] fibrinolysis (referred to as fibrinolysis). Fibrinolytic activity is abnormally enhanced, which is called hyperfibrinolysis. Hyperfibrinolysis is divided into two types: primary and secondary.

Hyperfibrinolysis

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The process of fibrin formed during blood coagulation is decomposed and liquefied, which is called fibrinolysis [phenomenon] fibrinolysis (referred to as fibrinolysis). Fibrinolytic activity is abnormally enhanced, which is called hyperfibrinolysis. Hyperfibrinolysis is divided into two types: primary and secondary.

Chinese name

Hyperfibrinolysis

Foreign name

fibrinolysis

Definition

Fibrin is broken down and liquefied

Classification

Primary and secondary

(1) Tissue plasminogen activator (t-PA): t-PA is a serine protease, which is synthesized by vascular endothelial cells. t-PA activates plasminogen, a process that is mainly performed on fibrin.

(2) Urokinase-type plasminogen activator (U-PA): u-PA is produced by renal tubular epithelial cells and vascular endothelial cells. U-PA can directly activate plasminogen without the need for fibrin as a cofactor.

(3) Plasminogen (PLG): PLG is synthesized by the liver. When blood coagulates, PLG is largely adsorbed on the fibrin net and is activated to plasmin by t-PA or u-PA to promote fiber Proteolysis. Plasminogen is a single-chain -globulin with a molecular weight of about 80,000 to 90,000. It's in the liver,

(1) Plasminogen activation pathway: PLG can be activated into PL through three pathways, namely internal activation pathway, external activation pathway and exogenous activation pathway.

(2) Fibrin (pro) degradation mechanism: PL can not only degrade fibrin, but also degrade fibrinogen. PL degrades fibrinogen to produce X fragments, Y fragments, and D, E fragments. Degradation of fibrin produces x ', Y', DD, E 'fragments. All these fragments are collectively referred to as fibrin degradation products (FDP).

The basic process of fibrinolysis can be divided into two stages: the activation of plasminogen and the degradation of fibrin.

Plasminogen activation

Normally, plasminogen is inactive in plasma. Only under the action of an activator can it be converted into a catalytically active plasmin. Plasminogen activators are found in blood, various tissues and tissue fluids, and can also be produced by microorganisms. There are three main categories:

(1) Vascular activator Vascular activator is synthesized in endothelial cells of small blood vessels and released into blood. If a blood clot appears in a blood vessel, it can cause vascular endothelial cells to release a large amount of this activator and be adsorbed on the blood fibrous clot. Muscle movement, vein occlusion, catecholamines and histamines can also increase the synthesis and release of this activator by vascular endothelial cells.

(2) Tissue activators Tissue activators exist in many types of tissue cells, with the highest content in uterus, thyroid and lymph nodes, followed by lung and ovary. Normally, tissue activators are present in the cells and released into the blood when the tissue is damaged, prompting plasminogen to become plasmin. Such as clinical patients, such as the implementation of certain organ surgery, bleeding is often prone to occur. Another example is that women's menstrual blood is not coagulated, which is related to the rich tissue activators in these tissues.

(3) Urine activator Urine contains plasminogen activator, called urokinase. It is released by kidney and urinary tract epithelial cells. In addition, in

6-aminocaproic acid (EACA)

Synthesized in 1953 and used for cardiac surgery in 1964 with a short half-life. EACA reversibly binds to the lysine binding site on plasminogen, blocks lysine from binding to lysine on fibrin, and inhibits the conversion of plasminogen to plasmin, which can be directly used at high doses. Inhibits plasmin, thereby reducing bleeding and blood transfusion after CPB. In different studies, EACA has different dosage application schemes. In general, the recommended standard dosage regimen for adults is 150 mg / kg as the intravenous load, followed by 15 mg / (kg · h) intraoperative intraoperative input.

Most literatures suggest that the preventive use of EACA before CPB can effectively inhibit the activation of the fibrinolytic system during CPB, reduce postoperative bleeding, and reduce the amount of postoperative blood transfusion. Further studies show that EACA is less effective than aprotinin in reducing postoperative bleeding in patients undergoing heart valve replacement, but does not increase postoperative blood transfusion. In the study of patients with initial CABG, compared with placebo, EACA not only reduced postoperative bleeding and blood transfusion, but also had no allergic reaction, did not increase stroke, cognitive dysfunction, renal insufficiency, myocardial infarction. , Thrombosis and bridge occlusion. Compared with the use of aprotinin, EACA was not significantly different in inhibiting fibrinolytic system activation and reducing postoperative bleeding.

In related studies of OPCABG, it was found that although EACA can inhibit hyperfibrinolysis after surgery, it cannot reduce the amount of bleeding after surgery. In summary, most studies suggest that EACA has similar or slightly weaker efficacy than aprotinin in reducing postoperative bleeding and transfusion, and there is no significant statistical difference in clinical results.

Tranexamic Acid (AMCA)

AMCA is a lysine homolog antifibrinolytic drug widely used in clinical practice, and its action intensity is 5-10 times that of EACA. Synthesized in 1964 and first used in CPB cardiac surgery in 1988. In addition to reversibly binding lysine binding sites on plasminogen to inhibit the conversion of plasminogen to plasmin, AMCA can also reduce bleeding by preventing plasmin-induced platelet activation. The dosage of AMCA varies from 10 to 20 g. As the dosage increases, the amount of postoperative bleeding cannot be further reduced. At present, it is generally believed that the preventive application of AMCA before CPB can effectively reduce the need for perioperative bleeding and allogeneic blood in cardiac surgery patients, reduce postoperative complications and improve prognosis. However, the results of various studies have differed as to whether the incidence of reoperation due to bleeding can be reduced. The relationship between the time of AMCA administration and the onset of CPB will affect its effect. In a randomized double-blind study of CABG patients, the same dose of AMCA was administered before CPB or after CPB, and compared with placebo. The results found that administration of AMCA after CPB did not significantly reduce postoperative bleeding and allogeneic blood transfusion requirements. The clinical effect is limited. A comparative study of the effects of antifibrinolytic drugs in cardiac surgery by Mangano et al. Showed that AMCA is similar to aprotinin in preventing perioperative blood loss in the heart, but the risk of adverse reactions and end-organ damage is lower than aprotinin , Questioned the safety of aprotinin, and recommended the use of AMCA instead of aprotinin as a drug to prevent blood loss during cardiac surgery.

Further research shows that patients undergoing aortic valve replacement (AVR) have no difference between AMCA and aprotinin in reducing blood transfusion, and AMCA is slightly inferior to aprotinin in CABG patients. The effect of surgery is limited. In terms of protecting platelet function, aprotinin is superior to AMCA. However, some studies have shown that AMCA is not different from aprotinin in protecting platelet function after CPB. This may be related to the experimental evaluation of platelet function using different methods. Studies on the risks of using antifibrinolytic drugs in cardiac surgery have shown that patients undergoing primary valve surgery and high-risk surgery have a significantly higher proportion of seizures than those using aprotinin after AMCA. At the same time, patients who underwent the first valvular surgery had more frequent atrial fibrillation and renal failure than the aprotinin group. In the group of patients who performed CABG for the first time, it was found that patients with aprotinin had a higher incidence of acute myocardial infarction and renal insufficiency than those in the AMCA group. In addition, among patients undergoing high-risk surgery, the one-year mortality rate was The aprotinin group is also significantly higher than the AMCA group. Therefore, it is suggested that aprotinin should be avoided in patients with CABG and high-risk surgery, and patients who perform valve surgery should avoid AMCA. Studies in OPCABG patients have also found that AMCA can reduce postoperative bleeding and use of blood products.

The adverse reactions of AMCA are relatively rare, mainly including nausea, diarrhea, and occasionally tonicity. Clinical application has not found that the use of AMCA increases the probability of thrombosis.

Aminomethylbenzoic Acid (PAMBA)

Synthesized in 1963. The stronger AMCA was synthesized in 1964. There are few reports on the application of PAMBA abroad. Some domestic studies have shown that PAMBA can inhibit the activation of fibrinolytic system in CPB, protect platelet function, reduce postoperative bleeding, and have no adverse reactions.

Studies have found that the prophylactic use of high-dose aprotinin PAMBA (20 mg / kg) during cardiac surgery can partially inhibit fibrinolysis in CPB. Both have similar effects on anti-fibrinolysis and reduction of first surgical bleeding. Studies on the protective effect of PAMBA on platelet function in CPB have shown that hemostatic acid and aprotinin have similar effects in protecting platelets and preventing their activation in CPB, and there is no significant difference in comparison of postoperative blood loss.

1 Risks of using antifibrinolytic drugs and future research prospects

When the fibrinolytic system is inhibited by antifibrinolytic drugs, thromboembolism is extremely easy to occur, especially for those patients who have underlying arteriosclerotic lesions and need cardiac surgery. Because aprotinin can lead to an increased incidence of adverse events such as severe renal failure, myocardial infarction or heart failure, stroke, etc., its use has been banned clinically. The lysine analogue is an artificial anti-fibrinolytic drug. Due to its simple structure, there are no obvious adverse reactions, and it will not affect the measurement of ACT. There are few reports about thrombosis, which can be used as a stop for the current research. Alternative medicine for blood protection in cardiac surgery after aprotinin.

However, it cannot be ignored that lysine analogues are not as widely used in the prevention of perioperative blood loss as aprotinin, and the number and number of samples involved in scientific evaluation are much less than aprotinin, so it is not yet possible to treat it. Security is too trusted. And the effect of lysine analogues in preventing perioperative blood loss is not as certain as aprotinin. Therefore, in the future research, it is necessary to further evaluate its safety and effectiveness, especially its safety and effectiveness in high-risk surgery. In addition, as a broad-spectrum serine protease inhibitor, aprotinin, in addition to its role in reducing bleeding, also has anti-inflammatory, myocardial and lung protective functions, and whether lysine analogues also have the above-mentioned effects needs further confirmation.

Antifibrinolytic drugs have a certain effect in reducing perioperative bleeding and blood transfusion during surgery, but due to its nature, it also inevitably brings the risk of thromboembolism and damage to heart, brain, kidney and other important organs . Therefore, the clinical use of such drugs requires weighing the pros and cons, especially in patients at risk for thromboembolism.