The process in which fibrin formed during blood coagulation is decomposed and liquefied is called fibrinolysis (fibrinolysis for short).Abnormal increase of fibrinolytic activity, i.eHyperfibrinolysis。HyperfibrinolysisAnd divided intoPrimary hyperfibrinolysisandSecondary hyperfibrinolysis, may cause bleeding.Blood fibrinolytic enzymeIt acts on fibrinogen or fibrin and can cut off the lysine binding site of its polypeptide chain to dissolve it.The resulting decomposition product is FDP.Fibrinolysis is also called the fourth phase of blood coagulation.
Fibrinolytic activators (plasminogen andFibrinolytic enzymeIt refers to a series of enzymatic reactions of plasmin, inhibitor and fibrinolysis, which are collectively called fibrinolysis system.
The substances in plasma that inhibit fibrinolysis are collectively referred to as fibrinolytic inhibitors.They exist in plasma, tissues and various body fluids.According to its function, it can be divided into two categories: one is to inhibit the activation of plasminogen, called anti activator;The other is to inhibit the action of plasmin, which is called anti plasmin.Hemostatic drugs that have been widely used clinically, such as clotting acid, hemostatic aromatic acid and 6-aminocaproic acid, are drugs that inhibit the production of plasmin and its effects.
Fibrinolysis system
Under normal circumstances, the content of anti plasmin in the blood is higher than that of plasmin, so the role of plasmin is not easy to play.But blood clots orthrombusLater, because fibrin can adsorb plasminogen and activator but not inhibitor, a large number of plasmins are formed and play a role, causing the dissolution and liquefaction of blood clots or thrombus.
(3) Plasminogen (PLG): PLG is synthesized by the liver. When blood clots, PLG is largely adsorbed on the fibrin network, and under the action of t-PA or u-PA, it is activated as fibrinolytic enzyme to promote fibrinolysis.Plasminogen is a single chain β - globulin with a molecular weight of 80000-90000.It is in the liverbone marrow、EosinophilsIt is synthesized in the kidney and then enters the blood.The content of adult plasma is 10-20mg/100ml.Its half-life in blood flow is 2 to 2.5 days.It is easily adsorbed by its substrate fibrin.
(4) Plasmin (PL): PL is a serine protease, which can degrade fibrin and fibrinogen;Hydrolyze various coagulation factors V, VIII, X, VII, XI, II, etc;Transforming plasminogen into plasmin;Hydrolyzed complement, etc.
(5) Fibrinolytic inhibitors: including plasminogen activation inhibitor (PAI) and α 2 antiplasmin (α 2-AP).PAI can specifically combine with t-PA in a 1:1 ratio to inactivate it, and simultaneously activate PLG. There are mainly two forms of PAI-1 and PAI-2.α 2-AP is synthesized by the liver. The mechanism of action: it combines with PL to form a complex in a 1:1 ratio to inhibit the activity of PL;F ⅩⅢ binds α 2-AP with fibrin by covalent bond, reducing the sensitivity of fibrin to the action of PL.
（6）Fibrinogen(Fg): participate in hemostasisThrombosisFibrin clot is the main substance of thrombus.Because its molecular weight is relatively large and it is easy to form a network structure in the bloodplasma viscosity There is close relationship.The normal value is 2-4g/L.When Fg increases, blood viscosity increasesthrombusThe possibility of arterial wall damage andatherosclerosis(AS), Fg can be deposited on its surface.Fg isThrombotic diseases Independent risk factors.
Dissolution mechanism
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(1) Plasminogen activation pathway: PLG can be activated into PL through three pathways, namely internal activation pathway, external activation pathway and external activation pathway.
(2) Fibrinogen degradation mechanism: PL not only degrades fibrin, but also can degrade fibrinogen.PL degrades fibrin to produce X segment, Y segment, D segment and E segment.Fibrin degradation produces x ', Y', D-D, E 'fragments.All the above fragments are collectively referred to asFibrin degradation products（FDP）。
Fibrinolytic process
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The basic process of fibrinolysis can be divided into two stages: the activation of plasminogen and the degradation of fibrin.
1. Activation of plasminogen
Under normal circumstances, plasminogen in plasma is inactive.Only under the action of activator, it can be transformed into a fibrinolytic enzyme with catalytic activity.Plasminogen activators exist in blood, various tissues and tissue fluids, and can also be produced by microorganisms.There are three main categories:
(1) Of or relating to small blood vesselsendothelial cellsAfter synthesis, it is released into the blood.If blood clots appear in blood vessels, it can make vascular endothelial cells release a large number of such activators and be adsorbed on the blood clots.Muscle movement, vein obstruction,catecholamineAnd histamine can also increase the synthesis and release of this activator by vascular endothelial cells.
(2) Tissue activator Tissue activator exists in many kindsHistiocyteThe highest content was found in uterus, thyroid and lymph nodes, followed by lungs and ovaries.Normally, tissue activators exist in cells, and when tissue is damaged, they are released into the blood, prompting plasminogen to become plasmin.For example, clinical patients, such as the implementation of certain organ surgery, often prone to bleeding phenomenon.For another example, women's menstrual blood is not coagulated, which is related to the rich tissue activators in these tissues.
(3) Urine activator The urine contains plasminogen activator, called urokinase.It is the kidney and urinary tractepithelial cellsReleased.In addition, on thebile、saliva、milk、cerebrospinal fluid、amniotic fluid、ascites、Articular cavityThe liquid contains activator or activator.These activators have the physiological function of preventing fibrin embolism and keeping the lumen unobstructed.
Some bacteria also contain substances that activate plasminogen.If streptococcus contains streptokinase,staphylococcusWithStaphylokinaseTherefore, the body infected with these bacteria can activate plasminogen to become plasmin.
2. Fibrin degradation
Plasmin is the most active protease in plasma, but its specificity is poor.It can hydrolyze the parts connected by lysine arginine on the peptide chain, thus gradually dividing the whole fibrin or fibrinogen molecule into many soluble small peptides (protein fragments), which are collectively called fibrin degradation products.This degradation product is generally no longer solidified.
Intravascular appearancethrombusFibrinolysis is mainly limited to the place where thrombus occurs and does not extend to the surrounding blood.This may be due to a large amount of anti fibrinolytic substances (i.e. inhibitors) andthrombusThe fibrin molecules in can adsorb or combine with a large number of plasmin activators.
It was synthesized in 1953 and used for heart surgery in 1964 with a short half-life.EACA can block the combination of plasminogen and lysine on fibrin by reversibly binding to the lysine binding site on plasminogen, and inhibit the conversion of plasminogen to plasmin. In large doses, EACA can directly inhibit plasmin, thus reducing bleeding and blood transfusion after CPB.In different studies, EACA has different dosage application schemes. Generally, the recommended adult standard dosage scheme is 150mg/kg as the intravenous injection load, followed by 15mg/(kg · h) intraoperative maintenance input.
Most literatures believe that preventive use of EACA before CPB can effectively inhibit the activation of fibrinolytic system during CPB, reduce postoperative bleeding, and reduce postoperative blood transfusion.Further research shows that EACA is less effective than aprotinin in reducing postoperative bleeding in patients undergoing heart valve replacement, but it does not increase postoperative blood transfusion.In the study of patients with initial CABG, it was found that compared with placebo, EACA can not only reduce postoperative bleeding and blood transfusion, but also has no allergic reaction, and does not increase strokeCognitive dysfunction、Renal insufficiency、myocardial infarction、ThrombosisAnd bridge occlusion.Compared with aprotinin, EACA has no significant difference in inhibiting the activation of fibrinolytic system and reducing postoperative bleeding.
In OPCABG related studies, it is found that although EACA can inhibit postoperativeHyperfibrinolysisHowever, it does not reduce the amount of postoperative bleeding.In conclusion, most studies believe that EACA is similar to or slightly weaker than aprotinin in reducing postoperative bleeding and blood transfusion, and there is no significant statistical difference in clinical results.
AMCA is a kind of lysine analogues antifibrinolytic drug widely used in clinic, and its action intensity is 5-10 times that of EACA.It was synthesized in 1964 and first used in CPB cardiac surgery in 1988.In addition to reversibly binding to the lysine binding site on plasminogen to inhibit the conversion of plasminogen to plasmin, AMCA can also reduce bleeding by preventing platelet activation induced by plasmin.The dosage of AMCA varies from 10 to 20g, and the increase of the dosage cannot further reduce the postoperative bleeding.It is generally believed that preventive application of AMCA before CPB can effectively reduce the number of patients undergoing cardiac surgeryPerioperative periodThe need for bleeding and allogeneic blood can reduce postoperative complications and improve the prognosis.However, the results of various studies are different as to whether the reoperation rate caused by bleeding can be reduced.The relationship between the administration time of AMCA and the beginning of CPB will affect its effect.In a randomized double-blind study of CABG patients, the same dose of AMCA was given before CPB or after CPB, and compared with placebo. The results showed that after CPB, AMCA did not significantly reduce postoperative bleeding and the need for allogeneic blood transfusion, and its clinical effect was limited.Mangano et al. conducted a comparative study on the effect of anti fibrinolytic drugs in cardiac surgery, which showed that AMCA was effective in preventing heart diseasePerioperative periodThe effect of blood loss is similar to aprotinin, but the risk of adverse reactions and end organ damage is lower than that of aprotinin. The safety of aprotinin is questioned, and AMCA is recommended to replace aprotinin as a drug to prevent blood loss in cardiac surgery.
Further research shows thatAortic valveFor patients with AVR, AMCA is no different from aprotinin in reducing blood transfusion, while for patients with CABG, AMCA is slightly inferior to aprotinin, so it is believed that AMCA is effective for patients withHigh blood transfusion riskThe effect of the operation is limited.Aprotinin is superior to AMCA in the protection of platelet function.However, some studies have shown that AMCA has no difference with aprotinin in protecting platelet function after CPB.This may be related to the evaluation of platelet function by different methods.The study on the risk of using anti fibrinolytic drugs in cardiac surgery shows that the proportion of epileptic seizures in patients undergoing initial valve surgery and high-risk surgery after using AMCA is significantly higher than that of patients using aprotinin.At the same time, patients with persistent atrial fibrillation andRenal failureThe incidence of TNF was also higher in aprotinin group than in aprotinin group.However, in the group of patients who performed initial CABG, it was found that patients who used aprotininacute myocardial infarction andRenal insufficiencyThe incidence of aprotinin is higher than that of AMCA group. In addition, the 1-year mortality rate of patients undergoing high-risk surgery is also significantly higher in aprotinin group than that of AMCA group. Therefore, it is suggested that aprotinin should be avoided in CABG and patients undergoing high-risk surgery, and AMCA should be avoided in patients undergoing valve surgery.Studies in OPCABG patients also found that AMCA can reduce postoperative bleeding and the use of blood products.
The adverse reactions of AMCA are rare, mainly including nausea, diarrhea, and occasionally ankylosis.In clinical application, it is not found that the use of AMCA will increase the probability of thrombosis.
It was synthesized in 1963. Because AMCA with stronger effect was synthesized in 1964.There are few reports on the application of PAMBA abroad. Some domestic studies show that PAMBA can inhibit the activation of fibrinolytic system in CPB, protect platelet function, reduce postoperative bleeding, and have no adverse reactions.
The study found that the prophylactic application of high dose aprotinin PAMBA (20 mg/kg) in cardiac surgery can partially inhibit the hyperfibrinolysis in CPB.Both of them have similar effects on anti fibrinolysis and reducing the amount of bleeding during the first operation.The research on the protective effect of PAMBA on platelet function in CPB shows that,Hemostatic aromatic acidSimilar to aprotinin in protecting platelets and preventing their activation in CPB, there was no significant difference in the amount of postoperative bleeding.
Risk of using antifibrinolytic drugs and future research prospects
It is easy to occur when the fibrinolytic system is inhibited by anti fibrinolytic drugsThromboembolism, especially for those who exist in themselvesArteriosclerosisPatients with underlying diseases who need cardiac surgery.Aprotinin has been banned from clinical use because it can lead to increased incidence of adverse events such as severe renal failure, myocardial infarction or heart failure, stroke and so on.However, lysine analogues are synthetic anti fibrinolytic drugs. Because of their simple structure, no obvious adverse reactions, and will not affect the ACT determination, there are fewThrombosisAccording to the relevant reports of, it can be used as an alternative drug for blood protection in cardiac surgery after stopping aprotinin.
However, it cannot be ignored that the application of lysine analogues in the prevention of perioperative blood loss is not as extensive as aprotinin, and the number and frequency of samples involved in scientific evaluation is much less than aprotinin, so we cannot trust its safety too much.Moreover, the efficacy of lysine analogues in preventing perioperative blood loss is not as certain as aprotinin.Therefore, in future research, it is necessary to further evaluate its safety and effectiveness, especially in high-risk surgery.In addition, as a broad-spectrum serine protease inhibitor, aprotinin not only has the effect of reducing bleeding, but also has anti-inflammatory, myocardial protection and lung protection functions. Whether lysine analogues also have the above effects needs further confirmation.
Antifibrinolytic drugs have a certain role in reducing perioperative bleeding and blood transfusion during surgery, but because of their own nature, it is also inevitable to bringThromboembolismAnd the risk of damage to heart, brain, kidney and other important organs.Therefore, it is necessary to weigh the advantages and disadvantages of such drugs in clinical use, especially in patients with thromboembolism risk.
