Primary fibrinolysis

Introduction to primary fibrinolysis Primary fibrinolysis (primary fibrinolysis), also known as primary fibrinolysis, is due to an abnormal increase in fibrinolytic system activity, leading to premature, excessive destruction of fibrin and/or extensive degradation of coagulation factors such as fibrinogen, and Bleeding is a type of fibrinolytic hyperactivity (fibrosis). basic knowledge The proportion of illness: 0.002% Susceptible people: no special people Mode of infection: non-infectious Complications: intracranial hemorrhage, blood in the stool, hematuria

Cause of primary fibrinolysis

(1) Causes of the disease

In theory, the main difference between primary fibrinolysis and secondary fibrinolysis is that the former only produces a large amount of plasmin, mostly due to increased plasminogen activator, while the latter is produced in large amounts of thrombin. On the basis of the formation of fibrinolytic enzymes, in fact, the true meaning of primary fibrinolysis is very rare, the primary fibrinolysis can be divided into congenital and acquired two, clinically the majority.

1. Congenital 2 anti-plasmin (2AP) lacks a rare autosomal recessive hemorrhagic disease. Since the first report in 1989, only 10 cases have been reported, due to normal platelet function and blood coagulation test. Physicians rarely think of this disease, and homozygous patients are often completely deficient in 2AP antigen and activity.

2. There are only a few reports of congenital plasminogen activator inhibitor-1 (PAI-1) deficiency, which can be summarized into the following types:

(1) PAI-1 antigen level is normal but lacks activity: In 1989, Sehleef et al reported the first 76-year-old male patient who suffered repeated trauma and postoperative bleeding during his lifetime. His mother had postpartum hemorrhage and routine coagulation tests (including Fibrinogen concentration is normal, but euglobulin lysis time is shortened, serum PAI-1 antigen level is normal, activity is reduced, and tissue plasminogen activator (t-PA) bound to PAI-1 in whole blood and serum Reduced, serum plasminogen and 2AP levels are low, this case is the only case of reported normal PAI-1 antigen level but functional defects.

(2) Lack of PAI-1 antigen and activity: In 1992, Fay et al reported a case of a 9-year-old girl who had repeated minor trauma and postoperative bleeding at the age of 3, and her grandfather and grandfather had similar experiences, coagulation and platelet function. Normal, 2AP level is normal, plasma t-PA antigen level is normal, PAI-1 antigen and activity in plasma and platelets are not detected, DNA sequence analysis shows TA insertion at the 3' end of exon 4, so that it appears early The termination code and abnormality of the gene structure make the RNA extremely unstable. Compared with the wild type PAI-1, the synthesized protein molecule has 169 amino acids deleted at the C-terminus, including the active center arginine 346-methionine 347, and the patient is homozygous. Four of his parents and six siblings were heterozygous, but none of them showed bleeding.

(3) PAI-1 antigen and activity in plasma is absent, but PAI-1 antigen and activity in platelets are normal or partially lacking Dieval et al. In 1991, a 36-year-old patient was reported. Repeated minor trauma and postoperative bleeding from childhood, given amino Caproic acid can correct bleeding, coagulation and platelet function tests are normal, only fibrinogen levels are low, euglobulin lysis time is shortened, plasminogen, 2AP and D-dimer levels are normal, plasmin-2AP complex Negative, t-PA antigen levels are normal but activity is elevated, and almost all t-PA is in free form, rarely forming a complex with PAI-1, PAI-1 antigen and its activity are not detected in plasma, but in platelets The PAI-1 antigen and activity are normal, and PAI-1 can be released when platelets aggregate. The study suggests that PAI-1 in plasma and platelets have different characteristics, and PAI-1 in platelets alone is insufficient to maintain normal hemostasis. A small amount of highly active PAI-1 in plasma is necessary for normal hemostasis. In 1993, Lee et al reported a case of 63-year-old man who had repeated episodes of hemorrhage and delayed bleeding from the time of childhood. All routine coagulation tests were normal except DIC, 2AP deficiency Or abnormal fibrinogenemia, the patient's plasma PAI-1 antigen and activity are lacking, the level of PAI-1 antigen and activity in platelets is about 1/2 of normal, low concentration of PAI-1 in plasma is not enough Neutralization of t-PA in the blood circulation caused normal but increased activity of t-PA antigen, leading to hyperfibrinolysis. Investigation of 7 members of the patient's family indicated that PAI-1 deficiency was autosomal inherited.

3. Increased congenital plasminogen activator There is no report of elevated congenital u-PA levels. Congenital t-PA levels are rare, and the genetic type is unclear. Booth et al. reported a male patient in 1983. He suffered serious bleeding after surgery such as minor trauma and tooth extraction, and eventually died of spontaneous intracranial hemorrhage at the age of 46. The patient's clotting factor and platelet function were normal.

4. Thrombolytic therapy If t-PA, urokinase or streptokinase excess can cause bleeding complications, this is due to the excessive production of fibrinogen in the plasmin degradation cycle causing primary fibrinolysis.

Severe liver disease (35%):

It is the most common cause of primary fibrinolysis. In severe liver disease, especially when it develops into cirrhosis, some fibrinolytic related proteins, such as plasminogen and 2AP, can be significantly reduced, which may be due to protein synthesis. In addition, under normal conditions, the liver can remove t-PA, u-PA and t-PA-PAI-1 complexes. In cirrhosis, plasma t-PA and u-PA levels are caused by impaired clearance. Elevated, PAI-1 levels are lowered, which may partly explain why plasminogen is reduced in cirrhosis but fibrinolysis is enhanced.

Tumor (20%):

Adenocarcinoma (especially prostate cancer, pancreatic cancer), acute promyelocytic leukemia (APL) and other tumor cells can release plasminogen activator, of which u-PA is common, this spontaneous fibrinolysis of tumor cells The activity can promote primary fibrinolysis, produce a large amount of plasmin, consume 2AP, and detect plasmin 2AP complex in the circulation.

Surgery and trauma (15%):

Prostate, pancreas, uterus, ovary, placenta, lung, thyroid and other tissues contain abundant t-PA. When tumors occur in these organs, trauma or surgery, fibrinolysis is induced by the release of t-PA into the blood. Urogenital Trauma and surgery can cause fibrinolysis due to the release of u-PA into the blood. Some venoms have direct activation of fibrinolysis, or have proteolytic activity, which can change fibrinogen by degrading fibrinogen and lowering 2AP levels. Systemic activity, when subjected to a bite, can quickly appear severe bleeding.

Other (10%):

Amniotic fluid has strong procoagulant and fibrinolytic activity. In amniotic fluid embolism, hemorrhage can be caused by fibrinolysis. It is said that extracorporeal circulation can induce primary fibrinolysis. The mechanism is unknown, and may be extracorporeal circulation. Equipment, abnormal blood vessel surface and accelerated blood flow activate the fibrinolytic system, hypotension and shock caused by various reasons, blood stasis and tissue hypoxia can promote the release of t-PA from endothelial cells, which also leads to fibrinolysis. possible reason.

(two) pathogenesis

Due to the loss of 2AP inhibition, the activity of plasmin in the body is abnormally increased, and the hemostatic thrombus dissolves prematurely, leading to bleeding tendency. Once bleeding, it is often heavier, mostly traumatic or bleeding several hours after surgery, spontaneously from blood, heterozygous patients Most of them are asymptomatic or only mildly hemorrhagic, and there are reports of abnormalities of 2AP molecules, that is, the antigenic level of 2AP in plasma is normal, but its activity of inhibiting plasmin is significantly reduced. Molecular biological studies have shown that this is a genetic mutation that makes the activity from 2AP. One alanine was inserted into the 10 amino acid residues at the N-terminal of the center, so that 2AP no longer has anti-plasmin activity, and instead becomes a substrate for plasmin. The clinical manifestations are prone to skin bruising and prolonged postoperative bleeding. .

The plasminogen activator in the blood is significantly elevated. This activator is similar to t-PA both physiologically and immunologically. Although no free plasmin is detected in the blood, fibrinolysis can always be detected in the blood. Enzyme-2AP complex, plasma PAI-1 antigen level is normal, but limited to the current technology, PAI-1 activity is not measured, the patient's circulating blood continues to have fibrin or fibrinogen dissolution, its whole blood clot Dissolved within 6h, fibrinogen levels decreased, fibrinogen-associated antigen levels continued to increase significantly, and when t-PA was abnormally elevated, fibrin premature dissolution and fibrinogen degradation due to massive formation of plasmin Causes bleeding.

Most scholars believe that APL bleeding is mainly caused by DIC and secondary fibrinolysis, but some authors have shown that although APL patients have severe hemorrhage, there is no definite evidence of thrombin formation and massive consumption of coagulation factors such as fibrinogen. They believe that although leukemia cells can release substances with procoagulant activity, intravascular coagulation is not serious, so the consumption of coagulation factors such as fibrinogen does not become the direct cause of bleeding. On the contrary, patients have obvious systemic fibers. The laboratory evidence of dissolution, in addition, unlike DIC secondary fibrinolysis, the formation of plasmin in APL patients is mostly related to u-PA, while the former is mostly due to endothelial cell damage, a large amount of t-PA released into the blood. In addition to the release of u-PA, APL promyelocytic cells release leukocyte elastase that inactivates 2AP.

Primary fibrinolysis prevention

Actively control the primary disease and reduce the predisposing factors. Pay attention to rest, work and rest.

Primary fibrinolysis complications Complications, intracranial hemorrhage, hematuria

No complications.

Symptoms of primary fibrinolysis Common symptoms Abnormal uterine bleeding Hemorrhoids Hemorrhoids Bleeding Hemorrhage Skin bleeds After tooth extraction Hemorrhage is not hemorrhagic hemoptysis Blood vaginal bleeding Internal bleeding

Mainly for hemorrhage, mostly spontaneous or minor traumatic hemorrhage in the whole body. It is characterized by skin stagnation and large ecchymosis. The puncture site, surgical wound and tooth oozing after tooth extraction are often accompanied by mucosal bleeding. Nose bleeding, bleeding gums, severe cases may have visceral bleeding, such as: hematemesis, blood in the stool, hemoptysis, hematuria, vaginal bleeding, and even intracranial hemorrhage.

In addition to the bleeding performance, patients with acquired primary fibrinolysis have the corresponding clinical manifestations of the primary disease. Patients with congenital primary fibrinolysis often have repeated traumatic or postoperative bleeding. The patient had a family history of abnormal bleeding.

Examination of primary fibrinolysis

1. Common screening test for fibrinolytic

(1) Whole blood clot dissolution time: The simplest test for detecting the enhancement of fibrinolytic activity. Under normal circumstances, the blood clot can shrink within 48 hours at 37 ° C, but there is no signs of dissolution, if blood clots within 8 hours The presence of lysis indicates an increase in systemic fibrinolytic activity, but this method does not distinguish fibrinolysis because of the high levels of plasminogen activator or free plasmin in plasma.

(2) euglobulin clot dissolution time: euglobulin contains fibrinogen, plasminogen, plasminogen activator and other active components of the fibrinolytic system, containing only a small amount of PAI-1, basically does not produce inhibition Function, under normal circumstances, the dissolution time of euglobulin clot is >90min, and the fibrinolysis can be shortened significantly. If a low concentration of aminocaproic acid is added to the assay, it can inhibit the plasminogen activator, but does not inhibit the free Plasmin, therefore, if the shortening of the dissolution time of the euglobulin clot is corrected after the addition of aminocaproic acid, it indicates that the fibrinolysis may be caused by an increase in plasminogen activator. If it cannot be corrected, it suggests free plasmin. increase.

(3) Fibrin plate dissolution test: The test plasma is added to the fibrin plate, and after incubation, the area where the fibrin plate is dissolved is observed, and compared with the normal human plasma, it can be judged whether or not there is fibrinolysis, if in the fiber The addition or absence of plasminogen in the protein plate can also distinguish whether fibrinolysis is caused by an increase in plasminogen activator or an increase in free plasmin. In addition, the heated fibrin plate can also be used to identify The principle is that the plasminogen activator is not heat resistant.

The advantages of the above three tests are that the operation is simple, and it is possible to indicate whether there is systemic fibrinolysis in a few hours. The latter two methods can be improved to determine whether the plasminogen activator is increased or the free plasmin is increased. However, none of the three methods can be confirmed to be primary or secondary fibrinolysis.

2. Laboratory tests reflecting plasmin production

(1) Determination of plasmin: It is difficult to detect free plasmin in circulating blood. Only in some cases, such as amniotic fluid embolism, when a large dose of plasminogen activator is injected, it is produced in a short time. The plasmin can exceed the inhibition ability of 2AP in the circulation to detect free plasmin.

(2) Determination of plasminogen: When active plasmin is produced in the body, plasma plasminogen levels are significantly reduced.

(3) Determination of plasmin 2AP complex: 2AP is the main plasmin inhibitor, which can rapidly form a complex with plasmin produced in the blood circulation. Under normal circumstances, there is only a trace amount of plasmin 2AP in the circulation. Compounds, if significantly increased, are strong evidence of plasmin production.

(4) Determination of 2AP: When a large amount of plasmin is produced in the body, 2AP in plasma is reduced due to consumption. At this time, it is necessary to exclude the presence or absence of 2AP synthesis, which is important for the diagnosis of congenital 2AP, if the synthesis function is normal. When the fibrinolysis episode stops or the plasminogen activator is stopped, 2AP can rapidly rise to normal within 48 hours.

(5) Determination of fibrin (original) degradation products (FDP): FDP; is a product of fibrinolytic degradation of fibrin and/or fibrinogen. Therefore, an increase in FDP indicates the formation of a new fibrinolytic enzyme. Easy to do, but can not distinguish between fibrinogen degradation products and fibrin degradation products.

3. Determination of plasminogen activator and plasminogen activator inhibitors, including the determination of antigens and activities such as t-PA, u-PA and PAI-1, is particularly important for the diagnosis of congenital fibrinolysis.

4. Other examinations of thrombin time (TT), prothrombin time (PT) and activated partial thromboplastin time (aPTT) can be extended because plasmin can degrade fibrinogen, factor V and factor VIII, etc. Coagulation factor, in addition, FDP has anticoagulant effect.

According to the condition, clinical manifestations, symptoms, signs, choose to do blood, urine routine, ECG, B-ultrasound, X-ray, CT, MRI biochemistry and other tests.

Diagnosis and identification of primary fibrinolysis

diagnosis

The diagnosis of primary fibrinolysis requires a comprehensive analysis of clinical manifestations and laboratory tests. First, it should be determined whether there is hyperfibrinolysis and then determine whether it is primary fibrinolysis.

Primary fibrinolysis and fibrinolysis secondary to DIC have similar clinical manifestations. Because the laboratory indicators are not clear, the clinical diagnosis rate is limited. It is generally believed that the so-called primary fibrinolysis is based on the absence of thrombin. In terms of fibrinolysis, its laboratory indicators still lack biochemical evidence. Generally, platelet counts, protamine paracoagulation test and anticoagulase III levels are normal, indicating that plasma plasmin is not increased. Because of thrombin activity, it is different from DIC secondary fibrinolysis. The platelet count in the index is also related to the primary disease, not a specific index.

At present, the diagnosis of this disease is based on clinical manifestations, laboratory tests and laboratory-assisted examinations, comprehensive analysis, and now combined with relevant domestic and foreign literature, summarized as follows.

Clinical manifestation

1 There are basic diseases that are easy to cause primary fibrinolysis;

2 clinical bleeding symptoms, such as: nose, mouth, digestive tract, urinary tract bleeding; puncture site and / or surgical wounds bleeding.

2. Laboratory examination

1 fibrinogen content is significantly reduced;

2 euglobulin dissolution time is significantly shortened;

3 fibrin (original) degradation products increased;

4 plasma plasminogen decreased and plasmin activity increased;

52-anti-plasmin is reduced.

3. Laboratory auxiliary inspection

1 thrombin time, partial thromboplastin time, antithrombin III are normal;

2 fibrin peptide B1 ~ 42 increased;

3 euglobulin dissolution time induction test, such as: A. beam arm 10 ~ 12min, B. injection DDAVP (0.4g / kg), dissolved in 0.9% sodium chloride injection 50 ~ 100ml, intravenous bolus injection 10 ~ 12min C. Injecting adrenaline, one of the above methods, can induce the release of t-PA from local vascular endothelial cells, shortening the dissolution time of euglobulin, and increasing plasma t-PA antigen and living parts.

Differential diagnosis

The clinical manifestations of primary fibrinolysis and secondary fibrinolysis are very similar, and the causes are mostly the same. The identification of the two mainly depends on laboratory tests, but in clinical work, it is sometimes difficult to make identification, many so-called Primary fibrinolysis is actually secondary fibrinolysis induced by DIC.

In theory, primary fibrinolysis only has experimental evidence of plasmin production, while secondary fibrinolysis has both experimental evidence of thrombin and plasmin production. Therefore, primary fibrinolysis mainly reflects Tests for thrombin generation and clotting factor consumption should be normal, for example, due to the absence of pathogenic thrombin generation, theoretically, plasma 1+2 (degradation products of prothrombin activation) and fibrin peptide A ( The thrombin-degraded fibrinogen-producing fragment did not increase, and the level of antithrombin was normal; the protamine para-coagulation test was negative due to the absence of fibrin monomer formation; unless the liver disease was combined, the platelet count was normal, In addition, D-dimer is a fragment produced by fibrinolytic degradation of fibrin, which reflects the formation of thrombin and reflects the formation of plasmin. Therefore, D-dimer in primary fibrinolysis Should not increase.

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