hereditary fibrinogen deficiency
Introduction
Introduction to hereditary fibrinogen deficiency Hereditary fibrinogen deficiency includes fibrinogenemia and hypofibrinogenemia. Hereditary afibrinogenemia is a very rare disease that has been found in about 150 cases since the first case report in 1920. Hereditary hypofibrinogenemia was first reported in 1935. Currently, about 40 cases have been reported in the literature. However, many so-called hypofibrinogenemias are actually abnormal fibrinogenemia with reduced circulating fibrinogen. basic knowledge The proportion of illness: 0.0003% Susceptible people: no special people Mode of infection: non-infectious Complications: intracranial hemorrhage
Cause
Cause of hereditary fibrinogen deficiency
(1) Causes of the disease
Mostly autosomal recessive or dominant hereditary fibrinogen deficiency.
(two) pathogenesis
Fibrinogen is a macromolecular glycoprotein containing 2964 amino acids with a molecular weight of 340,000. A symmetric dimer composed of A, B, 3 polypeptide chains linked by interchain disulfide bonds, ie, ACys28, Cys8 and Cys9. (Aa, B, ) 2, (A, B, ). In addition, a disulfide bond composed of ACys36 in a monomer and another monomer, CC65, also plays a key role in forming a dimer molecule.
A, B 3 polypeptide chains synthesize their precursor proteins (including 19, 30, 26 signal peptides) in the liver by independent polyribosomes, excision of signal peptides in the rough endoplasmic reticulum, hydrophobic reaction and disulfide After the bond formation and the like, it is folded, assembled into a mature dimer molecule, and finally glycosylated, and partially phosphorylated and secreted extracellularly.
In the mature fibrinogen dimer molecule, the central region (E region) consists of the amino terminus of six polypeptide chains, forming a disulfide bond (DSK); the two peripheral regions (D region) are composed of B chains and The carboxyl terminal of the chain is composed, and the carboxyl end of the A chain is folded back to participate in the structure of the E region. The E region and the D region are connected by a banded structure (coiled-coil region), and the coiled-coil region is formed by A, B, and 3 chains. The alpha-helical structure consists of approximately 110 amino acid residues, and the disulfide bond at both ends of the coiled-coil region is critical for the formation of the mature dimeric structure of the fibrinogen molecule.
In the coagulation common pathway, thrombin first cleaves fibrinogen, two A chain amino terminisArgl6-Gly17 releases a pair of fibrin peptide A (FPA), forming fibrin monomer I (FMI); re-cracking fibrinogen 2 The B chain amino terminus Arg14-Gly15 releases a pair of fibrin peptide B (FPB) to form fibrin monomer II (FM2), at which time the molecular structure of fibrinogen is changed from (A, B, )2 ( ,,)2, exposing the polymerization site of fibrin monomer, forming an unstable soluble fibrin monomer (SFM) through the non-covalent bonding of the ED region, the DD region and the edge-edge, in the activation Under the action of coagulation factor XIII (FXIIIa) and Ca2, fibrin monomers (SFM) cross-link each other to form stable soluble fibrin, and the formation of blood is surrounded by it to form a firm hemostatic thrombus.
Fibrinogen also has a site that binds to the platelet membrane glycoprotein GPIIb-IIIa, thereby mediating platelet aggregation and synergistically functions as a hemostatic effect.
The fibrinogen A, B, 3 polypeptide chains are encoded by three independent genes FGA, FGB, FGG, respectively, concentrated in the region of 4q28~4q31 about 50 kb, and the order of the three genes from 5' to 3' is The FGG, FGA, FGB, and FGA genes are 5.4 kb in length. Under physiological conditions, two different transcripts can be generated due to different splicing at the 3' end: 98% to 99% of the population is spliced into 5 exons, and 1 %~2% can produce E transcripts of 6 exons. The FGB gene is 8.2 kb in length, with 8 exons and arranged in reverse order. The FGG gene is 8.4 kb in length and has 10 exons.
When fibrinogen is reduced and dysfunctional, fibrinogen genes are present, but fibrinogen synthesis, secretion or intracellular treatment of the final product are abnormal, when the newly synthesized fibrinogen is not normally secreted. The retention in the rough endoplasmic reticulum of hepatocytes may lead to liver disease.
Exclusion of the mouse A chain gene in animal experiments can result in the deletion of all three strands of fibrinogen. There is no obvious abnormality in the embryonic development of the knockout mice, but there are 1/3 of the mice at birth. Significant bleeding occurred. The main bleeding site included abdominal cavity, skin and joint cavity. Because bleeding occurred at birth, it can be controlled. Therefore, although there are repeated bleeding, most mice can live to adulthood, but females are small. The rat was unable to perform normal pregnancy.
In true hypofibrinogenemia, the patient's two alleles of fibrinogen are normal. In contrast, the two genes without fibrinogenemia are heterozygous, one normal, and the other Abnormalities, whether fibrinogenemia or hypofibrinogenemia, fibrinolysis system and other coagulation pathways are completely normal, there should be no activation in the body to activate the blood coagulation mechanism, fibrinogen consumption or degradation In addition, the three independent genes , and contained in the fibrinogen gene located on chromosome 4 are present in patients without fibrinogenemia, leading to the molecular mechanism of fibrinogen-free. It is not entirely clear that fibrinogenemia is an autosomal recessive hereditary disease, and many cases are caused by close relatives.
The most common gene mutation leading to fibrinogenemia is the splicing mutation of the FGA gene IVS4+1G>T, that is, the first base G of the FGA gene intron 4 is replaced by T, thereby changing the intron 4 The conserved sequence of the 5' splice junction affects its binding to U1snRNP, which ultimately leads to abnormal splicing of the FGA gene. Shanghai Institute of Hematology, Shanghai Ruijin Hospital found a family of hereditary afibrinemia, FgFGA gene of the paternal family. At the junction of sub-intron 3, AGTA or GTAA is deleted, and the other members of the maternal family are missing. The proband is a complex heterozygote of these two mutations.
The relationship between genotype and phenotype of fibrinogen-free is not certain. Generally, the more fibrinogen gene is truncated, the lower the fibrinogen level, resulting in low or no fibrinogenemia, but the same Genotypes can also produce different phenotypes. In general, in some patients with fibrinogenemia, although some screening tests, such as APTT, have obvious abnormal bleeding time, clinical manifestations of bleeding are not serious. This phenomenon is consistent with the phenomenon observed in fibrinogen knockout mice, but there is no significant increase in the probability of miscarriage in pregnant women without fibrinogenemia in the clinic, and even thrombosis in some patients. The mechanism may be related to abnormal aggregation of intravascular platelets.
Prevention
Hereditary fibrinogen deficiency prevention
1. Placental rupture and postpartum hemorrhage can also be observed in these women. If no alternative treatment is given, most women with no fibrinogenemia will have premature birth, and some may be in the first trimester (the first 3). Abortion occurs in the month, and fibrinogen supplementation may have a certain preventive effect.
2. Heparin can be used to prevent the occurrence of blood clots.
Complication
Hereditary fibrinogen deficiency complications Complications intracranial hemorrhage rupture
The main cause of death is concurrent intracranial hemorrhage in infants and young children. Hemorrhage can occur in any part of the child, sometimes bleeding is fatal, and patients with hereditary fibrinogenemia have a risk of spontaneous spleen rupture. .
Symptom
Hereditary fibrinogen deficiency symptoms Common symptoms Coagulation factor function disorder Coagulopathy internal bleeding
Although the blood of patients without fibrinogenemia does not normally coagulate, but bleeding rarely occurs, and fatal bleeding may occur in patients with reduced fibrinogenemia, but in many cases, It is much lighter than hemophilia, and no fibrinogenemia is diagnosed in the infancy due to bleeding in the umbilical cord root. Clinical manifestations include gastrointestinal bleeding and mucosal bleeding, such as excessive menstrual bleeding.
Although 20% of patients with fibrinogenemia have had joint bleeding, the severity and consequences are not as good as those of hemophilia patients. The probability of developing thrombotic disease in patients receiving fibrinogen replacement therapy is higher than that of normal people. The mechanism is still unclear. Unless fibrinogen levels are below 50 mg/dl, patients with hypofibrinogenemia generally do not develop spontaneous blood. These patients may actually be patients with low abnormal fibrinogenemia. .
Examine
Examination of hereditary fibrinogen deficiency
1. Prothrombin time (PT), activated partial thromboplastin time (APTT) and clotting time are prolonged, and abnormalities in these tests can be corrected by the addition of normal plasma.
2. The specific detection of circulating fibrinogen antigen in plasma is a specific examination of fibrinogen-free.
3. The absence of fibrinogen in platelets is also a specific test for fibrinogen-free.
4. Peripheral blood In most cases, the number of platelets will not be lower than 100 × 109 / L, white blood cells, red blood cells, hemoglobin is normal.
5. Poor platelet aggregation.
6. The bleeding time is prolonged.
Patients with fibrinogenemia with hypersensitivity to the skin do not develop induration because their subsequent reactions require the accumulation of subcutaneous fibrinogen, so they only show skin erythema under the action of allergens, in real In patients with low fibrinogen, plasma fibrinogen levels are about half normal, but lower levels of expression can be observed in some patients.
Diagnosis
Diagnosis and identification of hereditary fibrinogen deficiency
diagnosis
Based on a positive family history, clinical performance can be diagnosed in conjunction with laboratory tests.
Differential diagnosis
Hereditary fibrinogen deficiency should be carefully identified with acquired fibrinogen deficiency, which is more common in liver disease or disseminated intravascular coagulation (DIC), because asparaginase can block liver synthesis of fibrinogen, so Fibrinogen may be reduced after the application of asparaginase, and patients with aplastic anemia are also prone to hypofibrinogenemia in patients receiving antithymocyte globulin (ATG) and glucocorticoids.
