Hemophilia B

Introduction to hemophilia B Hemophilia B (HB) is a hereditary disease with a genetic pattern and hemorrhagic performance similar to that of hemophilia A, and its pathogenesis is the lack of factor IX. basic knowledge The proportion of illness: 0.005% Susceptible people: no special people Mode of infection: non-infectious Complications: gastrointestinal bleeding

Hemophilia B cause

(1) Causes of the disease

Defects and molecular structural abnormalities of FIX are fundamental pathophysiological changes in hemophilia B.

1. Structure and function of FIX: Mature human FIX is a single-chain glycoprotein consisting of 415 amino acid residues (416 amino acids of bovine FIX) with a molecular weight of 55,000, of which about 20% are sugars, which are synthesized in hepatocytes. In the process of FIX modified secretion, releasing 28 amino acid signal peptide and 18 amino acid propeptide, FIX is one of vitamin K-dependent factors. Compared with other vitamin K-dependent factors, its amino acid sequence and functional structure are surprising. Similarity, starting from the N-terminus, FIX consists of four functional regions, the r-carboxyglutamic acid region (G1a region), the epidermal growth factor-like region (EGF region), the activating peptide region and the catalytic region.

There are 12 glutamic acid residues in the Gla region. In the presence of vitamin K, carboxylase acts as r-carboxyglutamic acid. FIX is linked to calcium ions and functions through the calcium bridge to the phospholipid surface. related.

EGF, the region including EGF1 and EGF2, has recently been considered to play an important role in the activation of FX, the activation peptide region contains 35 amino acid residues, namely alanine 146-arginine 180 peptide, in FXIa or FVIIa and tissue factor Under the action of the complex, FIX is cleaved at two sites of arginine 145-alanine 146 peptide bond and arginine 180-valine 181 peptide bond, releasing the above 35 amino acid acidic peptides, and FXa can also Lysis of these two sites, the resulting active FIX is called FIXa, forming the N-terminal tyrosine 1-arginine 145 light chain and the C-terminal proline 181-threonine 415 heavy chain, light chain The heavy chain is linked by a disulfide bond at cysteine 132-cysteine 289.

There is another non-physiological activation pathway in FIX. Russell snake venom protein only cleaves the above second site, does not release peptides, and also has biological activity, called FIX, so the cleavage of the second site is essential for FIX activation. Only the first site cleavage is biologically inactive, and the catalytic region is equivalent to the heavy chain of FIXa. It has a catalytic triad possessed by a typical serine protease. At the site of FIX, it is histidine 221, aspartic acid 269 and serine. At 365, activated Factor IX (FIX) activates FX in the presence of the cofactor FVIIIa, calcium ions and phospholipids.

2. FIX gene and gene defect: FIX gene is located at the long arm end of X chromosome (Xq27), gene length is 34kb, including 8 exons and 7 introns, its mRNA length is 2.8kb, gene defect of hemophilia B There have been many reports, including point mutations, framework shifts, deletions, insertions, and other abnormalities that cause changes in the structure and function of FIX proteins. More than 400 genetic defects have caused hemophilia B, distributed in various functional areas of FIX, 1 shows the number of different mutations known to each functional region of FIX before 1996. Table 2 lists some known mutations in the FIX gene, and about 30% of the mutations occur in the CPG dinucleotide sequence, including C. T,GA conversion, a molecule that often affects the dysfunction of arginine residues, can also generate a stop codon to form an unintentional mutation, and is of particular interest in a mutation that occurs in the 5' promoter region leading to FIX Leiden. Phenotype hemophilia FIX: C and FIX: Ag are very low at birth or early childhood, but gradually rise to more than 60% in late adolescence (Table 2). It is currently believed that mutations in some promoter regions disrupt transcription factors. Linkage, resulting in transcription down of the FIX gene After puberty, androgen can overcome transcriptional defects and maintain a certain level of FIX. Hemophilia B is characterized by normal prothrombin test (Prr) of rabbit brain thromboplastin and prolongation of bovine brain thromboplastin. The missense mutation affects the amino acid residues at 180, 181 and 182 of the FIX protein and several residues close to the active site region, resulting in a FIXBm variant with an abnormal reaction with bovine brain thromboplastin.

(two) pathogenesis

1. Anti-Factor IX antibody: Complete loss of Factor IX gene causes severe antigen-negative hemophilia B, which may cause Factor IX replacement therapy to produce anti-Factor IX antibody, but it is difficult to explain antibody completely by the complete loss of Factor IX gene. This is because not all such patients produce such reactions, and some patients with anti-Factor IX antibodies do not show all gene loss, such as a plasma containing anti-Factor IX antibody, the genetic test is still positive, so it can be considered factor IX The lack of genes is not the only factor that replaces the formation of therapeutic antibodies, and the mechanism remains to be elucidated.

2. Cross-reactant (CRM): Nearly one-third of patients with hemophilia B showed cross-reactive substance positive (CRM). The level of factor IX antibody was normal in these patients, and the activity of factor IX was decreased to some extent. There are functionally inactive or non-functional Factor IX molecules whose mechanism is a mutation that affects post-translational protein processing, -carboxylation, lipid binding, zymogen activation and recognition of substrates and enzyme activity, and a class of CRM In patients, the human brain extract was used as the plasma phase I prothrombin time, while the bovine brain extract was used as the plasma phase 1 prothrombin time. These hemophilia patients were referred to as BM type (M is the first patient) The last name of the letter), the mechanism may be that the mutation leads to the abnormal structure of the factor IX and the competitive inhibition of the action of the factor IX.

3. Gene mutations: 378 point mutations (including missense mutations and nonsense mutations) have been discovered so far, and several reports have emphasized that the CPG dinucleotide sequence is a mutation hotspot, and the CPG sequence consists of six It is composed of four of the arginine reproductive genotypes, which is an important cause of spontaneous point mutations. The CPG dinucleotides discovered so far encode 20 factor IX sequences with a mutation rate 150 times that of the original expected transfer rate. In a group of 51 single base pair substitutions, 27 cases were CPG dinucleotides. The phenotype of the above arginine genotype was located on the surface of Factor IX protein, which stabilized protein structure and arginine mutation. Significant reductions in additional amino acids, or arginine, affect protein function, resulting in decreased Factor IX activity.

4. Gene deletion: Factor IX Seattle-1 occurs in the endogenous loss of exons 5 and 6 in the gene, resulting in the factor IX protein being cleaved to a relative molecular mass of 36,000, excluded from the urine, factor IX Yemen and factor IX Tubingen There are deletions of exon 1 to 3, which cause different degrees of 5' deletion, Factor IX Hanover lacks exons 4 and 5, and Factor IX Strasboarg has a 2.8 kb including exon 4. Deletion, that is, unable to encode each EGF-like region, 30% of factor IX normal antigen can still appear severe hemophilia B phenotype, factor IX Seattle-2 has 1769 adenine nucleotide deletion, this deletion occurs At the frameshift, the translational reading frame is altered such that the deletion and subsequent portions are not translated, resulting in an inactive protein, and mutations at the junction of exons 6 and 3 cause improper linkage of the transcribed mRNA, translation If it is not possible, no Factor IX antigen is produced, and some missense mutations also cause a decrease in Factor IX activity, such as Factor IX London-8 (cys 336Arg).

5. Gene insertion: gene insertion can also cause hemophilia B. For example, hemophilia B Elsalvador inserts a 6.1 kb fragment near exon 4, resulting in only 1% of factor IX activity and 6% of antigen. The insertion of the 2 kb fragment occurring at the intron 6 and the deletion of the 1 kb fragment are called hemophilia B Sydney, and the peripheral blood is completely free of the factor IX antigen.

Hemophilia B prevention

1. As with hemophilia A, severe cases should be given alternative treatment before traumatic examination and traumatic treatment. Muscle exercise and preventive treatment have the same meaning for hemophilia B.

2. Activities that are severe or prone to injury, exercise and work should be avoided to reduce the risk of bleeding.

3. Establish genetic counseling, strict premarital examination, and strengthen prenatal diagnosis to reduce the birth of children with hemophilia.

Hemophilia B complications Complications, gastrointestinal bleeding

The most common comorbidities are urinary tract bleeding, gastrointestinal bleeding, and other areas of mucosal bleeding. Central nervous system bleeding is a fatal complication.

Symptoms of hemophilia B common symptoms bleeding after extraction is not limited to bleeding tendency abnormal uterine bleeding hematoma formation intra-articular bleeding

The clinical manifestations of hemophilia B are similar to those of hemophilia A, mainly due to complications caused by hemorrhage and hemorrhage, and complications caused by alternative treatment. Clinical manifestations cannot be differentiated from hemophilia A, the severity of bleeding tendency and FIX: C Horizontal correlation, repeated joint bleeding leading to chronic hemophilic joint disease and hematoma formation, is the characteristic clinical manifestations of bleeding, post-traumatic bleeding, tooth extraction bleeding and postoperative bleeding are common, and more serious, need alternative treatment to stop bleeding, blood The bleeding of You B is related to trauma, and there is also trauma during "spontaneous bleeding", but the trauma is not easy to attract attention.

According to the severity of bleeding and FIX: C level, it can be divided into heavy (FIX: C < 2%), medium (FIX: C2% ~ 5%), light (FIX: C 5% ~ 25%) and subclinical (FIX: t225% ~ 45%), there are also FIX: t25% ~ 40% divided into light and no subclinical type, should pay attention to FIX: C measurement error fluctuations, the classification must be combined with the severity of clinical manifestations, Heavy, intermediate and light, each accounted for 1/3 of hemophilia B.

Hemophilia B examination

The screening test used to diagnose hemophilia A is also applicable to hemophilia B, prolonged PTT, normal PT and TT, serum can correct prolonged PTT time, but barium sulfate (or aluminum hydroxide gel) can not correct plasma adsorption, Biggs TGT can be used to identify FIX deficiency. A small number of FIX:C levels above 35% may not be obvious or even normal. The Biggs TGT may still be abnormal, while the FIX:C measurement has diagnostic significance. The first-stage FIX:C measurement requires no FIX plasma is used as matrix plasma. FIX:Ag determination has value for further classification of hemophilia B. FIX:Ag is normal or slightly decreased, while FIX:C is significantly lower than cross-reactive substance positive type (CRM). Is a variant of hemophilia B, PT is normal in most cases of hemophilia B, but occasionally prolonged, variant hemophilia B Bm with bovine brain thromboplastin for PT test PPT prolonged, due to Rabbit brain-derived thromboplastin for PT test can miss the hemophilia B Bm variant.

According to the condition, clinical manifestations, symptoms, signs, choose B-ultrasound, electrocardiogram, X-ray, CT, MRI, hematuria, routine liver and kidney function and biochemical examination.

Hemophilia B diagnosis and identification

diagnosis

According to medical history, family history and laboratory examination, the diagnosis of typical cases is not difficult. The FIX:C measurement has diagnostic significance. Some mild cases or subclinical cases are easily missed because of no obvious history of bleeding, often in trauma, abnormalities after extraction and surgery. Hemorrhage is diagnosed.

Differential diagnosis

1. First, it should be differentiated from hemophilia A: Both have the same genetic type and bleeding symptoms, but laboratory tests are easy to identify.

2. Other bleeding disorders such as von Willebrand disease and other coagulation factor deficiencies can be identified based on clinical characteristics, genetic type, and laboratory tests.

3. Hemophilia B also needs to be differentiated from acquired vitamin K-dependent factors. Liver disease, dicoumarins, and long-term use of antibiotics can cause vitamin K deficiency, but in these cases there are generally multiple vitamin K-dependent factors instead of FIX deficiency is rare, and acquired FIX inhibitors that occur in non-hemophilia are very rare.

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