Hereditary factor XI deficiency

Introduction to hereditary coagulation factor XI deficiency Hereditary factor XI deficiency is autosomal recessive, and FXI reduction can cause bleeding, but the severity of bleeding is not completely proportional to FXI levels. Hereditary coagulation factor XI deficiency was first described in the early 1950s by Rosenthal et al. Deficient cases of hereditary coagulation factor XI (FXI). Since hemophilia A and hemophilia B have just been named shortly, Rosenthal named the case he found hemophilia C. However, the disease has now been officially named "coagulation factor XI deficiency." basic knowledge The proportion of illness: 0.0002% Susceptible people: no special people Mode of infection: non-infectious Complications: edema, muscle atrophy

Hereditary factor XI deficiency etiology

(1) Causes of the disease

Autosomal recessive inheritance, lack of factor XI.

(two) pathogenesis

Coagulation factor XI (formerly known as "plasma thromboplastin precursor"), consisting of homodimers, has a molecular weight of 12,500 to 16,000, is synthesized in the liver, but is not dependent on vitamin K, FXI and high molecular weight rejuvenation (HMWK), a skin-releasing enzyme (PK) and FXI together form a so-called contact factor.

The gene encoding FXI is located on the long arm of chromosome 4 (4q35), which is 23 kb in length and contains 15 exons and 14 introns (A to N). The exon 1 is encoded as a 5' untranslated region. The exon 2 is encoded as a 18 amino acid signal peptide, and the exon 3 to exon 10 encodes a spherical domain formed by four 90 or 91 amino acid tandem repeats of the mature protein at the amino terminus ( Apple domain), in which every 2 exons encode a sequential repeat, each of which has six conserved sarcosines (Cys) encoded in it, and the introns between them are in the four sequential The positions in the repeat are basically the same.

The mature FXI in the cycle is a homodimer composed of two subunits. The two monomers are connected by disulfide bonds. Each FXI subunit polypeptide chain contains 607 amino acids. Therefore, each FXI dimer The CCP contains 1214 amino acids. FXI is catalytically cleaved into activated FXI (FXIa) at Arg369 to Ile370. FXIa is composed of two light chains and two heavy chains. The heavy chain is partially derived from the amino terminus of the zymogen and binds to HMWK. Related to calcium-dependent FXI, the light chain portion is an enzymatically active site, homologous to the serine protease (trypsin) family, and four repetitive spherical domains in the FXI polypeptide chain, of which the first globular domain is In terms of HMWK binding, the second globular domain is involved in the formation of FXI dimers, and the fourth globular domain is involved in the binding of FXI.

The enzyme active center contains a serine protease domain. FXI has great structural homology with other serine proteases, such as fibrin. The amino acid sequence of FXI is highly homologous to the plasma-releasing zymogen in plasma. (58% identical), but the two functions are quite different.

In circulation, FXI is a complex that is non-covalently associated with a high molecular weight agonist, which is also associated with a skin-releasing zymogen. After contact with a negatively charged surface, FXIa cleaves FXI each single. The activation site on the chain activates FXI, and the light chain of FXIa contains the necessary groups for the catalytic group. However, the heavy chain is essential for both high molecular weight agonists and its substrate FIX, and FXIa is present in calcium ions. In the case of activated FIX, the FXI knockout mouse model, the mice can develop normally without a tendency to spontaneously erupt blood.

Since Asakai R et al. first reported three genetic mutations (type I, type II, type III) lacking hereditary factor XI in Ashkenazi Jews in 1989, at least 35 species have been found to be associated with hereditary coagulation factor XI deficiency. Gene mutations, 19 of which are missense mutations caused by point mutations, others are nonsense mutations (5 species), insertions or deletions of bases or nucleic acid fragments (5 species), and abnormal cleavage sites lead to abnormal mRNA cleavage ( 6 kinds).

In some races, some gene mutations have a higher frequency of occurrence. Type I, type II, type III and type IV mutations are the main molecular mechanisms of the hereditary factor XI deficiency in Ashkenazi Jews, and type II and type III mutations account for 49% to 52% and 36% to 47% of all mutations, the frequency of alleles of type II mutations in 531 Ashkenazi Jews was 0.0217, and the frequency of alleles of type III mutations was 0.0254, which occurred severely in Ashkenazi Jews. The probability of factor XI deficiency was 0.22%, and Cys38Arg accounted for a large proportion (8/12) in patients with hereditary factor XI deficiency in Basques, France. The frequency of this allele in the Basques population was 0.005, but No similar phenomena were observed in other races.

Usually, factor XI deficiency is caused by a decrease in the amount of FXI synthesis. Only a few cases are caused by abnormal FXI function. In the contact factor, only factor XI is deficient, bleeding tendency occurs, and there may be other regulation of hemostasis. Factors, therefore, FXI levels are not completely consistent with clinical bleeding performance, but patients with lower FXI levels may be more prone to bleeding, especially in areas with high fibrinolytic activity, such as oral cavity, urinary system, etc. Afterwards, bleeding is more likely to occur. The use of aspirin is also the cause of bleeding in some patients. Other mechanisms that activate FXI, such as FVIIa/TF complexes, may compensate for the effects of factor XI deficiency on the coagulation mechanism and the presence of FXI in platelets. Molecules may be another possible mechanism of compensation. Such FXI analogues may exist even in patients with complete FXI deficiency in certain plasmas. At present, it is not possible to speculate which patients with factor XI deficiency are more likely to develop bleeding. Shanghai Ruijin Hospital Shanghai Institute of Hematology applied APTT, FXI: C and FXI: Ag To diagnose a family of hereditary factor XI deficiency, PCR amplification of all exons and flanking intron sequences of FXI gene, and DNA sequencing, the result is a hybrid heterozygous type, and the second generation of its family Heterozygous type with single mutation, but no clinical symptoms. FXI gene exon 7 and exon 11 encode 228 and 383 amino acid bases. Mutation TGG TGA (Trp228stop) and TGG TAG (Trp383stop).

Hereditary coagulation factor XI deficiency prevention

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

Hereditary factor XI deficiency complications Complications, edema, muscle atrophy

The disease is mainly hemorrhage. For deep tissue hematoma can compress nearby blood vessels to cause tissue necrosis. Compression nerve can cause limb or local pain, numbness and muscle atrophy. Compression of blood vessels can cause ischemic necrosis or congestion and edema of the corresponding blood supply site. Bleeding at the bottom of the mouth, posterior pharyngeal wall, throat and neck can cause difficulty breathing or even suffocation. Patients may be unable to completely absorb blood due to repeated joint cavity hemorrhage, resulting in chronic inflammation, synovial thickening, fibrosis, cartilage degeneration and necrosis, eventually joint stiffness, deformity, peripheral muscle atrophy, resulting in limited normal activities.

Hereditary coagulation factor XI deficiency symptoms Common symptoms Coagulopathy skin ecchymosis after tooth extraction bleeding more than nose bleeding postpartum hemorrhage hematuria congenital X factor deficiency

The bleeding caused by factor XI deficiency is very mild, subcutaneous ecchymosis, nosebleeds, excessive menstrual blood, hematuria, postpartum hemorrhage and postpartum hemorrhage are the most common. Joint bleeding and intramuscular hemorrhage are very rare. It is worth noting that FXI activity reduces the severity of bleeding. Not fully relevant, some patients with reduced FXI will not undergo coagulopathy when undergoing surgery, but some patients may have severe postoperative bleeding, requiring a large number of alternative treatments, if one patient does not have excessive bleeding during subsequent surgery Phenomenon, then coagulopathy may not occur when undergoing surgery again. A study of clinical bleeding in patients with factor XI deficiency in the Iranian population found that FXI was less than 1% to 5% and FXI was less than 6% to 30%. There was no significant difference in the rate of severe bleeding such as muscle bleeding or joint bleeding (about 25%). The most common bleeding in factor XI deficiency was oral and postoperative bleeding, and about 50% of patients had bleeding. The mechanism of factor XI deficiency in patients with FXI activity and clinical manifestations is not yet clear, and the possible solutions are The method for detecting FXI activity based on the APTT assay in vitro does not reflect the true FXI hemostasis function in vivo. It is hypothesized that whether FXI and platelet intercropping (APTT experiments do not reveal this physiological process) is affected is the determinant factor XI deficiency. An important factor in the severity of clinical bleeding in patients.

Examination of hereditary coagulation factor XI deficiency

1. Activated partial thromboplastin time (APTT) is prolonged, while prothrombin time (PT) is normal, and prolonged APTT can be corrected for plasma fraction of strontium or aluminum salt adsorption.

2. The diagnosis of factor XI deficiency requires detection of FXI activity (FXI:C) and antigen (FXI:Ag) levels. Freezing and thawing can activate contact factors and significantly shorten the APTT deficiency of factor XI. Therefore, when performing related tests, it should be taken. Fresh plasma collected in plastic test tubes is used as a specimen. The reference range of FXI is 72% to 130%, the FXI level of homozygotes is less than 1% to 15%, and the level of heterozygous FXI is between 20% and 70%. According to the plasma FXI: C level, it is divided into severe deficiency (0% to 20% of normal level) and partial deficiency (30% to 70% of normal level). The FXI detection varies greatly among laboratories. Therefore, there is doubt. Cases should be tested repeatedly.

Diagnosis and identification of hereditary coagulation factor XI

Diagnosis is based on clinical bleeding symptoms, genetic type and laboratory tests, and the FXI:C assay or the Biggs thromboplastin assay can determine the diagnosis.

Factor XI deficiency must be differentiated from other normal PT, APTT prolonged mild hemorrhagic disease. The specific detection of FXI can be clearly diagnosed. Lupus anticoagulant can also have normal PT, ATTT prolongation, and factor XI deficiency. After mixing normal plasma and plasma to be tested, the former APTT prolongation cannot be corrected, the latter can return to normal, and cases of factor XI deficiency caused by autoantibodies have also been reported. Serious bleeding may occur in patients with FXI antibodies. .

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