Hereditary factor XIII deficiency
Introduction
Introduction to hereditary coagulation factor XIII deficiency Hereditary coagulation factor XIII deficiency is a rare recessive hereditary coagulation factor deficiency. In the plasma of patients with hereditary coagulation factor XIII deficiency, the activity and antigen of FXIII-A are usually undetectable, while the level of FXIII-B is decreased. However, it can still be detected. basic knowledge The proportion of sickness: 0.00001% Susceptible people: no special people Mode of infection: non-infectious Complications: edema
Cause
Hereditary factor XIII deficiency etiology
Causes:
Plasma factor XIII is a tetrameric glycoprotein consisting of two a subunits and two b subunits, namely a2b2, with a molecular weight of approximately 340 kD. The a-chain protein has an active site cysteine acting as amidase. The b-chain has no enzymatic action and has the function of a carrier protein. The thrombin cleaves the arginine 37-glycine 38 peptide bond of the a chain, and exposes the active site cysteine to activate the factor XIII, and the activated factor XIII ( XIIIa) is a transamidase that, under the participation of calcium ions, catalyzes the hydrogen bonding between fibrin monomers and multimers, and converts them into covalent bond amide bonds, ie, forms -glutamine- a lysine bond which increases the stability of the fibrin clot, and the factor XIIIa crosslinks through the A-chain of fibrin and inhibits the plasminogen attached to the cross-linked fibrin, to fibrinolysis Resistant, factor XIIIa also crosslinks 2-antiplasmin to fibrin, which also increases fibrinolysis resistance, a severe deficiency of factor XIII makes fibrin unstable and readily soluble, and attenuates inhibition of plasminogen and Cross-linking 2-antiplasmin to make blood clots The solution resistance weakened, causing bleeding, which is characterized by retardation occurs after trauma.
Factor XIII is not only present in plasma but also in platelets, megakaryocytes and mononuclear macrophages. Plasma factor XIII is a2b2 structure, while factor XII in the above cells has no b chain and the molecule has an a2 structure. The multi-phenotypic expression of factor XIII may be related to this distribution and the difference in molecular structure. Although the b chain is absent, the a2 factor XIII formed in the cell also has fibrin cross-linking, and the special function of factor XIII in the cell is still not clear. Understand that infusion therapy suggests its physiological function, bleeding symptoms stop after infusion, plasma factor XIII rises, but can not produce a completely normal blood clot, because some patients lack the factor XIII in plasma and cells, infusion Treatment only corrected the deficiency of plasma factor XIII, suggesting that intracellular factor XIII may play a role in the generation of normal blood clots.
The gene encoding the a-chain protein is located on the sixth pair of chromosomes (6p24-p25), while the gene of the b-chain is located on the first pair of chromosomes (1q31-q32.1). In addition to the tetrameric factor XIII, there is also unbound in plasma. The concentration of free b-chain protein, free b protein is almost constant in normal human, heterozygous and homozygous patients, so the deficiency of factor XIII is due to the lack of a-chain protein, and the change of a-chain also causes the concentration of b-chain in a2b2 complex. The change, but the free b-chain is still nearly constant, heterozygous patients have these XIII factor proteins, the hemostatic mechanism is normal, the clinical factor of bleeding occurs when the concentration of factor XIII is less than 1%, and the concentration of 2% to 3% can make Bleeding stops, the X-factor half-life is about 10 days, so a small amount of plasma can be infused to achieve therapeutic purposes. Only 3 cases of b-chain protein deficiency causing XIII deficiency are reported. Many a-chain gene defects have been elucidated. Common, there are also nonsense mutations, insertion mutations, base deletions and so on.
Pathogenesis:
FXIII-A and FXIII-B have different gene codes on chromosomes 6 and 1, respectively, one of which is 200 kb long and consists of 15 exons; the other is 28 kb long and consists of 12 exons. Of the 50 known gene mutations, 47 are located in the A gene and 3 in the B gene. A total of 26 missense mutations have been found, 4 nonsense mutations, 8 cleavage site mutations, and 11 small ones. Deletion (insertion) and 1 large deletion, there is no obvious hot spot in the site of gene mutation, which is distributed in multiple sites of FXIII gene. Studies have shown that mutation of FXIII often leads to decreased protein stability and intracellular production. degradation.
Shanghai Ruijin Hospital Shanghai Institute of Hematology used the urea dissolution test and FXIII antigen (FXIII: Ag) to diagnose the probands of two families as factor XIII deficiency. PCR, nucleotide sequencing and RT-PCR were used to measure FXIII gene. The results of mRNA and other methods showed that the proband of the family 1 was at the 1241th position of exon 10 from CG, resulting in Ser413Trp (TCGTGG); the parents of the proband were married to the close relatives at the DNA level. There are also mutations in the same locus, which are heterozygous. The family 2 proband and their sisters in the exon 232 nucleotides from CT, resulting in Arg77Cys (CGCTGC); parents of the proband For the close relatives, the father and the father both had the same site mutation at the DNA level. The above two mutations led to the lack of factor XIII in family 1 and family 2, respectively. These two gene mutations were reported for the first time.
Prevention
Hereditary coagulation factor XIII deficiency prevention
Patients who start prophylactic treatment in childhood can survive, as long-term 2% to 5% of FXIII factor can meet the need for hemostasis, and FXIII half-life is longer (11 to 14 days), therefore, interval 1 The treatment can be achieved by replacing treatment (such as plasma cryoprecipitate or concentrate) for a month. The incidence of oral and postoperative bleeding in patients with factor XIII deficiency is relatively lower than that of other coagulation factors that affect thrombin formation, and the wound healing is poor. The incidence is not as high as expected. In general, as long as preventive treatment is appropriate, factor XIII deficiency can be converted from a very dangerous bleeding disease to a clinically mild disease, but the success of preventive treatment is very large. The extent is largely related to the ability to conduct early diagnosis, but in most developing countries, this diagnosis is often difficult to implement.
Complication
Hereditary coagulation factor XIII lacks complications Complications edema
Hematoma in the deep tissue can compress the nearby blood vessels to cause tissue necrosis. Compression of the nerve can cause limb or local pain, numbness and muscle atrophy. Compression of the 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.
Symptom
Hereditary coagulation factor XIII deficiency symptoms Common symptoms Gum bleeding bleeding after tooth extraction more than nose bleeding skin ecchymosis hematuria menstrual volume more congenital X factor deficiency
The hemorrhagic manifestations of factor XIII deficiency are usually more severe, especially in childhood, when fatal umbilical cord hemorrhage and central nervous system hemorrhage may occur, umbilical cord hemorrhage may occur in 80% of untreated patients, and central nervous system bleeding may occur. The ratio is also as high as 30%. In all clotting factor deficiencies including hemophilia A and hemophilia B, factor XIII deficiency has the highest probability of severe bleeding. Therefore, factor XIII deficiency is also the most easily detected and early diagnosis. .
Examine
Examination of hereditary coagulation factor XIII deficiency
All common coagulation screening tests are normal. These experiments are based on the formation of fibrin clots. Factor XIII does not participate in clot formation (ie fibrinogen becomes fibrin) and the coagulation process in the above stages. Screening of factor XIII is commonly used. The lack of laboratory tests is a clot stability test: placing the fibrin clot in 5M urea solution or 2% acetic acid or 1% monochloroacetic acid solution, the clot lysis within 24h indicates a serious deficiency of factor XIII (<1) %) or 2-antiplasmin is severely deficient. Negative test results often cause missed diagnosis of patients with low XIII factor but no complete deficiency (1% with E) and some patients with factor XII inhibitors. Of course, it is even more difficult to identify Zygo.
Further, a method for confirming the activity of the enzyme and the protein concentration, and for the lack of typing of factor XIII, a method for infiltrating a protein (such as casein) with a radiolabeled amine substance in a patient's fibrin clot, an immunochemical method, and Scanning is performed by quantifying the cross-linking of - and -chains. These methods are sensitive and sensitive, and are also used to determine the half-life of therapeutic preparations in the body to aid treatment. There are two types of factor XIII deficiency: the most common type of homozygous a protein And enzyme activity is not measured (<1%), b protein is about 50% of normal level, heterozygous a protein is about 50% normal, b protein is about 80%; another rare type is found in Japanese and Italian Human, characterized by b protein deficiency and low protein level, there is 1 patient with a protein of 24% and b protein of about 2%, a protein half-life of only 3 days, significantly lower than normal, platelet factor XII is normal, patients have bleeding Symptoms, only a small number of cases (<3%) in the most common types have a small amount of detectable a protein.
Diagnosis
Diagnosis and identification of hereditary coagulation factor XIII
According to the medical history, clinical manifestations and laboratory tests, the diagnosis of this disease is not difficult. Because all coagulation screening tests are normal, it is not difficult to identify with other hemorrhagic diseases, and congenital 2-antiplasmin deficiency and congenital Identification of plasminogen activator inhibitor-1 (PAI-1) deficiency, both of which are less common than hemorrhagic disease with factor XIII deficiency, also autosomal recessive, bleeding symptoms Similar to factor XIII deficiency, but there is hyperfibrinolysis, fibrinogen reduction; identification is not difficult, clinical treatment is helpful to identify, patients with factor XIII deficiency must be infused with blood products to have a good effect, single The use of antifibrinolytic drugs such as 6-aminocaproic acid is not effective, and the latter two drugs use these drugs well.
Generally not confused with other diseases.
