Hereditary factor VII deficiency
Introduction
Introduction to hereditary factor VII deficiency Hereditary factor VII (FVII) deficiency is an autosomal recessive disorder caused by mutation of FVII gene. Most patients are type I deficient, that is, FVII activity and antigen level are decreased, but there are also a small number of patients. It is a type II deficiency with a normal or normal low level of antigen and a markedly reduced activity. basic knowledge The proportion of illness: 0.002% Susceptible people: no special people Mode of infection: non-infectious Complications: intracranial hemorrhage, hematuria, epistaxis
Cause
Hereditary factor VII deficiency etiology
(1) Causes of the disease
The hereditary factor VII deficiency is mostly reduced by coagulation factor organisms, and the cause of coagulation defects is caused by abnormal molecular structure and gene mutation.
(two) pathogenesis
FVII is a vitamin K-dependent coagulation factor and is an important component of the exogenous coagulation pathway. The gene encoding FVII protein is located on the long arm of chromosome 13 (13q34) and is 12.8 kb in length, close to the 2.8 kb upstream of the coagulation factor X gene. , consisting of 9 exons (1a, 1b, 2-8) and 8 introns. The prepro-leader sequence is encoded by exon 1 and contains 38 or 60 amino acids. Since exon 1b is an alternative splicing exon, about 90% of FVII mRNA does not transcribe exon 1b, only exon 1a is transcribed, exon 2 encodes the Gla region; exon 3 encodes a small The hydrophobic region; exon 4, 5 encodes the EGF region; exons 6 to 8 encode the catalytic region.
Normal molecular structure
Mature FVII is a single-chain glycoproteinase consisting of 406 amino acids. Its signal peptide and precursor peptide consist of 38 amino acid residues of methionine (methionine)-38 arginine-1, which are involved in blood vessels. After the injury, tissue factor (TF) exposure, FVII or activated FVII (FVIIa) and TF form a complex, under the action of FXa, thrombin, etc., FVII cleavage to arginine at the 153 position of arginine 152-isoleucine The light chain of acid 1-arginine 152 and the heavy chain of isoleucine 153-valine 406 are activated, and the light and heavy chains are linked by a disulfide bond (between 135 and 262 cysteine) Disulfide bond), FVII is divided into four structural regions: -carboxyglutamic acid (Gla) region, two epidermal growth factor-like regions (EGF) and catalytic region, and the Gla region consists of about 40 amino acids at the amino terminus, 10 Gla is required for the binding and function of F VII and Ca2. The two EGF regions are each composed of 45 amino acid residues, each containing three disulfide bonds. The asparaginase at position 63 is subjected to carboxyl group. Conversion to -carboxyasparaginase, this process is carried out after protein translation is completed, its function is still unclear, EGF1 is necessary for FVII and TF binding, in EG The F1 region also contains a high affinity binding site for Ca2 independent of Gla, the catalytic region including the activation region and the protease region, the activation region is the site where FVII is activated to FVIIa, and the protease region recognizes and cleaves the substrate (FIX, FX, The site of FVII), the catalytic region of histidine-193, aspartic acid-242 and serine-344 constitute a unique enzyme active center of serine protease, which is an important part of maintaining FVII function and structure.
The FVII zymogen has been subjected to limited proteolysis to become the active protease FVIIa. The specific mechanism of FVII activation in vivo is still unclear, but it is clear that FVII is activated soon after it binds to its cofactor TF, and TF is a membrane. The endoprotein is not expressed in cells in contact with blood, but is expressed in extracellular cells and extracellular matrix. Under the action of inflammatory cytokines, monocytes and endothelial cells can be induced to express TF. When blood comes into contact with TF, such as lesions or sites of inflammation, FVII is quickly activated to become FVIIa, FVIIa and TF complexes subsequently cleave and activate FX and FIX to initiate the coagulation process, and factor VII deficiency leads to barriers to the initiation of exogenous coagulation mechanisms. .
Gene mutation
Hereditary Factor VII deficiency may be due to reduced or absent FVII synthesis. Comparing the antigen detection and functional tests of FVII, it is found that about 20% of patients have FVII dysfunction. According to the latest FVII database, there are 124 FVII mutations. , including missense, nonsense, cleavage site, promoter, small insertion and deletion of 6 mutations, of which missense mutations accounted for 70%, deletion mutations accounted for 10%, splice site mutations accounted for 9%, promoter mutations 6%, the other are insertion mutations and nonsense mutations, the higher frequency mutations in non-related patients are R79Q/w, 6071G is greater than A, Q100R, 1055310554insCTCAGCGCACGAC, 1055310568del, A244C, A294V, M98I, R304Q , C310F, G342E, T359M and 11125del9, wherein R79Q/W, 6071G is greater than A, A244C, R304Q, T359M 5 mutations occur in the CpG mutation hotspot, the mutation site is mostly in the exon, followed by the splice site, at the initiation Mutations in the sub-region (eg, -61T is greater than G) can also result in a severe factor VII deficiency, fewer mutations in the intron region, and factor VII deficiency due to a combination of two different mutations.
Polymorphism
It should be noted that the FVII gene polymorphism can also affect the FVII:C and FVII:Ag levels, and the FVII353 polymorphism (M2) can reduce the FVII secretion efficiency and reduce the VII level by 48%, while -323P0/ P10 polymorphism can reduce FVII levels by affecting FVII transcription rate. Since the presence of these polymorphisms can make the clinical phenotype of factor VII deficiency more serious, most FVII knockout mice can survive normally and Development, only a very small part died before and after birth.
Prevention
Hereditary factor VII deficiency prevention
Establish genetic counseling, strict premarital examination, strengthen prenatal diagnosis, and reduce the birth of children. The lack of congenital hereditary factor VII is rare, and acquired acquiredness is mostly associated with vitamin K deficiency, neonatal hepatitis or hypoxia. Regular review, if it is acquired, it will return to normal after a period of time. If it is really a lack of hereditary factor VII, it is usually treated with fresh frozen plasma or prothrombin complex. Prophylactic treatment depends on the bleeding situation. If there is repeated bleeding, fresh frozen plasma or prothrombin complex can be infused regularly in small doses. Occasionally, bleeding does not treat bleeding. Chinese medicine practitioners can consult relevant Chinese medicine practitioners.
Complication
Hereditary factor VII deficiency complications Complications intracranial hemorrhage
The most common bleeding symptoms are nosebleeds, skin ecchymosis, post-traumatic bleeding, joint bleeding, menorrhagia, hematuria, gastrointestinal bleeding, gum bleeding and retroperitoneal hematoma, and uncontrollable menstrual blood and deadly cranial Internal bleeding and so on.
Symptom
Hereditary coagulation factor VII deficiency symptoms Common symptoms Gingival bleeding bleeding after tooth extraction More than skin ecchymosis Hematuria Pulmonary embolism Muscle bleeding Intracranial hemorrhage Congenital X-factor deficiency
Coagulation factor VII deficiency is an autosomal recessive disorder. Heterozygotes generally have no hemorrhagic manifestations. Homozygous or double heterozygotes can cause life-threatening major bleeding. The most common hemorrhagic symptoms are epistaxis, skin ecchymosis, and post-traumatic bleeding. , joint bleeding, menorrhagia, hematuria, gastrointestinal bleeding, bleeding gums and retroperitoneal hematoma, difficult to control excessive menstrual bleeding and fatal intracranial hemorrhage, although not as high as hemophilia A and hemophilia B, But sometimes it can happen.
The severity of clinical manifestations in patients with factor VII deficiency is highly variable, and the severity of bleeding does not always correspond to FVII levels. It is generally believed that there is no good correlation with plasma FVII levels, and some patients even need it. Strong hemostasis to stop bleeding, such as trauma, surgery, etc., there is still no bleeding, some patients with homozygous mutations may have only a slight clinical manifestation even if the FVII level is below normal 10%, but when When the FVII level is less than 1%, the bleeding symptoms may be similar to those of hemophilia A or hemophilia B. Repeated joint bleeding may occur in very severe patients, leading to chronic disabling hemophilic joints. Sick and dangerous hematoma, occasionally reported in patients with factor VII deficiency, and the cause of death in some patients with hereditary factor VII deficiency is also related to pulmonary embolism and thrombosis of the inferior vena cava. There are not many patients with fatal or disabling bleeding. The most common bleeding manifestations are nosebleeds and menorrhagia. For patients with factor VII deficiency. No fatal central nervous system hemorrhage or disabling joint muscle hemorrhage occurs. The current case reports are inconsistent and may vary among different races. Ragni et al. found that among 75 infants with factor VII deficiency There were 12 cases of intracranial hemorrhage, and the study of factor VII deficiency in Iranians did not find such a high rate of intracranial hemorrhage.
Examine
Examination of hereditary factor VII deficiency
The characteristic manifestation of hereditary factor VII deficiency is prolonged prothrombin time (PT) and normalized partial thromboplastin time (APTT). In coagulation factor screening test, factor VII deficiency is the only coagulation with this manifestation. Factor, rare patients with prolonged APTT, may be related to coagulation FVII mutations, the diagnosis of hereditary factor VII deficiency requires specific examination of FVII, and patients with mild (middle) factor VII deficiency have FVII:C levels of 1% in vitro. ~52%, however, the use of FVII:C or FVII:Ag levels in plasma alone to distinguish between severe and mild (middle) factor VII deficiency is not reliable, so its genotype must be tested, asymptomatic factor VII deficiency patients FVII: C level is normal 4% ~ 61%, FVII: Ag content is 5% ~ 113% of normal level, light (moderate) and asymptomatic hereditary factor VII deficiency are almost caused by missense mutations.
According to the condition, clinical manifestations, symptoms, signs, choice of electrocardiogram, B-ultrasound, liver and kidney function and biochemistry, hematuria and other tests.
Diagnosis
Diagnosis and identification of hereditary factor VII deficiency
According to the history of bleeding, clinical manifestations and laboratory tests, the diagnosis is not difficult, and the FVII measurement is diagnostic.
Vitamin K deficiency caused by liver disease, warfarin poisoning or malnutrition is the most common cause of acquired factor VII deficiency. In these cases, other vitamin K-deficient factors may be present at the same time, and the lack of hereditary factor VII Diagnosis must exclude the above, homocysteineemia, Gilbert syndrome, Dubin-Johnson syndrome can also occur secondary coagulation factor VII deficiency.
