hereditary prothrombin deficiency
Introduction
Introduction to hereditary prothrombin deficiency Hereditary prothrombin (Factor II) deficiency is one of the rarest hereditary hemorrhagic diseases, which can divide prothrombin deficiency into two categories: 1 low prothrombinemia (type I deficiency), with both antigen and activity Degradation is characterized; 2 abnormal prothrombinemia (type II deficiency), characterized by normal or normal low antigen levels, reduced prothrombin activity. basic knowledge The proportion of illness: 0.001% Susceptible people: no special people Mode of infection: non-infectious Complications: muscle atrophy
Cause
Hereditary prothrombin deficiency
(1) Causes of the disease
It is caused by defects in prothrombin gene and abnormal molecular structure, including decreased prothrombin content and blood coagulation activity. Severe cases are common in homozygous patients, occasionally in a small number of cases, accompanied by mild factor VII deficiency.
(two) pathogenesis
Prothrombin is a vitamin K-dependent coagulation factor synthesized by the liver. The liver first synthesizes a prothrombin precursor including a leader peptide of 43 amino acid residues, followed by the action of signal peptidase and proteolytic enzymes. The leader peptide was removed and transformed into a mature prothrombin single-chain glycoprotein. The mature prothrombin had a molecular weight of 71,600 and a sugar content of 8.2%, and consisted of 579 amino acids and three N-terminal connexin sugar chains.
1. Normal molecular structure: Prothrombin protein contains four functional domains: one -carboxyglutamic acid region (Gla), two annular regions (Kringle, K) and one catalytic region, and the Gla region (aa 1 ~aa 40) is located at the amino terminus of the peptide chain, including 10 Gla, located at the 6th, 7th, 14th, 16th, 19th, 20th, 25th, 26th, 29th and 32nd amino acids, and is a vitamin K-dependent carboxylase system The main function of this region is that it binds to Ca2 and further binds to the phospholipid membrane. In the absence of Ca2, the steric structure of the region is completely irregular, and the two K regions each contain about 80 amino acids, both of which By means of disulfide bonds, a three-ring structure is formed, which is also present in other plasma proteins, such as plasminogen, tissue plasminogen activator, FXII, urokinase and apolipoprotein a, etc., K1 region The effect of (aa 65 to aa 143) may be related to the binding of FVa in the prothrombin to prothrombin complex, and the K2 region (aa 170 to aa 248) is similar in sequence and structure to K1 and binds to Ca2. Is the main site of binding to FVa and can change the molecular conformation to make the cleavage point on the prothrombin molecule and FXa Closer, next to the K region is the catalytic region (aa 321 ~ aa 579), the active amino acids include serine, histidine and aspartic acid, which in turn includes the activation region and the serine protease region, the activation region is thrombin The site that was originally activated to convert to thrombin, and the serine protease region contains sites that recognize and cleave the substrate.
Prothrombin is converted to thrombin by the FXa-FVa complex on the surface of activated platelets, which in turn catalyzes prothrombin, producing prothrombin fragment 1+2 and thrombin composed of two chains linked by disulfide bonds. Thrombin can cleave fibrinogen into fibrin monomer. At the same time, thrombin also has a very strong ability to activate platelets. Abnormal prothrombin causes a decrease in thrombin production and an abnormal hemostatic mechanism.
The human prothrombin gene is located on chromosome 11 (11p11-q12) and is about 21 kb in length. It contains 14 exons and 13 introns. The length of exons (1-14) is 25-315 bp. The length of the sub-(A~M) is 849447bp, the exons 1 and 2 encode the leader peptide; the exons 2 and 3 encode the Gla region; the exons 3-7 encode the K1 region; the K2 region is composed of the exon 7 and 8 coding; exons 8 and 9 encode the A chain of thrombin; the proximal carboxy-terminal serine protease catalytic region is encoded by exons 9-14, and the human prothrombin gene also includes 30 copies of the Alu repeat. And 2 copies of partial KpnI repeats, which account for 40% of the entire gene length, human prothrombin mRNA is about 2000 bp long, of which 1866 bp encodes a 43 amino acid leader peptide and 597 amino acid mature prothrombin peptide chain.
Both prothrombinemia and abnormal prothrombinemia are autosomal recessive, and heterozygous (low prothrombinemia plus abnormal prothrombinemia and two abnormal prothrombinemia) have also been reported. .
2. Gene mutations: Hereditary hypothromboticemia is very rare, but abnormal prothrombinemia is relatively common. Abnormal prothrombin may be a calcium-binding disorder that cannot be activated by FX or produced by coagulation. The enzyme function is abnormal. Although the amino acid composition and nucleotide sequence of prothrombin are clear, the molecular genetics study of abnormal thrombin is not as clear as FVIII or FIX. Like FVIII or FIX, mutation is most likely to occur. In the CpG dinucleotide site, Arg mutations usually occur in other amino acids. The genetic variants of hypoprothrombinemia occur mostly in the Gla region and two K regions (Tyr44Cys, ArglGln, Arg2Trp, Cys138Tyr, Trp357Cys, etc.). Mutations at other sites, such as those occurring at the cleavage site of FXa at the prothrombin molecule and at the subsequent serine protease region (Arg271His, Gly319Arg, Lys556Thr, etc.), may procoagulant procoagulant function Decline, resulting in abnormal prothrombinemia, Shanghai Ruijin Hospital Shanghai Institute of Hematology first discovered in the international area due to exon2 area 601AG (Glu29Gly) and exo Factor II deficiency caused by n6 region 4 203CT (Thr165Met).
Prevention
Hereditary prothrombin deficiency prevention
Establish genetic counseling, strict premarital examination, strengthen prenatal diagnosis, and reduce the birth of children.
Complication
Hereditary prothrombin deficiency Complications muscle atrophy
Muscle atrophy.
Symptom
Hereditary prothrombin deficiency symptoms Common symptoms Nasal bleeding Skin mucosal bleeding Gastrointestinal bleeding Intra-articular bleeding Muscle atrophy Intracranial hemorrhage
Patients with homozygous or complex heterozygous prothrombin deficiency may have mild to severe bleeding depending on the severity of thrombin-producing disorders. Most heterozygous patients do not exhibit bleeding symptoms, and occasionally have mild clinical bleeding. In the vast majority of patients, bleeding occurs after trauma, mucosal hemorrhage is most common, and joint bleeding can sometimes occur. The most common severe bleeding symptoms in patients with prothrombin deficiency are joint bleeding and muscle hematoma, although in plasma. Prothrombin can still be detected, but in some patients, muscle atrophy may still occur due to bleeding. A small number of patients may have gastrointestinal bleeding or intracranial hemorrhage, and some children may have fatal umbilical cord bleeding, although in coagulation Frequent nasal bleeding and menorrhagia in patients with zymogen deficiency, but most of them are not serious, there are no cases of postpartum hemorrhage, and surgery including tooth extraction or circumcision is often performed in patients without prophylactic replacement therapy. Can cause major bleeding.
Examine
Examination of hereditary prothrombin deficiency
Prothrombin deficiency usually leads to prolonged prothrombin time (PT) and activated partial thromboplastin time (APTT), but prothrombin time is normal, homozygous low prothrombinemia patients, coagulation The zymogen activity is 1% to 25% of normal people; the prothrombin activity level of heterozygous patients is about 50% of normal people.
According to the condition, clinical manifestations, symptoms, signs selected for gastrointestinal endoscopy, CT, MRI, B-ultrasound and other tests.
Diagnosis
Diagnosis of hereditary prothrombin deficiency
diagnosis
The diagnosis of prothrombin deficiency requires prothrombin activity and antigen testing, medical history and family studies. Before the diagnosis of hereditary prothrombin deficiency is made, it is necessary to exclude vitamin K caused by liver disease, warfarin excess, etc. Lack of associated secondary prothrombin deficiency, which can be distinguished by detailed physical examination, medical history analysis and laboratory testing.
Differential diagnosis
Prothrombin reduction due to the production of acquired circulating anti-prothrombin antibodies associated with systemic lupus erythematosus should also be identified, in which specific antibodies bind to prothrombin causing rapid clearance of the latter, resulting in true Acquired hypoprothrombinemia.
