Pediatric hemophilia

Introduction to pediatric hemophilia Hemophilia is a group of hemorrhagic diseases of a hereditary coagulopathy caused by the absence of factor VIII (FVIII), IX (FIX) or factor XI, including hemophilia A, factor VIII (also known as factor VIII) Antihemophilic globulin, AHG) deficiency. Hemophilia B, a factor IX (also known as plasma thromboplastin component, PTC) deficiency. Hemophilia C, a factor XI (also known as plasma prothrombin precursor, PTA) deficiency. Hemophilia is the most common in congenital hemorrhagic diseases, especially hemophilia A accounts for about 85%. Hemophilia in children begins in the neonatal period, but most of them are around 2 years old. With the increase of developmental activities, the bleeding tendency becomes more and more obvious. basic knowledge The proportion of illness: 0.001% Susceptible people: children Mode of infection: non-infectious Complications: anemia, shock, jaundice, gastrointestinal bleeding, headache

Causes of hemophilia in children

(1) Causes of the disease

Hemophilia A, B are X-linked recessive inheritance, female transmission, male onset, hemophilia C is autosomal dominant or incomplete recessive inheritance, both men and women can be morbid or transmitted, about 1/3 The patient has no family history, which may be caused by genetic or genetic mutations. The factor VIII gene is large and 186 kb long. The common mutation methods are point mutation, gene deletion, insertion of abnormal fragments and intron 22 inversion, due to factors. Defects in VIII gene cause hemophilia, and about 50% of severe cases are associated with inversion of intron 22.

(two) pathogenesis

Both FVIII and FIX genes are located at the end of the long arm of the X chromosome, so both hemophilia A and hemophilia B are X-linked genetic diseases. According to the genetic laws of hemophilia, there are four cases:

1. Male boys and normal female boys are normal, and the girls born are carriers.

2. Female carriers and boys born to normal males have a 50% probability of being hemophiliacs, and girls born with a 50% probability of being carriers.

3. Boys born to female carriers and male patients have a 50% chance of being hemophilia, and girls born to girls and hemophilia each account for 50%. This type of marriage is rare.

4. Boys and girls born to male hemophiliacs and female hemophiliacs are suffering from hemophilia. This marriage has not yet been found. Factor (vWF) combines in the form of non-covalent bonds to form complexes. Where VIII:C is only 1% of the complex, Factor VIII is a water-soluble glycoprotein that can be activated by Xa or thrombin to VIIIa, in the endogenous coagulation system, in the presence of Ca2 and phospholipids, VIIIa Participation in the activation of factor X by factor IXa in the form of coenzyme greatly increases the rate of activation of factor X by factor IXa. In the absence of factor VIII or factor IX, thromboplastin production is reduced, fibrin clot formation is delayed, and clotting time is prolonged. Causes bleeding symptoms, vWF as a carrier of factor VIII to stabilize it, and participate in platelet adhesion, aggregation, vWF levels or decreased function, can cause factor VIII deficiency and bleeding tendency, VIII: C 80% by sinusoidal endothelial cells Synthesis, the rest is synthesized by spleen, lung, kidney, mononuclear macrophages, etc.; its activity is extremely unstable, it can lose 20% after storage for 24h at 4°C, VIII:C plasma content is 5g/L, activity is 50%150% , half life 8 ~ 12h Factor IX is synthesized by the liver and belongs to vitamin K-dependent coagulation factor. Its half-life is 18-24 hours, plasma activity is 80%-120%, factor XI is synthesized by the liver, and its half-life is 40-48h. It is stable at 4°C, so the patient is replaced by this disease. Factor XI can be added by entering the stock plasma during treatment.

Pediatric hemophilia prevention

Strengthen the detection of hemophilia carriers, prenatal diagnosis of pregnant women in the hemophilia family, hemophilia fetus should terminate pregnancy, will undoubtedly reduce the incidence of hemophilia, according to the genetic pattern of this group of diseases, the patient Family members need to be screened to identify patients and carriers, and to conduct genetic counseling on the disease in this group, so that they can understand the genetic laws, and use genetic analysis for prenatal diagnosis in pregnant women in the family, such as Determining the fetus as a patient with hemophilia A, can terminate the pregnancy in time, prevent bleeding should develop a quiet living habits from childhood, to reduce and avoid traumatic bleeding, as far as possible to avoid intramuscular injection, such as surgery for surgical diseases, should be treated Note the blood transfusion or supplementation of the lack of clotting factors before, during and after surgery.

Pediatric hemophilia complications Complications anemia shock jaundice gastrointestinal bleeding headache

Complicated joints or internal organs, muscle bleeding, post-traumatic bleeding, can be complicated by anemia, shock, jaundice, etc. Repeated hemorrhage of the joint often leads to destruction of articular cartilage, narrowing of the joint cavity, and muscle atrophy around the joint to form chronic hemophilic arthritis. Even joint deformity, loss of function, such as bleeding in the throat can be complicated by asphyxia, can be complicated by gastrointestinal bleeding, hematuria, etc., intracranial hemorrhage is rare, for children with hemophilia with severe headache should be alert to intracranial hemorrhage or subdural hemorrhage may.

Symptoms of hemophilia in children Common symptoms Hemorrhagic tendency Repeated bleeding Muscle bleeding Skin mucosal bleeding Huangqi Intracranial hemorrhage Joint deformity Muscle atrophy Joint cavity hemorrhage Asphyxia

Clinical manifestation

(1) bleeding symptoms: the main manifestations of this disease, lifelong minor injury or prolonged bleeding after surgery, hemophilia A, B clinical manifestations similar, the earlier the bleeding symptoms appear more serious, hemophilia A more in the baby Begin to learn to climb, learn to go on the disease, less than 9 months after birth, occasionally bleeding from the newborn when the umbilical cord is broken, mild children can not be found until adulthood, hemophilia B severe children are rare, mild There are many children, mostly within 2 years of age, and a few are 5 to 6 years old.

(2) joint bleeding: is one of the special manifestations of hemophilia A children, about 75% of hemophilia A patients, often occur after exercise and trauma, infants are mostly ankle involvement, children with knee involvement Common, mild discomfort before bleeding, followed by local redness, swelling, heat, pain, limited mobility, such as less bleeding, timely treatment, joint hematoma can be absorbed, but repeated bleeding of joints often lead to destruction of articular cartilage, joints The cavity is narrowed, muscle atrophy around the joint forms chronic hemophilic arthritis, and even joint deformity and loss of function.

(3) hemophilia muscle hemorrhage and hematoma: the lower limbs, forearms, buttocks are more common, deep hematoma has corresponding parts of pain, compression symptoms, such as more bleeding, can cause shock, anemia, jaundice and body heat, subcutaneous, gums, Oral and nasal mucosa is easy to be injured, so it is a frequent site of bleeding, but skin mucosal bleeding is not a characteristic of this disease. Skin defects, ecchymoses are rare, such as bleeding occurs in the pharynx, throat is easy to cause asphyxia, gastrointestinal bleeding, hematuria is also common. Children with hematuria can be misdiagnosed as "nephritis". Children with tooth removal or surgery such as tooth extraction, tonsillectomy, etc., if they do not take corresponding measures, will cause long-term oozing or bleeding. Intracranial hemorrhage is rare, but it is spontaneous, but usually caused by trauma. Caused, often life-threatening, hemophilia children with severe headache should be alert to the possibility of intracranial hemorrhage or subdural hemorrhage, hemophilia C homozygous children have bleeding tendency, bleeding is lighter, more often after surgery Or traumatic, spontaneous bleeding is rare; occasional skin mucosal bleeding, adolescent women may have menorrhagia, bleeding degree and factor XI concentration has no significant relationship, children Often combined with factor V, factor VII and other coagulation factors, children with heterozygotes have no bleeding symptoms.

2. Clinical classification of hemophilia

(1) Heavy: Factor VIII or factor IX activity <1%, more spontaneous bleeding before the age of 1 year, more and more bleeding sites, repeated intra-articular or deep tissue (muscle, visceral) bleeding, joint deformity more common.

(2) Intermediate type: Factor VIII or factor IX activity is 1% to 5%, mostly in the case of 1-2 years old, can cause major bleeding after trauma, joint, muscle bleeding is more common, but the number of repeated episodes is less, rarely in There were joint deformities in the early years, and spontaneous bleeding was rare.

(3) Light type: Factor VIII or factor IX activity is 6% to 25%, mostly after 2 years of age, slight injury or bleeding after surgery, no spontaneous bleeding and joint bleeding.

(4) Subclinical type: Factor VIII or factor IX activity is 26% to 45%. It is only in severe trauma. The bleeding is not only found after major surgery, but it is easy to miss diagnosis. According to bleeding symptoms, medical history and family history can be initially established. The diagnosis of hemophilia, further, the relevant examination of coagulation can confirm the diagnosis, the identification of hemophilia A, B, C can be identified by the prothrombin consumption test and the corrective test of thromboplastin test, if necessary Further genetic analysis can be done during genetic counseling or prenatal diagnosis.

Pediatric hemophilia check

1. Prolonged clotting time prolonged activation of partial thromboplastin time, poor prothrombin consumption, abnormal thromboplastin production test, bleeding time, platelet count, prothrombin time are normal, when prothrombin consumption test, thromboplastin When a test abnormality is generated, it can be identified by a corrective test. Factor VIII, XI does not contain factor IX in normal plasma adsorbed by barium sulfate, and contains factor IX and XI in normal serum without factor VIII. If the above two tests can be corrected by normal plasma after adsorption by barium sulfate, but not corrected by normal serum, it is hemophilia A; if the above two tests are corrected by normal serum and are not corrected by the adsorbed plasma, it is blood Disease B; if the above two tests can be corrected by normal serum and adsorbed plasma, it is hemophilia C.

2. Determination of Factor VII:C or Factor IX Activity in Plasma (Phase I Method) This method is simple and commonly used, and is also the main basis for clinical classification of hemophilia.

3. Genetic diagnosis

(1) DNA polymorphism analysis: including restriction endonuclease fragment length polymorphism (RFLP), variable number of tandem repeat (VNIR) and short repeat (STR) analyses for probands and The mother of the proband is the heterozygote of the restriction site, and the fragment length polymorphism related to hemophilia in the gene or the gene is used as a genetic marker to determine whether the disease gene exists, if all the existing The RFLP was analyzed by linkage analysis, and the reliability of genetic diagnosis of hemophilia family was 99.9%.

(2) Direct detection and analysis of pathogenic defects: including denaturing gradient gel electrophoresis (DGGE) and single-strand conformation polymorphism analysis (SSCP), which can detect point mutations, which are mostly used for genetic analysis of probands, and the detection rate of mutations It is 80% to 90%.

(3) Southern blotting: The main defect of detecting the gene inversion of the large fragment of intron 22, which is mostly for severe patients, for genetic counseling of members of hemophilia family, and selecting imaging examination according to clinical needs, such as X Line, B-ultrasound, CT examination, etc., can be found in joint deformities, visceral bleeding and so on.

Diagnosis and diagnosis of hemophilia in children

This disease should be distinguished from vWD, which may cause platelet dysfunction due to abnormality of vWF quality or quantity. It can be induced by aspirin tolerance test, platelet-induced statin-free agglutination and vWF factor antigen (vWF: Ag) Determination, etc., the total amount of coagulation factors contained in 1 ml of normal plasma is defined as a factor of 1 unit, and the level of the factor is expressed as a percentage of the activity, that is, the level of 100% (1 U/ml) is equal to 1 ml of the factor in normal plasma. The activity is classified into 4 types according to the level of FVIII or FIX.

1. The differential diagnosis of hemophilia A and hemophilia B is similar to the clinical hemorrhagic manifestations of hemophilia A and hemophilia B. Both APTTs are prolonged and difficult to identify. TGT and corrective tests can identify both. The most reliable diagnostic means is the FVIII:C assay supplemented with the vWF:Ag assay and the FIX:C assay supplemented with the FIX:Ag assay.

2. Identification with acquired factor deficiency Acquired factor deficiency is common in acquired FVIII deficiency, while acquired FIX deficiency is rare, clinical manifestations and hemophilia are similar, but the degree of bleeding is heavier, more occurs in Pregnant women, malignant tumors and patients with abnormal immune function, laboratory examination of APTT prolonged, a small amount of normal plasma can not be corrected, determination of inhibitor titer can be clearly diagnosed, but should pay attention to the long-term application of factor replacement therapy in patients with severe hemophilia It can produce factor inhibitors, and the incidence of hemophilia A factor inhibitors is much higher than that of hemophilia B. Such patients are very difficult to treat and have high bleeding mortality.

3. Identification of von Willebrand disease These diseases should be distinguished from hemophilia A, which is characterized by a family history or family history. The family history is consistent with autosomal dominant or recessive inheritance. May occur, bleeding symptoms similar to hemophilia, laboratory tests: prolonged bleeding time, aspirin tolerance test positive, Ristomycin (Ristocetin) induced platelet aggregation, APTT prolonged, FVIII: Ag decreased or normal, vWF: Ag decreased or Normal (if normal, it is necessary to further check whether it is a variant).

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