Hemophilia is a group of bleeding disorders with inherited coagulation disorders, including.
1. hemophilia A (hemophilia A): i.e., factor VIII deficiency.
2. hemophilia B (hemophilia B): i.e., factor IX deficiency
3. Hereditary FXI deficiency (hemophilia C): i.e. factor D deficiency.
This group of diseases is not uncommon, with an incidence of 5 – 10/100,000. Hemophilia A is more common and accounts for about 85% of congenital bleeding disorders. The common feature is a tendency to prolonged bleeding after lifelong minor injuries.
Etiology
Hemophilia A and B are both X-linked recessive, with male onset and female transmission. Hemophilia C is autosomal dominant or incomplete recessive and can develop or pass on the disease in both sexes. Deficiencies in factors VIII, IX and D can reduce the production of prothrombin in the first stage of the coagulation process and cause impaired blood clotting, leading to bleeding tendencies. Factor VIII is a large-molecule complex consisting of a small molecular weight of clotting-active factor VIII:C and a large molecular weight of vascular pseudohemophilic factor (vonWiliehrandFactor; VWF), of which the amount of factor VIII:C is very low, accounting for only 1% of the factor VIII complex. C is a water-soluble globulin, 80% of which is synthesized by the liver and the remaining 20% by the spleen, kidney and monocytes. VWF is the carrier of factor VIII, which has the function of making platelets adhere to the blood vessel wall, and when VWF is deficient, it can cause bleeding and factor VIII deficiency.
Factor IX is a glycoprotein synthesized by the liver and requires vitamin K for its synthesis. Factor D is also synthesized in the liver, and its activity is stable when stored in vitro, therefore, factor D can be replenished by transfusion of appropriate amount of stored blood.
Clinical manifestations
Hemorrhagic symptoms are the main manifestation of this group, with a lifelong tendency to bleed for prolonged periods after minor injuries or minor surgery, although hemophilia C generally has milder bleeding symptoms.
Hemophilia A and B can develop in the neonatal period, but most develop by age 2. The severity of bleeding in the former is related to the level of plasma activity of VIII:C: 0-1% is considered heavy, with spontaneous bleeding, recurrent joint bleeding or deep tissue (muscle, viscera) bleeding since early childhood, and often leading to joint deformities; 2%-5% is considered medium-sized, with patients having spontaneous bleeding, recurrent joint bleeding or deep tissue (muscle, viscera) bleeding since early childhood. -The patients with spontaneous bleeding and joint bleeding are less common; 6% – 25% have a mild form, with prolonged bleeding after minor injury or surgery, but without spontaneous bleeding or joint bleeding; 25% – – 50% have a subclinical form. -The subclinical type, in which patients bleed only after severe trauma or surgery, is seen in 25% to 50% of cases.
The bleeding symptoms and severity of hemophilia B are similar to those of hemophilia A. Those with less than 2% factor IX activity are considered severe, which is rare; the majority of patients are mild. Therefore, most of the bleeding symptoms of the disease are mild.
Hemophilia C is rare, and heterozygous children have no bleeding symptoms; only pure heterozygotes have a tendency to bleed. Bleeding occurs most often after trauma or surgery, and spontaneous bleeding is rare. The degree of bleeding does not correlate with the activity of factor D. Some patients have only 1% factor D activity, but the bleeding symptoms are not serious, while others have 20% factor D activity, but can have serious bleeding. Patients with this disease are often combined with other factor deficiencies such as V and VII.
Laboratory tests
The common features of laboratory tests for hemophilia A, B and C are
1. prolonged clotting time (normal in mild cases)
2, poor depletion of prothrombinogen.
3. prolonged prothrombin time in the white clay fraction.
4, abnormal prothrombin generation test. Bleeding time, prothrombin time and platelets are normal.
When prothrombin depletion test and prothrombin generation test are abnormal, in order to further identify the three types of hemophilia, a correction test can be performed. The principle is that normal plasma still contains factors VIII and D and does not contain factor IX after barium sulfate adsorption, and normal serum contains factors IX and D and does not contain factor VIII. Accordingly, if the patient’s prothrombin depletion time and prothrombin production time are corrected by normal plasma after barium sulfate adsorption, but not by normal blood situation, hemophilia A. If the above two tests are corrected by normal serum but not by normal plasma after barium sulfate adsorption, hemophilia B. If the above two tests can be corrected by normal serum and normal plasma after barium sulfate adsorption, hemophilia C. If the above two tests can be corrected by normal plasma after barium sulfate adsorption, hemophilia C.
Measurement of the activity of VIII:C and factor IX by immunological methods has diagnostic significance for hemophilia A or B.
Treatment
There is no curative therapy for this group of diseases.
1. Prevention of bleeding
If surgical treatment is required for a surgical disease, attention should be paid to blood transfusion or supplementation of the lacking coagulation factors before, during and after the operation.
2.Local hemostasis
For surface trauma, nasal or oral bleeding, local pressure can be applied to stop bleeding, or fibrin foam or gelatin sponge with fresh blood or plasma can be used to stop bleeding, or cotton ball or gauze with tissue coagulase or coagulase can be applied to the wound. In the early stage of joint bleeding, bed rest is recommended, and the limb should be fixed in a splint and placed in a functional position, or with local cold compresses and wrapped with elastic bandages. When the joint bleeding stops and the swelling and pain disappears, appropriate physical therapy can be done to prevent joint deformity, and surgical orthopedic treatment can be used for serious joint deformity.
3.Replacement therapy The purpose of this therapy is to raise the factor lacked by the patient to the level of hemostasis in order to treat or prevent bleeding.
(1) Fresh whole blood transfusion
The dose of 1m1/kg can increase factor VIII in the patient’s blood by 1% when transfused within 6 hours after blood collection. Factor VIII has a half-life of 8 to 12 hours and its activity mostly disappears 48 to 72 hours after each transfusion, so its efficacy can only be maintained for about 2 days. Blood transfusion is suitable for patients with mild disease.
(2) Fresh plasma transfusion
Patients with hemophilia A should have fresh plasma transfusion, and factor VIII level can be increased by 2% with 1ml/kg transfusion. Patients with hemophilia B can have stored plasma transfused within 5 days, and the amount of plasma should not be too much at one time, 10ml/kg is appropriate.
(3) Cold precipitate
The cold precipitate is extracted from frozen fresh plasma and contains concentrated factor VIII and fibrinogen. Usually, the cold precipitate contains 100 units (U) of factor VIII in 400 ml of blood (each unit of factor VIII is equivalent to the amount of factor VIII in 1 ml of normal fresh plasma). Depending on the severity of the bleeding, the concentration of Factor VIII required to stop the bleeding varies, and it is often necessary to repeatedly inject it every 12 hours to maintain the concentration of Factor VIII in the patient’s blood.
(4) Factor VIII and IX concentrates
It is a dried and frozen product. Factor VIII can increase the activity of factor VIII in plasma by about 1% for every 1U/kg of factor VIII, but the same dose of factor IX can only increase its activity by 0.5% to 1%. Infusion of either of these two factors should be given every 12 hours to maintain the effective concentration in plasma and control bleeding.
Drug therapy
1. prothrombin complex: contains factor IX and is indicated for the treatment of hemophilia B.
2.1-Deamino-8-arginine pressin (DDAVP): It has the effect of increasing factor VIII activity in plasma and anti-diuretic effect, and can be used to treat patients with mild hemophilia A to reduce their bleeding symptoms at a dose of 0.2–0.3ug/kg, dissolved in 20ml of saline and slowly injected, which can activate the fibrinolytic system. This drug can activate the fibrinolytic system, so it should be used in combination with 6-aminocaproic acid or hemostatic cyclic acid.
3, other: androgenic hormone danazol (danazol) and female contraceptive drug compound norethindrone have the effect of reducing bleeding in patients with hemophilia A, but their efficacy is inferior to that of replacement therapy.
Prevention
Screening of family members of patients to identify patients and carriers, and genetic counseling on this group of diseases to make them aware of the inheritance pattern is required to purse the inheritance pattern of this group of diseases. Pregnant women in the family should be diagnosed prenatally using genetic analysis, and if the fetus is determined to be a hemophilia A patient, the pregnancy can be terminated in time.