Hemophilia is a common clinical bleeding disorder caused by congenital coagulation factor deficiency and impaired production of prothrombin, including hemophilia A, hemophilia B, and hereditary factor Ⅺ deficiency. Factor VIII (F VIII) deficiency is hemophilia A, and hemophilia B is factor Ⅸ (F IX) deficiency. The overall incidence of these diseases is about 5-10 per 100,000 population, with no significant regional or racial differences, and clinical hemophilia A is common. The incidence of hemophilia A in China is about 80%, hemophilia B is about 15%, and hereditary factor Ⅺ deficiency is extremely rare.
Etiology and pathogenesis
Hemophilia A and hemophilia B are sex-linked recessive inheritance, and hereditary factor D deficiency is autosomal incomplete recessive inheritance. Hemophilia A is caused by deletion of the FⅧ:C expression gene located at the end of the long arm of the X chromosome (Xq28); hemophilia B is also known as hereditary FIX deficiency, which is a single-chain glycoprotein whose expression gene is located at the end of the long arm of the X chromosome (Xq26-q).
For hemophilia A, the mode of inheritance is as follows: a hemophilia A patient married to a normal female will have sons who are normal and daughters who are carriers; a normal male married to a female carrier will have sons who are 50% likely to have hemophilia A and daughters who are 50% likely to be carriers; a hemophilia A patient married to a female carrier will have daughters who are each 50% likely to be hemophiliacs and carriers and will have sons who are The probability of having a son with hemophilia A is 50%; a marriage between a man and a woman who are both carriers of hemophilia A will result in children who are both hemophiliacs.
The mode of inheritance of hemophilia B is similar to that of hemophilia A. The daughters of hemophilia B patients are carriers and the sons are normal. The mode of inheritance of hemophilia C is autosomal incomplete recessive, and both men and women can have the disease. If a female hemophiliac is encountered in the clinic, hemophilia C should be considered.
Hemophilia A is also known as hereditary anti-hemophilic globulin deficiency or FV VIII:C deficiency. FV VIII:C consists of two parts: the clotting active fraction (F VIII:C) and vWD factor vWF, both of which are present in plasma in the form of a complex.
The former has clotting activity, while the latter is an adhesion molecule and has a role in adhesion to platelets and damaged vascular endothelial cells, stabilizing and protecting FⅧ:C. FⅧ:C deficiency results in the inactivation of FX involved in the endogenous coagulation pathway. In hemophilia B and hereditary factor D, FIX deficiency and FIX and FXI deficiency can cause the effect of FXII activation in the endogenous coagulation pathway to fail to continue downstream and affect the activation of FX and cause coagulation dysfunction.
Clinical manifestations
Hemorrhage Most often starts in childhood, and exudative bleeding is the only manifestation, with the characteristics of delayed, continuous and slow bleeding. The bleeding is mostly spontaneous or after minor injury, and does not stop easily; the bleeding is more severe in FⅧ and FIX deficient patients, and there is no difference in clinical manifestations; the symptoms are mild in factor D deficient patients, and spontaneous bleeding is rare. The degree of bleeding in this type of disease is related to the concentration of coagulation factors in the patient’s body, and the lower the concentration of factors, the more serious the bleeding.
According to the activity of plasma FⅧ:C, hemophilia A can be divided into three types: ① heavy: the activity of FⅧ:C is less than 1% of that of a healthy person; ② medium: the activity of FⅧ:C is equal to 1-5% of that of a healthy person; ③ light: the activity of FⅧ:C is equal to 5-25% of that of a healthy person.
Hemorrhage manifestations.
1. Skin and mucous membrane hemorrhage: the most common, occurring mostly after minor injuries and manifesting as continuous blood oozing, which can last for days or weeks, such as skin purpura or petechiae, epistaxis and bleeding after tooth extraction.
2, muscle bleeding: subcutaneous and deep muscle bleeding, more common in the thighs and buttocks, can form hematomas, mostly formed a few days after trauma, and can bleed spontaneously in a state of low coagulation factor concentration.
3. Bleeding in the joint cavity: a characteristic symptom of hemophilia, with an incidence of about 70-80%, and rare in lighter patients. It occurs mainly in hemophilia A. All joints can be involved, in order, knee, ankle, hip, elbow, wrist, shoulder and small finger joints.
4. Visceral bleeding: hematuria and blood in the stool are more common. Intra-abdominal or mesenteric hemorrhage may also occur, but it is rare. The incidence of intracranial hemorrhage is 2.5-7.8%, usually epidural hemorrhage or subsarcoid hemorrhage, and the mortality rate of patients is high.
Second, hematoma compression symptoms and signs In cases of prolonged muscle bleeding, a pseudo-envelope may form around the hematoma, called hemophilic hematocyst. In severe hemorrhage, due to the large amount of bleeding and compression of blood vessels, stasis and edema of the corresponding blood supply area may result, and in severe cases, necrosis may result.
Throat and neck hematomas may cause respiratory distress or even asphyxia due to compression. Bleeding in the joint cavity is manifested by joint pain and pressure, and joint swelling. In mild cases, there is no sequelae, but repeated bleeding or severe bleeding may cause destruction of the synovial membrane and lead to joint ankylosis and deformity and muscle atrophy in the corresponding area. Intra-abdominal or mesenteric hemorrhage is manifested as abdominal pain, which is easily misdiagnosed as acute abdomen.
Laboratory tests
I. Routine examination
Bleeding time, platelet count, and prothrombin time are normal. Coagulation time (test tube method) is prolonged in heavy hemophilia (prolonged when the concentration of VIII:C is lower than 1 to 2%, and can be normal if it is >4%).
II. Primary screening tests
①Prothrombin depletion test (PCT) is normal or shortened (normal >25 seconds, <20 seconds is abnormal).
② prolonged white clay partial thromboplastin time (KPTT) is a sensitive over-screening test (35-45 seconds is normal, more than 10 seconds above normal control is meaningful) can also be prolonged in chronic liver disease or in other pathological states with reduced VII, V, X, prothrombinogen and fibrinogen, and must be differentiated.
(③) Simple thrombin generation test (STGT) has abnormalities (normal value is 10-14 seconds, >15 seconds is abnormal).
Confirmation test
The type of hemophilia can be further defined by prothrombin generation test (TGT, Biggs TGT) and correction test.
Common corrective agents for confirming the type of hemophilia.
Plasma type
FⅧ
F IX
F D
Normal plasma
Yes
Yes
Yes
Stored plasma
No
Yes
Yes
Normal barium sulfate adsorption plasma
Yes
no
Yes
Normal serum
No
Yes
Yes
Three types of hemophilia STGT correction test results
Plasma type
Hemophilia A
Hemophilia B
Hereditary Factor D-D deficiency
Patient plasma
Prolongation
Prolongation
Prolonged
Patient plasma + normal serum
Cannot be corrected
Correct
Correct
Patient plasma + barium sulfate adsorbed normal plasma
Correct
Cannot be corrected
Correct
IV. Special tests Clinically, the above tests can clarify the diagnosis of hemophilia, but special tests are required for special cases or identification of hemophilia carriers, including
1.FVIII: C, FIX antigen and activity determination;
2. vWF antigen determination;
3.Gene diagnosis. Among them, FVIII:C, FIX antigen and activity determination are of certain significance to judge the severity of patients and guide clinical treatment.
Diagnosis
Based on male patients (FⅧ, FIX deficiency), family history (sex-linked recessive inheritance, FⅪ deficiency is autosomal incomplete recessive inheritance), symptoms of bleeding in joints and muscles; laboratory tests such as abnormal KPTT, STGT, corrective tests and reduction of corresponding clotting factors, the diagnosis can be clearly defined and the diagnostic criteria are
(A) Hemophilia A
1. Clinical manifestations
① Male, with or without family similar cases;
② Spontaneous bleeding from joint cavities, muscles, deep tissues, or bleeding more than once after mild injury and minor surgery.
2.Laboratory examination
①CT is normal or prolonged;
② Most of the APTT is prolonged, and most of the PCT and STGT are abnormal;
③ TGT is abnormal and corrected by barium adsorption of normal plasma;
④ FⅧ:C level is obviously low;
⑤ vWFAg was normal and FⅧ:C/vWFAg ratio was decreased.
⑥platelet count, bleeding time, and clot contraction time are normal.
(II) Hemophilia B
1. Clinical manifestations are basically similar to hemophilia A, but the clinical bleeding is less severe.
2, Laboratory tests.
①Prolonged APTT and shortened PCT;
②TGT is prolonged and cannot be corrected by barium adsorption of normal plasma;
(iii) FIX antigen activity is significantly reduced.
(iii) hereditary FXI deficiency This disease is extremely rare in China, and the diagnostic criteria are omitted.
(iv) Prenatal diagnosis of carriers and fetuses The diagnosis of carriers and fetuses can be made by using FⅧ:C, FIX quantitative test, PCR technology and gene chip and other technologies for related genetic testing.
Differential diagnosis
(A) Vascular pseudohemophilia (Von Willebrand disease) The disease is characterized by autosomal dominant inheritance and the lack of FⅧ-related vW factor (VIIIR:WF) and FⅧ-related antigen (VIIIR:Ag) in plasma. The clinical picture is dominated by bleeding from the skin and mucous membranes. Laboratory tests: prolonged BT, positive aspirin tolerance test, reduced platelet adhesion function, non-aggregation to Restoromyces, reduced factor VIII:C and VIIIR:Ag in plasma, and increased ratio of VIII:C/VIII:Ag.
(ii) Vitamin K deficiency
Vitamin K deficiency is an acquired compound hemorrhagic disease, mostly caused by insufficient intake of vitamin K, chronic liver disease, oral vitamin K antagonists, etc. Neonates can bleed due to vitamin K deficiency caused by depletion of vitamin K stores in the body 2~7 days after birth and endogenous inability. Vitamin k malabsorption can be caused by patients with chronic under-eating, biliary tract diseases, intestinal fistula, extensive small bowel resection, chronic diarrhea, etc. Vitamin k production and absorption disorders due to intestinal flora disorders, liver diseases such as decompensated cirrhosis and advanced hepatocellular carcinoma can lead to vitamin k utilization disorders.
. Clinical manifestations are: bleeding from skin and mucous membranes, gums, excessive menstrual flow, some patients may have visceral bleeding and vomiting blood black feces and hematuria. Laboratory tests: PT, APTT prolongation, FⅩ, FIX, FⅦ and prothrombin antigen and activity reduction. Treatment is mainly based on treatment for related underlying diseases and vitamin K supplementation, and those with severe bleeding need intravenous cold precipitation or fresh plasma, fresh frozen plasma.
【Treatment and prevention
1.General local hemostatic treatment is based on local compression and cold compresses with ice packs. If there is skin breakdown can be localized with plasma, thrombin or gelatin sponge dressing, etc.
2.Alternative treatment
The long-term infusion of plasma products is easy to produce the corresponding antibodies in the patient’s body, and the therapeutic effect decreases after several infusions, and the patients are prone to allergic reactions. In recent years, recombinant human FⅧ has been used in clinical practice and has achieved good clinical efficacy, but there is also the production of recombinant human FⅧ antibodies. Commonly used and alternative therapies are as follows.
1) Plasma transfusion The first choice of effective therapy for mild hemophilia. Fresh plasma and fresh frozen plasma contain all the coagulation factors, and because factor IX is more stable, it contains relatively more factor IX, while factor VIII:C is unstable and has a biological half-life of 8 to 12 hours, so it contains less. The maximum safe dosage is 10-15 ml/kg at a time, and 1.000 ml of plasma can increase factor VIII by 20-25% of normal, and 25-40% of normal in severe bleeding.
Factor Ⅸ can be easily dispersed outside the blood vessels, and a plasma transfusion of 15-20 ml/kg can only raise it by 5-10%, so for serious bleeding, factor Ⅸ concentrate must be used. Factor Ⅺ is not easily diffused, and a single transfusion of 7-20 ml/kg of plasma can increase the factor concentration by 30-50%, and it can last for 1 to 2 days, and it can reach the hemostatic concentration for severe bleeding. The maintenance amount can be 5-10ml/kg/every 12 hours or daily as appropriate. It is used for 10 to 14 days after surgery or until the wound heals.
Calculation of the theoretical value of coagulation factors to be injected.
Plasma volume to be input (ml) = (% of required plasma level – % of measured plasma) x plasma volume.
Plasma volume (L) = body weight (kg) × 0.07 × (1 – % of red blood cell pressure)
After calculating the theoretical value, it is still necessary to decide whether the first dose of loading volume is needed and how much time between replenishment according to the diffusion and biological half-life and the actual efficiency.
2) Cold precipitates are plasma products, mainly containing FⅧ, XIII, vWF and fibrinogen, etc. The content of FⅧ is 5-10 times higher than that of fresh plasma. However, it must be freeze-dried and stored at -20°C. It loses 50% of its activity when it is left at room temperature for 1 hour, and should be transfused within 1 hour after melting in a 37°C water bath for clinical application.
3) Thrombospondin Complex i.e. F IX concentrate (mainly containing FII, FVII, FIX, FX), 5-10U/kg/dose for 1-2 times for light bleeding, 30U/kg/dose for moderate bleeding and 50U/kg for severe bleeding, for 4-5 days or for wound healing. Each unit of factor is equivalent to 1 ml of fresh male plasma.
4) FⅧ concentrate or recombinant human FⅧ (rhFⅧ) rhFⅧ is a high-purity preparation expressed by gene cloning technology and approved by the U.S. FDA in 1990. Its biological activity, half-life is similar to plasma FⅧ, safe and free from viral contamination, and is now widely used in clinical practice. It is often stored in a refrigerator at 4°C. When used, it is dissolved in distilled water and injected intravenously. The level of FⅧ in circulating blood can be increased by about 2.5% with the input of 1 IU of FⅧ per kg of body weight. In case of mild bleeding, it is necessary to increase the level of FⅧ in the patient’s blood to about 15% of the normal level and maintain it for 24 to 72 hours.
In the case of moderate bleeding or minor surgery, the level should be raised to 20% to 30% and maintained for 48 to 96 hours. In the case of heavy bleeding or major surgery, it is necessary to raise the level to 30% to 50% or higher and maintain it for more than 4 to 14 days. The maintenance amount in the later period can be reduced appropriately and treated until the wound heals. In clinical use, FⅧ is usually infused at 8-hour intervals to ensure that the circulating blood reaches the level of hemostasis.
III. Drug treatment
1.Desmopressin (DDAVP) This drug can promote the release of FⅧ:C from vascular endothelial cells and other cells or increase the stability of FⅧ:C by promoting the release of vWF, which can increase the activity of FⅧ:C by 2-3 times, but it is not effective for severe hemophilia. It is commonly used for light hemophilia A and vascular pseudohemophilia. 16 to 32ug/dose, diluted with 30ml of saline and finished intravenous drip within 20 minutes. Once every 12 hours, 2-5 times per course, can also be applied locally, but the dose must be increased.
DDAVP can promote the release of fibrinogen activator and activate the fibrinolytic system, so it should be applied with 1g of 6-amino acid orally three times a day, or it can be injected with 1g orally first and then taken orally.
2.Danazol can increase the concentration of FⅧ, 300-600mg/d for 14 days, which is more effective for light and medium-sized patients, but the specific mechanism of action is unknown.
Adrenal glucocorticoids work by improving capillary permeability and reducing the production of FⅧ:C antibodies, and have a certain effect on controlling hematuria and accelerating the absorption of acute joint blood accumulation.
4.Antifibrinolytic drugs play a hemostatic role by preventing the formation of fibrin clots from being dissolved. 6-Amino acid is commonly used, but it is prohibited for those with hematuria and cerebral hemorrhage.
5.Surgical treatment In case of joint bleeding, the joint should be bedridden, the limb should be fixed with a splint and placed in a functional position to limit movement, and local cold compresses and elastic bandages can be applied. After the joint bleeding stops and the swelling and pain disappear, appropriate joint activities can be performed to prevent deformity and stiffness caused by prolonged joint fixation. For patients with repeated joint bleeding resulting in ankylosing deformities, arthroplasty or replacement can be performed with adequate amounts of FⅧ:C or FIX.
6. Currently, research is being conducted to transfer the normal genes that determine the synthesis of FⅧ:C, FIX, and FXI into the patients through vectors directly or indirectly and to make the relevant genes expressed in the patients to correct the patients’ genetic defects and generate sufficient FⅧ:C, FIX, or FXI to maintain the patients’ physiological coagulation function.
Prevention and care
1. Avoid trauma or heavy physical activities, and avoid injections and surgery as much as possible.
2.Prohibit drugs that affect platelet function, such as aspirin, botaxone, anti-inflammatory pain, and pentoxifylline, etc. Chinese herbs that activate blood circulation and resolve blood stasis should also be avoided.
3.Carry out diagnostic consultation for transmitters, conduct genetic diagnosis in early pregnancy and terminate pregnancy for hemophilic fetuses.