(2022 Edition)

Hemophilia A (HA) is an inherited bleeding disorder with X-chromosome linked recessive inheritance. The main clinical manifestation is a qualitative or quantitative abnormality of coagulation factor VIII (FVIII). The clinical manifestations are characterized by bleeding that is difficult to stop after spontaneous or minor trauma to joints, muscles, viscera, and deep tissues, often starting in childhood. The prevalence of HA is about 1 in 5,000 men, and hemophilia is extremely rare in women. The prevalence of hemophilia in China is 2.73/100,000 population, of which HA accounts for 80 ～The prevalence of haemophilia is 2.73 per 100,000 population, with HA accounting for 80.

HA is a disease caused by deficiency or abnormal quality of a single clotting factor. Early recognition and diagnosis of hemophilia allows patients to live a normal life by avoiding bleeding and the joint damage and disability caused by bleeding through proper and correct preventive treatment or timely replacement therapy after bleeding.

Due to the important role of FⅧ in the endogenous coagulation pathway, patients with HA The clinical presentation is characterized by bleeding that can occur anywhere in the body. The most common sites of bleeding are joints, muscles, and deep tissues, but also the gastrointestinal , urinary , central nervous system bleeding, and after tooth extraction bleeding, etc. If left untreated it can lead to joint deformities and pseudotumors, etc., and can even be life-threatening in severe cases. Persistent bleeding after trauma or surgery is also a feature of this disease.

The degree of bleeding correlates with FVIII activity. Activity correlates with lighter patients, who generally bleed rarely and only after injury or surgery; heavy patients, who bleed from an early age and can bleed from any part of the body; and intermediate patients, who bleed to a degree of severity between light and heavy.

A bleeding disorder, including hemophilia, should be considered when a male patient, especially a child, presents with spontaneous bleeding, or bleeding that does not stop after trauma or surgery. Follow up with the patient’s family history and further refine laboratory tests to confirm the diagnosis.

(i) Screening test.

Including platelet count, peripheral blood smear (platelet morphology), prothrombin time (PT), activated partial thromboplastin time (APTT) Patients with HA show only prolonged APTT, but some patients with mild HA have only mildly prolonged or high limit of normal APTT. The platelet count and morphology, as well as other coagulation parameters, should be normal.

(ii) Confirmatory tests.

Clotting factor testing: A prolonged APTT suggests an abnormal endogenous coagulation process, and coagulation markers associated with this should be examined, including FVIII, FIX, FXII activity, and vascular hemophilia factor antigen (VWF:Ag).

VIII:C) is reduced or absent, VWF:Ag is normal, and FVIII:C/VWF:Ag is markedly reduced, suggesting HA.

(iii) Inhibitor assay.

1.

Patients with HA should be tested for FⅧ inhibitors when they have a lower treatment effect than before and before they undergo surgery. In pediatric patients, testing is recommended every 5 exposure days for the first 20 exposure days after initial treatment with F VIII products and every 21 to 50 exposure days after initial treatment with F VIII products.

every 10 exposure days for the first 20 exposure days and at least 2 times per year thereafter.

up to 150 exposure days. 2. Inhibitor screening.

An APTT correction test was performed, in which normal plasma and patient plasma were mixed 1:1, incubated immediately and at 37°C for 2 hours, and then the APTT was measured and compared with the APTT of normal subjects and the patient itself, and corrected immediately. If the incubation is not corrected at 2 hours, the presence of coagulation factor inhibitors is indicated (see Table 1 for interpretation of the APTT correction test).

3. Inhibitor titer.

Inhibitor titers must be measured to confirm the diagnosis of inhibitor. A patient is considered positive if he/she has an inhibitor titer ≥0.6 BU/ml on 2 consecutive occasions within 1 to 4 weeks by the Bethesda or Nijmegen method. If the inhibitor titer >5 BU/ml, the inhibitor is a high titer inhibitor; if the inhibitor titer is ≤5 BU/ml, the inhibitor is a low titer inhibitor.

(iv) Genetic testing.

Genetic testing of patients is recommended to identify the causative gene and to provide a basis for carrier testing and prenatal diagnosis in the same family. In addition, mutations can be used to determine a patient’s risk of developing a suppressor.

According to the activity level of FⅧ, HA can be classified into mild, moderate, and heavy types (see ). medium and heavy types (see Table 2). Factor activity <1 is considered heavy; activity 1 to 5 for medium; activity >5 to 40 for light.

(a) Diagnosis.

Based on the patient’s clinical presentation with severe recurrent bleeding since childhood, especially joint bleeding, combined with FVIII factor The diagnosis is confirmed by laboratory tests for decreased activity and antigen with mutations in the FⅧ gene.

(ii) Differential diagnosis.

• Vascular hemophilia (VWD): VWD is an autosomal inherited disease due to a qualitative or quantitative defect in vWF. It is mostly dominant. Patients have a tendency to bleed, but mainly from the skin and mucous membranes. Because vWF has the ability to increase the stability of FVIII:C, prevent its degradation, and promote its production and release, patients with VWD may develop FⅧdecreased activity. Therefore, patients with decreased FVIIIactivity need to be excluded from VWD, especially in women. vWF antigens and activity (ristocetin cofactor activity, vWF cofactor activity) are required for the diagnosis and staging of VWD. VWD can be diagnosed and typed with vWF antigen and activity (ristomycin cofactor activity, vWF R:Co), collagen binding assay, FVIIIbinding assay, platelet adhesion and aggregation assay, vWF protein electrophoresis, etc. vWF protein electrophoresis, etc. Genetic diagnosis is also a diagnostic tool.
  
• Acquired HA: is the presence of circulating anti-FVIIIautoantibodies in the circulation leading to FⅧa form of autoimmune disease with decreased activity that needs to be differentiated from HA, especially in patients with HA combined with suppressors. Acquired HA is characterized by no previous history of bleeding or positive family history and occurs most often in patients with malignancy, autoimmune disease, and perinatal women, although approximately half of patients have no apparent trigger and are effectively treated with immunosuppression.
  

Measure pharmacokinetic parameters, such as recovery and half-life, in patients and guide therapy based on the results.

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• Implementation of alternative therapies.
  

Alternative treatment is divided into on-demand treatment and regular alternative treatment (preventive treatment).

• On-demand treatment: refers to the treatment of patients with acute bleeding or when the most effective current The most effective hemostatic measure remains FVIIIreplacement therapy, with the principle of early, adequate, and full course of treatment. Replacement therapy FVIIIdose and duration should take into account the site and severity of bleeding (see Table 3).
  
• Perioperative replacement therapy: refers to replacement therapy before, during, and after surgery. The purpose is to ensure the smooth implementation of surgery and the smooth recovery of HA patients after surgery. See Exhibit 4 for specific alternative treatment options.
  
• Prophylactic therapy: is a regular replacement therapy given periodically to prevent bleeding. Since on-demand treatment is only post-bleeding and cannot prevent recurrent bleeding leading to joint disability in patients with severe HA, prophylactic treatment is particularly critical as the goal is to maintain normal joint and muscle function. Prophylactic therapy is the treatment of choice for pediatric HA patients. A goal of less than 3 joint bleeds per year should be set for pediatric patients to minimize the occurrence of joint damage and irreversible joint disability due to joint bleeding.
  

  There is no consensus on adherence to prophylaxis in adult patients, but experience both nationally and internationally has demonstrated that short-term tertiary prophylaxis can reduce the number of bleeds and improve quality of life. In addition, for patients with recent bleeding exacerbations, particularly in target joints where the frequency of bleeding has increased, short-term prophylaxis for 4 to 8 weeks is recommended to interrupt the vicious cycle of bleeding-joint injury. This treatment can be combined with intensive physical therapy or radiation therapy.

Radiation synovectomy.

There are usually three types of prophylactic treatment: 1) primary prophylaxis: after diagnosis, before the second joint bleed, and in children younger than 3 years of age with no clear evidence

Regular continuous replacement therapy is initiated when the presence of an arthropathy is confirmed (on examination or imaging); (ii) Secondary prevention therapy: Regular continuous replacement therapy is initiated after two or more bleeds in the joint, but no arthropathy is found on examination and/or imaging; (iii) Tertiary prevention therapy: Regular continuous replacement therapy is initiated after two or more bleeds in the joint, but no arthropathy is found on examination and/or imaging; and (iv) Tertiary prevention therapy. (3) Tertiary prophylaxis: regular continuous replacement therapy is started only after the presence of arthropathy is confirmed by physical examination and imaging.

To prevent joint disability, it is recommended that prophylaxis be initiated in children with severe disease after the first joint bleed, severe muscle bleed, intracranial bleed, or other life-threatening bleed. Children with a history of joint bleeding and arthropathy should start prophylaxis early, depending on their condition, and achieve a goal of <3 joint bleeds per year or <3 bleeds per year if possible.

Preventive therapy should theoretically maintain FVIII trough levels >1, but there is no internationally standardized protocol for preventive therapy. 25-40 IU/kg per dose, once every other day. (2) Medium-dose regimen: 15 to 25 IU/kg per dose, 3 times per week.

③Small dose regimen: 10-15 IU/kg per dose, 2 to 3 times per week; followed by

30 IU/kg twice a week; followed by 25 IU/kg every other day. The pharmacokinetic-guided prophylaxis profile: individual pharmacokinetic parameters are used to develop a prophylactic regimen based on the patient’s actual needs, which allows for optimal dose and frequency of therapy and optimal resource allocation compared to a high-dose regimen, while maintaining efficacy.

While the optimal prophylaxis regimen remains to be determined, a low-dose regimen may significantly reduce bleeding in children with hemophilia compared with on-demand therapy, but does not reduce the incidence of arthropathy. It is recommended that medium-dose prophylaxis regimens be implemented in children with hemophilia who are financially able to do so, or that individualized regimens be optimized based on age, venous access, bleeding phenotype, pharmacokinetic characteristics, and availability of coagulation factor preparations.

(iii) Non-factor therapy.

• Emicizumab: a bispecific monoclonal antibody that mimics F. family:Times New Roman”>VIIIa by mimicking the cofactor function of FVIIIa, which can simultaneously bridge the FVIIIa span style=”font-family:Arial”>a and FX, making FXin the absence of FVIII. span>is able to continue activation in the absence of F, restoring the physiological coagulation pathway. It is approved for routine prophylactic treatment of patients with HA in combination with FVIIIinhibitors in China and in the US and EU without Finhibitors. span>VIIIinhibitors in the United States and the European Union, and for routine prophylactic treatment of HA patients without Finhibitors in the United States and the European Union. The recommended dosing regimen is a loading dose of 3 mg/kg administered subcutaneously once weekly for the first 4 weeks to rapidly achieve target blood concentrations, and a dose of 3 mg/kg for the first 4 weeks.
  

  A maintenance dose of 1.5 mg/kg once weekly was given starting in week 5.

• Deamino-8-D-arginine pressor (DDAVP): light HA DDAVP is optional in patients with bleeding, and may be effective in a few intermediate HA types but not in patients with heavy HA. The recommended dose is 0.3-0.4μg/kg, diluted in 50 ml of physiological saline and administered slowly intravenously (at least 30 minutes) every 12 hours. The dose is administered once every 12 hours for 1 to 3 days. Increase in coagulation factor concentration >30 or higher after use
  

  >3-fold is considered effective. The drug has poor efficacy after multiple doses and should be supplemented with FVIII preparations in case of poor results. Adverse reactions include temporary flushing and sodium retention. Due to adverse reactions such as sodium and water retention, the

It is contraindicated in children under 2 years of age. Water restriction and pre-testing are required for use in young children. Children with a valid pretest may also use DDAVP nasal spray, which is designed for use in patients with hemophilia, to control minor bleeding.

• Antifibrinolytic drugs: Commonly used drugs include tranexamic acid, 6-aminohexanoic acid, and aminolevulinic acid. These drugs are effective for bleeding in the mouth, tongue, tonsils, throat and bleeding caused by tooth extraction, but they are less effective for bleeding in joint cavities, deep muscles and internal organs. Dosage: 6-Aminohexanoic acid 50-100mg/kg every 8-12 hours; tranexamic acid 10mg/kg intravenously or 25mg/kg orally; aminolevulinic acid 2-6mg/kg every 8 hours. It can also be used as a mouth rinse, especially during tooth extraction and oral bleeding, 5 of tranexamic acid solution 10ml Rinse for 2 minutes, 4 times a day for 7 days.
  
• Analgesic treatment: acetaminophen or opioid depending on the degree of pain, or COX-2 The pain is treated with acetaminophen or opioids, or COX-2 analgesics. In principle, aspirin or other non-steroidal analgesics are contraindicated, as well as all drugs that may affect platelet function.
  

  (iv) Physical therapy.

  Patients are encouraged to perform appropriate, safe aerobic exercise (swimming, power cycling, jogging, brisk walking, etc.) with appropriate load resistance strength training and self-stretching during the non-bleeding period to prevent and reduce recurrent bleeding.

  Treatment of bleeding should follow the PRICE principles of Prohibition, Rest, Ice, Compression, and Elevation.

  (Elevation). In the case of muscle and joint bleeding, the PRICE principle is to infuse coagulation before the

The PRICE principle is an important management measure based on the infusion of clotting factors to raise clotting factor levels, and timely use of splints, molds, crutches, or The timely use of splints, molds, crutches or wheelchair braking can put the bleeding muscles and joints in a resting position, and the use of ice or cold wet compresses can effectively reduce the inflammatory response. It is recommended that ice be applied every 4 to 6 hours for about 5 to 10 minutes (no more than 10 minutes at a time) until swelling and pain are reduced.

In addition, a trained rehabilitation physician/therapist can assess the patient in terms of physical function, individual mobility, and social participation and, based on the results of the assessment, guide the patient through rehabilitation exercises to prevent, reduce, and minimize muscle and joint dysfunction and improve daily living. The patient’s assessment results are used to guide the patient’s rehabilitation to prevent, reduce, and minimize muscle dysfunction and improve daily activity and quality of life.

The homo-neutralizing antibodies produced by HA patients receiving FⅧ replacement therapy are called suppressors, and the rate of suppressor production in heavy HA patients is 20to 30, and about 5 in medium or light HA to 10 chance of producing inhibitors. The continued presence of inhibitors is a serious complication of hemophilia, resulting in more difficult to control bleeding symptoms, increased risk of fatal bleeding, and a further reduction in quality of life. The presence of inhibitors is divided into two treatments: hemostasis and removal of inhibitors.

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• Hemostatic therapy.
  

Patients with acute bleeding should be treated with hemostasis as soon as possible. There are several ways to stop bleeding.