Hemophilia: causes, symptoms, diagnosis, treatment

Hemophilia is usually a congenital disease caused by deficiency of factors VIII or IX. The severity of factor deficiency determines the likelihood of development and severity of bleeding. Bleeding in soft tissues or joints usually develops within a few hours of trauma. The diagnosis is suspected in patients with an increase in partial thromboplastin time, normal prothrombin time and blood platelet level and is confirmed by the determination of the content of individual factors. Treatment consists in replacing the deficit factor, if acute bleeding is suspected, confirmed or can develop (for example, before surgery).

[1], [2]

Causes of the hemophilia

Hemophilia A (factor VIII deficiency), which is diagnosed in 80% of patients, and hemophilia B (factor IX deficiency) have identical clinical manifestations, violations of screening tests, and a type of inheritance linked to the X-chromosome. It is necessary to determine the content of individual coagulation factors for the difference of these diseases.

Hemophilia is a congenital disease, is the result of mutations, deletions or inversions of the factor VIII or IX gene. Since these genes are localized in the X chromosome, hemophilia affects mainly men only. Daughters suffering from hemophilia of men are obligate carriers, but sons are healthy. Each of the sons of the carrier of the hemophilia gene has a 50% risk of being sick with hemophilia and each of the daughters has a 50% risk of becoming a carrier of the hemophilia gene.

To ensure normal hemostasis, more than 30% of the level of factors VIII and IX is needed. Most patients with hemophilia have a level of these factors less than 5%. Carriers usually have a factor level of about 50%; Occasionally, the random inactivation of a normal X chromosome during the early embryonic period results in the carrier having a factor level of VIII and IX of less than 30%.

A large number of patients with hemophilia who received plasma concentrate treatment in the early 1980s were infected with HIV due to viral contamination of factor concentrates. Individual patients develop immune thrombocytopenia on the background of HIV infection, which can increase bleeding.

[3],

Symptoms of the hemophilia

In patients with hemophilia, bleeding occurs in the tissues (eg, hemarthrosis, muscle hematomas, retroperitoneal bleeding), the onset of bleeding after an injury can be delayed. Pain often accompanies the development of hemorrhage, sometimes precedes the manifestation of any other signs of bleeding. Chronic, recurrent hemarthroses can lead to the development of synovitis and arthropathy. Even a small blow to the head can cause intracranial hemorrhage. Hemorrhage into the root of the tongue can cause life-threatening airway compression.

Severe hemophilia (with factor VIII and IX levels less than 1% of normal) leads to severe bleeding throughout life, which begins to manifest soon after birth (eg, head hematoma after childbirth or severe bleeding after circumcision). Hemophilia of moderate severity (level of factors from 1 to 5% of normal) is usually manifested by bleeding after minor injuries. With mild hemophilia (a factor level of 5 to 25%), intensive bleeding may occur after surgery or removal of the teeth.

[4], [5], [6]

Diagnostics of the hemophilia

Hemophilia is suspected in patients with recurrent bleeding, unexplained hemarthrosis, or an enlarged TTV. If you suspect a hemophilia, you need to determine the number of platelets and the levels of factors VIII and IX. In patients with hemophilia there is an increase in TTV, but the PI test and the platelet count are normal. The determination of the level of factors VIII and IX determines the type and severity of hemophilia. Since the level of factor VIII can be reduced in von Willebrand disease, it is necessary to determine the activity of von Willebrand factor (PV), antigen and the content of PV multimers in patients with newly diagnosed hemophilia, especially if the disease is mild and the family history indicates a lesion of both men , and women. To determine whether a woman is a true carrier of the hemophilia A or B gene is sometimes possible by measuring the level of factors VIII and IX. PCR analysis of DNA containing a factor VIII gene is available in specialized centers and can be used to diagnose the carriage of hemophilia A and for prenatal diagnosis of hemophilia A in samples of villi of the chorion epithelium at week 12 or amniocentesis at week 16. In this procedure, the risk of obtaining an erroneous result is 0.5 to 1%.

After frequent substitution therapy for factor VIII, in 15-35% of patients with hemophilia A, isoantibodies (alloantibodies) to factor VIII are detected, which inhibit the activity of additional factor VIII infusions. Patients should be screened for isoantibodies (for example, by determining the degree of shortening of the PVT immediately after mixing equal volumes of plasma of the patient and normal plasma and then repeating the test after 1 hour of incubation of the mixture), especially before procedures requiring replacement therapy. In the presence of isoantibles, it is necessary to determine their titer by measuring the degree of inhibition of factor VIII in a series of dilutions of the patient's plasma.

[7], [8]

Treatment of the hemophilia

If there are bleeding symptoms, treatment should be started immediately, even before the end of the diagnostic tests. For example, treatment in the presence of a headache that indicates the possible presence of intracranial hemorrhage should be initiated before the CT scan is performed.

Substitution of the deficit factor is the basis of therapy. In hemophilia A, the level of factor VIII should be increased to 30% to prevent bleeding during extraction of the tooth or stopping the onset of intraarticular hemorrhage; up to 50% in the presence of signs of hemorrhage into a large joint or intramuscular hemorrhage; up to 100% before a large surgical operation or with intracranial, intracardial or life-threatening hemorrhage.

Repeated transfusions of 50% of the initial dose should be administered 8 to 12 hours to maintain a factor level above 50% within 7-10 days after major surgical interventions or life-threatening hemorrhages. Each introduced unit / kg of factor VIII increases the level of factor VIII in the blood by approximately 2%. Thus, to increase the level from 0 to 50%, it is necessary to introduce approximately 25 U / kg of factor VIII.

Factor VIII can be administered as a concentrate of purified factor VIII, which is prepared from the blood of many donors. The drug undergoes viral inactivation, which, however, may not eliminate parvovirus or hepatitis A virus. Recombinant factor VIII is free of viruses, but it has a high price and an increased tendency to cause the formation of isoantibodies. It is usually preferred until the patient becomes seropositive for HIV or hepatitis B or C viruses.

In hemophilia B, factor IX can be administered as a purified or recombinant virus-inactivated product every 24 hours. The required initial and supporting level is similar to that of hemophilia A; however, to achieve the same level, the dose of factor IX should be higher than in hemophilia A, since factor IX is less than factor VIII and, unlike factor VIII, it has a pronounced extravascular distribution.

Freshly frozen plasma contains factors VIII and IX. However, as long as there is no need for plasma exchange, whole plasma is usually not prescribed for patients with severe hemophilia to increase the levels of factors VIII and IX in order to control bleeding. Freshly frozen plasma should be prescribed if immediate replacement therapy is necessary in the absence of a concentrated factor or if the cause of coagulopathy is not precisely established.

When developing a factor VIII inhibitor for treatment, it is better to use the recombinant Vila factor in subsequent administrations (90 μg / kg).

For treatment, desmopressin or antifibrinolytic drugs may be used. As described for von Willebrand disease, desmopressin may temporarily raise the level of factor VIII. For therapeutic use, the patient's response to prescribing desmopressin should be assessed beforehand. The drug is used after minor injuries or before some types of dental care, when substitution therapy can be avoided. Desmopressin should be used only in patients with hemophilia A (basal level of factor VIII> 5%), which have a good response to the administration of the drug.

Antifibrinolytic drugs (e-aminocaproic acid 2.5 to 4 grams orally 4 times a day for 1 week or tranexamic acid 1.0 to 1.5 g 3 or 4 times daily for 1 week) is prescribed for bleeding prophylaxis after tooth extraction or injury to the mucosa of the oropharyngeal zone (for example, tongue rupture).

Prevention

Patients with hemophilia should avoid the use of aspirin and non-steroidal anti-inflammatory drugs that depress the function of platelets less than aspirin. New COX-2 inhibitors have a small antiplatelet activity and cause less gastrointestinal erosion than aspirin and other non-steroidal anti-inflammatory drugs, and can be used with caution in hemophilia. A regular dental check is necessary, as it is desirable to avoid extraction of teeth and other dental surgical procedures. Drugs should be administered orally or intravenously, as intramuscular injections can cause hematomas. Patients with hemophilia should be vaccinated against hepatitis B.

[9], [10], [11], [12], [13], [14]