Hemophilia – causes, development mechanisms

An anomaly in which blood coagulates very poorly due to changes in blood factors and increases the bleeding of the body, is called hemophilia. This disease belongs to the classification of hemorrhagic diathesis, in which changes in the process of blood coagulation are considered normal. There were cases when patients with this disease died very quickly due to bleeding that suddenly opened.

In the cell nucleus are chromosomes. They store all the data about a person. Similarity with parents is determined by a special genetic code that is a member of the chromosome. When changes in genes occur, the gene mutates, and diseases arise. 23 pairs of chromosomes store all the data about any person. Then this information is transmitted hereditarily. Sexuals are the last pair of a series of chromosomes, we will designate them with the letters X and Y. For women, these are chromosomes XX, and for men XY.

The chromosome X contains the gene that mutated. He is responsible for the hereditary transmission of hemophilia. Will a child necessarily suffer from the same hereditary diseases as his parent? Not at all.

Every baby who is born has two genes. They are responsible for one of the signs, for example, hair color. One from the mother, and the other from the father. Distinguish between dominant and recessive genes. That is, predominant (or strong) and secondary (weak). If this happened with two dominant genes, then the strongest will manifest.

The mutated gene, by which the disease is transmitted, is recessive. And it is transmitted only with the X chromosome. A child will inherit a disease if it has two recessive genes that mutate this disease with two X chromosomes. When this phenomenon occurs, the baby dies at 4 weeks of gestation.

Therefore, women do not suffer from this disease, but are only carriers. The essence of a disease such as hemophilia, the cause of which only a genetic doctor will accurately reveal, is a violation of blood coagulation.

Causes of hemophilia are genes

Hemophilia affected only men, while women were responsible for the genetic component that they passed on to their descendants. This path of inheritance arises from the fact that the genetic predisposition to the disease is associated with the X chromosome.

Briefly consider the structure of sex chromosomes. In women, both have the same length and shape, so a pair of chromosomes is denoted by the letters XX. In men, one of them is the same as in women, but the second has a different shape and length, for this reason a pair of chromosomes is called XY. Each descendant receives one chromosome of the mother and one father with all the combination opportunities that are available in this conformation.

If a woman has a patient, that is, associated with a predisposition to a blood disease, the X chromosome, then this does not have direct consequences for the carrier, because the second, healthy one compensates for this chromosome. The woman herself has no symptoms, but she can pass on her predisposition to the disease by inheritance.

The X chromosome carries the genetic information that is necessary for the fetus to develop normal coagulation factors in the maternal womb. Hemophilic precisely in this place has a defect in the gene information. This pathological hereditary predisposition causes a bleeding disorder that underlies hemophilia.

It is known that in a normal individual, bleeding resulting from a wound soon stops due to three mechanisms: blood vessels are compressed, platelets are deposited in the damaged area and blood coagulates, thus closing the open wound.

Blood coagulation is a complex biochemical process in which fibrinogen — a protein in the plasma — changes its structure. This occurs under the influence of various factors, among which the release of tissue thromboplastin is very important. The formation of thromboplastin occurs with the help of numerous substances that are found in small amounts in the blood.

Clinical manifestations

• Light, characterized by a factor level of 5 to 15%. The debut of the disease usually occurs in the school years, in rare cases after 20 years, and is associated with surgery or injuries. Bleeding is rare and non-intense.

• Moderate. With a concentration of antihemophilic factor up to 6% of the norm. Appears in preschool age in the form of a moderate hemorrhagic syndrome, exacerbating up to 3 times a year.

• Severe is exposed when the concentration of the missing factor is up to 3% of the norm. It is accompanied by severe hemorrhagic syndrome from an early childhood. A newborn baby has prolonged bleeding from the umbilical cord, melena, cephalohematoma. With the development of the child – post-traumatic or spontaneous hemorrhages in the muscles, internal organs, joints. There may be prolonged bleeding from eruption or change of milk teeth.

• Hidden (latent) form. With a factor of more than 15% of the norm.

• Subclinical. The antihemophilic factor does not decrease below 16–35%.

In young children, bleeding can occur from biting the lips, cheeks, tongue. After infections (chickenpox, influenza, acute respiratory viral infections, measles), exacerbations of hemorrhagic diathesis are possible. Due to frequent and prolonged bleeding, thrombocytopenia and anemia of a different type and severity are detected.

• Hemarthrosis – heavy bleeding in the joints. According to the purity of hemorrhages, they account for from 70 to 80%. Ankles, elbows, knees suffer more often, less often – hip, shoulder and small joints of fingers and toes. After the first hemorrhages in the synovial capsules, the blood gradually dissolves without any complications, the function of the joint is fully restored.

Repeated bleeding leads to incomplete resorption, the formation of fibrinous clots, deposited in the capsule of the joint and cartilage with their gradual germination by connective tissue. It manifests itself as severe pain and restriction of movement in the joint. Recurrent hemarthrosis causes obliteration, joint ankylosis, hemophilic osteoarthrosis and chronic synovitis.

• Bleeding into bone tissue results in bone decalcification and aseptic necrosis.

• Hemorrhages in the muscles and subcutaneous tissue (10 to 20%). Blood poured into the muscles or intermuscular spaces does not clot for a long time, so it easily penetrates the fascia and nearby tissue. Clinic of subcutaneous and intramuscular hematomas – poorly absorbable bruises of various sizes. As complications, gangrene or paralysis is possible, resulting from compression of large arteries or peripheral nerve trunks by volume hematomas. This is accompanied by severe pain.

Statistics On the territory of Russia, there are about 15 thousand men with hemophilia, of whom about 6 thousand are children. More than 400 thousand people with this disease live in the world.

• Prolonged bleeding from the mucous membranes of the gums, nose, mouth, different parts of the stomach or intestines, as well as from the kidneys. The frequency of occurrence up to 8% of the total number of all bleeding. Any medical manipulations or surgeries, be it tooth extraction, tonsillectomy, intramuscular injection or vaccination, result in heavy and prolonged bleeding. Bleeding from the mucous membrane of the larynx and pharynx is extremely dangerous, as this can result in airway obstruction.

• Hemorrhages in different parts of the brain and meninges lead to disorders of the nervous system and associated symptoms, often ending in the death of the patient.

• Hematuria spontaneous or due to lumbar injuries. It is found in 15–20% of cases. Symptoms and disorders that precede her are urination disorders, pyelonephritis, hydronephrosis, pyeloectasia. Patients pay attention to the appearance of blood in the urine.

Hemorrhagic syndrome is characterized by a delayed appearance of bleeding. Depending on the intensity of the injury, it can occur after 6-12 hours and later.

Acquired hemophilia is accompanied by a violation of color perception (color blindness). It is rare in childhood, only with myeloproliferative and autoimmune diseases, when antibodies to factors begin to develop. Only 40% of patients manage to identify the causes of acquired hemophilia; these include pregnancy, autoimmune diseases, certain medications, and malignant neoplasms.

If the above manifestations appear, a person should contact a specialized hemophilia treatment center, where he will be prescribed an examination and, if necessary, treatment.

The clinical picture is characterized by an increased tendency of patients to lose blood. A few days after birth, non-stop bleeding may appear, which jeopardizes the life of the newborn. But in some cases, hemophilia appears only when the child starts to run. Then parents can observe an increased tendency to bruises, bruises and bleeding in the skin and mucous membranes after commonplace microtraumas, such as light tremors, concussions, etc., which indicates this blood disease.

At this age, nosebleeds or bleeding of the oral mucosa (teething) are also common. In older children, after tooth extraction or tonsillectomy, heavy bleeding follows. These are the first signs of hemophilia. Bleeding can also occur in internal organs – the liver, spleen, intestines, kidneys and brain, or, as often happens, in joints.

In this case, they talk about hemophilic arthropathy or hemarthrosis. As a result of such intraarticular bleeding, especially in the knee, there is a danger of destruction of bones and cartilage and a significant restriction of the movements of the affected joint, up to their complete absence.

Hemophilia is a disease in which symptoms can occur with different intensities. The severity of the symptoms is proportional to the severity of the genetic defect. If this coagulation factor is completely absent, then the patient is in extreme danger. In severe cases, death occurs already in early childhood due to cerebral hemorrhage, too much blood loss after injuries, or even because blood accumulates in the neck, and this leads to suffocation.

The grown-up child is increasingly aware that he is sick, and is learning to control his activity, and if possible, to avoid accidents and injuries. If young patients survived early childhood, then they can rightfully hope for a long active life. It is impossible to predict more precisely what kind of development the disease will take over time.

There is a period when injuries cause only slight loss of blood or even are not accompanied by bleeding at all, then again the time comes when there are extensive, almost unprovoked bleeding. Those. hemophilia and its symptoms can manifest in waves.

Hemophilia is a congenital disease. Therefore, newly born children already have this disease. Signs of hemophilia in newborns are manifested in the form of: bleeding from the umbilical cord, various types of subcutaneous hematomas. All this is due to the fact that in patients with this disease, the vessels are very susceptible to various, even the most insignificant, injuries.

When milk teeth grow, they can injure the tongue, lips, cheeks. Also, a similar phenomenon can provoke bleeding from the oral mucosa. But in newborns who are breastfed, hemophilia is rarely manifested. Because active thrombokinase, which is found in breast milk, temporarily blocks the development of the disease. Therefore, women who have just given birth are recommended to breastfeed their babies.

As soon as the child gets up and takes his first steps, post-traumatic bleeding can become a very common occurrence. This is how hemophilia manifests itself. This disease in a child after a year can manifest itself as frequent nosebleeds, hematomas in the body, as well as hemorrhages in large joints. In a baby with hemophilia, after passing the infections (chickenpox, acute respiratory viral infections, rubella, measles, flu), hemorrhagic diathesis may be exacerbated.

Hemophilia hemorrhages manifest themselves in different ways. In 70-80% of the blood can accumulate in the joints. This phenomenon is called hemarthrosis. The occurrence of hematomas occurs in 10% of cases. In urine, blood is found in 14-20%, bleeding in the digestive tract is possible in 8% of patients, and 5% of patients are prone to hemorrhages in the central nervous system.

Severity of illness

By the level of blood coagulation, you can determine the severity of hemophilia:

  • if blood coagulation is very low, due to factors VIII, IX or XI, and their level is 0-1%;
  • a factor level of 1-2% characterizes a severe form;
  • coagulation factor 2-5% is characteristic for moderate hemophilia;
  • if blood coagulation is below normal and at a factor level of 5%, then a mild form of hemophilia is assigned. But in case of severe injury, severe bleeding is possible, which can result in death.


At the stage of pregnancy planning, future parents can undergo a genetic consultation with molecular genetic research and genealogy data collection.

Perinatal diagnosis consists of an amniocentesis or chorin biopsy followed by DNA testing of the resulting cellular material.

The diagnosis is established after a detailed examination and differential diagnosis of the patient.

A physical examination is mandatory with examination, auscultation, palpation, collection of family history to identify possible inheritance.

– coagulogram; – quantitative determination of factors IX and VIII; – definition of INR – international normalized relations; – a blood test to calculate the amount of fibrinogen; – thromboelastography; – thrombodynamics; – prothrombin index; – calculation of APTT (activated partial thromboplastin time).

The appearance of hemarthrosis in a person requires an x-ray of the affected joint, and hematuria requires an additional study of urine and kidney function. Ultrasound diagnosis is performed with retroperitoneal hemorrhages and hematomas in the fascia of internal organs. If you suspect a hemorrhage in the brain, a CT scan or an MRI scan is mandatory.

Differential diagnosis is performed with Glanzmann thrombasthenia, thrombocytopenic purpura, von Willebrand disease, thrombocytopathy.

To diagnose hemophilia, a person will have to visit certain specialists, such as a pediatrician, geneticist, hematologist and neonatologist. If the disease manifests itself in childhood, then you should consult with a pediatric gastroenterologist, otolaryngologist, traumatologist and neurologist.

If the couple is at risk, then the best option is a full examination at the planning stage of the child. To identify the carriage of a defective gene, it is necessary to undergo a molecular genetic examination and pass an analysis on genealogical data. You can also make a diagnosis using a chorionic biopsy or amniocentesis, as well as DNA testing of cellular material.

After birth, it is possible to diagnose diseases with the help of laboratory studies of hemostasis.

To clarify the diagnosis, tests may be required:

  • determining the amount of fibrinogen
  • prothrombin index determination
  • thrombin time
  • mixed definitions

Couples who are expecting a baby and are at risk should consult with specialists and conduct appropriate studies from the beginning and throughout pregnancy.

Hemophilia in men

In medical practice, male hemophilia does not have distinctive features. If the carrier of the altered gene is the mother, then the first signs of pathology can be diagnosed in early childhood. Boys experience minor bleeding that occurs even with minor injuries. More serious hemorrhages are indicated by bruising, which can provoke the formation of serious pathologies, such as tissue necrosis.

If a man is sick with hemophilia, then antihemophilic drugs are required before any surgical intervention, which helps to avoid excessive blood loss.

The most serious hemorrhages are those that occur in the meninges. They can provoke severe forms of central nervous system damage and even lead to death. Also, retroperitoneal hemorrhages are classified as complex in men, because they can become the basis for the occurrence of acute pathologies, which can only be eliminated surgically.

No less dangerous are bleeding that occurs in the larynx and throat from the mucous membranes. They can lead to severe attacks of coughing and tension of the vocal cords and, as a result, airway obstruction.

When joint hemorrhages occur in men, soreness appears, and a temperature increase of up to 38 degrees is observed. Such deviations can cause osteoarthrosis and muscle atrophy of the limbs.


Hemarthrosis occurs most often. It is believed that hemophilia appears in this very specific way. This disease is quite insidious. And for the first time, such hemorrhages occur at the age of children from a year to 8 years after bruises and injuries. It can also occur spontaneously. Hemarthrosis is expressed as an enlarged joint, the presence of pain.

Hyperthermia of the skin also appears. The constant occurrence of hemarthrosis in hemophilia is fraught with the occurrence of a chronic inflammatory process in the joint, as well as its deformation and restriction of movements. Such consequences lead to the disruption of the dynamics of the musculoskeletal system, and disability occurs in childhood.

Hemophilia in women

Hemophilia in women is rarely diagnosed. That is why the nature and features are difficult to identify.

Cases of hemophilia in women are most often diagnosed if girls are born from a mother who is recognized as the carrier of the gene and father of the person suffering from this disease. As for the severity of the pathology, it is fully consistent with the degree of deficiency. In women, the following forms of pathology can be detected:

  1. Severe – characterized by a coagulation index of less than 2%. Symptoms are most pronounced in childhood. An ailment in this case can be manifested by systematic bouts of hemorrhages in the muscles, joints and internal organs. Gum bleeding can occur during shifts or teething. As they grow older, the symptoms progress rapidly.
  2. Moderate – progression of the pathology occurs if the level of the factor varies from 2 to 5 percent. Then the symptomatology is moderate and manifests itself as a joint-muscular hemorrhage, and the frequency of exacerbation is once every several months.
  3. Easy – the value of the deficit factor exceeds 5 percent. The first symptoms appear in school age as a result of surgery or injury. Bleeding has a low intensity and is expressed relatively infrequently. In the process of laboratory research, the ailment may not be detected.
  4. Erased – does not show any signs. A person in such a case may not be aware of the disease at all. It is detected most often only after any surgical intervention.

In women, even when a pathology is detected, it proceeds in a less severe form. The fact that the woman was the carrier of the gene and suffers from this disease is evidenced by the following symptoms:

  • intense discharge during menstruation;
  • bleeding from the nose;
  • bleeding that occurs after dental interventions;
  • coagulation deficiency.


Hemophilia is a disease that is manifested by the occurrence of hemorrhages in the soft tissues, that is, in the subcutaneous tissue and muscles, permanent bruises that remain on the body, and non-absorbable and intramuscular hematomas. The latter spread, since blood does not clot as it should.

Hemophilia is characterized by increased bleeding. In this case, even a regular intramuscular injection can cause bleeding. It can be dangerous for both health and life. For example, bleeding from the pharynx and nasopharynx can lead to airway obstruction. Then emergency tracheotomy will be needed. Severe CNS lesions can result from cerebral hemorrhages.

Spontaneously or due to trauma to the lumbar region, blood in the urine can be caused. In this case, the process of urination is disturbed. Then the blood coagulates in such a way that blood clots form in the urine. Hemophilia can often cause kidney diseases that are characterized by a strong inflammatory process, which will subsequently affect the functioning of the whole organism.

If you take anti-inflammatory and antipyretic drugs, then gastrointestinal bleeding may occur if the patient has hemophilia. As a result, a stomach ulcer, duodenal ulcer, erosive gastritis, hemorrhoids may worsen. Bleeding with hemophilia after an injury may not occur immediately, but only after an incident of 6-12 hours.

A child is examined by several doctors: a neonatologist, pediatrician, geneticist and hematologist. And only after that hemophilia is diagnosed. If the child has a pathology or complication of the underlying disease, then an examination of children’s doctors is necessary: ​​a gastroenterologist, an orthopedic traumatologist, an otolaryngologist and a neurologist to monitor how hemophilia develops. What kind of disease can you find out from a doctor who specializes in blood diseases.

Pregnancy Planning and Hemophilia

Since hemophilia carries the possibility of significant blood loss, during the gestation of a child, the processes can be not only unexpected, but sometimes irreversible. Having become pregnant, a woman must visit many specialists, such as an orthopedist, therapist, surgeon, and geneticist. Childbirth should occur only in a specialized clinic under the close supervision of highly qualified specialists.

Determined delivery tactics should be clearly defined already from the third trimester. In this case, all factors must be taken into account, such as the type of disease, the condition of the woman. All the nuances should be carefully thought out and the likelihood of severe blood loss to be minimized, and a favorable delivery should be ensured.

In addition, the following risks should be excluded by all possible means:

  • death during cesarean section;
  • the formation of cerebral hemorrhages during childbirth;
  • the likelihood of vascular pathologies and the penetration of infections;
  • the development of articular pathological processes that can be caused by tissue deformation;
  • the likelihood of immobility of the joints.

At present, practically nothing is known about the potential dangers for the fetus, except for the fact that a woman may have severe bleeding.

As practice shows, if the birth takes place in the normal mode, then in this case the probability of injuries and dangers is minimized, but there is always the possibility of exceptions, therefore, with hemophilia, all safety measures should be taken in advance, and the birth should be done only by qualified doctors.

If only a birth is planned, then future parents who are at risk should be consulted by a geneticist. This should be done before the pregnancy has been determined. Genealogical data and molecular genetic diagnostics determine who carries the defective gene.


a) intestinal obstruction or compression of the ureters with extensive hematomas; b) deformations of the musculoskeletal system – muscle hypotrophy, overdose of the cartilage, curvature of the pelvis or spinal column, as a complication of hemophilic osteoarthritis; c) infection with hematomas; d) airway abstraction.

• Associated with the immune system – the appearance of inhibitors of factors that impede treatment.

They are at greater risk of contracting HIV infection, herpetic and cytomegalovirus infections, and viral hepatitis.

As a consequence of the pathology or during the treatment of hemophilia in a person, certain complications may begin to develop. Bleeding can lead to anemia of varying severity. Deaths are not excluded, this applies mainly to women who have a caesarean section.

With the formation of a hematoma, gangrene formation may occur or paralysis may develop. This occurs as a result of compression of blood vessels or nerves. Necrosis and osteoporosis, which appear due to frequent hemorrhages in the bone tissue, are not excluded. With bleeding, obstruction of the airways may form. More serious complications, such as hemorrhage, in the brain or spinal cord, which leads to death, are not excluded.

A complication of chronic hemophilia is arthropathy. It develops if bleeding occurs spontaneously and mainly in one joint. Under the influence of blood components, the synovial membrane is inflamed, which thickens over time, outgrowths form on it, penetrating the articular cavity.

In the process of joint mobility, outgrowths are infringed, which provokes new hemorrhages, but already without injury. This leads to the gradual destruction of the tissue of the cartilage joint and exposure of the surface of the bone. In some cases, there is a possibility of developing renal amyloidosis with subsequent chronic renal failure.

With this kind of disease, viral hepatitis and HIV infections are not excluded, but thanks to modern conditions and the latest cleaning methods, the risk of infection is minimized.

In rare cases, a person may be triggered by a reaction of the immune system in the form of producing antibodies stopping the ability to maintain blood coagulation. In medical practice, this is expressed by the impossibility of stopping bleeding with the help of replacement therapy.


With a mild form, the prognosis is favorable. In severe cases, it worsens significantly. In general, it depends on the type, severity, timeliness of treatment and its effectiveness. The patient is registered, given disability.

How many live with different types of hemophilia? The mild form does not affect the patient’s life expectancy. Effective and constant treatment with moderate and severe form helps the patient live as much as healthy people. Death occurs in most cases after cerebral hemorrhages.

As for the forecast, it will directly depend on how carefully a person will relate to his health and follow all the recommendations of specialists.

The prognosis for severe hemophilia worsens significantly if a person experiences rapid bleeding due to injuries or surgery. As for the mild degree of hemophilia, the life expectancy remains the same and the pathology does not have a negative effect on the body.

Relatives of the patient must have an idea of ​​the features of the disease and, if necessary, be able to provide first aid.

What to do in cases of cut?

Even with the smallest hemorrhages, serious measures must be taken. Because with hemophilia, it can become fatal.

If this is a cut, then you can apply a hemostatic sponge on it, a pressure bandage and treat the wound with thrombin. Complete peace is needed even when an uncomplicated hemorrhage has occurred. In this case, the patient should be placed in a cool room, you need to fix the damaged joint with a longet. In the future, his condition should be monitored using diagnostics. Compliance with a certain diet is also important. Food should be enriched with vitamins A, B, C, D and calcium and phosphorus salts.


There is no specific prophylaxis. Only medical prophylaxis is possible, which prevents the occurrence of bleeding.

The main method of hemophilia prevention is consultation and a complete medical examination of couples immediately before marriage. In this case, a special gene diagnosis is carried out, according to the results of which the probable risks of transmission of the pathology by inheritance are revealed. If couples are diagnosed with an ailment, then they are not recommended to plan the conception of children in a natural way.

If for some reason the diagnosis was not carried out before pregnancy, then it is advisable to organize a diagnosis after conception. Since subsequently, if hemophilia is detected in childhood, therapeutic and preventive measures are appropriate.

Patients diagnosed with hemophilia should be under constant follow-up. They are then registered in early childhood. When diagnosing a disease in a child, he is exempted from physical education, as there is a high risk of injury. But, despite all the restrictions, moderate physical activity must be present.

They are necessary, especially for a growing body for normal functioning. There are no special restrictions on nutrition. The baby must be vaccinated against the maximum number of infections, but vaccinations are given only subcutaneously and with extreme caution, since extensive hematomas may appear after intramuscular administration.

In order to minimize the risk of complications, you should try to avoid excessive physical exertion, various injuries, as well as go through all the procedures recommended by your doctor and follow the dosage regimen. In viral diseases, it is strictly forbidden for a hemophilia patient to take Aspirin, since this drug helps to thin the blood and can cause bleeding.

To prevent hemophilia, a person is injected with a missing blood factor at specific time intervals. In some cases, special venous catheters can even be installed that minimize the risk of injury.

Important Note

If the therapy is carried out for a long time, which consists of the introduction of concentrates of the missing factors, the body will begin to produce antibodies. The latter will block the effectiveness of the introduced factors. In such cases, hemostatic therapy becomes ineffective.

Therefore, immunosuppressants and plasmapheresis are additionally prescribed. Patients with hemophilia often receive blood transfusions, and there is a risk of contracting HIV infection, hepatitis B, C, D. You need to be very attentive to this event and find out if all checks have been carried out.

Life with ailment

Life expectancy does not change, if the patient has a mild degree of hemophilia, if not, then the consequences of massive bleeding can affect not only its quality. Therefore, people with hemophilia can live a short period of time.

Also, preventive measures of hemophilia include consultation in the field of medical and genetic research of married couples who have relatives who are ill with this disease.

Children with this diagnosis should always have a passport with the indicated disease, blood type and Rh factor. Such babies must be observed by a pediatrician, hematologist and other doctors.

In addition, people with this disease should be on specialized medical records. They need to be constantly observed in order to monitor the dynamics of the course of hemophilia. Also for the selection and use of the latest methods of treatment for this disease.

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Svetlana Borszavich

General practitioner, cardiologist, with active work in therapy, gastroenterology, cardiology, rheumatology, immunology with allergology.
Fluent in general clinical methods for the diagnosis and treatment of heart disease, as well as electrocardiography, echocardiography, monitoring of cholera on an ECG and daily monitoring of blood pressure.
The treatment complex developed by the author significantly helps with cerebrovascular injuries and metabolic disorders in the brain and vascular diseases: hypertension and complications caused by diabetes.
The author is a member of the European Society of Therapists, a regular participant in scientific conferences and congresses in the field of cardiology and general medicine. She has repeatedly participated in a research program at a private university in Japan in the field of reconstructive medicine.