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Introduction

Hemophilia is a rare genetic disease caused by a lack of a blood clotting factor. Affected people bleed longer than healthy individuals when injured.

There are various types of haemophilia but the most common forms are:

  • hemophilia A, characterized by a deficiency of coagulation factor VIII. It is the most common form with 1 case in 10,000. The gene that provides (encodes) the information for factor VIII production is located on the X chromosome
  • hemophilia B, caused by a lack of coagulation factor IX. It concerns 1 case in 30,000. The gene that provides (encodes) the information for factor IX production is also located on the X chromosome
  • hemophilia C, much rarer it is caused by the lack of factor XI. The gene that provides (encodes) the information for the production of factor XI is located on chromosome 4

Haemophilia, both type A and B, mainly affects men. Type C haemophilia, on the other hand, affects both males and females.

Symptoms

The main disorder (symptom) that characterizes haemophilia is prolonged bleeding that can occur following an injury or after a medical intervention such as, for example, the extraction of a tooth, or, in some cases, for no apparent reason .

Some examples of spontaneous bleeding are:

  • sudden nosebleed (epistaxis)
  • bleeding gums
  • bleeding inside the joints, for example elbows or knees (joint bleeding)
  • muscle bleeding (hematomas)

Bleeding can also occur after surgery such as tooth extraction.

The severity of haemophilia is determined by the amount of the specific clotting factor present in the blood and is classified into:

  • mild, when the level of the coagulation factor is between 5 and 50% of the normal amount
  • moderate, if the level of the coagulation factor is between 1 and 5%
  • serious, when the percentage of the coagulation factor is less than 1%

Mild hemophilia

People with mild hemophilia may have no complaints (symptoms) for many years. The disease can manifest itself as unusually prolonged bleeding following slightly more serious injuries, after surgery or after tooth extraction.

Moderate hemophilia

People with moderate haemophilia are affected in the same way as those with mild haemophilia, but they tend to bruise more easily (blood spills into the tissues). They may also have bleeding inside the joints, particularly as a result of trauma caused by bumps or falls. This phenomenon is referred to as joint bleeding or hemarthrosis. The symptoms (symptoms) usually begin with a feeling of irritation and mild pain in the affected joint, most commonly ankle, knee and elbow. Less commonly, it can affect the shoulder, wrist and hip joints. If joint bleeding is not stopped quickly it can cause more severe joint pain and stiffness in the limb. The area where the bleeding occurred also becomes hot, swollen and painful.

Severe hemophilia

The disorders (symptoms) of severe hemophilia are similar to those of the moderate form. However, joint bleeding is more frequent and severe. People with severe hemophilia also have spontaneous bleeding and, if left untreated, can develop:

  • joint deformity (until surgery is required)
  • soft tissue bleeding
  • internal bleeding, even severe
  • spontaneous bleeding or haemorrhage within the skull, rare events (3%) that usually occur only after head injuries

Disorders (symptoms) of an "intracranial hemorrhage" include:

  • bad headache
  • stiff neck
  • He retched
  • mental confusion
  • difficulty speaking
  • changes in vision, such as double vision
  • loss of coordination and balance
  • paralysis of the facial muscles, some or all

If you suspect an intracranial hemorrhage, even a slight one, you should immediately go to the emergency room.

Causes

Hemophilia (A and B), mainly affects males, and is caused by a mutation of the genes that contain the information for the production of coagulation Factors VIII and IX.

Coagulation factors are blood proteins that are activated one after the other (cascade mechanism) and participate in the complex process of coagulation by platelets.

A genetic mutation is a "permanent alteration in the area of ​​the DNA that constitutes a gene. If the mutation of one or more genes causes the altered production of a protein that is the basis of some physiological processes of the organism, they will never be able to function in normal way. In the specific case of haemophilia, the lack / lack of a coagulation factor does not allow the formation of the clot that stops the leakage of blood. Consequently, a "haemorrhage" occurs which, depending on the severity, can be more or less unstoppable .

How the mutation is inherited

The genes involved in the production of coagulation factors VIII and IX are found on the X chromosome or one of the two chromosomes (the other is the Y chromosome) that define sex.Two X chromosomes are present in the cells of female individuals while in males there are one X chromosome and one Y chromosome. The X chromosome with the mutated gene can be inherited from the mother, father, or both.

The likelihood that a child will inherit the defective gene responsible for haemophilia depends on the parent who passes it on and on the possible chromosomal combinations:

  • if only the mother has the changed gene, the chances of having a healthy or sick child are:
    • a one in four chance of having a healthy male
    • a one in four chance of having a boy with haemophilia
    • a one in four chance of having a healthy female
    • a one in four chance of having a female with a mutated X chromosome and therefore being healthy carrier. The healthy woman carrying the mutated gene can pass haemophilia to her children, but usually has no serious complaints (symptoms). However, some healthy women with the mutated gene may have problems with bleeding or bleeding, especially during menstrual periods.

  • if only the father has the changed gene the chances of having a healthy or sick child are:
    • two in four chances of having a female with a mutated X chromosome and, therefore, a healthy carrier
    • no chance of having a male with hemophilia. In fact, the male child of a man with haemophilia inherits the X chromosome from his mother, who, being healthy, does not have the mutated gene.

  • if both parents have the mutated gene the chances of having a healthy or sick child are:
    • a one in four chance of having a healthy male
    • a one in four chance of having a boy with haemophilia
    • a one in four chance of having a healthy female with haemophilia
    • a one in four chance of having a female with haemophilia. This means that it is possible for a female to have hemophilia, although this condition is very rare

  • if no family member has haemophilia (no family history of haemophilia):
    • one third of new haemophilia cases are unfamiliar with this disease. A child, therefore, can be born with haemophilia even if there is no precedent in the family. In these cases, the mutation occurred spontaneously, on the X chromosome, at the time of gene transmission

Diagnosis

The assessment (diagnosis) of haemophilia can be done with a simple blood test (coagulation test) that verifies the time it takes to clot. The most used test is thepartial thromboplastin time examination (PTT). In haemophiliacs it is longer than normal. Subsequently, the individual deficient / absent coagulation factors are measured (VIII and IX).

If there have never been any cases of the disease in the family, the assessment (diagnosis) of severe haemophilia usually occurs when the child begins to crawl or walk; in the mild form, it occurs later, usually after a bleeding event.

Pregnancy

If you are planning a pregnancy and have a family history of haemophilia, you can undergo:

  • genetic counseling and genetic testing, to determine the risk of transmitting the disease to the child

If you are pregnant you can check the disease before birth (prenatal diagnosis) by:

  • Chorionic villus sampling or villus sampling: it consists in the removal of a fragment of the chorionic villi, that is the fine extroflexions that are part of the placenta and allow to analyze the DNA of the fetus and to identify the mutation for the haemophilia gene. Usually it is carried out between the 11th and the 14th week of pregnancy
  • amniocentesis: it consists in taking a small amount of amniotic fluid and allows to analyze the chromosomes of the fetus and to identify the mutation for the haemophilia gene. It is usually carried out between the 15th and 20th week of pregnancy

Since both procedures involve a percentage, even if minimal, of risk of causing miscarriage or premature birth, it is always advisable to talk to your doctor to evaluate their execution.

Assessment after birth

If prenatal diagnosis tests have not been performed during pregnancy, a simple blood test will be enough after the birth of the baby to ascertain whether or not the disease is present. Blood drawn from the umbilical cord can also be examined at birth.

Therapy

Today the haemophilia sufferer, thanks to scientific advances, can lead a fairly normal life. Quickly treating and stopping bleeding is essential to limit the damage. The treatment of haemophilia consists in administering the missing clotting factor and depends on the severity of the disease.

There are currently two main treatments:

  • preventive therapy (prophylaxis), consists of administering the missing coagulation factor (factor VIII for haemophilia A and factor IX for haemophilia B) to prevent bleeding and consequent damage to the joints and muscles
  • therapy on demand, involves the administration of the missing coagulation factor (factor VIII for haemophilia A and factor IX for haemophilia B) to block prolonged bleeding in progress

Hemophilia is usually treated by a team of doctors and nurses from a specialized hospital ward (Hemophilia Center).

Preventive therapy

In most cases, haemophilia is severe and requires a treatment (therapy) preventive (prophylaxis) with regular injections of the missing clotting factor. It can come from blood donor plasma or be synthetic in nature, i.e. obtained by genetic engineering. Usually, parents of sick children are taught how to inject the clotting factor.Later, when they are older, they will learn to self-inject the missing factor to avoid having to go to the hospital regularly. In some cases, injections can be done using an implantable device that is applied under the skin. Connected to a blood vessel located close to the heart, the device offers the advantage of not having to search for the vein every time clotting factor needs to be injected.

Haemophiliacs who undergo preventive therapy (treatment) need regular appointments at the hospital ward treating them so that they can be monitored over time. Preventive treatment is usually done throughout life. In some cases it is possible to switch to on-demand treatment but, in the event of significant bleeding episodes, it will be advised to return to preventive therapy.

The preventive therapy of haemophilia A and B includes:

  • hemophilia A, regular injections of a drug (octocog alfa) obtained synthetically thanks to recombinant DNA technology. This drug is an engineered version of coagulation factor VIII. Injections are recommended every 48 hours. Side effects of the drug are rare but sometimes an itchy rash, redness and pain at the injection site may appear.
  • hemophilia B, regular injections of a drug (nonacog alfa) obtained synthetically thanks to recombinant DNA technology. This drug is an engineered version of clotting factor IX. Injections are recommended twice a week. Undesirable effects (side effects) of the drug are rare but, at times, headaches, altered taste, nausea, discomfort and swelling at the injection site may occur

Therapy on request

In cases of mild or moderate haemophilia, therapy may only be needed to immediately stop a "bleed".

  • hemophilia A, injections of octocog alfa or with a drug called desmopressin. Desmopressin is a synthetic hormone. Hormones are chemicals that, by transmitting signals to cells, control various physiological functions of the body. Desmopressin works by stimulating the production of clotting factor VIII and is usually given as an injection. Possible side effects of desmopressin include headache, stomach pain, and nausea
  • hemophilia B, injections of nonacog alfa

Complications

Complications due to haemophilia can include the development of inhibitors (antibodies that inhibit the replacement factor), joint and muscle problems, infections.

Development of inhibitors

Some people treated with drugs based on clotting factors can develop antibodies, called inhibitors, which make replacement therapy less effective. Inhibitors can be counteracted by inducing immunological tolerance (ITI) or by giving the sick person high doses of concentrate of the missing factor every day so that their immune system learns to tolerate the replacement therapy, eliminating the production of antibodies that they neutralize its effectiveness. There induction therapy it is usually given to people with severe haemophilia A. People with haemophilia B can also do this therapy even if it is less effective and carries the risk of developing a severe allergic reaction and / or anaphylactic shock.

People with mild or moderate haemophilia A who develop inhibitors can be treated with "bypassing" agents that aim to bypass the factor in the clotting process and stop bleeding.
Studies are currently underway to treat the inhibitor problem.

Joint problems

Joint hemorrhages can damage the cartilage of the soft spongy tissues present in the joints and the thin membrane that covers them (synovium); the more a joint is damaged, the more vulnerable it is to bleeding. If left untreated, frequent internal bleeding can cause arthritis or joint destruction. Joint damage is more common in the elderly with severe hemophilia. Surgery can remove the damaged membrane that lines the joints (synovium) so that a new one can grow and / or insert a prosthesis, for example, of the hip or knee. It is hoped, however, that the advancement of the joints knowledge and new treatments can prevent hemophilic children from developing joint damage.

Deep internal bleeding

Bleeding that occurs deep inside the muscle can cause swelling of the limbs, which pressing on the nerves can lead to numbness or pain.

Intracranial hemorrhages

A simple blow to the head can cause small hemorrhages in the brain for some people who have severe hemophilia. This rarely happens but it is one of the more serious complications that can occur.

Symptoms include:

  • painful and prolonged headache
  • repeated vomiting
  • drowsiness or lethargy
  • double vision
  • sudden weakness or clumsiness
  • convulsions

Infections

People with hemophilia are more prone to blood transfusions. This increases the risk of receiving contaminated blood products. However, blood-derived products became safer after the mid-1980s thanks to blood control from donors.

Living with

Most people with haemophilia can live a normal life thanks to therapy with missing clotting factors (replacement therapy).

There are, however, some precautions to take and behaviors to avoid. They include:

  • avoid contact sports, such as rugby, soccer, etc.
  • avoid certain pain medications, especially those that can affect the blood's ability to clot, such as aspirin and ibuprofen
  • practice good oral hygiene, the goal is to prevent tooth extraction, which can lead to excessive bleeding. Caring for your teeth and gums helps avoid problems such as gum disease which can cause bleeding. Most non-surgical dental treatments can be done at a general dental office
  • exercise regularlyActivities such as swimming, cycling and walking can strengthen muscles while protecting joints
  • protect the child from possible trauma, to avoid bleeding. The use of knee pads, elbow pads, helmets and seat belts can help prevent injuries from falls and other accidents
  • keep the house free of sharp-edged furniture

Useful information

The haemophilic person should wear a medical alert bracelet that allows healthcare professionals to know immediately which therapy to administer in the event of an accident. Parents of a hemophilic child should be counseled by an expert in striking the right balance between wanting to protect them and encouraging them to do as many normal activities as possible.

A social worker or therapist with knowledge of haemophilia can help address parental concerns and identify the minimum boundaries needed for each child. Inform the people around and care for the child of his or her condition: babysitters, caregivers. schools, relatives, friends, teachers and coaches if the child plays any sports.

Bibliography

NHS. Haemophilia (English)

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