Hemophilia

Hemophilia is an inherited bleeding disorder in which the blood does not clot properly. This can cause bleeding both spontaneously and after an operation or injury. It is related to the X chromosome in the two main types: hemophilia A, when there is a deficiency of coagulation factor VIII, and hemophilia B, when there is a deficiency of coagulation factor IX. In almost all cases, this disease is recessive for women, because if one of the parents is a hemophiliac, the other inherited chromosome will come from a healthy father. This is not the case with sons, since there is a high probability of inheriting the diseased X chromosome in them.

History

Antiquity

The oldest studies date back to the II century AD. C., when Jewish rabbis realized that some male children, when they were circumcised, bled a lot. The rabbis discovered that these problems only occurred in certain families, so they made new regulations to help these bleeding children. Rabbi Judah stated that a boy who had older brothers with bleeding problems did not have to be circumcised and Rabbi Simeon ben Gamliel prevented a boy from being circumcised because the sons of the mother's three sisters had bled to death.

Among the later written references, it is worth highlighting the description of the disease made in the XI century by an Arab doctor from Córdoba, called Abulcasis.

In the 12th century, another rabbi named Maimonides discovered that if children had hemophilia, it was the mothers who they transmitted it. He then made a new law: if a mother had sons with this bleeding problem and she remarried, none of her new male descendants should be circumcised.

The first reference in Central Europe is given in Italy, in 1525, by Alejandro Benedicto.

Contemporary Ages

In the 1800s, an American physician named John Conrad Otto (1774-1844) conducted his first study of hemophilia families, and in 1803 discovered the genetics of hemophilia A. He found that mothers without a bleeding problem could transmit hemophilia to their sons, and their daughters could pass it on to their grandchildren and great-grandchildren.

In 1928, Dr. Hopff first described the disease with the word "hemophilia."

The history of hemophilia treatment begins in the 1900s, when fresh blood transfusions were given to increase the longevity of people with hemophilia, since the average lifespan was approximately 13 years.

• In 1950 the plasma provision for treatment was initiated.
• In 1965 it was made available to the plasma cryoprecipitate.
• In 1970, the production of concentrates by coagulation factors began.
• In 1980, there was a drop in this treatment because 80% of those who suffered hemophilia were infected with HIV/AIDS.
• As a result, in 1985, each of the factors were subjected to viral inactivation, increasingly making the process more antiseptic.
• In 1992, the first factor that was not derived from plasma, obtained by recombinant DNA technology, came to the market.
• In 1995, the first prophylactic treatment was introduced, capable of replacing the weakened factor.

The most famous case of hemophilia was that of the last Tsarevich of Russia, Alexei Nikolayevich Romanov (1904-1918), passed on by his transmitting mother, Alexandra Fedorovna Romanova (1872-1918), granddaughter of Queen Victoria of the United Kingdom (1819-1901), also a transmitter of this disease. Also noteworthy are the cases of hemophilia in Spanish royalty in the children of Alfonso XIII (1886-1941) and Queen Victoria Eugenia (1887-1969), also a granddaughter of Queen Victoria of the United Kingdom, and which profoundly affected the monarchy. Spanish.

Classification

Hemophilia A

Hemophilia A occurs when there is a deficiency in coagulation factor VIII.

Hemophilia B

When there is a deficiency of coagulation factor IX. The incidence of hemophilia B is 1 in 32,000 living males.

Hemophilia B of Leyden

This is a variant form of hemophilia B, it is less common. It shows an extremely unusual feature of age-dependent expression. Factor IX values are less than 1% during childhood, making the disease very severe in children; after puberty, values rise to around 50% of normal and the disorder becomes asymptomatic.

Hemophilia C

When there is a deficiency of coagulation factor XI.

Etiology

In each human cell there are 46 chromosomes: half we inherit from the mother and the other half from the father. Chromosomes contain the instructions needed to tell cells how to make the proteins the body needs to function. These instructions are contained in small formations called genes, made up of DNA, which are the basic structure of life.

Chromosomes come in pairs, so we have two copies of all our genes; if there is damage to a gene or chromosome, there is a backup copy of that gene or chromosome that can function normally. But there is an exception, the sexual chromosomes: X and Y.

The female sex is determined by two X chromosomes (XX), and the male sex has one X and one Y (XY) chromosome. The X chromosome contains many genes that are common to both sexes, such as the genes for the production of factor VIII and factor IX, which are related to blood clotting.

Women have two copies of those specific genes while men only have one. If the male inherits a chromosome with a damaged factor VIII gene, it is the only gene he receives and has no supporting information, so he will not be able to make that clotting factor.

This hereditary anomaly manifests itself in women, but in a very low percentage, since women normally carry the gene, they are also exposed to its consequences, since to manifest the disease they would need two defective copies, which is highly unlikely. Currently, in Spain, the incidence of people born with hemophilia is 1 in 15,000. Even due to the inactivation of the X chromosome that all women do, it may be that women carrying the defective gene show a mild hemophilia genotype.

Symptoms

The main feature of hemophilia A and B is hemarthrosis and prolonged spontaneous bleeding. The most serious hemorrhages are those that occur in the joints, brain, eye, tongue, throat, kidneys, digestive, genital, nasal, etc.

The most common clinical manifestation in patients with hemophilia is hemarthrosis, intra-articular bleeding that especially affects single-axis joints such as the knee, elbow or ankle. If hemarthrosis occurs repeatedly in a joint, it causes a muscle deformity and atrophy called hemophilic arthropathy.

As possible symptoms can be classified into three states: I, II and III; State I includes tingling in the joints and fever in that part of the body, this is related to having a hemorrhage with trauma. In stage II, this tingling begins to be felt as pain, the fever still remains in the affected part of the body and is accompanied by inflammation due to the accumulation of blood present in the bone joint, due to spontaneous hemorrhage with severe bleeding. As the last state, stage III presents the viscous and inflamed joint due to muscle weakness, morning stiffness (everything related to the morning), chronic pain and limited movement due to joint obstruction. Interpreted as spontaneous hemorrhage in muscle and joint.

Diagnosis

The diagnosis of the type of hemophilia and its level of severity is made through the clinical history and a blood test to measure, in the laboratory, through special coagulation tests, the degrees of the different factors. The objective is to establish the severity of the disease and decide the most appropriate treatment to be followed by the patient. Currently, the values of the different factors are rarely used for carrier detection or prenatal diagnosis, since linkage analysis or direct analysis of mutations allow more reliable results.

Laboratory tests

Treatment

There is currently no curative treatment available (with the exception of liver transplantation), and the only thing that can be done is to correct the bleeding tendency by administering the missing clotting factor, factor VIII, or IX intravenously.

As possible treatments, there is a home treatment that consists of resting the body and on the affected area, leaving ice for two hours on that part of the body and subsequently elevating the joint.

Substitution treatment represented a major advance both for the quality of life and for the survival of patients. Obtaining coagulation factors from human plasma gave rise, on many occasions, to the transmission of viruses, especially the HIV virus (which causes AIDS) in the eighties, which meant a serious setback in the lives of patients. hemophilia patients.

In the middle of that same decade, the first viral inactivation methods were introduced in lyophilized concentrates, transforming them into much safer products.

Currently, double-inactivated lyophilized concentrates are safer plasma derivatives and state-of-the-art technology is constantly being evaluated and introduced into these products to inactivate new viruses and other infectious agents, such as prions, that could pose a threat to those that use products derived from human plasma.

In recent years, the development of genetic engineering has made it possible to start a new era in the treatment of disease. For the past few years, more pure preparations of coagulation factors have been developed, without the need for human plasma. Recombinant factor VIII, the most widespread, is produced from cells grown in the laboratory.

In recent decades, the focus of hemophilia therapies has been on replacing the missing clotting factor; however, biotechnology combined with a greater understanding of the biochemistry of coagulation is currently changing the treatment paradigm.

Different types of hemostatic agents are available for the management of hemophilia A. These are divided into replacement therapies and non-replacement therapies. Replacement therapies, better known as factor concentrates, are the treatment of choice for people with hemophilia, because they are safe and effective to treat and prevent bleeding, for example: factor eight, factor nine, extended half-life products, bridging or bypassing agents, recombinant factor seven, prothrombin complex concentrate. There are also non-replacement therapies that are not factors, such as Emicizumab, the first and only replacement therapy to date. The key benefits of this therapy are its subcutaneous route of administration and the reduction in the frequency of bleeding episodes in patients with or without inhibitors.

The World Federation of Hemophilia recommends: The use of virus-inactivated recombinant or plasma-derived factor concentrates, avoiding the use of fresh frozen or cryoprecipitated plasma, due to quality, safety, and efficacy issues. All patients with exogenous factor eight inhibitors should be considered for regular prophylaxis to prevent bleeding. Patients with hemophilia A and exogenous factor eight inhibitors should be on emicizumab prophylaxis.

As a medication, desmopressin is mainly used to release factor VIII from blood vessels, It should be noted that conventional aspirin (acetylsalicylic acid) should not be used as this is an antiplatelet agent, and it will not allow a thrombus to form in any body laceration, this would be an aggravating factor for the patient's condition. And as an obvious measure, there is the supply of the missing factor intravenously, either by means of reserves such as fresh frozen plasma, cryoprecipitates, but as a recommended measure, lyophilized factor of the factor to be used.

There are enormous expectations for treatment through gene therapy, which consists of introducing genes into certain cells of the patient that are capable of combining with the existing genetic material, providing the information that is missing to manufacture the deficient protein that causes the disease. Hemophilia is a good candidate for gene therapy as it does not require regulation of the inserted factor VIII or IX genes (even gene overexpression would not be counterproductive as genes naturally have great variability), it is easy to access to cells for ex vivo therapy, there are good animal models, and a small increase in plasma levels would be enough to convert a severe pathology into a milder form (in addition, the levels are easily measurable in any hospital).

The objective of physiotherapy in the treatment of hemophilia, as prophylaxis, is to advise and program physical activities and sports with minimal risks, which prevent the appearance of musculoskeletal injuries secondary to poor physical condition.

On the other hand, regarding the treatment of injuries, physiotherapy shows its collaboration and its resolution of the bleeding episode, it acts on inflammation, reduces pain and recovers lost function, trying to avoid or reduce sequelae.

There are two types of treatment: Prophylaxis (the patient injects his corresponding medicine intravenously several times a week), or on demand (the patient injects the medicine every time hemorrhage occurs).

Similarly, the meeting of medical specialists in Buenos Aires, ―in conjunction with the World Federation of Hemophilia― agree on the use of the equation for the replacement of factor VIII (with results in UI) that corresponds to:

patient weight × missing percentage of factor VIII × 0.5

It is said that it is better to handle the infusion of lyophilized factor by pharmaceutical products, the use of cryoprecipitates is not recommended, since they have not undergone a viral sweep, and due to the use of this, there may be many more pathologies. They consider the stability of the patient 8 hours before any surgical intervention for at least 8 hours of follow-up and supplying the missing or deficient factor. He emphasizes that the use of Desmopressin is exclusively for prevention but not for surgical treatment. Drawing a difference limit between the factors, and more specifically between the equation for the supply, factor IX handles almost the same equation, but it is more specific in the life cycle of people, since the calculation for children is different than for Adults; for children the calculation is:

weight × factor percentage to infuse × 1.5

On the other hand, for adults it is:

weight × factor percentage to infuse × 1.2.

Forecast

Today, the survival of a patient with hemophilia is high, thanks to the intravenous supply of antihemophilic factor. People with this disease can lead a completely normal life with proper treatment.

Guidelines for action with patients with hemophilia

• Never supply aspirin (acetylsalicylic acid) to a patient with hemophilia.
• Intramuscular injection is totally contraindicated.
• The use of ibuprofen-type anti-inflammatory drugs is unknown.
• Wetatic coverage with factor.

Situations in which you need to go to the hospital

It's important to know when to go to the hospital and who to contact about a bleeding problem before it occurs. Certain personal circumstances or local conditions due to proximity to a specialized center may modify the possibility of obtaining hospital care, but all these situations are those that require prompt consultation and immediate treatment:

• Pain in joints or muscles. Do not wait for the swelling to be visible.
• External hemorrhagia that cannot be stopped or used after first aid treatment.
• Blood in the urine or in the feces.
• After a fall with a blow to the head or other head injury, or if there is a headache or nausea and prolonged vomiting without justified cause.
• Hemorrhage or swelling in the area around the neck.
• Inexplicable abdominal pain.
• It is important to get to a hospital center, say the condition of hemophilia and ask for the hematologist in the center.

Inheritance

Hemophilia transmission table

Hemophilia A and hemophilia B are Gonosonomic inheritance (sexual, linked to chromosome X); the altered gene in hemophilia A is located in the locus Xq28{displaystyle Xq28}and hemophilia B, in Xq27.1− − q27.2{displaystyle Xq27.1-q27.2}.

Thus, it has a much higher prevalence in males, where it acts as a holandric character:

• With an unbearing father with hemophilia and healthy mother: 100% of their daughters will be healthy carriers (herit the mutated allele of the father), and 100% of the children will be healthy non-bearers (they have no one to receive the mutated X).
• With a father with hemophilia and a healthy mother carrier (heterozygota): 50% of the daughters will be healthy carriers and 50% of the daughters will be hemophilic. As for male children, 50% will be patients with hemophilia (because they receive a single X mother, which in this case is the mutate) and 50% will be healthy non-bearers (have received the X without defect).
• With a healthy father and healthy mother: 50% of the daughters will be healthy non-bearers, and 50% will be healthy bearers. As for male children, as in the previous case, 50% will be patients with hemophilia and 50% will be healthy non-bearers.

Hemophilia C is of autosomal recessive inheritance, with equal frequency in both sexes.

Hemophilia is a condition suffered almost exclusively by men, and almost all patients with hemophilia are the children of healthy mothers, carriers of the gene, that is to say that in their ancestors there was some patient, but in almost a third of the patients has occurred without a family history. In these cases, hemophilia is caused by a mutation in the mother's or child's gene.

The disease has been specially studied because it affects a large part of the European royal families, at least those whose members descend from Queen Victoria of England who transmitted hemophilia to one of her sons (who died of internal bleeding after a fall) and at least two of his daughters who were the ones who spread the disease through the European royal families. There were no known cases of hemophilia among Queen Victoria's ancestors and this was normal, it is assumed that the disease appeared by mutation of one of the normal alleles of this one of hers.

A living example of how this disease spreads is the family tree of Queen Victoria of the United Kingdom.

Genetic counseling

In families where a member is affected, it is important to detect women at risk of being carriers and carry out genetic counselling. Ideally, this counseling should be carried out before any woman in the family at risk considers having children.

Counseling should consider two aspects: data indicating the severity of bleeding manifestations and knowledge that women in a family with relatives with hemophilia are carriers of the disease.

The family should be aware of the implications of the disease, how it is inherited, the probability of its recurrence, and the alternatives that exist. Genetic counseling should be an educational and informative process, but in no way taxing.