Hemophilia: Disease, Prenatal Diagnosis And New Therapies

What is hemophilia

It is a rare blood disease spread almost exclusively in males and characterized by coagulation defects, the mechanism that allows the formation of a sort of plug every time an injury to a blood vessel occurs, to prevent the blood from escaping the same. Frequent bleeding can occur, sometimes external but above all internal, in particular on muscles and joints.

Blood clotting depends on a cascade of biochemical reactions involving various proteins, including two called factor VIII and factor IX. It is precisely the absence or deficiency of one of these two proteins that cause hemophilia.

If factor VIII is missing, we speak of type hemophilia (the most common), while if factor IX is missing, we speak of type B hemophilia.

For both types, mild, moderate, or severe forms are distinguished, depending on the concentration of coagulation factor still functioning in the blood.

How widespread hemophilia is

One person in every 10,000 is affected by hemophilia: one in 5000 has type A, and one in 30 thousand has type B.

Hemophilia, symptoms

The malfunction of the coagulation leads to excessive bleeding (hemorrhage) even after small traumas or injuries (a common fall to the ground of a child who starts walking, a push during a game, and so on) or even spontaneously.

We must not think of people who lose rivers of blood at the slightest scratch. If it is true that there may be visible external bleeding, for example when milk teeth fall, it is equally true that in general, the bleeding is internal, and mainly affects the joints of knees, elbows, ankles (haemarthrosis, which in the long run can cause disability), muscles (hematomas), subcutaneous tissue. Furthermore, bleeding in the central nervous system, stomach and intestines, eyes can occur. As an article from the Rare Disease Observatory explains, “although rare, some of these bleeds represent medical emergencies that need to be diagnosed and treated early. ” Otherwise, they could endanger life itself.

How do you live with hemophilia

Until a few decades ago, hemophilia was a disabling disease associated with chronic pain, disability, and reduced life expectancy. People with severe hemophilia were unable to lead “normal” lives and often died at a young age due to significant bleeding, for example, in the brain.

In recent years things have improved further. Thanks to replacement products that last longer and therefore require fewer infusions, especially for hemophilia B. At the same time, on the horizon, there are also non-replacement therapies that can be administered once a month and gene therapy.

Unless the therapy works (unfortunately it can happen), today few limits are placed on patients with hemophilia, even serious ones, who follow it correctly. As for sport, for example, many activities are allowed, in some cases, even at a competitive level. Swimming and other aquatic disciplines (except water polo) and gymnastics are highly recommended. Rugby, boxing, and martial arts are not recommended, where the possibility of trauma is very high. In the middle, there are various activities that are a bit riskier, but which can be practiced with appropriate precautions, such as football, basketball, or cycling.

How it is transmitted: the genetics of hemophilia

Hemophilia is a hereditary disease and is transmitted with a particular mechanism, linked to the fact that the genes involved are located on the X chromosome. In the vast majority of cases, therefore, it is the males who are affected, to whom carrier mothers transmit the disease.

We have 23 pairs of chromosomes, including a pair of sex chromosomes: XX in the female and XY in the male. Since the genes for factor VIII and factor IX are located on the X chromosome, it is sufficient for a male child to inherit a chromosome containing an altered gene from his mother to have hemophilia. In the case of females, on the other hand, the defect on one X chromosome is generally compensated by the healthy gene on the other chromosome, and there are no problems: the child will only be the carrier.

In very rare cases, however – when the mother is a carrier and the father is hemophilic – even female daughters can have the disease. Couples of this type have a 25% chance of having a sick female daughter.

What is described is the mode of transmission of the disease that occurs in about 70% of cases. In the remaining ones, hemophilia is caused by a mutation that was not present in the mother, but that arose spontaneously during the development of some of her egg cells. Any male child born from one of these cells will have the disease even if there are no other cases in the family.

There is also an acquired hemophilia, an autoimmune disease that usually occurs during the elderly. Associated with cancer or after pregnancy, and that depends on whether the body develops antibodies against coagulation factors, which are inactivated even though they are entirely normal. These are sporadic forms.

How the diagnosis takes place

Some symptoms may make the disease suspect, but confirmation is based on blood tests, such as clotting time and the dosage of factors VIII and IX. Genetic analysis can also be performed to search for mutations in the genes responsible for these proteins.

Choose prenatal diagnosis: screening test, fetal DNA test, or amniocentesis.

The majority of couples decide to carry on pregnancy even if the fetus is diagnosed with hemophilia. Knowing in advance that there is an illness can be very useful, for example, to try to avoid, during childbirth, maneuvers such as the use of the sucker that could cause brain microhemorrhages to the baby.

As an alternative to prenatal diagnosis, starting from 2015, it is also possible to use the preimplantation genetic diagnosis technique, in which the couple carrying the genetic disease can undergo a path of in vitro fertilization with an analysis of the embryos produced, to identify those healthy. However, there are still few public centers that offer this servic.

If there is family history, but no prenatal diagnosis is made, it is enough to do a blood test on the umbilical cord after birth to find out if the baby is affected or not.

If hemophilia appears suddenly

The most complicated situation occurs when there is no family history, and the parents are suddenly faced with the diagnosis of a rare, potentially serious, and potentially demanding disease of their child.

The first symptoms generally appear in childhood, often already in the first months of life, when the baby starts to move, crawl. Therefore have some small trauma that is usually absolutely without consequences, but in a small with hemophilia can lead to internal bleeding. For example, bleeding at the joints of the elbows and knees can occur: from the outside, you can’t see anything, but the parents realize that something is wrong, perhaps because the baby looks sore.

Sometimes the diagnosis is not immediate, and the child and family are referred from one specialist to another before they understand what it is exactly. Since the diagnosis can be a very critical moment for the family, psychological support would be fundamental, which instead is not always offered.

How hemophilia is treated

Since something is missing in hemophilia (factor VIII or factor IX), therapy is based on the administration of this something, and therefore we speak of replacement therapy. This administration can be carried out “on-demand, “that is, following an emergency (a trauma, a wound, which will surely cause bleeding), or as prevention, that is, to prevent bleeding.

The substituting factors can be derived from the plasma (a component of the blood, obtained from donors) or recombinant, that is, produced in the laboratory. In both cases, the missing factor is administered with an intravenous infusion. This is why replacement therapy is quite demanding.

In the beginning, the therapy is done in the hemophilia centers, which establish a personalized therapeutic plan for each patient. Still, then it can also be done at home by the patients themselves or by their families if they are children. In this case, it usually takes a little longer. Sometimes, to facilitate the routine of the infusions, a central venous catheter is implanted. In practice, a tube that remains in place in the chest even after the infusions, with all the discomforts that this can entail for a child.

Traditionally, prophylactic therapy required a fairly large number of infusions: roughly two to three per week. In recent years, however, replacement therapy products have come with a longer action. In the case of hemophilia B, infusions can be reduced to one per week or every two weeks. The result for hemophilia A is less striking but still very significant, where it passes to two infusions per week, with an annual reduction of about 30%.

And on the horizon, there seems to be a real therapeutic revolution, with products that are no more extended replacement in the strict sense, but intervene in other ways in the cascade of coagulation, to favor the process. These products must be injected subcutaneously and no longer intravenously. Generally, once a week or once a month, and perhaps in the future even more rarely.

Hopes for gene therapy

What if instead of supplying the sick organism with the factor it lacks, VIII or IX, it would put it in a position to produce it? In short, this is the goal of gene therapy, which aims to transfer a healthy version of the defective gene to the patient.

Doing it is not as simple as saying it, starting from the fact that the new gene cannot be transferred as it is, but must “travel” within a vector, a kind of molecular taxi that has the task of carrying it, where it is needed most, namely in particular towards the liver cells, which generally produce coagulation factors.

Yet it seems that we are here and that gene therapy for hemophilia may soon become a reality. In the last months of 2017, the first positive results of two clinical studies were announced. Conducted both for hemophilia A and for type B. And an experiment should start soon, with a particularly innovative vector, which should circumvent the limits of the vectors used in other cases.

The (big) problem of inhibition

In theory, hemophilia therapy is a very linear thing: a coagulation factor is missing; it is integrated with a substitute factor. The reality, however, is always more complicated than theory. So one of the main limitations of this approach is the fact that some patients develop a kind of resistance to the therapy itself.

It may happen that after a few administrations of the substitution factor antibodies appear against the factor itself – we call them inhibitors, which recognize it as foreign and therefore attack it as if it were a virus or a bacterium.

The development of inhibitors is more frequent in the case of hemophilia A, where it affects 20-30% of patients with the most severe form. Patients who, at this point, return to risk of continuous joint bleeding and severe bleeding.

When inhibition occurs, our goal is to make it disappear, that is, to eradicate the antibodies responsible for the phenomenon. The approach is somewhat similar to that of allergy-specific immunotherapy: It is a matter of getting the immune system used to the presence of the foreign protein, making sure that it no longer recognizes it as such. How? With very frequent infusions with increasing dosages of substitute factors.

In general, the strategy – which takes quite a long time, of the order of the year – works in about two-thirds of the patients, which is why research on the topic does not stop. To begin with, it is still necessary to understand well what the formation of inhibitors depends on. The only certainty is that several aspects are involved, starting with the type of mutation that affects factor VIII and the type of substitute factor that is used. A large international study, for example, has highlighted the fact that the risk of developing inhibitors is higher if recombinant factors are used in the first fifty days of replacement therapy.

Finally, there may be other elements at play that can modulate the state of activation of the immune system. Fallarino’s research team has identified a molecule involved in the regulation of immune activity, the functioning of which seems altered precisely in patients who develop inhibitors. Now we are trying to understand, with a series of experiments carried out on animal models, if the administration of this molecule can attenuate the response against factor VIII, without however compromising the ability of the immune system to react to infections. The first results seem to go precisely in this direction.

The Hemophilia Centers and the current limits of treatment

Preventing and managing to bleed isn’t everything. Treating hemophilia also means dealing with its possible consequences such as joint or liver problems, pain, but also anxiety and depression, quite common in those suffering from chronic diseases. That’s why multidisciplinary centers would be needed, with analysis laboratories and a team made up of various specialists: hematologists, geneticists, physiatrists and physiotherapists, orthopedists, hepatologists, psychologists. The reality, however, is far enough away from this optimal situation.

Indeed, the Hemophilia Centers are now present in all regions (here is the list). Still, it is also true that many are little more than surgeries for the infusion of therapies and the drawing up of the therapeutic plan.

A “real” disease

A king’s disease: many have defined hemophilia in this way, because it affected, in the nineteenth and twentieth centuries, many members of various European royal families. It all started with Queen Victoria of England (1819-1901), the carrier of hemophilia B. Her son Leopold died at 31 years of age from a cerebral hemorrhage, while the daughters Alice and Beatrice, also carriers, spread it in the royal families of Spain, Prussia, and Russia. For example, we remember the figure of Alexei Romanov, son of the last Tsar of Russia, Nicholas II, and Alexandra, daughter of Alice. No current descendant of the British royal family has inherited the gene responsible for the disease.

Leave a Reply

Your email address will not be published. Required fields are marked *