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| Tsarevich of Russia |
Hemophilia is a recessive X-linked hereditary disorder (X-linked recessive diseases usually occurs in males who have inherited a recessive X-linked mutation from their mother) caused by a deficiency of coagulation factor VIII (hemophilia A) or IX (hemophilia B). The disease is considered to be severe when factor levels are below 1% of normal values, moderate when they are between 1 and 5% and mild when levels range between 5% and 40% [1].
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| Hemophilia inheritance |
As other medical conditions, hemophilia is a chronic disease associated with substantial healthcare and pharmaceutical costs which, in less advantaged countries, could result in disabling clinical conditions if not in a higher mortality rate.
Contrary to other rare diseases, over the last few decades hemophilia has benefited from a greater understanding of the causes and mechanisms responsible for its development as well as of the molecular and physiological characteristics of the disease and its proper diagnostic and clinical management. This has undoubtedly aided in the design of highly appropriate treatment schedules.
The etiopathogenesis of the disease is related to different kinds of mutations (large deletions and insertions, inversions and point mutations) that occur in the gene expressing the deficient coagulation factor.
Symptoms
The clinical characteristics of both types of hemophilia are very similar: spontaneous or traumatic hemorrhages, muscle hematomas, hemophilic arthropathy resulting from the articular damage caused by repetitive bleeding episodes in the target joints, or hemorrhages in the central nervous system, abnormal bleeding as a result of minor injuries, or following surgery or tooth extraction.
In the absence of appropriate replacement treatment with exogenous coagulation factors, these manifestations of the disease can have disabling or even fatal consequences thus negatively impacting patients' quality of life and reducing their life expectancy. Bleeding episodes may be spontaneous in the severe and (less so) in the moderate forms of the disease, with 70% of them being articular, 15% muscular and 15% visceral.
Diagnosis
Diagnosis of hemophilia is aimed at identifying type of hemophilia and degree of involvement as well as detecting symptomatic or asymptomatic carriers of the disease, either obligate (daughters of hemophiliacs) or de novo (women by sporadic and spontaneous mutations).
Diagnostic methods are based on the determination of coagulation factor levels in plasma and the detection of the mutation in the DNA extracted from peripheral blood leucocytes by means of direct or indirect genetic methods (detection of genetic polymorphism).
Genetic guidance
As hemophilia is a gender-related condition, genetic guidance is provided to couples on the basis of an odds analysis based on genealogy and coagulation factor data and a study of the mutation responsible for the disease. Moreover, either a prenatal diagnosis, —which can now be carried out non-invasively—, or a pre-implantational diagnosis are provided. In this respect, it is necessary to emphasize that access to prenatal or pre-implantation genetic diagnosis is not universally available but rather depends on the economic constraints imposed by different countries in accordance with their development status.
The conventional treatment
At present, patients with hemophilia benefit from optimized treatment schedules based on the intravenous systemic delivery of exogenous coagulation factors, either prophylactically or on demand protocols.
The current policy in developed countries is in general to administer a prophylactic treatment (2 or 3 times a week) from early childhood into adulthood. Such prophylactic protocols result in a marked improvement in patients' quality of life on account of the prevention of hemophilic arthropathy and other fatal manifestations of the disease as well as a reduction in the long-term costs of treatment because of a decrease in the need of surgical procedures such as arthrodesis, arthroplasty or synovectomy.
Conventional treatment of hemophilia is currently based on the use of plasma-derived products —duly treated with heat and detergent to inactivate lipid-coated viruses—, or the recently developed recombinant high-purity coagulation factor concentrates which do not contain proteins of human or animal origin.
Both kinds of factor boast high efficacy and safety profiles, at least for the inactivation-susceptible pathogens known to date. The choice of one product over the other is usually based on the clinical characteristics of the patient and on cost and availability considerations.
The inhibitors problem
Now that infections by pathogenic viruses (VIH, HCV) that were common a few decades ago have been eradicated, the most distressing adverse effect observed when using both recombinant and plasma-derived products is the development of antibodies (inhibitors) against the perfused exogenous factors. The appearance of inhibitors renders current treatment with factor concentrates inefficient, increasing morbidity and mortality, leading to the early onset of hemophilic arthropathy and disability and to a consequent reduction in patients' quality of life. Inhibitors also result in higher costs as treatment must be provided both for bleeding episodes and inhibitor eradication (immune tolerance induction). The incidence of inhibitors is around 30% in hemophilia A and 6% in hemophilia B. The immunologic mechanism whereby these neutralizing antibodies are generated is highly complex and involves several messenger molecules (tumor necrosis factor, interleukins…), and cells (T-lymphocytes B-lymphocytes, macrophages …). They are directed at certain regions in the factor molecule that interact with other components of the coagulation cascade and, depending on their titre level and on whether they are transient or persistent, they will bring about greater or lesser alterations in the coagulation cascade. The causes that influence inhibitor development may be genetic —inherent in the patients themselves—, such as ethnicity, familial history, type of mutation or certain changes in some of the genes involved in the immune response; or non-genetic —environmental—, such as stimulation of the immune system by other antigens or the treatment regimen used (prophylactic vs. on demand). The influence of type of factor concentrate used (plasma-derived or recombinant) is still a subject for debated .
Perspectives
Short and medium-term perspectives for the treatment of hemophilia strongly rely on the current research efforts directed increasing the safety levels of (especially) plasma-derived factors with respect to the detection and subsequent inactivation of blood-borne pathogens in donors, such as prions and other potential emerging agents.
It is also important to enhance the efficiency of recombinant factors increasing their half-life (by PEGylating the factor molecule or using fusion proteins, both for factor VIII and factor IX). These studies are now in progress and no definite statements can be made about the safety of long-acting products as none of them have yet been authorized for clinical use.
Another strategy could be to attenuate their immunogenic capacity to produce inhibitors by chemically modifying them or by developing recombinant factors of human origin.
In the long term, efforts must be directed at the development of advanced therapies, particularly strategies in the field of gene therapy (by using adeno-associated viral vectors) and cell therapy (by using adult stem cells or induced pluripotent stem cells).
The chief goal of these new strategies will be to address some of the limitations associated with current treatment options such as the short in vivo half-life of administered factors, the risk of a pathogen-induced infection and the development of inhibitors. Another goal of the advanced therapies (cell therapy) will be palliative treatment of the articular consequences derived from hemophilic arthropathy.