1.0 Effect of FVIII mutation on private and public research
The government and the private sector have been extensively involved in the funding and executing research on HA in a bid to unravel the mystery of the disease and particularly to identify effective preventive and treatment of HA. One of the widely known organizations that carry out research on hemophilia is the world federation of hemophilia (WFH) that does epidemiological surveys and monitors the reporting of HA around the world with a broad aim of establishing systems and resources to provide treatment to HA patients. This organization aims at evaluating the discrepancies in prevalence reporting as well as the discrepancies in the treatment so as to inform the formulation of surveillance and treatment policies to bridge the gaps in the two areas. WFH works with research collaborators from different Universities and other organizations such as the National Center for Birth Defects and Developmental Disabilities of CDC.
Suffice to say that despite HA affecting only 1 in 5,000 live male births or 1 in 10,000 live births, the disease has had very significant effect on public and private and has attracted various International, regional, National and local research initiatives. An example of a regional organization is the European Hemophilia Consortium (EHC) and National organizations include the Irish/U.S.A/Australia/British Hemophilia Society (HS) . The Hemophilia Societies gather do research for the purposes of advocating for policies and funding that are favorable for the Hemophilia population. Some countries, such as Ireland, Georgia, Tunisia, Jordan, Thailand, and Ecuador have also established National Hemophilia Committees (NHCs) that work towards the formulation of cohesive national strategies for hemophilia and involvement of hemophiliacs in decisions and policies that affect them. This is particularly useful in these hard economic times of global cutbacks that threaten funding for hemophilia treatment. The relatively high-cost of treatment of HA and other high-cost condition has caused budgetary concerns from policy makers resulting in a methodical scrutiny of the treatment options even in the atmosphere of increasing prevalence of non-communicable diseases such as diabetes, heart diseases, ulcers and high cholesterol levels. The national committees are mainly involved in gathering evidence (evidence-based medicine) to advocate for more government funding and for other fundraising options. An example of a local organization is the Indiana Hemophilia & Thrombosis Center among others.
It is also important to say that there are many private researches in mutations leading to HA to the extent that there is a journal dedicated to hemophilia for publication and often-free dissemination of information on hemophilia. Some of the areas that have attracted significant research include the efficacy and cost effectiveness of various treatment strategies, use of prophylaxis, the development of inhibitors following treatment and the treatment for those with inhibitors (including immune tolerance therapy). Despite the profound research and development on HA, the developing countries (particularly in Africa) have been left behind. One of the private initiatives aimed at bridging the gap is the “save one life project” that aims at raising the awareness of the plight of hemophiliacs in developing countries and raising funds to provide treatment for this neglected population.
2.0 Protein function, cellular effects, organism effects and mode of inheritance
Hemophilia A (HA) is an inherited recessive X-linked bleeding disorder that is associated with the absence or quantitative and/or qualitative deficiency of the blood clotting factor VIII (FVIII) (Jacquemin, et al., 2000; Aronova-Tiuntseva & Herreid, 2003; Guillet, et al., 2006; Venceslá, et al., 2008). FVIII has no enzymatic activity per se but a cofactor for FIX which is a serine protease. FVIII is presumed to be synthesized in the liver, hepatocytes or sinusoidal cells, and endothelial cells in other sites such as the glomerular, and is released into the bloodstream. In the blood vessels, FVIII circulates in an inactive form (pro-cofactor) bound to its carrier protein, Von Willebrand factor (VWF).
An injury leading to blood vessel damages signals the beginning of the coagulation cascade, which begins with the activation of FVIII by thrombin-dependent cleavage. Once activated in the presence of Ca2+ and phospholipid (provided by activated platelets), FVIII releases VWF protein and interacts with FIX to form a complex (intrinsic Xase/tenase complex) which in turn activates FX through cleavage of a single peptide bond. Together its cofactor (FVa), FX activates more thrombin which in turn converts fibrinogen to fibrin which forms a cross linked polymer that is the blood clot. As such, FVIII has no direct cellular effect because it is a cofactor but the net effect of its activation by thrombin is formation of blood clot and thus stops bleeding. It therefore means that the absence or deficiency of this protein results in HA which is characterized by spontaneous bleeding that can be fatal. Activated FIXa or protein C promptly clears FVIII from circulation through inactivation
3.0 Degrees of homology between FVIII genes among different species
Phylogenic studies attempt, using mathematical models, to explain the evolution of species (and their genetic makeup) as well as the relationship (homology) between different species and their genes. The assumption of phylogeny is that though different species differ significantly because of evolution, they have some similar aspects because they are assumed to have simply evolved from common ancestors. Using mathematical models, phylogenic trees are drawn to show the relationship between different species at organism level and even genetic levels. The two most commonly used models of drawing phylogenic trees are percent identity and BLOSUM62.
While there are no specific studies that have indicated the actual extent of homology between the FVIII gene in humans and other species, phylogenic studies show that the gene is closely related in mammals. More than 98% of the human genome is shared with the primates and there is 95-98% similarity between genes . The most closely related species, with regard to FVIII gene, are pan troglodytes (chimpanzee), the rats, mice, porcine (pig family) and Danio rerio (zebra fish). These species with related HVIII are relatively good models for studies on HVIII gene/protein and HA.
4.0 Government’s role and systems that assist research and development to prevent HA
The government a wide range of roles and has put up a number of systems that assist research and development to prevent and treat HA. One of the major government roles with regard to HA is funding research and general healthcare that benefits HA patients as wells. Through organizations like the National Hemophilia foundation and CDC, the government funds research on various aspects of the treatment (efficacy and safety) and prevention of HA. The government is also responsible for putting up surveillance systems that guide policy formulation and management of HA. For, instance recently the two aforementioned organizations carried out a national survey on the knowledge on, behavior associated with and attitudes towards preventive activities and used the information gathered to formulate a health promotion campaign.
In the economic hard times the government has had to cut the budgets for healthcare and HA, rare yet costly to manage, could easily suffer the blunt of budget cuts. The ever-rising cost of clotting factor concentrates (CFCs) used in treatment of HA, treating inhibitors and prophylaxis have made HA a target for cost-cutting measures. The government has engaged economists in evaluating the cost of HA management and advice on how to reduce these costs. In partnership with the private sector, the government has developed disease management programs aimed at reducing the cost of HA management. These programs are executed through federally designated hemophilia treatment centers (HTCs). The government and her partners also use this centers to disseminate information and train hemophiliacs and their families to help them in self management, which reduces the cost of HA management. The government allows the HCTs the benefit of participating in the 340 billion Drug Purchasing Program through which they can get safe pharmaceuticals at government discounted prices. This initiatives helps the government to reduce the cost of HA management by lowering the per-unit cost of the CFC.
Another role of government in HA prevention and treatment is the regulatory and policy formulation. NHCs work to develop cohesive national strategy for HA care. To ensure patient inclusions, NHCs work with Hemophilia societies at all decision making process. In addition, the government regulates the practice of HCTs to protect the rights of the patients. Following the HIV and Hepatitis C contaminations of the early treatments for HA, the government participated in ensuring the safety of pharmaceuticals through scrutiny and approval of only safe drugs by drug regulation authorities.
4.0 The impact Of HA on public health practice and public health intervention
As earlier stated HA is a very rare disease and thus does not have a significant impact on public health practice. However, the fact that it is a chronic disease requiring lifelong treatment and care, HA raises several public health concerns. The first concern is the high cost of prevention and treatment at a time when the health sector is threatened by budget cuts. As a result, the current HA care is financially challenged and the government has been working towards the centralization of HA in HTCs. This financial constrains have also led to the adoption of comprehensive care that is more home than hospital based. Hemophilia practitioners (nurses, physicians and physiotherapists are not only working with the patients but with their families to train them on home treatment. To disseminate the necessary information, the said practitioners visit schools and hospitals near the patients’ home. This goes a long way in preventing or reducing the bleeding incidences and helping friends and relatives to know the right steps to take when they occur. They provide information on joint protection, exercise, joint function examination and the suitable recreation activities for hemophiliacs.
Other public health concerns have to do with the efficacy and the safety of the available treatments. Following the contamination of plasma infusions and concentrates with HIV and hepatitis viruses, safety concerns were raised leading to a change of treatment strategies to the use recombinant FVIII concentrates. The efficacy of various treatment strategies as well as the development of inhibitors after treatment have been extensively studied . The impact of the disease on the patient’s quality of life, particularly the ability to participate in physical activities in the light of joint function complication is another public health concern. This has led to shift from mere treatment of the disease with FVIII concentrates to specialized physiotherapy targeted at delaying or reducing joint involvement. Another impact on the public health has to do with diagnosis. While ethical issues have been raised about prenatal diagnosis and genetic cancelling, the diagnosis and prevention strategy respectively have been made available for mothers suspected to be carriers of the mutant gene.
While pharmaceutical therapy using FVIII concentrates is the most widely use intervention there are several other useful public health intervention. Key among them is training patients and family on home care aimed at managing the symptoms e.g. joint pains and preventing bleeding episodes. Another public health intervention is the use of specialized physiotherapy modalities to manage bleeding and hemophilic arthropathy that causes dilapidating pain in the joints. Physiotherapy strategies like balance training, strength training, hydrotherapy and sports therapy have been found to be helpful in the management of joint pains and improvement of movement. Finally yet importantly, wellness approaches designed to benefit people with bleeding disorders have also been applied for HA. These approaches target the physical, social, emotional, mental and spiritual wellness of the patient through holistic treatment.
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