Hemophilia as a Genetically Inherited Bleeding Disorder - Essay Example

HEMOPHILIA A Hemophilia A The study of human genetics has been greatly facilitated by the completion of the human genome project, highlighting that humans have about 30,000 genes. The human genome project would help in the unravelling of various genetic mysteries associated with diseases and transmission of the diseases. Human diseases can be divided broadly into three categories. These include, 1) those that are genetically determined, (2) those that are determined on the basis of environmental factors entirely and, (3) those to which nurture and nature contribute in an equal manner. According to the survey studies, 20 percent of the paediatric patients admitted in the university hospitals have diseases associated to genetic origin. 50% of the spontaneous abortions during the first trimester have been related to chromosomal aberrations in the fetus. It is important to understand three different terms when discussing the genetic diseases; hereditary, congenital and familial. Hereditary disorders are transmitted by the parents to their offsprings and are passed on through the generations and are, therefore, familial. Congenital disorders are defined as conditions present at birth and not all congenital disorders are genetic such as congenital syphilis (Kumar, Abbas, Fautso, & Mitchell, 2008). It was because of the efforts of Gregor Mendel, that we are now able to understand how genes are transmitted from parents to offsprings (Yashon & Cummings, 2009). To understand the genetic basis of various diseases, it is vital to know the various types of mutations which lead to alterations in the normal human genome. Mutations refer to permanent damage in human DNA. There are three major categories of genetic disorders: (1) those that are related to mutant genes, (2) diseases with multifactorial inheritance and, (3) those originating from chromosomal structural abnormalities. The first group of diseases is called Mendelian disorders, which mostly occur as a result of single-gene mutations of large effect. These mutations are classified into three patterns of inheritance: autosomal recessive, autosomal dominant and X-linked (Kumar, Abbas, Fautso, & Mitchell, 2008; Yashon & Cummings, 2009). With the help of Mendelian genetic studies, several terminologies were brough forward to understand the patterns of inhertiance. Mendel described the distinguishing characterisitic of an organism as a trait and different forms of a gene as “alleles”. Homozygous condition is described as having two similar alleles of the same gene and hetrozygous conditions is having two different alleles of the same gene. Dominat diseases are those in which the disease is expressed in the homozygous or hetrozygous condition and recessive conditions are those in which the disease is expressed only in homozygous condition (Yashon & Cummings, 2009). Hemophilia A is an X-linked recessive disease which is characteristically a bleeding disorder due to deficency of the coagulation factor VIII. In majority of the hemophilia cases, the coagulant protein assays are quantitatively reduced, but in small number of cases the coagulation factor is defective. Hemophilia is classified as a severe case if the assays of the coagulaton factor are less than 1 percent. Moderate if levels are 1-5 percent and mild if the factor assays are greater than 5 percent. Due to its pattern of inheritance, hemophilia A is more common in males and in rare instances female carries may also clinically express the disease. Approximately 10,000 males are affected and it is the most common severe bleeding disorder. The reason of the hetrozygous expression of the disease in females is because of the random X chromosome inactivation in females. This random inactivation, in rare cases, can disporpotionately inactivate the normal chromosome leading to expression of the disease. As a rule, all but one X chromosome is inactivated and the inactivated chromosome forms a Barr body. Females may also be affected if they are the offsprings of a hemophilic father and a carrier mother (McPhee, Papadakis, & Tierney, 2007). Hemophilia A presents with bleeding into joints such as elbows, knees, ankles, into muscles and from the gastrointestinal tract. Although these are the major sites of bleeding, hemophilic patients have the tendency to bleed from anywhere. Spontaneous hemarthroses are a characteristic sign of hemophilia and are almost characteristic of the disorder. The presentation of the disorder might also differ with the severity of the condition. Very sever cases, bleed spontaneously, moderate deficiencies of the factor present with bleeding after minor trauma or surgery and mild cases present with bleeding only after major trauma or surgery. Currently, many hemophilics are also seropositive for HIV. This is because of transmission of the infection via the factor VIII concentrate. Some patients might already present with AIDS and the associated thrombocytopenia exacerbates the bleeding complications. The laboratory studies are important to differentiate hemophilia A from other bleeding disorders. PTT is prolonged while, bleeding time, prothrombin time and fibrinogen time are all normal. These studies indicate that the defect is only in the coagulation factors rather than arising from a primary hemostasis etiology. On factor assays, the levels of factor VIII are reduced, with normal levels of von-Willebrand factor. Another important laboratory analysis performed is, mixing the patient’s plasma with normal plasma. If the PTT becomes normal, it confirms Hemophilia A, however, if the PTT does not correct than it indicates the presence of a factor VIII inhibitor (McPhee, Papadakis, & Tierney, 2007). Standard treatment of hemophilia A involves the infusion of factor VIII concentrates according to the severity of the coagulant deficiencies. A level of 100 percent factor VIII levels should be maintained before any major sugery. For mild hemophilias, DDAVP can be helpful which is given per day and can be used for minor surgeries. It causes the release of factor VIII and raises the levels by three-four folds. In cases of severe persistent bleeding, after the administeration of factor VIII or desmopressin acetate, pateints should be given EACA (Amicar) for several days (McPhee, Papadakis, & Tierney, 2007). It has also been shown by studies that administration of factor VIII concentrates containing con Willebrand factor has more clinical benefits over pure factor VIII concentrates. This reduces the possibilities of inhibitor development and inhibitor eradication (Auerswald, Spranger, & Brackmann, 2003). Aspirin should be avoided in such patients. Hemophilia A is an X-linked recessive condition and follows a specific pattern of inheritance. X-linked diseases have the mutant gene on the X chromosome and the mutant genes are fully expressed in males as they have only one copy of X chromosome. Males are therefore hemizygous for X-linked diseases. Females have two X chromosomes but one of them is genetically inactive, a process termed as lyonization (Gelehrter, Collins, & Ginsburg, 1998). Hemophilia A, being an X-linked recessive disorder has specific features of inhertiance. It is transmitted by hetrozygous female carriers to their sons who are hemizygous for the disease. Hetrozygous females rarely express the disease, because of the remote possibility of normal X chromosome inactivation, as discussed earlier. An affected does not transmit the diease to his sons, but all daughters will be carriers. This shows that sons of hetrozygous females have a risk of one in two of receiving the mutant gene from the mother (Kumar, Abbas, Fautso, & Mitchell, 2008). Two possible mating patterns can be discussed to understand the inheritance of hemophilia A. The most common one is mating between a normal man and heterozygous woman. Each son has a 50percent chance of having the mutant gene and being affected , and daughters have 50 percent chance as well of inheriting the mutant gene, however, they will be carriers. A second type of mating is between an affected man and a homozygous normal woman. In such a case, all the sons will be normal because they receive the normal Y chromosome from their father, and a normal X chromosome from their mother. But, all the daughters will be carriers for the disorder, because they receive the mutant gene from their father (Gelehrter, Collins, & Ginsburg, 1998). Fig 1. Inheritance of Hemophilia A (Kent 2000). Fig 2. The figure represents the mating between an affected father (xY) with a normal mother (XX) which results in carrier daughters (Xx) with a risk of 50percent and normal sons (XY) with a probability of 50 percent. The second case shows a carrier mother (xX) marrying a normal male (XY). Sons have 25 percent risk of having the disease and daughters have 25 percent of being a carrier (World Federation of Hemophilia , 2013). Factor VIII is important in the cleavage of factor X in the coagulation cascade and absence or low levels lead to disruption of normal coagulation. Many kinds of mutations have resulted in the deficiency of defect of the factor VIII. 5 percent of patients with Hemophilia A present with deletions in the factor VIII gene. The dimer TCGA is considered an important site for mutation. Taq1 is a significant restriction endonuclease which recognizes the restriction sites for the genetic mutations in Hemophilia A. Out of the seven recognition sites, five result in the formation of a stop codon TGA in the Hemophilia A cases. 80 or more missense mutations have also been exhibited as a cause of mutation in factor VIII gene (Hoyer, 1994). According to a survey of 240 patients, CG-to-TG transitions in an exon were found in nine cases. These patients were severely affected. In one patient the Taq1 site was lost in exon 24 and in another it was lost in exon 23 (Youssoufian, Antonarakis, Bell, Griffin, & Kazazian, 1988). X-linked Hemophilia is an X-linked recessive disorder and hence, it is highly recommended that genetic counselling is provided to individuals. Families, who have a history of disease, should come forward to test for carrier state in females. Factor VIII assays can be assessed to reach an accurate diagnosis of carrier state. DNA analysis can also be performed to determine carrier state (Hoyer, 1994). Hemophilia A is a genetically inherited bleeding disorder, which is also the most common severe bleeding disorder. It is associated with a prominent male dominance of inheritance with females mainly being the carriers. Very low levels of the factor VIII can lead to severe bleeding episodes which have to be managed actively. To prevent the transmission of the disease, it is important to consider factors such as consanguinity (marriage within the close family members), awareness regarding the disease inheritance and genetic inheritance have to be emphasized. Consanguinity is an important practice, which leads to the recurrence and prevalence of recessive disorders within family pedigrees. Although new treatments such as gene therapy and modern DNA analysis techniques have been formulated, Hemophilia is a severe bleeding disorder which not only affects the diseased person physically but also burdens him financially, socially and psychologically. Hence, it is crucial to spread awareness regarding the disorder and the risks of inheriting the disease. Bibliography Auerswald, G., Spranger, T., & Brackmann, H. (2003). The role of plasma derived factor VIII/von Willebrand factor concentrates in the treatment of Hemophilia A patients. Haematologica. Gelehrter, T. D., Collins, F. S., & Ginsburg, D. (1998). Principles of medical genetics. Baltimore: Williams & Wilkins. Hoyer, L. W. (1994). Medical Progress: Hemophilia A. The New England Journal of Medicine, 38-47. Kent, M. (2000). Advanced Biology. Oxford: Oxford University Press. Kumar, V., Abbas, A. K., Fautso, N., & Mitchell, R. N. (2008). Robbins Basic Pathology. Philadelphia: Elsevier Inc. McPhee, S., Papadakis, M. A., & Tierney, L. M. (2007). Current Medical Diagnosis and Treatment. New York: The McGraw-Hill Companies. World Federation of Hemophilia . (2013). How do you get Hemophilia? Retrieved from World Federation of Hemophilia: http://www.wfh.org/en/page.aspx?pid=644 Yashon, R. K., & Cummings, M. R. (2009). Human genetics and society. Belmont, CA: Brooks/ Cole, Cengage Learning. Youssoufian, H., Antonarakis, S. E., Bell, W., Griffin, A. M., & Kazazian, H. H. (1988). Nonsense and misense mutations in hemophilia A: estimate of the relative mutation rate at CG dinucleotides. American Journal of Human Genetics, 718-725. Read More