Hemophilia sometimes also known as the "royal disease" is an inherited disease in which blood clots do not form properly and the affected individual has a longer than normal time to clot. Hemophilia is caused by an X-linked recessive trait. In X-linked recessive hemophilia, a female carrier has one bad gene on chromosome X, but the good gene on the other X chromosome produces enough of the good clotting enzyme to maintain health. Since men are XY a man with the bad gene on the X chromosome must get the disease, because there is no second X chromosome. In an X-linked recessive disorder males are typically the ones who get the disease whereas females are carriers. There are also certain transmissions or gene inheritance patterns that are characteristic of these types of disorders. Hemophilia in father to son transmission is 0% chance of disease and 100% chance of disease-free unless the mother is also a carrier males always get their single X from the mother not father and cannot get a bad gene from the father, 0% chance of carrier (males cannot be carriers; in father to daughter transmission: 0% chance of disease since females can only be carriers, 100% chance the female child is a carrier because the father gives a bad X gene as there is only the bad one to give. If the mother is also a carrier, the female can be fully afflicted with the rare double-recessive female version of the disease. From a carrier mother to son transmission there is 50% chance of disease, 50% chance disease-free, 0% chance of carrier since males cannot be carriers and in mother to daughter transmission there is 0% chance of disease since females can only be carriers, 50% chance of female carrier and 50% chance neither affected nor carrier.
Human cell contains 23 pairs of chromosomes for a total of 46 chromosomes. Chromosomes are the carriers of genes. They are composed of DNA and proteins and are located within the nucleus of the cell. Chromosomes determine everything from hair color to eye color to sex. There are 22 pairs of autosomal chromosomes and one pair of sex chromosomes. Autosomes are chromosomes that do not affect the sex of the individual. The sex chromosomes are the X chromosome and the Y chromosome. In human sexual reproduction two gametes fuse to form a zygote, the sperm from the male with the egg of the female. Gametes are reproductive cells formed by meiosis which is a type of cell division in which the daughter cells have only half the number of chromosomes then what the parent cell contains. Sperm cells undergo spermatogenesis and egg cells undergo oogenesis. It is essential that the gametes only half the number of chromosomes because they will fuse to form an individual that must have only 46 chromosomes. If the gametes are missing or have an additional chromosome this can result in serious consequences for the individual. When the haploid male and female gametes unite in a process called fertilization, they form what is called a zygote. The zygote is diploid, meaning that it contains two sets of chromosomes. The male gametes or sperm cells in humans and mammals are heterogametic and contain one of two types of sex chromosomes which is either X or Y. The female gametes or eggs however, contain only the X sex chromosome and are homogametic. The Y chromosomes in these cases determines the sex of an individual. If a sperm cell containing an X chromosome fertilizes an egg, the resulting zygote will be XX or female. If the sperm cell contains a Y chromosome, then the resulting zygote will be XY or male.
In humans there are dominant and recessive genes. A dominant gene means that a single allele can control whether the disease develops. If only one parents which are usually the affected passes on an autosomal, defective gene which results in the child having a genetic disorder, then the disorder is called autosomal dominant. A recessive gene means that there is enough normal protein product to function properly from the normal gene and, therefore, two copies of the defective gene are necessary for the disease to develop. If both parents are unaffected they are called carriers and they each pass on a defective gene causing their child to be affected. The genetic disorder is autosomal recessive. , Many other genetic disorders are caused by defects related to the sex chromosomes, or the X and Y chromosomes. If a defective gene on the X-chromosome is inherited, it is called X-linked. Like autosomal disorders, X-linked genetic diseases also can be inherited by dominant and recessive mechanisms. X-linked dominant means that if the father passes on the defective gene on his only X chromosome, all his offspring which will be females will be affected. If he passes on his Y chromosome, none of these males will be affected. There is no male-to-male transmission. If it is X-linked recessive, all daughters will be carriers. If the mother passes on a recessive X-linked gene, then all her sons will be affected and all her daughters will be carriers.
The hemostatic system, consisting of the blood vessels and blood plays a very important role in human survival. The importance of the plasma coagulation system in protecting life by preventing further blood loss following transection of a blood vessel is well recognized. Hemophilia A is a deficiency in clotting factor VIII also known as anti-hemophilic factor. The gene for Factor VIII is located on the X chromosome Xq28. Factor VIII participates as a cofactor in the second burst of thrombin generation, which leads to clot formation. Primary sites of factor VIII-C production are thought to be the liver and the reticuloendothelial system. The liver however is thought to be the major site of Factor VIII because a liver transplant corrects factor VIII deficiency in persons with hemophilia and progressive liver disease has a rise in levels of Factor VIII (Schwartz). Factor VIII mRNA has been detected in the liver, spleen, and other tissues as well. The synthesis of factor VIII starts when factor VIII moves to the lumen of the endoplasmic reticulum, where it is bound to several proteins that regulate secretion, particularly immunoglobulin binding protein. Cleavage of factor VIII's signal peptide and the addition of oligosaccharides also occur in the endoplasmic reticulum. The chaperone proteins, calnexin and calreticulin, enhance both factor VIII secretion and degradation. A part of the factor VIII protein in the endoplasmic reticulum is degraded within the cell. The other part enters the Golgi apparatus, where several changes occur to produce the heavy and light chains and to modify the carbohydrates. The addition of sulfates to tyrosine residues of the heavy and light chains is necessary for full procoagulant activity, with the sulfated region playing a role in thrombin interaction. ERGIC-53 is a chaperone protein in the Golgi apparatus that facilitates secretion of factor VIII. The secreted factor VIII-C glycoprotein in plasma is a heterodimer having a carboxy terminal derived light chain in a metal-dependent association with the amino terminal derived heavy chain. Activation of coagulation is accomplished by the conversion of a series of zymogens to enzymes, with participation of cofactors leading to the conversion of fibrinogen to a stable fibrin clot. Activation of factor VIII is followed by an immediate dissociation of the A2 subunit, leading to loss of activity of factor VIIIa; prolonged reaction of factor VIIIa with factor IXa leads to proteolysis of the A1 subunit and subsequent loss of factor VIIIa activity. The rapid decay of factor VIIIa results in loss of activity of the intrinsic tenase complex which limits its proteolytic activity. Protein C determines the length of survival of factor VIIIa also along with its cofactor free protein S which is an anticoagulant (Schwartz).
The second type of hemophilia that is rarer is Hemophilia B. This second most common type is caused by lack of enough clotting factor IX and has a variety of defects in the FIX gene. It is also called the Christmas disease because it was discovered after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to hemophilia, in 1952. Factor IX is the precursor to Factor IXa, which is a Vitamin K-dependent serine protease that catalyzes the activation of Factor X to Xa. FIX normally circulates in the plasma in an inactive form. Factor VIIIa plays a role in the enzymatic activation of FIX to FIXa and can also be activated directly by Tissue Factor. Factor IX is inactive unless activated by factor XIa of the contact pathway or factor VIIa of the tissue factor pathway. When activated into factor IXa, in the presence of Ca2+, membrane phospholipids, and a Factor VIII cofactor, it hydrolyses one arginine-isoleucine bond in factor X to form factor Xa. Factor IX is a single-chain, vitamin K-dependent glycoprotein serine protease with a molecular weight of approximately 55,400 and a plasma concentration of 3 - 5 microgram/mL as well as a half-life of approximately 18 to 24 hours. FIX undergoes extensive posttranslational modification to become a fully gamma-carboxylated mature zymogen that is secreted into the blood. The precursor protein has several parts starting with a signal peptide at the amino terminal end which directs the protein to the endoplasmic reticulum in the liver, and continuing with the prepro leader sequence recognized by the gamma-glutamylcarboxylase, which is responsible for the posttranslational modification (carboxylation) of the glutamic acid residues (Gla) in the amino terminal portion of the molecule. The Gla domain is responsible for Ca2+ binding, which is necessary for the binding of FIX to phospholipid membranes. The Gla region is followed by two epidermal growth factor regions, the activation peptide, which is removed when the single-chain zymogen FIX is converted to activated factor IX (FIXa) and the catalytic domain, which contains the enzymatic activity (Schwartz). Before secretion from the hepatocyte, the FIX protein undergoes extensive posttranslational modifications, which include gamma-carboxylation, beta-hydroxylation, and removal of the signal peptide and propeptides, addition of carbohydrates, sulfation, and phosphorylation. These Gla regions are the high affinity Ca2+ binding sites necessary for binding FIXa to lipid membranes so FIXa can express its full procoagulant activity. All of the vitamin K-dependent procoagulants and anticoagulants are biologically inactive unless the glutamic acid residues at the amino terminal end are carboxylated. Tissue factor (TF) is a glycosylated membrane protein present in cells surrounding blood vessels and in many organs. On the other hand, endothelial cells, tissue macrophages, and smooth muscle cells express TF only when stimulated by serine proteases, such as thrombin, and by inflammatory cytokines. When TF becomes available, it complexes with FVII or FVIIa, and current concepts support the view that activation of FIX to FIXa is more rapid with the TF-FVII complex than with activated factor XI (FXIa). Following activation, the single-chain FIX becomes a 2-chain molecule, in which the 2 chains are linked by a disulfide bond attaching the enzyme to the Gla domain. Activated factor VIII (FVIIIa) is the specific cofactor for the full expression of FIXa activity (Schwartz). Platelets not only provide the lipid surface on which solid-phase reactions occur, but they also possess a binding site for FIXa that promotes complex formation with FVIIIa and Ca2+. The complex of FIXa, FVIIIa, Ca2+,and activated platelet (phospholipid surface) reaches its maximum potential to activate FX to activated factor X (FXa) (Riley). Hemophilia B occur 1 in 30,000 live male births. The gene for factor IX is located on the X chromosome (Xq27.1-q27.2). It is encoded by a 34-kb gene located near the terminal end of the long arm of the X chromosome. Factor IX disease is heterogenous, with nearly 700 point mutations, additions, deletions, and other molecular abnormalities. It was first cloned in 1982 by Kotoku Kurachi and Earl Davie (Kurachi).
There are certain symptoms that are associated with hemophilia the most important being the prolonged clotting time. The symptoms can range widely in their severity depending on how deficient the patient is in the clot-forming proteins. If levels of the deficient clotting factor are very low, the patient may experience spontaneous bleeding. If however the levels of the deficient clotting factor are slightly to moderately low the patient may bleed only after surgery or trauma. Symptoms of spontaneous bleeding include many large or deep bruises, joint pain and swelling caused by internal bleeding, unexplained bleeding or bruising, blood in the urine or stool, prolonged bleeding from cuts or injuries or after surgery or tooth extraction, nosebleeds with no obvious cause and tightness in the joints. Emergency signs and symptoms of hemophilia include sudden pain, swelling, and warmth of large joints, such as knees, elbows, hips and shoulders, and of the muscles of the arms and legs, bleeding from an injury, especially if the patient has a severe form of hemophilia, painful lasting headache, repeated vomiting, extreme fatigue, neck pain and double vision. In the early months hemophilia in babies is not detected because they are not mobile but as the baby begins to move around, falling and bumping into things, superficial bruises can occur. This bleeding into soft tissue becomes more frequent the more active the baby becomes. Hemophilia is very easily detected in a circumcised baby boy because of the prolonged bleeding after the circumcision. This may be the first indication of hemophilia. The first episode of bleeding generally occurs by the time a child is 2 years old because of the fact that they are a lot more active (Riley). In worst case scenarios death can result from central nervous system (CNS) bleeding, progressive hepatitis with hepatic failure, anaphylaxis in children, development of inhibitors with severe bleeding, and AIDS.
There are two types of Hemophilia as mentioned above which are Hemophilia A and Hemophilia B. Hemophilia A is the most common type of hemophilia and is caused by factor VIIIÂ deficiency. It is largely an inherited disorder in which one of the proteins needed to form blood clots is missing or reduced. In about 30% of cases, there is no family history of the disorder and the condition is the result of a spontaneous gene mutation. Normal plasma levels of FVIII range from 50% to 150%. People with mild hemophiliaÂ have 5% up to 50% of the normal clotting factor in their blood.Â Â Most patients usually have problems with bleeding only after serious injury, trauma or surgery. The first episode may not occur until adulthood and women with mild hemophilia often experience menorrhagia, heavy menstrual periods, and can hemorrhage after childbirth. People with moderate hemophilia have about 1% up to 5% of the normal clotting factor in their blood (Riley). They tend to have bleeding episodes after injuries and some without obvious cause which are called spontaneous bleeding episodes. People with severe hemophilia have less than 1% of the normal clotting factor in their blood. They have bleeding following an injury and may have frequent spontaneous bleeding episodes, often into their joints and muscles. The presence of blood in the joint leads to synovial hypertrophy, with a tendency to rebleed, which results in chronic synovitis, with destruction of synovium, cartilage, and bone leading to chronic pain, stiffness of the joints, and limitation of movement because of progressive severe joint damage.
There is no cure for hemophilia but most people that have hemophilia can and do lead normal lives. For mild hemophilia treatment may involve slow injection of the hormone desmopressin (DDAVP) into a vein to stimulate a release of more clotting factor to stop the bleeding (Riley). For moderate to severe hemophilia bleeding may stop only after an infusion of clotting factor derived from donated human blood or from genetically engineered products called recombinant clotting factors. Repeated infusions may be needed if the internal bleeding is serious. Regular, preventive infusions of a clotting factor two or three times a week may also help prevent bleeding. This approach may reduce time spent in the hospital and away from home, work or school, and limit side effects such as damage to joints. If internal bleeding has damaged joints, physical therapy can help them function better. Therapy can preserve their mobility and help prevent frozen or badly deformed joints. In cases where repeated bouts of internal bleeding has damaged or destroyed joints, an artificial joint may be needed (CNN Health). As preventive care especially for Hemophilia B individuals, a Hepatitis B vaccine should be given because of their exposure to blood. Patients with hemophilia B should establish regular care with a hematologist, especially one who is associated with a hemophilia treatment center. The ability to have quick and easy access to medical records documenting the patient's history of factor IX levels, factor transfusions including the type and amount, complications, and amount of any inhibitors can be lifesaving in the event of an emergency situation (Dugdale).
One of the more long term treatment options is gene therapy. There have been several clinical trials and several methods of gene therapy are still underway to determine which way is the best. The benefits of gene therapy are that the DNA is in concentrated form, it is targeted to specific cell types, it results in long-term gene expression with stable levels for years, is nontoxic, and is nonimmunogenic (Schwartz). There are two very promising options in gene therapy. One of the options is an adenoviral vector encoding a human B-domain-deleted factor VIII complementary DNA. This corrected bleeding in hemophilic mice and dogs and can be a promising form of gene therapy in humans. Another approach consists of transducing human umbilical vein endothelial cells with a retroviral construct to create a store of factor VIII-C and von Willebrand factor in the Weibel-Palade bodies, which can then be released in a functional state. The vascular endothelium could also be an appropriate target of gene therapy (Schwartz). There are many treatment options for hemophiliacs but gene therapy seems the most promising idea where the affected individual can lead a normal life. The research on gene therapy is ongoing and one day there might be a permanent cure.