Asian Journal of Pharmaceutical Research and Development Vol. 5 (2) March–April. 2017:1-10

Asian Journal of Pharmaceutical Research and Development (An International Peer-Reviewed Journal of Pharmaceutical Research and Development) www.ajprd.com ISSN 2320-4850 Review Article

HAEMOPHILIA: AN OVERVIEW Lokesh Kumar Nagar*, Neha Sharma, M.P.Khinchi, Mohd. Shahid Khan Atul Kumar Department of Pharmacology, Kota College of , Kota, Rajasthan, India

ABSTRACT also called hemophilia, is a mostly inherited, genetic disorder that impairs the body's ability to make blood clots, a process needed to stop . This results in people bleeding longer after an injury, easy bruising, and an increased risk of bleeding inside joints or the brain. Those with mild disease may only have symptoms after an accident or during . Bleeding into a joint can result in permanent damage while bleeding in the brain can result in long term headaches, seizures, or a decreased level of consciousness.There are two main types of haemophilia, due to not enough clotting factor VIII and due to not enough clotting factor IX. They are typically due to inheriting from one's parents an X chromosome with a non functional gene.

Keywords: Haemophillia, , Human body fluids, Requirments

INTRODUCTION:-

aemophilia also called hemophilia, In the 1800s haemophilia was common is a mostly inherited, genetic within the royal families of Europe. The H disorder that impairs the body's difference between haemophilia A and B was ability to make blood clots, a process needed determined in 1952. . to stop bleeding. This results in In fact, more than 80% of patients with FVIII people bleeding longer after an injury, autoantibodies hemorrhage into the skin, easy bruising, and an increased risk muscles, or soft tissues and mucous of bleeding inside joints or the brain. Those membranes (e.g., epistaxis, gastrointestinal with mild disease may only have symptoms and urological bleeds, retroperitoneal after an accident or during surgery. Bleeding ), whereas hemarthroses, typical into a joint can result in permanent damage of congenital factor VIII deficiency, are while bleeding in the brain can result in long unusual. The hemorrhages in AHA are often term headaches, seizures, or a decreased level serious or life threatening, such as in the case of consciousness. There are two main types of rapidly progressive retroperitoneal of haemophilia, haemophilia A due to not hematomas or the enough clotting factor VIII and haemophilia B due to not enough clotting factor IX. . The A person with less than 1% of normal clotting factors are made either from human clotting activity is described as having severe blood or by recombinant methods haemophilia. A person with between 1% and .Haemophilia A affects about 1 in 5,000- 5% of normal clotting activity is described as 10,000, while haemophilia B affects about 1 having moderate haemophilia and a person in 40,000, males at birth. with over 5% but less than 50% of normal activity is described as having mild *Corresponding author: Lokesh Kumar Nagar haemophilia. B.Pharm Kota College of Pharmacy, Kota, Rajasthan, India E mail: [email protected] Mobile. -9950098963

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Signs and Symptoms:- least 30% of people with haemophilia have The of hemophilia will no family history of haemophilia. It is vary depending on a person’s lack of clotting difficult to be exact about this because of the factors due to the condition. way in which haemophilia is inherited.  Many large or deep Technically, it is a sex-linked recessive  Joint pain and swelling (caused by inheritance condition. The sex of a newly bleeding) conceived baby is determined by the type of  Unexplained bruises or bleeding chromosomes it receives – one from each  Blood in urine or stool parent. A boy inherits his mother’s X  Bleeding for longer than normal from a chromosome and his father’s Y chromosome, cut or injury, or after a lost tooth or and a girl has two X chromosomes, one from surgery each parent. The defect that causes  for no apparent reason haemophilia resides in the X chromosome. A carrier female has one normal and one  A painful, lasting headache defective X chromosome. If she has a son,  Repeated vomiting the son has a 50:50 chance of receiving his  Extreme tiredness or a change in normal mothers defective X chromosome and behaviour therefore has a 50:50 chance of having

haemophilia. The daughter of a carrier also Inheritance Pattern:- has a 50:50 chance of being a carrier herself. Haemophilia is an inherited condition. However, it is possible for the condition to appear in any family – it is thought that at

Table: 1 Classification of haemophilia. Adapted from

Factor level (IU/mL) Classification Predisposition to bleeding Haemarthrosis >0.05 to 0.40 Mild With severe injury, surgery Rarely (>5 to 40% of normal) 0.01 to 0.05 Moderate With slight injury Sometimes (1–5% of normal) <0.01 Severe Spontaneous, with little or Very frequently (<1% of normal) no trauma compartment syndrome due to intramuscular bleed.

Figure- 1.1: Severe bilateral hemophilic arthropathy of the knee in a 37-yearold male.

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Figure-1.2: Inheritance pattern when the Figure-1.3: Inheritance pattern when mother is a carrier of Haemophilia the father has Haemophilia.

TYPES OF HAEMOPHILIA In terms of the symptoms of Haemophilia A there are internal or external bleeding The main types of hemophillia consist- episodes. Prolonged bleeding from a vene puncture or heel prick is another common  Haemophilia A early sign of haemophilia; these signs may  Haemophilia B lead to blood tests which indicates  Haemophilia C haemophilia. Haemophilia A:- While superficial bleeding is troublesome, some of the more serious sites of bleeding Haemophilia A is a genetic deficiency in are:- clotting factor VIII, which causes increased  Joints bleeding and usually affects males.In severe  Muscles cases, heavy bleeding occurs after minor  Digestive tract injury or even when there is no injury  Brain (spontaneous bleeding). Serious complications can result from bleeding into  Genetics :- the joints, muscles, brain, or other internal Haemophilia A is inherited as an X- organs. In milder forms there is no linked recessive trait, and occurs in males and spontaneous bleeding, and the disorder may in homozygous females (only possible in the not become apparent until after a surgery or offspring of a carrier female and a serious injury. The main treatment is haemophilic male. However, mild haemophili called replacement , during which a A is known to occur in heterozygous female clotting factor VIII is dripped or injected into s due to X-inactivation, so it is recommended a vein. that levels of factor VIII and IX be measured in all known/potential carriers prior to  Signs and symptoms :- surgery and in the event of clinically significant bleeding.

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Figure-2.1. X linked recessive inheritance

Diagnosis:-  Life-threatening haemorrhage.

Two of the most common differential Epidemiology:- diagnoses are haemophilia B which is a deficiency in Factor IX and von Willebrand  Haemophilia A occurs in approximately 1 Disease which is a deficiency in von in 5,000 males, while the incidence of Willebrand factor (needed for the proper haemophilia B is 1 in 30,000 in male functioning of Factor VIII), haemophilia C is population, of these, 85% have also a possible, differential diagnosis). haemophilia A and 15% have hemophilia Desmopressin raises the levels of factor VIII B. It affects 1:4,000 to 1:5,000 live male in the blood and may be taken intravenously births worldwide. or through a nasal spray. Drugs known as  It is five times as common as haemophilia antifibrinolytics, which slow the breakdown B (factor IX deficiency). of clotting factors in the blood, can also be  Acquired haemophilia affects around 1 to used to treat those with a mild form of the 3 people per million of the population. disorder. Heamophillia B:-

Treatment:- Hemophilia B is the second most common In regards to the treatment of this genetic type of hemophilia and is estimated to occur disorder, most individuals with severe in about 1 in 25,000 male births. It affects all haemophilia require regular supplementation races equally. Hemophilia B is also known as with intravenous recombinant or plasma conc factor IX deficiency or Christmas disease. entraFactor VIII. Treatment primarily Although the focus of this report is the consists of replacing the missing clotting genetic, or inherited, form of hemophilia B, it factor VIII (replacement therapy) and should be noted that another form called preventing complications that are associated acquired hemophilia B can develop later in with the disorder. life (see "Related Disorders" section below). This is thought to be due to the effects of Complications:- testosterone at maturity.  Antibody inhibitor formation affects about 25–30%, reducing efficacy of therapy.

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Figure-2.2: X-Linked Recessive Inheritance

Signs And Symptoms:- For a female carrier, there are four possible outcomes for each pregnancy: Bleeding into joints with associated pain and swelling  A girl who is not a carrier Blood in the urine or stool  A girl who is a carrier Bruising  A boy without hemophilia Gastrointestinal tract and urinary tract  A boy with haemophilia hemorrhage Causes :- Nosebleeds Prolonged bleeding from cuts, tooth Hemophilia B is caused by an inherited X- extraction, and surgery linked recessive trait, with the defective gene Spontaneous bleeding located on the X chromosome. Females have Hemorrhage two copies of the X chromosome. If the Prolonged bleeding factor IX gene on one chromosome does not Spontaneous bleeding work, the gene on the other chromosome can Easy bruising do the job of making enough factor IX. Males Joint pain have only one X chromosome. If the factor Bone deformities IX gene is missing on a boy's X chromosome, he will have Hemophilia B.

Genetics:- Diagnosis:-

The gene for factor IX—like the gene for The best place for patients with hemophilia to factor VIII—is located on the long arm of be diagnosed and treated is at one of the chromosome X, within the Xq27 region. The federally.A medical health history is X and Y chromosomes are called sex important to help determine if other relatives chromosomes. The gene for hemophilia is have been diagnosed with a bleeding disorder carried on the X chromosome. Hemophilia is or have experienced symptoms. Tests that inherited in an X-linked recessive manner. evaluate clotting time and a patient’s ability Females inherit two X chromosomes, one to form a clot may be ordered. A clotting from their mother and one from their father factor test, called an assay, will determine the (XX). Males inherit an X chromosome from type of hemophilia and its severity their mother and a Y chromosome from their father (XY).

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Treatment:- line. If this is unavailable then plasma- derived factor IX or prothrombin complex Treatment includes replacing the missing concentrates are available. The latter should clotting factor. You will receive factor IX be avoided if at all possible, as it has been concentrates. How much you get depends on: associated with an increased risk of .  Severity of bleeding  Site of bleeding In the acute situation  Your weight and height  Attention must be paid to trying to secure You should get the hepatitis B vaccine. haemostasis. In the established patient, he People with hemophilia are more likely to get or she may be able to self-administer hepatitis because they may receive blood factor concentrate. Get as much history as products. The main medication to treat possible from the patient, who probably hemophilia B is concentrated FIX product, knows his or her disease well. called clotting factor or simply factor.  Minor haemorrhage requires between one Recombinant factor products, which are and three doses of factor IX. Major developed in a lab through the use of DNA haemorrhage needs many doses and technology, preclude the use of human- continued factor IX activity monitoring, derived pools of donor-sourced plasma. with the goal of keeping the trough Amino caproic acid is an anti fibrinolytic, activity level of at least 50%. Continuous preventing the breakdown of blood clots. infusions of factor IX may be required. Complication:- In the chronic state The bleeding can cause many problems,  Patient/carer information and consent, including neurological deficits; however, a with advice regarding advantages and very common finding is that recurrent disadvantages of factor concentrates. bleeding into joints leads to destruction of the joint. Before the advent of recombinant  All patients should be offered vaccination factor IX, patients used to receive factor IX against hepatitis A and hepatitis B - give concentrate that was derived from the plasma SC, not IM (may also need to be offered of many donors. to carers who might inject blood products). Prognosis:-  Patients should wear a medical emergency The life expectancy and quality of life of identification bracelet or similar stating patients with haemophilia have dramatically the disease, the normal level of factor IX improved over a number of years, mainly due and any other important information. to new therapeutic options and the awareness to the risk of HCV and HIV infections. Haemophilia C:- Prophylaxis and early treatment with factor concentrate that is safe from viral While factor VIII and factor IX deficiencies contamination have dramatically improved are the best known and most common types the prognosis of patients regarding morbidity of hemophilia, other clotting factor and mortality due to severe hemophilia. deficiencies also exist. Low levels of factor XI (FXI) cause hemophilia C. FXI plays an Management:- important role in tissue factor-dependent thrombin generation on the surface of The major concerns, even with recombinant activated . The formation of the products, are the possibility of transmission initiating complex, TF-FVIIa-FXa, results in of infections and inhibitor formation. If the generation of a small amount of thrombin. patients have never been exposed to plasma This is insufficient to produce a stable fibrin products then recombinant factor IX is first- clot but stimulates a number of reactions in

Lokesh Kumar Nagar et al www.ajprd.com 6 Asian Journal of Pharmaceutical Research and Development Vol. 5 (2) March–April. 2017:1-10 the amplification loop, including the is also known as plasma thromboplastin activation of FXI. Subsequent formation of antecedent (PTA) deficiency or Rosenthal the tenase complex (FIXa-FVIIIa), followed syndrome. Like the other hemophilias, by the prothrombinase complex (FXa-FVa), hemophilia C is associated with bleeding, but leads to a large burst of thrombin.For a it differs from hemophilia A and B in several schematic of these processes, Haemophilia C ways.

Figure-2.3: Haemophillia c

The clotting mechanism:- the components responsible for come together to form a plug at Blood is carried throughout the body in a the break. Several steps are involved in system of blood vessels. When we are forming a plug. The platelets, very small injured, one or more blood vessels may be cells, are the first to arrive at the site where punctured, resulting in loss of blood. Or the the vessel is ruptured. They stick to one blood vessel can be damaged deep inside the another and attach themselves to the damaged body, causing a or internal vessel wall. hemorrhage. As soon as a vessel wall breaks,

Figure-2.4: The following diagram shows schematically the order of the cascade activation of different coagulation factors to form a clot.

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Sign & symptoms:- In Israel, hemophilia C has been estimated to be approximately 8% among Ashkenazi In terms of the signs/symptoms of hemophilia Jews, making it one of the most common C, unlike individuals with Haemophilia genetic disorders in this group. In hemophilia A and B, people affected by it are not ones to C. bleed spontaneously. However, people affected with haemophilia C might Diagnosis of Hemophilia C experience symptoms closely related to those of other forms of haemophilia such as the Obtaining a detailed personal and family following: bleeding history of a patient is very important in the diagnosis of hemophilia C. Although  Oral bleeding. this condition is found in all racial and ethnic  Nosebleeds. groups, it is helpful to establish the patient’s  Blood in the urine. background, as this may give an indication of  Post-partum hemorrhage (20% of cases) the likely disorder.

Treatment of Hemophilia C Gene mutations:- Patients with severe hemophilia C do not Mutations in the factor XI gene cause the require treatment or prophylactic (preventive) congenital deficiency of factor XI clotting therapy for daily activities. However, activity. The inheritance pattern of factor XI replacement therapy is required for dental is autosomal but not completely recessive, extractions and surgery, and treatment because heterozygotes may have options depend on the type of procedure. bleeding. The gene for factor XI is near the However, since FXI is not concentrated in gene for prekallikrein on the distal arm of , a large volume of this chromosome 4 (4q35). It is 23 kb, with 15 product may be required to raise the FXI exons and 14 introns. Factor XI is activity to a hemostatic level. Two such synthesized in the liver and circulates in the products are available in Europe, but their use plasma as a complex with high-molecular- in patients has been limited because of weight kininogen. Factor XI has a half-life of reports of thrombotic complications after the about 52 hours. More than 200 other use of both available concentrates. mutations that cause factor XI deficiency have been described and are listed in online Fresh frozen plasma databases. The first patients who were diagnosed with this disease were treated effectively with Causes of Haemophilia C :- fresh frozen plasma. Plasma is a blood Hemophilia C is primarily an inherited derivative, a yellowish liquid that is rich in disorder, but unlike hemophilia A and B, the coagulation factors. There is a potential inheritance of hemophilia C follows danger of transmission of viruses such as an autosomal recessive pattern. The gene that HIV and hepatitis A, B and C via plasma, causes FXI deficiency is not present on a sex since it is provided by donors and is not chromosome and the condition, subjected to any virus inactivation procedure. therefore, affects both genders equally. The Factor XI Concentrate FXI gene is 23kb in length, has 15 exons, and Factor XI concentrate is delivered in is found on chromosome 4q32-35. Factor XI lyophilized (powder) form in glass is produced by the liver and circulates in the containers. It is distributed to hospitals by blood in an inactive form. The plasma half- Héma-Québec or Canadian Blood Services. life of FXI is approximately 52 hours. These factor concentrates are fully treated to However, hemophilia C may be diagnosed in inactivate blood-borne viruses such as HIV many other ethnic groups. In the United and the viruses responsible for hepatitis A, B States, the estimated prevalence of severe and C. hemophilia C is 1 case per 100,000 persons.

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Hormone Therapy persons of Ashkenazi or Iraqi Jewish Hormone therapy is administered in the form descent ; in Israel, the estimated rate for of birth control pills, injections and, in the heterozygosity is 8%. In the United Kingdom past few years, intra-uterine devices (IUDs). national database. Hemophilia C equally Hormone therapy is an excellent way for affects males and females. women with factor XI deficiency to protect themselves against abundant menstrual Complications of Hemophilia C bleeding, since it acts by adjusting hormone The complications of hemophilia C are those levels to imitate pregnancy primarily associated with the use of fresh frozen plasma. While today’s blood products DDAVP are much safer than those of the past, transmission of hepatitis A, hepatitis C, and DDAVP taken intravenously is used newly discovered blood-borne diseases especially for rapid control of occasional remain a risk for people treated with plasma- bleeding or to prevent excessive bleeding derived products. Immunization against during surgery. DDAVP acts for 8 to 12 hepatitis A and B is recommended for all hours, with maximum effectiveness about individuals with hemophilia. No vaccination thirty minutes to one hour after injection. It currently exists for hepatitis C. should therefore ideally be administered within an hour before surgery Epidemiology:-

Cyklokapron Internationally, deficiency of factor XI is reported in most racial groups, with the Cyklokapron (the commercial name of highest frequency in persons of Ashkenazi or ) acts by helping hold the clot Iraqi Jewish descent ; in Israel, the estimated in place after it has formed. It has proven rate for heterozygosity is 8%. In the United very useful in controlling mucosal bleeding Kingdom national database, 1696 patients (bleeding of the soft tissues, such as the (many of whom were non-Jewish) with factor mouth, nose, vagina, etc.). XI deficiency were registered in a population of about 60 million (data for 2006), but most Complications of Hemophilia C of these have partial deficiency. Hemophilia The complications of hemophilia C are those C equally affects males and females. primarily associated with the use of fresh Etiology frozen plasma. While today’s blood products are much safer than those of the past, The severity of the deficiency is based on transmission of hepatitis A, hepatitis C, and plasma factor XIC (clotting) activity. Severe newly discovered blood-borne diseases factor XI deficiency is present when the remain a risk for people treated with plasma- activity of factor XI in plasma is less than 1- derived products. 15 IU/dL.

Epidemiology:- Also, thrombin directly activates factor XI, and this direct activation may be more Hemophilia C (severe form) occurs with an important than the activation due to factor estimated prevalence of 1 case per 100,000 XII. Recently, it has been shown that population in the United States, a rate that thrombin activation of factor XI is triggered makes hemophilia A 10 times more common by polyphosphate release from activated than hemophilia C. Internationally, platelets. These molecules provide a template deficiency of factor XI is reported in most for assembly of factor XI and factor IX. racial groups, with the highest frequency in

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