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NORD is very grateful to Amy D. Shapiro, MD, Medical Director, and Whitney Sealls, PhD, Indiana Hemophilia and Thrombosis Center, for the preparation of this report.
Hemophilia B is a rare genetic bleeding disorder in which affected individuals have insufficient levels of a blood protein called factor IX. Factor IX is a clotting factor. Clotting factors are specialized proteins needed for blood clotting, the process by which blood seals a wound to stop bleeding. Individuals with hemophilia B do not bleed faster than unaffected individuals, they bleed longer. This is because they are missing a protein involved in blood clotting and are unable to effectively stop the flow of blood from the site of a wound. This is sometimes referred to as prolonged bleeding or a bleeding episode.
Hemophilia B is classified as mild, moderate or severe. In mild cases, bleeding symptoms may occur only after surgery, major injury or a dental procedure. In some moderate and most severe cases, bleeding symptoms may occur after a minor injury or spontaneously with no known cause.
Hemophilia B is caused by disruptions, or changes, to the factor IX gene. The factor IX gene is located on one of two sex chromosomes - the X chromosome. Males have one X chromosome and one Y chromosome and thus one altered copy of the factor IX gene in a male is enough to cause him to have hemophilia. Females have two X chromosomes and must have two altered copies of the factor IX gene to have hemophilia. Hemophilia in females is very uncommon and therefore the disorder almost always affects males. It is possible for some females with only one altered copy of the factor IX gene to have bleeding symptoms most often seen in mild hemophilia.
Hemophilia B is the second most common type of hemophilia and is estimated to occur in about 1 in 25,000 male births. It affects all races equally. Hemophilia B is also known as factor IX deficiency or Christmas disease. The disorder was first reported in the medical literature in 1952 in a patient with the name of Stephen Christmas. The most famous family with hemophilia B was that of Queen Victoria of England. Through her descendants, the disorder was passed down to the royal families of Germany, Spain and Russia and thus hemophilia B is also known as the "royal disease."
Although the focus of this report is the genetic, or inherited, form of hemophilia B, it should be noted that another form called acquired hemophilia B can develop later in life (see "Related Disorders" section below). An individual with acquired hemophilia B is not born with the condition. Acquired hemophilia B is caused by the body's production of antibodies against its own factor IX protein. The factor IX antibodies destroy circulating factor IX in the blood causing bleeding symptoms. Acquired hemophilia B is extremely rare; most cases of acquired hemophilia are in those with hemophilia A.
The symptoms and severity of hemophilia B may vary greatly from one person to another. Hemophilia B can range from mild to moderate to severe. Individuals with mild hemophilia have factor IX levels between 5 and 40% of normal; those with moderate hemophilia have factor levels from 1 to 5% of normal; and individuals with severe hemophilia have factor levels less than 1% of normal. The age an individual becomes aware that he has hemophilia B, known as age of diagnosis, and the frequency of bleeding episodes depends upon the amount of factor IX present in the blood.
In mild cases of hemophilia B, individuals may experience bruising, bleeding from mucous membranes such as the nose and mouth, and more serious bleeding after surgery, dental procedures, injury, or trauma. Although some bleeding occurs in individuals without hemophilia after injury or trauma, individuals with hemophilia B often have longer bleeding episodes with these occurrences. In many cases, individuals with mild hemophilia B may go undiagnosed until a surgical procedure is needed or an injury occurs. Individuals with mild hemophilia may not experience their first bleeding episode until adulthood. Additionally, individuals with the mild form of hemophilia B may go many years between bleeding episodes.
Individuals with moderate hemophilia B may have occasional episodes of spontaneous bleeding from mucous membranes and deep tissues such as joints and muscles. These episodes are usually associated with some injury. Individuals with moderate hemophilia B are at risk for prolonged bleeding following surgery or trauma. Affected individuals are usually diagnosed by five or six years of age. Spontaneous bleeding refers to bleeding episodes that occur without a known cause. The frequency of spontaneous bleeding episodes in individuals with moderate hemophilia B varies, ranging from once a month to once a year.
In severe cases of hemophilia B, frequent, spontaneous bleeding episodes are the most common symptom. Spontaneous bleeding episodes may result in bleeding into the muscles and joints. This often causes pain and swelling and restricts movement of the joint. Bleeding into a joint is called a hemarthrosis. If left untreated, this may result in long-term muscle weakness and/or swelling, tightness and restricted movement in the affected joint. Permanent joint damage may occur. Spontaneous joint bleeding is the most common symptom of severe hemophilia B. Additional symptoms affecting individuals with severe hemophilia B include frequent nosebleeds without cause; and easy, frequent and severe bruising.
Individuals with a moderate or severe form of hemophilia can potentially experience spontaneous bleeding into any organ including the kidneys, stomach, intestines, and brain. Bleeding within the kidneys or stomach and intestines may cause blood in the urine, called hematuria, and stool, called melena or hematochezia, respectively. Bleeding within the brain may cause headaches, stiff neck, vomiting, seizures, and mental status changes including excessive sleepiness and poor arousability.
Severe cases of hemophilia B usually become apparent early during infancy or early childhood. Without preventative treatment, called prophylaxis, affected infants may experience two to five spontaneous bleeding episodes per month. Infants are diagnosed with hemophilia B on the basis of a known family history of hemophilia or after they develop bleeding following circumcision, another neonatal procedure or bleeding within the brain, called an intracranial bleed, resulting from delivery. If an infant is not diagnosed at birth, hemophilia may be suspected if the child develops excessive bruising or deep tissue bleeding in areas such as the buttock muscles from falling while learning to walk; bleeding into the joints; or prolonged bleeding in the mouth due to an injury such as a fall.
Hemophilia B is caused by changes, or variations, to the factor IX gene. The factor IX gene is located on the X chromosome and thus is inherited as an X-linked recessive trait. In about 30% of new cases of hemophilia B, the variation in the gene occurs spontaneously without a previous family history.
Genetics of Hemophilia B: X-linked recessive disorders, including hemophilia B, are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes (XX). If only one of their X chromosomes contains a disease-causing variation on a gene, they are called "carriers" of that disorder. It is rare for "carrier" females of hemophilia to have bleeding symptoms as their other X-chromosome has a normal copy of the gene. Carrier females that have bleeding symptoms may need factor replacement therapy following childbirth due to postpartum bleeding or for dental and surgical procedures.
Males have one X chromosome and one Y chromosome (XY). Thus, if a male inherits an X chromosome from his mother that contains a disease-causing gene, he will develop the disease. Males with an X chromosome containing the disease-causing gene will pass that gene on to all of their daughters. These daughters will be carriers if the X chromosome they inherit from their mother is normal or they will have hemophilia if they inherit another disease-causing gene from their mother. This is very rare. A male cannot pass an X-linked gene on to his sons because males only pass their Y chromosome on to their sons. Female carriers of an X-linked disorder have a 25% chance that their daughter will be a carrier; a 25% chance of having a non-carrier daughter; a 25% chance of having a son with the disease; and a 25% chance of having an unaffected son. For pictorial examples of hemophilia inheritance please visit the National Heart, Lung and Blood Institute's website at: http://www.nhlbi.nih.gov/health/health-topics/topics/hemophilia/causes.html.
Investigators have determined that hemophilia B is caused by mutations on the factor IX gene located on the long arm of the X chromosome (Xq27.1-q27.2). Chromosomes, which are present in the nucleus of human cells, carry hereditary or genetic information unique to each individual. Cells in the human body normally have 23 pairs of chromosomes; 46 chromosomes total. Pairs of human chromosomes are numbered from 1 through 22. The sex chromosomes make up the 23rd pair and are designated as X and Y. Each chromosome has a short arm designated as "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome Xq27.1-27.2" refers to bands 27.1 through 27.2 on the long arm, "q", of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome. For a pictorial representation of the information described in this paragraph, please visit http://ghr.nlm.nih.gov/gene/F9.
The factor IX gene contains instructions for creating the factor IX protein. Various changes called mutations on the factor IX gene can lead to deficient levels of functional factor IX protein. The bleeding symptoms associated with hemophilia B occur due to this deficiency.
Hemophilia B Leyden: There is one unusual form of hemophilia B called hemophilia B Leyden. Hemophilia B Leyden is named after the place in the Netherlands where it was first described. Whereas hemophilia B is typically a life-long disorder, individuals with hemophilia B Leyden usually outgrow the disorder in puberty or adulthood. Depending upon the particular hemophilia B Leyden mutation present, there are undetectable levels of factor IX present early in life that increase over time. By midlife, these patients have factor IX levels at the low end of the normal range and thus may no longer require treatment for bleeding episodes. Hemophilia B Leyden represents approximately 3% of all hemophilia B cases.
Hemophilia B occurs in approximately 1 in 25,000 male births. It is less prevalent than hemophilia A which occurs in approximately 1 in 5,000 male births. Although most hemophilia B carrier females do not have symptoms, an estimated 10% will develop mild symptoms. All races and ethnic groups are affected equally. Individuals with severe hemophilia B are usually diagnosed shortly after birth; those with moderate hemophilia B, five to six years of age; and individuals with mild hemophilia B, later during life and even into adulthood.
Symptoms of the following disorders may be similar to those of hemophilia B. Comparisons may be useful for a differential diagnosis.
Hemophilia A and C: Hemophilia is a general term for a group of rare bleeding disorders. Most forms of hemophilia are inherited blood clotting, or coagulation, disorders caused by inactive or deficient blood proteins. There are three major forms of inherited hemophilia: hemophilia A, also known as classical hemophilia, factor VIII deficiency or antihemophilic globulin [AHG] deficiency); hemophilia B, known as Christmas disease, factor IX deficiency or the royal disease; and hemophilia C, known as factor XI deficiency or Rosenthal's disease. Hemophilia A and B are inherited as X-linked recessive genetic disorders, while hemophilia C is inherited as an autosomal genetic disorder. Autosomal disorders are disorders caused by variations in genes located on non-sex chromosomes (sex chromosomes are the X and Y). While hemophilia A and B are most common in males, hemophilia C affects both males and females equally. (For more information on hemophilia A, B and C, choose "hemophilia" as your search term in the Rare Disease Database.)
Acquired Hemophilia: Acquired hemophilia is a type of autoimmune disorder. Autoimmune disorders occur when the body's immune system mistakenly attacks healthy cells or tissue. Acquired hemophilia occurs when individuals without a previous bleeding history develop antibodies against a clotting factor, most commonly factor VIII. This can cause affected individuals to develop symptoms of hemophilia such as nosebleeds, bruising, swelling in tissues due to accumulation of blood called hematomas, blood in the urine, or bleeding from the stomach, intestines or urogenital area. Acquired hemophilia can potentially cause severe, life-threatening bleeding complications in some cases. In approximately half of all cases of acquired hemophilia, there is an associated condition (e.g., pregnancy, allergy, inflammatory bowel disease, etc.); in the other half, no cause can be identified. (For more information on this disorder, choose "acquired hemophilia" as your search term in the Rare Disease Database.)
Von Willebrand Disease: Von Willebrand disease (VWD) is the most common inherited bleeding disorder in the general population. It affects males and females equally. There are several types of VWD (VWD Type 1, VWD type 2, VWD Type 3, and Pseudo-VWD) each with differing degrees of severity and inheritance patterns. The more severe types of VWD are similar to hemophilia and are characterized by prolonged bleeding.
VWD is caused by a defect or deficiency in an individual's von Willebrand Factor (VWF), a large protein made up of multiple subunits. VWF binds to clotting factor VIII in the circulation and protects it from being broken down. VWF also helps platelets bind to the inside of injured blood vessels. This leads to the formation of a stable blood clot which plugs an injured blood vessel and stops bleeding. If there is an insufficient quantity of VWF or it is defective, an individual may have difficulty forming a blood clot.
The majority of people have the relatively mild form of the disease, VWD Type 1, and are not be diagnosed until adulthood. A small percentage of these individuals may have prolonged bleeding during infancy or early childhood. Symptoms can include bleeding from the stomach and intestines, nosebleeds, bleeding from the gums, and easy bruising. Affected individuals may bleed easily after injury, childbirth, and/or surgery. (For more information on this disorder, choose "Von Willebrand" as your search term in the Rare Disease Database.)
Congenital Fibrinogen Disorders: Congenital fibrinogen disorders are a group of rare bleeding disorders characterized by a deficiency or absence of a certain protein, called fibrinogen or coagulation factor I. This condition is inherited and thus is present at birth. Fibrinogen is essential in the blood clotting process. Two major types of fibrinogen disorders have been identified. Type I, or quantitative abnormalities, include afibrinogenemia and hypofibrinogenemia. Quantitative abnormalities result in an absence or reduced amount of the fibrinogen protein. Type 2, or qualitative abnormalities, include dysfibrinogenemia and hypodysfibrinogenemia. Individuals with qualitative abnormalities may have adequate levels of fibrinogen; however, the fibrinogen present does not function properly.
Individuals with afibrinogenemia may be susceptible to severe bleeding episodes, commonly at birth or following circumcision, and prolonged bleeding from minor cuts. In some circumstances, afibrinogenemia may also predispose an individual to developing a blood clot, called a thrombosis. Individuals with hypofibrinogenemia or dysfibrinogenemia may not have symptoms or may develop mild bleeding episodes. (For more information on this disorder, choose "fibrinogen" as your search term in the Rare Disease Database.)
Platelet Disorders: Platelets are small, disc-shaped cells that help the blood clot. Platelet disorders are disorders that can predispose an individual to prolonged bleeding. Platelet disorders can be divided into two groups: quantitative and qualitative platelet disorders. Platelets are either not made in sufficient amounts to stop bleeding or they are destroyed by the body too quickly resulting in an inadequate number when needed.
The most common symptoms of platelet disorders include bruising, recurrent nose bleeds, bleeding of the mouth or gums, heavy menstrual bleeding, excessive postpartum bleeding, and bleeding following surgery or other invasive procedure. The severity and symptoms of the disorder vary depending upon which platelet disorder is present.
Other bleeding disorders may also be considered in an individual with symptoms of abnormal bleeding or bruising including deficiencies of other coagulation factors such as factors VII, X, V, II and XIII, etc.
Diagnosis of hemophilia B is made with attention to the following: the patient's personal history of bleeding, the patient's family history of bleeding and inheritance, and laboratory testing. Several different specialized tests are necessary to confirm a diagnosis of hemophilia B.
To determine if an individual has hemophilia B, specialized blood coagulation tests are used that measure how long it takes the blood to clot. The specialized test measures the activated partial thromboplastin time (aPTT). If the results of the aPTT test are abnormal, more specific blood tests must be used to determine if the cause of the abnormal aPTT is due to a deficiency of factor IX/hemophilia B, factor VIII/hemophilia A or other clotting factor. A specific factor assay also determines the severity level of the factor deficiency. It should be noted that the aPTT is not sensitive enough to detect mild hemophilia B. If this diagnosis is suspected, a specific factor IX activity level should be performed.
Once an individual is diagnosed with hemophilia B, the specific abnormality or mutation on the factor IX gene responsible for causing hemophilia may be identified. Identifying the type of mutation may assist in determining an individual's risk of developing an inhibitor, a serious complication in those with hemophilia (see "Complications" section below). Understanding the specific factor IX gene mutation can also help identify female carriers within a family as factor IX levels are not adequate to determine carrier status.
The fundamental treatment of hemophilia B is to replace factor IX to achieve adequate blood clotting and to prevent complications associated with the disorder. Currently, replacement of factor IX to achieve a sufficient level is commonly done utilizing a recombinant product or with products derived from human blood or plasma. Many physicians and voluntary health organizations favor the use of recombinant factor IX because it does not contain human blood. Human blood donations carry a risk of transmitting viral infections such as hepatitis and HIV; however, newer techniques for screening and treating blood donations have made such a risk extremely low.
Current Treatment Options
Recombinant Factor IX: Recombinant factor IX is artificially made in a laboratory. The current product does not contain any animal or human protein and is not derived from human blood; therefore, it is theoretically considered to be free of the risk of transmitting viruses. Recombinant factor IX therapy is the recommended treatment for individuals with hemophilia B. In the U.S., the only commercially available recombinant factor IX product is BeneFIX®.
Plasma-Derived Factor IX Concentrates: There are two available types of plasma-derived factor IX concentrates available; highly purified plasma-derived products and intermediate purity plasma-derived products. Plasma-derived products come from human donations of blood or plasma. Highly purified products are essentially free of other clotting factor proteins and are virally inactivated using various methods. There are two high purity products available in the U.S., Alphanine® SD and Mononine®. Intermediate purity products contain factor IX and small amounts of other clotting factor proteins and are virally inactivated; however, they are only recommended for individuals with hemophilia B in very special circumstances. The two intermediate purity products available are Bebulin® VH and Profilnine SD®. To find a list of recommended treatment options for the individuals with hemophilia B and other bleeding disorders please visit the National Hemophilia Foundation's website at: http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=57&contentid=693.
Fresh Frozen Plasma: Fresh frozen plasma is also derived from human blood and is used to treat patients with factor IX deficiency only if factor IX concentrate is not available. Fresh frozen plasma contains all of the coagulation factors in the blood but is not virally inactivated. In addition, fresh frozen plasma is quite inefficient in raising factor IX activity to a hemostatic level.
History of Treatment Options
Whole Blood: Until the 1960s, highly reliable treatment for hemophilia did not exist. Patients experiencing bleeding episodes were treated with whole blood transfusions. This was an ineffective treatment option as whole blood does not contain enough clotting factor to effectively stop a bleed. During this time, individuals often had repeated bleeding into the joints or central nervous system which led to permanent joint damage, seizures and a variety of permanent intellectual and movement disorders. The average life expectancy of a male with severe hemophilia during this time was 12 years of age.
Cryoprecipitate: In the mid-1960s, Dr. Judith Pool discovered cryoprecipitate, a human plasma-derived material rich in clotting factor VIII, the clotting factor that is deficient in those with hemophilia A. Cryoprecipitate settles to the bottom of containers of frozen plasma when thawed at refrigerator temperature. Upon warming to room temperature, the cryoprecipitate returns to solution. In its frozen form, cryoprecipitate was stored in blood banks and administered to persons with hemophilia A in place of whole blood or plasma. The effect of the more concentrated factor VIII found in cryoprecipitate, compared to whole blood, was more rapid blood clot formation and decreased problems associated with bleeding episodes. The disadvantage was that patients had to remain in the hospital to infuse cryoprecipitate. Cryoprecipitate does not contain any factor IX clotting factor.
Plasma-Derived Clotting Factor Concentrates: In the late 1960s and early 1970s clotting factors became available in more concentrated forms that remained stable as powders when stored at refrigerator temperature. This allowed hemophilia patients to store and administer the clotting factor at home without medical supervision. The first available factor IX product was approved for use in the U.S. in 1969.
One of the main problems with early factor therapy was that the products available came from human plasma. This carried the risk of transmitting viruses such as hepatitis A, B and C and human immunodeficiency virus (HIV) from the donor to the patient. Until the mid-1980s many individuals receiving factor products became infected with one or more of these viruses due to inability to effectively screen donors or treat the concentrate to inactivate viruses.
Recombinant Products: It was not until the late 1980s to the early 1990s, that the efficacy of recombinant factor products was reported and products made commercially available. In 1992, the first genetically engineered factor VIII concentrate was approved by the Food and Drug Administration. It was not until 1997 that the first recombinant factor IX product became available. Use of genetically engineered factor concentrates may eliminate the risk of blood borne infections or transmittable diseases dependent on the method of manufacturing and exposure or use of human or animal proteins in the manufacturing process.
Administration of Factor Concentrate
Individuals with mild or moderate hemophilia B may be treated with replacement therapy as needed to treat a bleeding episode. This is called episodic infusion therapy and is usually used to stop a bleed that has already started. Individuals with severe hemophilia B may receive more frequent weekly infusions to prevent bleeding episodes. This is called prophylactic therapy and is intended to prevent bleeds before they occur. Prophylactic therapy has been shown to reduce many complications associated with recurrent bleeding such as joint damage in patients with severe hemophilia A and B. Parents and affected individuals can be trained to administer factor IX at home. Home therapy is especially important for individuals with severe disease because infusion of factor IX concentrate is most effective within one hour of the onset of a bleeding episode.
Infusion Reactions: Individuals with factor IX deficiency may experience itching, hives, redness of the skin or, uncommonly, wheezing during or immediately after infusing with clotting factor concentrate. This is most common in individuals using fresh frozen plasma. The reaction caused by using fresh frozen plasma is typically an allergic-like reaction to some part of the donor's blood. These reactions can usually be treated with antihistamines; however, a physician should always be notified of such an event. These symptoms may also occur with the use of factor IX concentrates, although rarely. If symptoms develop or are very severe, the infusion should be stopped and the patient should notify their hemophilia care provider immediately as well as be seen in the emergency room. Infusion reactions in patients with severe factor IX deficiency may be associated with the development of inhibitors.
Inhibitors: It is estimated that = 5% of individuals with severe hemophilia B develop "inhibitors" against factor IX replacement therapy. 44 Inhibitors are antibodies, specialized proteins created by the body's immune system to combat foreign or invading substances such as toxins or bacteria. The immune system may recognize replacement factor IX as "foreign" and create antibodies, or "inhibitors", against it. These antibodies destroy the replacement factor. This complication can seriously "inhibit" the effectiveness of standard treatment. In such cases, alternate treatment is used to treat bleeding. In addition, therapy to eradicate these antibodies may be instituted. The therapy is called immune tolerance induction therapy. Immune tolerance induction therapy is uncommonly attempted in patients with hemophilia B and inhibitors due to the risk of allergic reactions and kidney disease.
Inhibitor development is considered the most severe problem in hemophilia care today as it affects patient treatment, risk of developing joint disease, cost of hemophilia care, and morbidity. Genetic testing can help determine whether an individual with factor IX deficiency is at a high risk of developing an inhibitor. The only product recommended for the treatment and prevention of bleeding in individuals with factor IX deficiency with inhibitors and infusion associated reactions is NovoSeven® RT.47 NovoSeven® RT is a recombinant product.
Federally Recognized Hemophilia Treatment Centers
Evidence has shown that individuals with hemophilia significantly benefit from receiving care from a federally recognized hemophilia treatment center. These specialized centers provide comprehensive care for individuals with hemophilia including the development of specific treatment plans, monitoring and follow-up of affected individuals, and state-of-the-art medical care. Treatment at a hemophilia treatment center ensures that individuals and their family members will be cared for by a professional healthcare team including physicians, nurses, physical therapists, social workers, and genetic counselors experienced in treating individuals with hemophilia. To locate a hemophilia treatment center, visit the Centers for Disease Control and Prevention website at: http://www.cdc.gov/ncbddd/hemophilia/HTC.html.
Future Treatment Options
The ultimate goal of hemophilia B therapy is to provide a treatment that allows for long-term expression of the missing or deficient factor in a patient's blood without continuous medical intervention; a so-called "cure." Gene therapy has the potential to fulfill this objective; however, it has been met with limited success. In hemophilia B gene therapy, the defective factor IX gene is replaced with a normal factor IX gene to enable an individual's body to produce a sufficient amount of the factor IX protein. Ideally, replacement of the defective gene with the new gene could be permanent and an individual will no longer have to infuse with clotting factor concentrate, or if required would only be used quite infrequently.
Some studies have detailed rapid increases in factor levels after gene therapy treatment but these levels slowly declined over time, requiring the patient to continue with factor IX infusions. However, in a 2011 New England Journal of Medicine report, investigators described a clinical trial in which factor IX gene therapy was successful at increasing factor levels from 2-11% of normal (severe hemophilia is classified as having a factor level of less than 1% of normal). In this study, six hemophilia B patients with severe deficiency were given a low, intermediate or high dose of the factor IX gene inserted into a virus. Patients were followed for 6 to 16 months. Four of the six patients were able to completely stop factor IX infusions after gene therapy and the other two patients were able to prolong the time between factor IX infusions. Overall, this study was considered a success; however, before gene therapy is approved for wide use in individuals with hemophilia B, larger studies with a longer follow-up time are needed.
To obtain information on hemophilia B clinical trials visit www.clinicaltrials.gov. Studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site. For information about clinical trials being conducted at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office at:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
(To become a member of NORD, an organization must meet established criteria and be approved by the NORD Board of Directors. If you're interested in becoming a member, please contact Susan Olivo, Membership Manager, at email@example.com.)
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Report last updated: 2012/08/28 00:00:00 GMT+0