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Who and when was the first human diagnosed with hemophilia, or considered a carrier?

Who and when was the first human diagnosed with hemophilia, or considered a carrier?


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The earliest case I can find is Queen Victoria of England, who ruled from 1837-1901. Is this the first hemophilia case on record?


The disease hemophilia has been known for much longer than that. At the time the Talmud was written, for example, it was known that if some boys in a family died from circumcision, the next were also at risk. This might have been because physicians recognized an inherited blood disorder.

Abulcasis, an Arab physicians of the 10th century, wrote about families in which male members died from bleeding out after injury.

In 1803, John Conrad Otto wrote about

a hemorrhagic disposition existing in certain familie

Tracing the condition back three generations in that family named Smith, who lived in Plymouth, New Hampshire. So there were definitely earlier cases where we even know the names of the patients, eben before the disease was named.

The word haemorrhaphilia, later shortened to hemophilia was first used in 1828 by Friedrich Hopff, before the birth of Queen Victoria.

Queen Victoria herself did not have the disease, though, she was a carrier. At least one of her sons had the disease and at least one of her daughters was also a carrier.

The history of hemophilia

History of Bleeding Disorders


Haemophilia

Haemophilia (also spelled hemophilia) [6] is a mostly inherited genetic disorder that impairs the body's ability to make blood clots, a process needed to stop bleeding. [2] [3] This results in people bleeding for a longer time after an injury, easy bruising, and an increased risk of bleeding inside joints or the brain. [1] Those with a mild case of the disease may have symptoms only after an accident or during surgery. [1] 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. [1]

There are two main types of haemophilia: haemophilia A, which occurs due to low amounts of clotting factor VIII, and haemophilia B, which occurs due to low levels of clotting factor IX. [2] They are typically inherited from one's parents through an X chromosome carrying a nonfunctional gene. [7] Rarely a new mutation may occur during early development or haemophilia may develop later in life due to antibodies forming against a clotting factor. [2] [7] Other types include haemophilia C, which occurs due to low levels of factor XI, and parahaemophilia, which occurs due to low levels of factor V. [8] [9] Acquired haemophilia is associated with cancers, autoimmune disorders, and pregnancy. [10] [11] Diagnosis is by testing the blood for its ability to clot and its levels of clotting factors. [4]

Prevention may occur by removing an egg, fertilizing it, and testing the embryo before transferring it to the uterus. [4] Treatment is by replacing the missing blood clotting factors. [3] This may be done on a regular basis or during bleeding episodes. [3] Replacement may take place at home or in hospital. [12] The clotting factors are made either from human blood or by recombinant methods. [12] Up to 20% of people develop antibodies to the clotting factors which makes treatment more difficult. [3] The medication desmopressin may be used in those with mild haemophilia A. [12] Studies of gene therapy are in early human trials. [13]

Haemophilia A affects about 1 in 5,000–10,000, while haemophilia B affects about 1 in 40,000, males at birth. [2] [5] As haemophilia A and B are both X-linked recessive disorders, females are rarely severely affected. [7] Some females with a nonfunctional gene on one of the X chromosomes may be mildly symptomatic. [7] Haemophilia C occurs equally in both sexes and is mostly found in Ashkenazi Jews. [5] In the 1800s haemophilia B was common within the royal families of Europe. [5] The difference between haemophilia A and B was determined in 1952. [5] The word is from the Greek haima αἷμα meaning blood and philia φιλία meaning love. [14]


Rare Disease Database

NORD gratefully acknowledges Amy D. Shapiro, MD, Medical Director, Indiana Hemophilia and Thrombosis Center, for the preparation of this report.

Synonyms of Hemophilia B

General Discussion

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 and promote healing. 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 a wound, injury or bleeding site. This is sometimes referred to as prolonged bleeding or a bleeding episode.

Hemophilia B is classified as mild, moderate or severe based upon the activity level of factor IX. In mild cases, bleeding symptoms may occur only after surgery, injury or a dental procedure. In some moderate and most severe cases, bleeding symptoms may occur after a minor injury or spontaneously, meaning without an identifiable cause.

Hemophilia B is caused by changes (mutations) in the factor IX (F9) gene on the X chromosome. Hemophilia B is mostly expressed in males but some females who carry the gene may have mild or, rarely, severe symptoms of bleeding.

Hemophilia B, also known as factor IX deficiency or Christmas disease, is the second most common type of hemophilia. 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, most commonly 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.

NORD Video: Hemophilia, Guillermo’s Story

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Signs & Symptoms

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 and the family history.

In mild cases of hemophilia B, individuals may experience bruising and 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. Many 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 deep tissues such as joints and muscles. These episodes are usually associated with some injury or inciting event. 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 an identifiable cause. The frequency of spontaneous bleeding episodes in individuals with moderate hemophilia B is highly variable.

In severe cases of hemophilia B, frequent, spontaneous bleeding episodes are the most common symptom. Spontaneous bleeding episodes may include 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 damage including inflammation of the membrane lining the joints (synovitis) and joint disease (arthropathy), 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 easy, frequent and severe bruising and muscle bleeds, and less commonly, nosebleeds, gastrointestinal and central nervous system bleeding.

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, and may result in death if left untreated.

Severe cases of hemophilia B usually become apparent early during infancy or childhood. Without preventative treatment, called prophylaxis, a young child 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, in some cases, 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 or abnormal bruising or bleeding with immunizations.

Causes

Hemophilia B is caused by mutations in the F9 gene. The F9 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 altered gene occurs spontaneously without a previous family history.

The F9 gene contains instructions for creating the factor IX protein. Mutations in the F9 gene can lead to deficient levels of functional factor IX protein. The bleeding symptoms associated with hemophilia B occur due to this deficiency.

X-linked recessive disorders are conditions caused by an altered 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. Carrier females of hemophilia may experience bleeding symptoms which may be related to their FIX activity level as carriers have a normal copy of their other X-chromosome carrier levels are most commonly higher than affected males.

Males have one X chromosome and one Y chromosome (XY). Thus, if a male inherits an X chromosome from his mother that contains a disorder-causing gene, he will develop the disorder. Males with an X chromosome containing the disorder-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 disorder-causing gene from their mother this is rare. A male cannot pass an X-linked gene on to his sons because males only pass their Y chromosome on to their sons. With each pregnancy, female carriers of an X-linked disorder have a 25% chance for each daughter to be a carrier a 25% chance of having a non-carrier daughter a 25% chance of having a son with the disorder and a 25% chance of having an unaffected son.

Hemophilia B Leyden: There is an unusual form of factor IX deficiency called hemophilia B Leyden. Hemophilia B Leyden is named after the place in the Netherlands where it was first described. 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.

Affected Populations

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 many hemophilia B carrier females do not have symptoms, an estimated 10-25% will develop mild symptoms and females have also been reported with moderate and severe symptoms. All races and ethnic groups are affected equally. Individuals with severe hemophilia B are usually diagnosed around birth or within the first 1-2 years of life those with moderate hemophilia B, five to six years of age and individuals with mild hemophilia B may not be diagnosed until later in life and even into adulthood.

Related Disorders

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, 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 recessive 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 identifies as foreign 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 approximately half of all cases of acquired hemophilia, there is an associated underlying condition (e.g., pregnancy, autoimmune disorders such as lupus or rheumatoid arthritis, myeloproliferative disorders, 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. These categories may be sub-classified into subtypes. The more severe types of VWD such as Type 3 may be 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 called multimers. VWF binds to clotting factor VIII in the circulation and protects it from being broken down. VWF also helps platelets bind to the site of injury in 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 with VWD have Type 1, which can range from relatively mild to more severe age of diagnosis varies, and it may not be diagnosed until adulthood. Some individuals may have symptoms during infancy or childhood depending on their level of severity and stressors that are experienced. Symptoms can include, nosebleeds, bleeding from the gums, easy bruising, and, less commonly, bleeding from the stomach and intestines. Affected individuals may bleed easily after injury, childbirth, and/or surgery. Women and girls often may present with excessive menstrual bleeding, or excessive bleeding after delivery. (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 an abnormality, 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 1, or quantitative abnormalities, includes afibrinogenemia and hypofibrinogenemia. Quantitative abnormalities result in an absence or reduced amount of the fibrinogen protein. Type 2, or qualitative abnormalities, includes dysfibrinogenemia and hypodysfibrinogenemia. Individuals with qualitative abnormalities may have adequate levels of fibrinogen however, the fibrinogen present does not function properly.

Individuals with afibrinogenemia are susceptible to severe bleeding episodes, commonly at birth or following interventions such as circumcision, and prolonged bleeding from minor cuts. Individuals with afibrinogenemia may also be predisposed to develop 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 or are defective in their function and therefore may not be adequate to stop bleeding in addition, some conditions are associated with increased destruction or turnover resulting in an inadequate number when needed.

The most common symptoms of platelet disorders include development of petechiae (small red or purple spots on the skin), 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 the platelet disorder.

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

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 initial test is 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 another clotting factor. A specific factor assay also determines the severity level of the factor deficiency. It should be noted that the aPTT is not consistently sensitive to detect mild hemophilia B. If this diagnosis is suspected, a specific factor IX activity level should be performed even in the face of a normal aPTT.

Once an individual is diagnosed with hemophilia B, the specific mutation in the F9 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 severe hemophilia (see “Complications” section below). Understanding the specific F9 gene mutation can also help identify female carriers within a family as factor IX levels are not adequate to determine carrier status.

Standard Therapies

Treatment
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 recombinant products 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 proteins. Human blood donations carry a very small risk of transmitting viral infections such as hepatitis and HIV however, newer techniques for screening and treating blood donations have this risk extremely low to negligible.

Carrier females that have bleeding symptoms may need factor replacement therapy following childbirth due to postpartum bleeding or for dental and surgical procedures depending on their factor IX activity level.

Current Treatment Options

Recombinant Factor IX: Recombinant factor IX products are manufactured in a laboratory. These genetically engineered products do not contain animal or human protein and are not derived from human blood they are 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 currently available recombinant factor IX products are BeneFIX, Rixubis, Ixinity, Alprolix Idelvion, and Rebinyn.

Plasma-Derived Factor IX Concentrates: There are two main categories 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 variable amounts of other clotting factor proteins and are virally inactivated however, they are rarely used in the United States and not recommended for treatment of FIX deficiency.

Fresh Frozen Plasma: Fresh frozen plasma is 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 inefficient in raising factor IX activity to a hemostatic level.

The document in the link below from the Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation provides recommendations for the treatment of hemophilia:

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 sufficient quantities of clotting factor to increase the level to a hemostatic range to effectively control bleeding. 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. Cryoprecipitate does not contain factor IX and is not recommended for use in the United States anymore for treatment of hemophilia.

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 an intermediate purity (PCC) and 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.

Treatment Regimens for Hemophilia

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 used to stop a bleed that has already started. Individuals with severe hemophilia B may receive regular 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 and intracranial hemorrhage 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 but is also important for moderate and mild hemophilia as infusion of factor IX concentrate is most effective at limiting bleeding when administered within one hour of the onset of a bleeding episode.

Complications

Infusion Reactions: Individuals with factor IX deficiency may experience itching, hives, redness of the skin or, uncommonly, wheezing during or immediately after infusion of replacement with FIX. Infusion reactions are most commonly seen in individuals using fresh frozen plasma where the reaction is typically an allergic-like reaction to some part of the donor’s blood. These reactions can usually be treated with antihistamines and corticosteroids however, a physician should always be notified of such an event. An important infusion reaction in hemophilia B can occur with the use of factor IX concentrates these are uncommon but must be recognized promptly for patient safety and monitoring. If symptoms develop or are 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.

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      Franchini M, Gandini G, Di Paolantonio T, Mariani G. Acquired hemophilia A: a concise review. Am J Hematol. 200580:55-63. http://www.ncbi.nlm.nih.gov/pubmed/16138334

      Giangrande P. Haemophilia B: Christmas disease. Expert Opin Pharmacother. 20056:1517-24. http://www.ncbi.nlm.nih.gov/pubmed/16086639

      Bolton-Maggs PH, Perry DJ, Chalmers EA, et al. The rare coagulation disorders–review with guidelines for management from the United Kingdom Haemophilia Centre Doctors’ Organisation. Haemophilia. 200410:593-628. http://www.ncbi.nlm.nih.gov/pubmed/15357789

      Powell JS, Ragni MV, White GC, et al. Phase 1 trial of FVIII gene transfer for severe hemophilia A using a retroviral construct administered by peripheral intravenous infusion. Blood. 2003102:2038-45. http://www.ncbi.nlm.nih.gov/pubmed/12763932

      Manno CS, Chew AJ, Hutchison S, et al. AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B. Blood. 2003101:2963-72. http://www.ncbi.nlm.nih.gov/pubmed/12515715

      Von Depka M. NovoSeven: mode of action and use in acquired haemophilia. Intensive Care Med. 200228 Suppl 2:S222-7. http://www.ncbi.nlm.nih.gov/pubmed/12404090

      Boggio LN, Green D. Acquired hemophilia. Rev Clin Exp Hematol. 20015:389-404 quiz following 31. http://www.ncbi.nlm.nih.gov/pubmed/11844135

      Soucie JM, Nuss R, Evatt BL, et al. Mortality among males with hemophilia: relations with source of medical care. Blood. 200096:437-42. http://www.ncbi.nlm.nih.gov/pubmed/10887103

      Hay CR. Acquired haemophilia. Baillieres Clin Haematol. 199811:287-303. http://www.ncbi.nlm.nih.gov/pubmed/10097808

      Dioun AF, Ewenstein BM, Geha RS, Schneider LC. IgE-mediated allergy and desensitization to factor IX in hemophilia B. The Journal of allergy and clinical immunology 1998102:113-7. http://www.ncbi.nlm.nih.gov/pubmed/9679854

      Williamson LM, Allain JP. Virally inactivated fresh frozen plasma. Vox Sang. 199569:159-65. http://www.ncbi.nlm.nih.gov/pubmed/8578727

      Berntorp E. Methods of haemophilia care delivery: regular prophylaxis versus episodic treatment. Haemophilia. 19951:3-7.

      Briet E, Bertina RM, van Tilburg NH, Veltkamp JJ. Hemophilia B Leyden: a sex-linked hereditary disorder that improves after puberty. N Engl J Med. 1982306:788-90. http://www.ncbi.nlm.nih.gov/pubmed/7062952

      Breen FA Jr, Tullis JL. Prothrombin concentrates in treatment of Christmas disease and allied disorders. JAMA. 1969208:1848-52. http://www.ncbi.nlm.nih.gov/pubmed/5818828

      Pool JG, Gershgold EJ, Pappenhagen AR. High-potency antihaemophilic factor concentrate prepared from cryoglobulin precipitate. Nature. 1964203:312.
      http://www.ncbi.nlm.nih.gov/pubmed/14201780

      Biggs R, Douglas AS, Macfarlane RG, et al. Christmas disease: a condition previously mistaken for haemophilia. Br Med J. 19522:1378-82. http://www.ncbi.nlm.nih.gov/pubmed/12997790

      INTERNET
      Konkle BA, Huston H, Nakaya Fletcher S. Hemophilia B. 2000 Oct 2 [Updated 2017 Jun 15]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1495/ Accessed June 6, 2018.

      Genetics Home Reference. F9. http://ghr.nlm.nih.gov/gene/F9 Reviewed May 2010. Accessed June 6, 2018.

      Years Published

      The information in NORD&rsquos Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.

      The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD&rsquos copyright.

      National Organization for Rare Disorders (NORD)
      55 Kenosia Ave., Danbury CT 06810 &bull (203)744-0100


      Who and when was the first human diagnosed with hemophilia, or considered a carrier? - Biology

      Hemophilia B, also called factor IX (FIX) deficiency or Christmas disease, is a genetic disorder caused by missing or defective factor IX, a clotting protein. Although it is passed down from parents to children, about 1/3 of cases are caused by a spontaneous mutation, a change in a gene.

      According to the US Centers for Disease Control and Prevention, hemophilia occurs in approximately 1 in 5,000 live births. There are about 20,000 people with hemophilia in the US. All races and ethnic groups are affected. Hemophilia B is four times less common than hemophilia A.

      Genetics

      The X and Y chromosomes are called sex chromosomes. The gene for hemophilia is carried on the X chromosome. Hemophilia is inherited in an X-linked recessive manner. Females inherit two X chromosomes, one from their mother and one from their father (XX). Males inherit an X chromosome from their mother and a Y chromosome from their father (XY). That means if a son inherits an X chromosome carrying hemophilia from his mother, he will have hemophilia. It also means that fathers cannot pass hemophilia on to their sons.

      But because daughters have two X chromosomes, even if they inherit the hemophilia gene from their mother, most likely they will inherit a healthy X chromosome from their father and not have hemophilia. A daughter who inherits an X chromosome that contains the gene for hemophilia is called a carrier. She can pass the gene on to her children. Hemophilia can occur in daughters, but is rare.

      For a female carrier, there are four possible outcomes for each pregnancy:

      1. A girl who is not a carrier
      2. A girl who is a carrier
      3. A boy without hemophilia
      4. A boy with hemophilia

      Symptoms

      People with hemophilia B bleed longer than other people. Bleeds can occur internally, into joints and muscles, or externally, from minor cuts, dental procedures or trauma. How frequently a person bleeds and how serious the bleeds are depends on how much FIX is in the plasma, the straw-colored fluid portion of blood.

      Normal plasma levels of FIX range from 50% to 150%. Levels below 50%, or half of what is needed to form a clot, determine a person’s symptoms.

      • Mild hemophilia B. 6% up to 49% of FIX in the blood. People with mild hemophilia B typically experience bleeding only after serious injury, trauma or surgery. In many cases, mild hemophilia is not diagnosed until an injury, surgery or tooth extraction results in prolonged bleeding. The first episode may not occur until adulthood. Women with mild hemophilia often experience menorrhagia, heavy menstrual periods, and can hemorrhage after childbirth.
      • Moderate hemophilia B. 1% up to 5% of FIX in the blood. People with moderate hemophilia B tend to have bleeding episodes after injuries. Bleeds that occur without obvious cause are called spontaneous bleeding episodes.
      • Severe hemophilia B. <1% of FIX in the blood. People with severe hemophilia B experience bleeding following an injury and may have frequent spontaneous bleeding episodes, often into their joints and muscles.

      Diagnosis

      The best place for patients with hemophilia to be diagnosed and treated is at one of the federally-funded hemophilia treatment centers (HTCs) that are spread throughout the country. HTCs provide comprehensive care from skilled hematologists and other professional staff, including nurses, physical therapists, social workers and sometimes dentists, dieticians and other healthcare providers.

      A medical health history is important to help determine if other relatives have been diagnosed with a bleeding disorder or have experienced symptoms. Tests that evaluate clotting time and a patient’s ability to form a clot may be ordered. A clotting factor test, called an assay, will determine the type of hemophilia and its severity.

      Treatment

      The main medication to treat hemophilia B is concentrated FIX product, called clotting factor or simply factor. Recombinant factor products, which are developed in a lab through the use of DNA technology, , preclude the use of human-derived pools of donor-sourced plasma. And while plasma-derived FIX products are still available, approximately 75% of the hemophilia community takes a recombinant FIX product.

      These factor therapies are infused intravenously through a vein in the arm or a port in the chest. The Medical and Scientific Advisory Council (MASAC) of the National Hemophilia Foundation encourages the use of recombinant clotting factor products because they are safer. Your doctor or your HTC will help you decide which is right for you.

      Patients with severe hemophilia may be on a routine treatment regimen, called prophylaxis, to maintain enough clotting factor in their bloodstream to prevent bleeds. MASAC recommends prophylaxis as optimal therapy for children with severe hemophilia B.

      Aminocaproic acid is an antifibrinolytic, preventing the breakdown of blood clots. It is often recommended before dental procedures, and to treat nose and mouth bleeds. It is taken orally, as a tablet or liquid. MASAC recommends that a dose of clotting factor be taken first to form a clot, then aminocaproic acid, to preserve the clot and keep it from being broken down prematurely.

      Living with Hemophilia B

      There's a lot to know about living with a bleeding disorder like hemophilia B. Visit NHF’s Steps for Living to explore resources, tools, tips and videos on living with hemophilia A through all life stages. Organized by life stages, Steps for Living provides information on recognizing the signs of bleeds in children, help on navigating school issues, how to exercise safely, helping teens manage their bleeding disorder, information on workplace accommodations, and much more. There are downloadable checklists, toolkits, videos, and more.


      Contents

      In terms of the symptoms of haemophilia A, there are internal or external bleeding episodes. Individuals with more severe haemophilia suffer more severe and more frequent bleeding, while others with mild haemophilia typically suffer more minor symptoms except after surgery or serious trauma. Moderate haemophiliacs have variable symptoms which manifest along a spectrum between severe and mild forms. [1]

      Prolonged bleeding from a venepuncture or heelprick is another common early sign of haemophilia, these signs may lead to blood tests which indicate haemophilia. [5] In other people, especially those with moderate or mild haemophilia, any trauma will lead to the first serious bleed. Haemophilia leads to a severely increased risk of prolonged bleeding from common injuries, or in severe cases bleeding may be spontaneous and without obvious cause. Bleeding may occur anywhere in the body, superficial bleeding such as those caused by abrasions, or shallow lacerations may be prolonged and the scab may easily be broken up due to the lack of fibrin, which may cause re-bleeding. [1] While superficial bleeding is troublesome, some of the more serious sites of bleeding are: [6]

      Muscle and joint haemorrhages – or haemarthrosis – are indicative of haemophilia, [7] while digestive tract and cerebral haemorrhages are also germane to other coagulation disorders. Though typically not life-threatening, joint bleeding is one of the most serious symptoms of haemophilia. Repeated bleeds into a joint capsule can cause permanent joint damage and disfigurement resulting in chronic arthritis and disability. Joint damage is not a result of blood in the capsule but rather the healing process. When blood in the joint is broken down by enzymes in the body, the bone in that area is also degraded, this exerts a lot of pain upon the person afflicted with the disease. [ medical citation needed ]

      Complications Edit

      One therapeutic conundrum is the development of inhibitor antibodies against factor VIII due to frequent infusions. These develop as the body recognises the infused factor VIII as foreign, as the body does not produce its own copy. In these individuals, activated factor VII, a precursor to factor VIII in the coagulation cascade, can be infused as a treatment for haemorrhage in individuals with haemophilia and antibodies against replacement factor VIII. [1] [8]

      Oral Manifestations Edit

      The oral manifestations are characterized by frequent bleeding of multiple sites, frequently seen as gingival and postextraction haemorrhages. The symptoms depend on the severity of haemophilia. In the case of severe haemophilia, patients may complain of multiple oral bleeding episodes throughout their life. Haemophilia patients are considered to be a special group of patients as routinely done procedures may be fatal in them. It was seen that almost 14% of all haemophilia patients and 30% of cases with a mild type of haemophilia have been diagnosed early following an episode of severe oral bleeding, of which the most common sites were the labial frenum and the tongue. [9]

      Haemophilia A is inherited as an X-linked recessive trait. It occurs in males and in homozygous females (which is only possible in the daughters of a haemophilic male and a carrier or haemophiliac female [10] ). However, mild haemophilia A is known to occur in heterozygous females due to X-inactivation, so it is recommended that levels of factor VIII and IX be measured in all known or potential carriers prior to surgery and in the event of clinically significant bleeding. [1] [11]

      About 5-10% of people with haemophilia A are affected because they make a dysfunctional version of the factor VIII protein, while the remainder are affected because they produce factor VIII in insufficient amounts (quantitative deficiency). [11] Of those who have severe deficiency (defined as <1% activity of factor VIII), 45-50% have the same mutation, an inversion within the factor VIII gene that results in total elimination of protein production. [11]

      Since both forms of haemophilia can be caused by a variety of different mutations, initial diagnosis and classification is done by measurement of protein activity rather than by genetic tests, though genetic tests are recommended for testing of family members once a known case of haemophilia is identified. [1] [11] Approximately 30% of patients have no family history their disease is presumably caused by new mutations. [12]

      The diagnosis of haemophilia A may be suspected as coagulation testing reveals an increased partial thromboplastin time (PTT) in the context of a normal prothrombin time (PT) and bleeding time. PTT tests are the first blood test done when haemophilia is indicated. [13] However, the diagnosis is made in the presence of very low levels of factor VIII. A family history is frequently present, although not essential. Recently, genetic testing has been made available to determine an individual's risk of attaining or passing on haemophilia. Diagnosis of haemophilia A also includes a severity level, which can range from mild to severe based on the amount of active and functioning factor VIII detected in the blood. Factor VIII levels do not typically change throughout an individual's lifetime. Severe haemophilia A is the most common severity, occurring in the majority of affected people. Individuals with mild haemophilia often experience few or no bleeding episodes except in the case of serious trauma (i.e. tooth extraction, or surgery). [1]

      Severity Edit

      There are numerous different mutations which can cause haemophilia A, due to differences in changes to the factor VIII gene (and the resulting protein). Individuals with haemophilia often have some level of active clotting factor. Individuals with less than 1% active factor are classified as having severe haemophilia, those with 1–5% active factor have moderate haemophilia, and those with mild haemophilia have between 5–40% of normal levels of active clotting factor. [14]

      Differential diagnosis Edit

      Two of the most common differential diagnoses are haemophilia B which is a deficiency in Factor IX and von Willebrand Disease which is a deficiency in von Willebrand factor (needed for the proper functioning of Factor VIII [15] ) haemophilia C is also considered. [3]

      In regards to the treatment of this genetic disorder, most individuals with severe haemophilia require regular supplementation with intravenous recombinant or plasma concentrate Factor VIII. The preventative treatment regime is highly variable and individually determined. [6] In children, an easily accessible intravenous port [16] may have to be inserted to minimise frequent traumatic intravenous cannulation. These devices have made prophylaxis in haemophilia much easier for families because the problems of finding a vein for infusion several times a week are eliminated. However, there are risks involved with their use, the most worrisome being that of infection, studies differ but some show an infection rate that is high. [17] These infections can usually be treated with intravenous antibiotics but sometimes the device must be removed, [18] also, there are other studies that show a risk of clots forming at the tip of the catheter, rendering it useless. Some individuals with severe haemophilia, and most with moderate and mild haemophilia, treat only as needed without a regular prophylactic schedule. [19] Mild haemophiliacs often manage their condition with desmopressin, a drug which releases stored factor VIII from blood vessel walls. [20]

      Dental considerations Edit

      The inferior alveolar nerve block should only be given after raising clotting factor levels by appropriate replacement therapy, as there is a risk of bleeding into the muscles along with potential airway compromise due to a haematoma in the retromolar or pterygoid space. The intraligamental technique or interosseous technique should be considered instead of the mandibular block. Articaine has been used as a buccal infiltration to anaesthetize the lower molar teeth. A lingual infiltration also requires appropriate factor replacement since the injection is into an area with a rich plexus of blood vessels and the needle is not adjacent to bone. [21]

      Gene therapy Edit

      In December 2017, it was reported that doctors had used a new form of gene therapy to treat haemophilia A. [22] [23] [24]

      Monoclonal antibodies Edit

      Monoclonal antibody emicizumab has been approved by the FDA in 2017 for therapy of hemophilia A. [25]

      Two Dutch studies have followed haemophilia patients for a number of years. [26] [27] Both studies found that viral infections were common in haemophiliacs due to the frequent blood transfusions which put them at risk of acquiring blood borne infections, such as HIV, hepatitis B and hepatitis C. In the latest study which followed patients from 1992 to 2001, the male life expectancy was 59 years. If cases with known viral infections were excluded, the life expectancy was 72, close to that of the general population. 26% of the cases died from AIDS and 22% from hepatitis C. [27] However, these statistics for prognosis are unreliable as there has been marked improvement of infection control and efficacy of anti-retroviral drugs since these studies were done. [ citation needed ]

      Haemophilia A occurs in approximately 1 in 5,000 males, [11] while the incidence of haemophilia B is 1 in 30,000 in the male population, [11] of these, 85% have haemophilia A and 15% have haemophilia B. [11]


      Who and when was the first human diagnosed with hemophilia, or considered a carrier? - Biology

      According to the Centers for Disease Control and Prevention (CDC):

      What Is Hemophilia A?


      Hemophilia A, also called factor VIII (8) deficiency or classic hemophilia, is a genetic disorder caused by missing or defective factor VIII (FVIII), a clotting protein. Although it is passed down from parents to children, about 1/3 of cases found have no previous family history.


      According to the US Centers for Disease Control and Prevention (CDC), hemophilia occurs in approximately 1 in 5,617 live male births. There are between 30,000 – 33,000 males with hemophilia in the US*. More than half of people diagnosed with hemophilia A have the severe form. Hemophilia A is four times as common as hemophilia B. Hemophilia affects all races and ethnic groups.

      The Genetics of Hemophilia

      Hemophilia A is an inheritable disease, meaning it is passed down from parents to children. The X and Y chromosomes are called sex chromosomes. The gene for hemophilia is carried on the X chromosome. Hemophilia is inherited in an X-linked recessive manner. Females inherit two X chromosomes, one from their mother and one from their father (XX). Males inherit an X chromosome from their mother and a Y chromosome from their father (XY). That means if a son inherits an X chromosome carrying hemophilia from his mother, he will have hemophilia. It also means that fathers cannot pass hemophilia on to their sons.

      But because daughters have two X chromosomes, even if they inherit the hemophilia gene from their mother, most likely they will inherit a healthy X chromosome from their father and not have hemophilia. A daughter who inherits an X chromosome that contains the gene for hemophilia is called a carrier. She can pass the gene on to her children. Many women who carry the hemophilia gene also have low factor expression, which can result in heavy menstrual bleeding, easy bruising, and joint bleeds. Some women who have the hemophilia gene have factor expression low enough to be diagnosed with hemophilia.


      For a female carrier, there are four possible outcomes for each pregnancy:
      1. A girl who is not a carrier
      2. A girl who is a carrier
      3. A boy without hemophilia
      4. A boy with hemophilia

      Severity


      (percentage breakdown of overall hemophilia population by severity)

      • Severe (factor levels less than 1%) represent approximately 60% of cases
      • Moderate (factor levels of 1-5%) represent approximately 15% of cases
      • Mild (factor levels of 6%-30%) represent approximately 25% of cases

      What are the Symptoms of Hemophilia A?

      People with hemophilia A bleed longer than other people. Bleeds can occur internally, into joints and muscles, or externally, from minor cuts, dental procedures, or injuries. How often a person bleeds and the severity of those bleeds depends on how much FVIII a person produces naturally.


      Normal levels of FVIII range from 50% to 150%. Levels below 50% – or half of what is needed to form a clot – determine a person’s symptoms.


      • Mild hemophilia A: 6% up to 49% of FVIII in the blood. People with mild hemophilia A generally experience bleeding typically only after serious injury, trauma, or surgery. In many cases, mild hemophilia is not diagnosed until an injury, surgery or tooth extraction results in prolonged bleeding. The first episode may not occur until adulthood. Women with mild hemophilia often experience heavy menstrual bleeding, and can hemorrhage (bleed extensively) after childbirth.
      • Moderate hemophilia A: 1% up to 5% of FVIII in the blood. People with moderate hemophilia A tend to have bleeding episodes after injuries.
      • Severe hemophilia A. <1% of FVIII in the blood. People with severe hemophilia A experience bleeding following an injury and may have frequent spontaneous bleeding episodes – bleeds that occur without obvious cause – often into their joints and muscles. Many males with severe hemophilia are diagnosed due to bleeding after circumcision.

      Diagnosis of Hemophilia A

      Doctors will perform tests that evaluate how long it takes for the blood to clot to determine if someone has hemophilia. A clotting factor test, called an assay, will show the type of hemophilia and the severity, or how much clotting factor the person produces on their own.
      Most people who have a family history of hemophilia will ask that their baby boys be tested soon after birth to see if they have hemophilia. If there is no family history of hemophilia, people often notice bleeding that takes longer to stop or lots of bruising. Many babies born with severe hemophilia are diagnosed if there is prolonged bleeding after circumcision.

      For girls, it often takes seeing worsening of symptoms for the diagnosis process to begin. Most girls are not tested for hemophilia before puberty. Heavy periods are a symptom of a bleeding disorder in women and girls. If there is a known family history, it is important to monitor for symptoms. It is recommended that women who have a family history of hemophilia get tested before getting pregnant, to help prevent complications during childbirth.


      The best place for patients with hemophilia to be diagnosed and treated is at one of the federally funded hemophilia treatment centers (HTCs) that are spread throughout the country. HTCs provide comprehensive care from skilled hematologists and other professional staff, including nurses, physical therapists, social workers and sometimes dentists, dieticians and other healthcare providers, including specialized labs for more accurate lab testing.

      How is Hemophilia A Treated?

      Most treatments for hemophilia A focus on replacing the missing protein, FVIII (8), so a person can form a clot, and so reduce or eliminate the bleeds associated with the disorder. Treatments that work to prevent bleeding through new mechanisms have recently come to the market or are in clinical trials. People with hemophilia A have several different medication options for treatment.


      The main medication to treat hemophilia A is concentrated FVIII product, called clotting factor or simply factor. There are two types of clotting factor: plasma-derived and recombinant. Plasma-derived factor is made from human plasma. Recombinant factor products are developed in a lab through the use of DNA technology. While plasma-derived FVIII products are still available, approximately 75% of the hemophilia community takes a recombinant FVIII product.


      These factor therapies are injected into a vein (called “infusion”) in the arm or hand, or through a port in the chest. The NHF's Medical and Scientific Advisory Council (MASAC) encourages the use of recombinant clotting factor products over plasma-derived because they are safer from blood-borne viruses and diseases.


      To maintain enough clotting factor in the bloodstream to prevent bleeds, patients with severe hemophilia are typically prescribed a regular treatment regimen, called prophylaxis – or prophy for short. This means a person will infuse their medication on a regular schedule – for example every day or every other day, depending on how long the factor lasts in the body. MASAC recommends prophylaxis as optimal therapy for all people with severe hemophilia A.

      New treatments that use other ways of preventing bleeds are also available. These treatments are known as non-factor replacement therapies. One available therapy is emicizumab, a laboratory-engineered protein that works by performing a key function in the clotting cascade that is normally carried out by the FVIII protein. It can be prescribed for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children of all ages, newborn and older, with hemophilia A with and without factor VIII inhibitors. Emicizumab is not infused, but injected under the skin (subcutaneously.)
      It is important to discuss all treatment options with your doctor or the staff at your HTC.

      DDAVP (desmopressin acetate) is the synthetic version of vasopressin, a natural antidiuretic hormone that helps stop bleeding. In patients with mild hemophilia, it can be used for joint and muscle bleeds, for nose and mouth bleeds, and before and after surgery. It comes in an injectable form and a nasal spray. The manufacturer of DDAVP nasal spray issued a recall of all US products and does not expect to begin resupplying until 2022.


      Aminocaproic acid prevents the breakdown of blood clots. It is often recommended before dental procedures, and to treat nose and mouth bleeds. It is taken orally, as a tablet or liquid. MASAC recommends that a dose of clotting factor be taken first to form a clot, then aminocaproic acid, to preserve the clot and keep it from being broken down prematurely.

      The Future of Hemophilia A Treatment

      There are many new treatments for hemophilia A being developed, from gene therapy to new non-factor replacement therapies. Visit the Future Therapies section for updated information on the pipeline of new therapies, as well as extensive information on the development of gene therapy as a treatment for hemophilia.

      Living with Hemophilia A

      There's a lot to know about living with a bleeding disorder like hemophilia A. Visit NHF’s Steps for Living to explore resources, tools, tips and videos on living with hemophilia A through all life stages. Organized by life stages, Steps for Living provides information on recognizing the signs of bleeds in children, help on navigating school issues, how to exercise safely, helping teens manage their bleeding disorder, information on workplace accommodations, and much more. There are downloadable checklists, toolkits, videos, and more.


      Recent Scientific Articles

      Evaluation of anti-factor VIII antibody levels in patients with haemophilia A receiving immune tolerance induction therapy or bypassing agents.
      Haemophilia 202027(1):e40-e50. https://doi.org/10.1111/hae.14202
      Boylan B, Niemeyer GP, Werner B, Miller CH.
      [Read article external icon ]

      Hemophilia without prophylaxis: Assessment of joint range of motion and factor activity.
      Res Pract Thromb Haemost 20204(6):1035-1045. https://doi.org/10.1002/rth2.12347
      Wang M, Recht M, Iyer NN, Cooper DL, Soucie JM.
      [Read article external icon ]

      Patient satisfaction with US Hemophilia Treatment Center Care, Teams and Services: The first national survey.
      Haemophilia 202026(6):991-998. https://doi.org/10.1111/hae.14176
      Riske B, Shearer R, Baker JR.
      [Read article external icon ]

      Evaluation of CDC&rsquos Hemophilia Surveillance Program &mdash Universal Data Collection (1998&ndash2011) and Community Counts (2011&ndash2019), United States.
      MMWR Surveill Summ 202069(No. SS-5):1&ndash18. http://dx.doi.org/10.15585/mmwr.ss6905a1
      Schieve LA, Byams VR, Dupervil B, Oakley MA, Miller CH, Soucie JM, Abe K, Bean CJ, Hooper WC.
      [Read article]

      Occurrence rates of haemophilia among males in the United States based on surveillance conducted in specialized haemophilia treatment centres.
      Haemophilia 202026(3):487-493. https://doi.org/10.1111/hae.13998
      Soucie JM, Miller CH, Dupervil B, Le B, Buckner TW.
      [Read article external icon ]

      Potential of the Community Counts registry to characterize rare bleeding disorders.
      Haemophilia 201925(6):1045-1050. https://doi.org/10.1111/hae.13847
      Gupta S, Acharya S, Roberson C, Lail A, Soucie JM, Shapiro A.
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      Population-based surveillance of haemophilia and patient outcomes in Indiana using multiple data sources.
      Haemophilia 201925(3):456-462. https://doi.org/10.1111/hae.13734
      Okolo AI, Soucie JM, Grosse SD, Roberson C, Janson IA, Allen M, Shapiro AD.
      [Read article external icon ]

      Reagent substitution in the chromogenic Bethesda assay for factor VIII inhibitors.
      Haemophilia 2019 25(5):e342-e344. https://doi.org/10.1111/hae.13827
      Payne AB, Miller CH, Ellingsen D, Driggers J, Boylan B, Bean CJ.
      [Read article external icon ]

      Origins and organization of the NHLBI State of the Science Workshop: Generating a national blueprint for future research on factor VIII inhibitors.
      Haemophilia 201925(4):575-580. https://doi.org/10.1111/hae.13737
      Sabatino DE, Pipe SW, Nugent DJ, Soucie JM, Hooper WC, Hoots WK, DiMichele DM.
      [Read article external icon ]

      Effects of pre-analytical heat treatment in factor VIII (FVIII) inhibitor assays on FVIII antibody levels.
      Haemophilia 201824(3):487-491. https://doi.org/10.1111/hae.13435
      Boylan B, Miller CH.
      [Read article external icon ] [View Public Data Access]

      Community counts: Evolution of a national surveillance system for bleeding disorders.
      Am J Hematol 201893(6):E137-E140. https://doi.org/10.1002/ajh.25076
      Manco-Johnson MJ, Byams VR, Recht M, Dudley B, Dupervil B, Aschman DJ, Oakley M, Kapica S, Voutsis M, Humes S, Kulkarni R, Grant AM U.S. Haemophilia Treatment Center Network.
      [Read article external icon ] [View Public Data Access]

      The frequency of joint hemorrhages and procedures in non-severe hemophilia A versus B.
      Blood Advances 20182(16):2136-2144. https://doi.org/10.1182/bloodadvances.2018020552
      Soucie JM, Monahan PE, Kulkarni R, Konkle BA, Mazepa MA U.S. Hemophilia Treatment Center Network.
      [Read article external icon ]

      Risk factors associated with invasive orthopedic interventions in males with hemophilia enrolled in the Universal Data Collection (UDC) program from 2000 to 2010.
      Haemophilia 201824(6):964-970. https://doi.org/10.1111/hae.13511
      Tobase P, Lane H, Siddiqi A-E-A, Soucie JM, Ingram-Rich R, Ward RS, Gill JC.
      [Read article external icon ]

      Relevance of abusive head trauma to intracranial hemorrhages and bleeding disorders.
      Pediatrics 2018141(5):e20173485. https://doi.org/10.1542/peds.2017-3485
      Anderst JD, Carpenter SL, Presley R, Berkoff MC, Wheeler AP, Sidonio RF, Soucie, JM.
      [Read article external icon ]

      Prophylaxis use among males with haemophilia B in the United States.
      Haemophilia 201723(6):910-917. https://doi.org/10.1111/hae.13317
      Ullman M, Zhang QC, Grosse SD, Recht M, Soucie JM U.S. Hemophilia Treatment Center Network Investigators.
      [Read article external icon ]

      Limit of detection and threshold for positivity of the Centers for Disease Control and Prevention assay for factor viii inhibitors.
      J Thromb Haemost 201715(1):1971-1976. https://doi.org/10.1111/jth.13795
      Miller CH, Boylan B, Shapiro AD, Lentz SR, Wicklund BM Hemophilia Inhibitor Research Study Investigators.
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      The effects of joint disease, inhibitors and other complications on health-related quality of life among males with severe hemophilia A in the United States.
      Haemophilia 201723(4):e287 &ndash e293. https://doi.org/10.1111/hae.13275
      Soucie JM, Grosse SD, Siddiqi A-E-A, Byams V, Thierry J, Zack MM, Shapiro A, Duncan N U.S. Hemophilia Treatment Center Network.
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      Prophylaxis usage, bleeding rates and joint outcomes of hemophilia 1999 &ndash 2010: A surveillance project.
      Blood 2017129(17):2368-2374. https://doi.org/10.1182/blood-2016-02-683169
      Manco-Johnson MJ, Soucie JM, Gill JC Joint Outcomes Committee of the Universal Data Collection, U.S. Hemophilia Treatment Center Network
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      Complications of haemophilia in babies (first two years of life): A report from the Centers for Disease Control and Prevention Universal Data Collection System.
      Haemophilia 201723(2):207-214. https://doi.org/10.1111/hae.13081
      Kulkarni R, Presley RJ, Lusher JM, Shapiro AD, Gill JC, Manco-Johnson M, Koerper MA, Abshire TC, DiMichele D, Hoots WK, Mathew P, Nugent DJ, Geraghty S, Evatt BL, Soucie JM.
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      Men with severe hemophilia in the United States: Birth cohort analysis of a large national database.
      Blood 2016127(24):3073-3081. https://doi.org/10.1182/blood-2015-10-675140
      Mazepa MA, Monahan PE, Baker JR, Riske BK, Soucie JM U.S. Hemophilia Treatment Center Network.
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      Survey of the anti-factor IX immunoglobulin profiles in patients with hemophilia B using a fluorescence-based immunoassay.
      J Thromb Haemost 201614(10):1931-1940. https://doi.org/10.1111/jth.13438
      Boylan B, Rice AS, Neff AT, Manco-Johnson MJ, Kempton CL, Miller CH Hemophilia Inhibitor Research Study Investigators.
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      Characterization of the anti-factor VIII immunoglobulin profile in patients with hemophilia A using a fluorescence-based immunoassay.
      J Thromb Haemost 201513(1):47-53. https://doi.org/10.1111/jth.12768
      Boylan B, Rice AS, Dunn AL, Tarantino MD, Brettler DB, Barrett JC, Miller CH Hemophilia Inhibitor Research Study Investigators.
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      Hemophilia: The Royal Disease - PowerPoint PPT Presentation

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      A Royal Shame: Prince Leopold’s Hemophilia and Its Effect on Medical Research

      In the late nineteenth century, hemophilia was an incredibly devastating disease, killing people as high in society as Prince Leopold, son of Great Britain’s Queen Victoria. Leopold’s case of hemophilia — a hereditary disease in which a patient’s blood does not coagulate property — appears to have led to an increase in hemophilia research and understanding in the late 1800s. Discoveries in the late nineteenth and early twentieth centuries laid the foundations for future scientists to develop treatments. Today, hemophilia is an almost completely controlled and less devastating disease.

      Research into the hereditary nature of hemophilia may also have increased the understanding of hereditary diseases in general. Ironically, however, the hereditary characteristic of Leopold’s disease shrouded the malady in society, since the Royal Family did not want to have its “tainted” blood known. But because of Leopold’s prominent position in society as a member of the Royal Family, his condition drew greater attention to the disease, resulting in a spike in publications in the 1880s and eventually more research towards a cure. This paper traces Leopold’s struggle with hemophilia and the shame it brought to the Royal Family. This paper also analyzes the breakthroughs that occurred after Leopold’s death and their later implications for hemophilia treatment.

      Prince Leopold’s Hemophilia

      In the normal body, lesions in blood vessels cause clotting factors in the blood to coagulate. In hemophilic patients, this clotting does not occur properly, resulting in excessive bleeding.

      Prince Leopold, Duke of Albany, was the fourth son of Queen Victoria. He was born in London on April 7, 1853. According to Leopold’s biographer Charlotte Zeepvat, he was first diagnosed with hemophilia in 1858 or 1859. From a very young age, Leopold began to exhibit symptoms of the disease. He appeared physically weak and clumsy and he bruised very easily. In addition to hemophilia, Leopold suffered from epileptic seizures during his lifetime.

      When Leopold was diagnosed, some doctors blamed his disease on Queen Victoria’s use of chloroform during childbirth. This was a new type of anesthetic, and many believed for religious or moral reasons that women’s bodies were meant to endure the pain of childbirth without anesthetics (1).

      It is a well-established fact, as evidenced by the appearance of hemophilia in her descendents, that Queen Victoria was a carrier of hemophilia. The Queen must have either received the gene from one of her parents or experienced a gene mutation causing her to become a carrier of hemophilia. Most historians agree that Victoria acquired the hemophilia gene through a mutation. According to Rosendaal, et al., the mutation rate for normal males producing carrier daughters is two to ten times higher than the mutation rate for normal females producing hemophilic males (2). Out of Victoria’s eight other children, two of her daughters, Princess Alice and Princess Beatrice, inherited the hemophilia gene, which they passed on to the Russian Royal Family and the Spanish Royal Family (3). This evidence indicates that a mutation occurred in Victoria’s DNA, introducing the gene to the British Royal Family (2).

      Prince Leopold’s Doctors

      While no treatment for hemophilia existed during Leopold’s lifetime to ease his suffering, prominent physicians of this period, such as Sir William Jenner, played a large role in attempting to treat Leopold. Jenner was the personal physician of the Queen, and also attended to her husband, Prince Albert, and other members of the Royal Family. He aided in caring for Leopold’s hemophilia from 1861 until Leopold’s death.

      It is very likely that Jenner contributed to the cover-up of Leopold’s disease since he had a close personal relationship with the Queen. According to Victoria’s biographer Stanley Weintraub, “Jenner often described Victoria’s health in language put into his mouth by his employer” (4).

      Jenner was also involved in researching the pathology of hemophilia. He was the second doctor ever to study the joints tissues of a hemophiliac under a microscope (5). He reported to the Clinical Society of London in 1876 that hemophilic blood was particularly slow to coagulate, but that this could not completely explain the disease because the bleeding episodes sometimes occur spontaneously in otherwise healthy patients. He believed that hemophiliacs’ bodies produce blood more rapidly and have an abundance of small blood vessels. Furthermore, Jenner’s report shows an uncertainty about the hereditary nature of the disease, because in some cases, it was possible to trace hemophilia back through several generations, whereas for other patients he could find no family history of the disease (6).

      It is important to note that in the late nineteenth century, information about medical ideas and discoveries was not well disseminated among doctors, even within London. While some earlier doctors in Germany, the United States, and England had come to the conclusion that hemophilia was a hereditary disease, this information did not necessarily reach Jenner. The restricted spread of information clearly impeded medical progress in this period.

      Jenner’s lack of certainty about the hereditary nature of hemophilia in his report tells us either that there is a good chance the Royal Family was not fully aware of this important characteristic of the disease, or that Jenner did not want to implicate the Queen’s family. Those members of the family who did know about Leopold’s hemophilia may have maintained a hope that the disease was isolated within Victoria’s youngest son and would not reappear in later descendents.

      John Wickham Legg, who studied under Jenner, served as Leopold’s personal physician from 1866-1867. During his medical training, Legg had witnessed the death of a hemophiliac boy from a nosebleed, and Legg subsequently developed a strong interest in bleeding disorders (7, 8). Legg only served as Leopold’s doctor for a year, but he also maintained a close relationship with Leopold throughout his career: in times of Leopold’s severe illness, Legg’s assistance was requested, and on certain occasions, Leopold called upon Legg to spend time with him as a friend (8).

      Legg’s best-known work is A Treatise on Haemophilia, which he published in 1872, just five years after he stopped attending to Leopold. This work became one of the most important sources on information on hemophilia in the nineteenth century (7).

      Legg’s 158-page treatise is a comprehensive overview of all the available information on hemophilia during this time period. Besides England, France, Germany, and the United States, Legg wrote that in “the civilized world, the disease seems to be unknown, or to be disregarded” (9).

      Legg did not portray hemophilia in an overly positive light. He wrote that while some doctors have asserted that hemophiliacs have special intellectual capabilities, he believed this was a myth. Also, he wrote that hemophiliacs sometimes seemed to take on “womanish characteristics” because of their inability to participate in athletic or other active pursuits (9).

      Legg reported that the excessive hemorrhaging of hemophiliacs most likely arose from a problem with the blood vessels, rather than with the blood itself, though he did admit “the pathology of haemophilia is still buried in the deepest obscurity” (9). Still, he reported that German doctors in this period had conducted analyses of the blood of hemophiliacs and normal patients and measured the amount of water, fibrin, albumen, and salts in it. They concluded that the blood composition of hemophiliacs was no different from that of healthy people (9). He was more inclined, therefore, to believe that the disease arose from some sort of variation of the blood vessels (9). However, studies of the organs of hemophiliacs after death, showed no abnormalities, which led to more confusion of the issue of pathology (9).

      Legg’s treatise reported that hemophilia is most likely a hereditary disease, but this fact was not absolutely certain in every case (9). The cases in which he found no history of the disease within the patient’s family were most likely cases in which either the disease was not previously correctly diagnosed or cases in which the disease arose from a mutation. Legg also acknowledged the common pattern of asymptomatic daughters of hemophiliacs transmitting the disease to their sons (9).

      One politically explosive facet of this work is its mention of marriage for hemophiliacs. Legg wrote, “Should a bleeder, or one of a bleeder family, be allowed to marry? I think that if the person himself be a bleeder, the question of marriage ought not to be entertained. His sons may possibly escape the disease, but it is almost sure to reappear in his daughters’ sons. The prospect of the certainty of so dreadful an entail of disease must repel every right thinking person from such a step, even at so great a sacrifice to himself and it seems only necessary for the facts to be known to prevent such marriages among the better classes” (9). Given Legg’s extensive knowledge of hemophilia and his firsthand experience with Leopold, there is no doubt that he knew Leopold suffered from hemophilia. Therefore, it is remarkable that Prince Leopold was allowed to marry, given that at least one of his doctors (and probably more) knew that this would perpetuate hemophilia in the British Royal Family.

      As for treatment, Legg took a somewhat fatalistic view of hemophilia. He warned against any drawing of blood, major surgeries, amputations, and cold or damp climates. He said that compression of bleeding wounds, application of ice to the wound, and sometimes compression of major arteries might help slow the bleeding, but not much else could be done to make a hemophiliac’s blood coagulate faster. He recommended that hemophiliacs spend as much time as possible in warm climates, a suggestion that Leopold followed as much as possible throughout his life (9). Overall, however, very little could be done to save hemophiliacs from painful experiences and early deaths. Legg wrote, “A sadder heritage of disease could scarcely be entailed” (9). Indeed, Leopold’s painful death would come when he was just thirty years old.

      Figure 1: In the 1880s, the decade of Leopold’s death, there was a peak in the number of articles published about hemophilia in Great Britain.

      A History of Hemophilia before Prince Leopold

      The knowledge of hemophilia that the medical journals summarized in the 1800s was a product of many centuries of reports on the disease. To briefly review the historical understanding of the malady, the earliest mention of hemophilia appeared in the second century A.D. in texts written by Jewish rabbis. There is evidence of two rabbis exempting boys from circumcision because of fear of haemorrhage. In one case, the rabbi decided that a woman’s third son did not need to be circumcised because the first two had died from haemorrhage after circumcision. In the other case, a boy was not circumcised because three of his male first cousins died from the procedure (10).

      Scattered records of males bleeding to death from small wounds exist from the tenth and twelfth centuries, as well as a few other mentions of the disease during the Renaissance period, but the definitive recognition of the disease came from the American physician John Otto in 1803. Otto stated that asymptomatic females transmitted the disease to their hemophiliac sons (11). American physician John Hay provided further confirmation of the transmission pattern of hemophilia in 1813 (12). Then, in 1820, German researcher and professor of medicine Christian Friedrich Nasse gave an accurate and detailed account of several aspects of hemophilia. Nasse is best known for confirming the fact that only males get the disease and females transmit it but do not show the clinical symptoms. This pattern of inheritance became known as Nasse’s Law (13).

      J. Grandidier, a German physician, published the important Die Hamophilia, oder die Bluterkrankheit (‘Hemophilia, or the sickness of the blood’) in Leipzig in 1855 (8). This substantial work was an overview of all current knowledge of the disease, and stated that hemophilia was the “most heritable of all heritable diseases” (13).

      The next major development was Legg’s Treatise on Haemophilia in 1872. By the 1880s, the hereditary nature of hemophilia was relatively well known and documented. In 1881, Legg published an article entitled, “Tissues of a case of haemophilia,” in which he tracked the disease through 200 years of a family’s history and further confirmed that the females acted as carriers, while the males experienced the symptoms of the disease (14).

      The fourth edition of John Syer Bristowe’s A Treatise on the Theory and Practice of Medicine, published in 1882, listed hemophilia for the first time. It also stated that bleeders should not be allowed to procreate (15).

      Although many articles were published about hemophilia in this period, there was no central source of medical information, so not all doctors knew of the latest breakthroughs in hemophilia research. This led to slower progression because doctors often repeated previous studies or experiments.

      Medical Literature Regarding Hemophilia

      Medical journals discuss Leopold’s death

      Prince Leopold’s sudden death on March 29, 1884 in Cannes, France was reported in every major newspaper throughout the United Kingdom and elsewhere, but the connection to hemophilia was not generally published. Prominent medical journals were also circumspect about Leopold’s hemophilia, but they did draw subtle connections between the Prince and the disease, publishing articles specifically about hemophilia at the time of Leopold’s death.

      The Lancet, perhaps the most well known British medical journal, published a standard obituary in the April 5, 1884 issue that was similar to those appearing in the general newspapers. The only medical-related comments in this article concern Leopold’s “oft-recurring pain and weariness of a weakly life worthily lived…” (16). In the same issue of The Lancet, there is an almost full-page article on hemophilia, with no mention of Prince Leopold (17). It is unlikely that doctors were unaware of Leopold’s condition (many of Leopold’s doctors, including Jenner and Legg, were leaders in the field of hemophilia research and would have clearly been able to identify Leopold’s symptoms as those of a hemophiliac over the course of treating him). It is more probable that the editors of The Lancet were respectful of the Royal Family’s privacy.

      The British Medical Journal, another leading medical journal, also published two articles in its April 5, 1884 issue relating to Prince Leopold and hemophilia. One is a simple announcement of his death, which states that right before his death, he was “breathing very stertorously” and had a “convulsion, with his face drawn to one side and his hands clenched.” This article contains no other medical information and no direct mention of hemophilia, but does end by stating, “The constitutional malady from which he suffered is the subject of a leader in the present member of the Journal” (18). The article to which this refers is titled “The Haemorrhagic Diathesis.” The terms haemorrhagic diathesis and hemophilia were synonymous in the late nineteenth century and the two terms are used interchangeably throughout the article. This article begins by stating, “The recent bereavement in the Royal Family will naturally turn the attention of the medical public towards the constitutional affection to which the illustrious deceased was subject.” The article goes on to give a final word on Leopold’s death as a result of a fall due to a weakness in his knee that was probably caused by hemophilia and an intracranial complication that arose from this fall (19).

      From these articles, it is clear that the medical public knew of Leopold’s hemophilia. The editors of these journals probably assumed that doctors would be particularly curious about a disease that had recently killed such a high-profile member of society.

      1880s peak in journal articles on hemophilia

      In the 1880s, the decade of Leopold’s death, there was a huge spike in the volume of literature published about hemophilia in the United Kingdom (Figure 1). Of the articles published in the 1880s, the vast majority were case studies rather than reviews of the current literature (20, 21). Nineteen of the articles published in the 1880s mentioned the hereditary nature of hemophilia and sixteen did not. This indicates a widespread knowledge of hemophilia, but as previously mentioned, during this period medical information was not well disseminated, so many physicians may not have known about the hereditary nature of the disease.

      During the 1880s, doctors started to speculate on the causes of hemophilia on a more scientific level. In the British Medical Journal in 1882, C. Francis theorized that the excessive hemorrhaging could arise due to a lack of fibrin in the blood, which would inhibit the blood’s ability to clot. In The Lancet in 1886, T. Oliver put forth a hypothesis about the mechanism that led to hemophilia. He wrote, “So far as the pathology of the disease is concerned, I believe the state of the blood and blood vessels and a defective control-action on the part of the vaso-motor centres are the important factors in its causation.” Similarly, Legg theorized that the disease arose from poorly developed blood vessels (8). Although twentieth-century doctors discovered that the latter two ideas were far from true, the fact that doctors were attempting to come up with scientific explanations marked progress in the field of hemophilia. Still, they were far from having a complete understanding of hemophilia.

      Breakthroughs in hemophilia research after Leopold’s death

      In the decade following Leopold’s death, significant breakthroughs in the treatment of hemophilia occurred. Sir Almoth Wright, an English medical scientist, made a great contribution to hemophilia treatment through his research on the coagulation of blood. Wright demonstrated in 1891 that the blood of hemophiliacs had a longer coagulation time than normal blood because of a deficiency of calcium in the blood. He recommended calcium salts as a possible treatment. Later research showed that calcium in fact had nothing to do with blood clotting instead a deficiency of certain blood proteins causes hemophiliac blood to coagulate more slowly, but Wright can still be noted for his experiments in measuring coagulation times (22).

      Following Wright’s work, in 1910, Scottish physician and scientist Thomas Addis reported that hemophilia arose because of an “abnormality in the nature of the coagulation [that] arises as the direct result of the great prolongation of the time required for coagulation to complete itself” (23). Over the course of the next year, Addis demonstrated that a blood enzyme called prothrombin, derived from normal blood, could be used to more rapidly coagulate hemophiliac blood (10).

      In 1911, William Bulloch and Paul Fildes produced parts V and VI of volume one of the Treasury of Human Inheritance, comprising a bibliography of 949 pieces of hemophilia literature in several different languages, as well as 235 pedigrees of families of hemophiliacs (24). Bulloch and Fildes defined the symptoms of hemophilia in simple and straightforward terms: “an inherited tendency in males to bleed.” The small amount of commentary that Bulloch and Fildes provided about this disease was not optimistic. The authors still considered hemophilia to be completely devastating, just as it had been a few decades earlier when Leopold was alive. In summarizing the effects of hemophilia, they wrote, “The disease runs in families, and in the course of time an attitude of fatalism is developed towards the resources of medicine…The barbarous treatment to which may bleeders have been subjected in the well-meant efforts of the physician or surgeon to stanch the haemorrhages must have a terrifying effect and leave an ineffaceable memory” (13).

      In the 1930s, doctors began using plasma from healthy patients to treat hemophiliacs and in 1944, an American biochemist named Edwin Cohn invented plasma fractionation to separate plasma into its individual components. Soon after, hemophiliacs began being treated with only factor VIII, which researchers had identified as the specific clotting factor that was lacking in the blood of most hemophiliacs. It was not until the 1960s that plasma fractionation became commercialized and was available on a broad scale. By the 1970s, hemophiliacs could inject themselves with these proteins whenever they started bleeding. Now, proteins are given to hemophiliacs prophylactically (before they have any type of accident that starts bleeding) so they can generally have normal and active lifestyles (25, 26, 27).

      Hemophilia devastated Leopold and the Royal Family and lead to the Prince’s premature death. Yet his death was not in vain. It accelerated research on hemophilia, and by the second half of the twentieth century, this previously fatal disease was completely controlled by injectable blood proteins. But research on hemophilia is not finished. According to a recent review, in the near future, “Haemophilia is likely to be the first common severe genetic condition to be cured by gene therapy” (28). The appearance of hemophilia in the British Royal Family increased the attention given to the disease by the medical community of Britain in the late 1800s, and it is unlikely that subsequent research would have progressed as quickly as it did if Prince Leopold had not had the disease.


      Hemophilia in Jewish traditions and genomes.

      "Had the advisers to the Russian Royal House, descendants of Queen Victoria, been equally well informed [as was the Talmud], the course of European modern history might have been quite different!" (JOSEPH 2010). This statement from The British Journal of General Practice refers to hemophilia, a bleeding disease that devastated European royalty in the nineteenth and twentieth centuries. (1) Hemophilia is a blood-clotting disorder associated with gene mutations resulting in the deficiency of proteins synthesized in the liver that are essential to normal blood-clotting function. This disorder is of unique significance to Jewish traditions in a variety of ways. Many hematology and medical textbooks acknowledge that the first recorded description of hemophilia and genetically transmitted disease is found in the Talmud (ARCECI et al. 2008 EMERY 1968 KELLY 2012 KUMAR and WEATHERALL 2008 SNUSTAD and SIMMONS 2003 STURGIS 1955). Halakhah (Jewish law) broadly deliberates upon how the Jewish obligation to circumcise an eight-day-old male infant is affected by hemophilia. Genetically, Jewish populations possess unique hemophilia-causing mutations that provide an interesting window into their early history and literature. A survey of this pathology will provide insight into the Talmudic discussions of hemorrhagic disorder and facilitate a broader understanding of the interface between Jewish traditions and modern medicine.

      When the walls of blood vessels are breached, the body uses a number of mechanisms to restore hemostasis. Upon blood vessel rupture, smooth muscle cells that form the vascular walls contract and reduce blood loss for a short period of time, thereby giving the body precious time to initiate more effective methods of hemostasis. Platelets, which are anucleate cell fragments derived from megakaryocytes formed in the bone marrow, plug the rupture by aggregating and adhering to the broken blood vessel. A platelet plug is temporary, as it is too weak and unsystematic to function as a permanent hemorrhagic barrier. The next stage of the clotting response involves the activation of a complex chain of enzymatic reactions known as the blood clotting cascade these reactions involve over twenty different proteins (CARSON-DEWITT 2004) and culminate in the formation of a tougher, insoluble, well-organized plug made of a thread-like protein called fibrin. This clot remains in place until the body repairs the underlying tissues (TORTORA and DERRICKSON 2009), and is subsequently dissolved by plasmin and the blood-lysing system.

      Hemophilia is a genetic disease characterized by the deficiency of protein crucial to blood clotting. There are many forms of hemophilia, each type affecting specific clotting factors. Hemophilia a results from mutations of a gene associated with producing factor viii, a protein of the blood clotting cascade. Hemophilia b is associated with mutations of a gene associated with factor IX. Hemophilia a and b result from over a thousand different mutations, including insertions, deletions, and missense and nonsense mutation, and their severities vary greatly among these mutations (KAUSHANSKY and WILLIAMS 2010). Hemophilia a and b are the most prevalent forms of hemophilia, representing 80 and 20 percent of hemophilia cases, respectively (KNOBE and Berntorp 2011). There are also many acquired coagulation disorders, which are more frequent and complex than genetic variation (HANDIN 1998). Hemophilia is diagnosed by examining familial history or, in modern times, through laboratory plasma evaluation of the levels of clotting factors VII, IX, and XI.

      SEX-LINKED RECESSIVE GENES

      Hemophilia a and b are genetic diseases that have a unique inheritance pattern due to their localization on the X chromosome. Whereas all female ova contain one X chromosome, a male produces both X-carrying sperm and Y-carrying sperm, in equal numbers (Figure 1).

      A son who inherited an X chromosome with a defective gene necessary for blood clotting will suffer from hemophilia. However, a daughter who inherited only one defective X chromosome still has a corresponding, normally functioning X chromosome and will be either asymptomatic or slightly symptomatic (Babul-Hirji et al. 2007). Because of a shorter expected lifespan for a fully hemophilic male, especially in pre-modern times, the disease is typically transmitted through an asymptomatic female carrier.

      THE TALMUD AND HEMOPHILIA

      A Talmudic passage regarding the laws of hazakah (recurring events that establish the presumption of future occurrence) seems to describe hemophilia and its unique inheritance pattern:

      . for it was taught: if she circumcised her first child and he died, and then a second one who also died, she must not circumcise her third child so ruled Rabbi Yehudah Ha'Nasi. Rabbi Shimon ben Gamliel said: She circumcises the third, but must not circumcise the fourth . Come and hear: Rabbi Hiyya ben Abba said in the name of Rabbi Yohanan: Once it took place with four sisters at Sepphoris that when the first [sister] circumcised her child, he died when the second [circumcised her child], he also died and when the third [circumcised her child], he also died. The fourth came to Rabbi Shimon ben Gamliel, who said to her, "You must not circumcise" . regarding circumcision, one can understand [why the operation endangers some children and not others] since one family may bleed profusely while another family may bleed slightly (TALMUD YEVAMOT 64B).

      The bleeding disorder described in this passage correlates with the modern description of hemophilia, and is widely cited in textbooks and research articles as the first recorded description of hemophilia (CAHILL and COLVIN 1997 FRANCHINI and MANNUCCI 2012 KAUSHANSKY and WILLIAMS 2010 Ponder 2011 ROSNER 1998). In addition, the maternal inheritance of the disease implicit in the Talmudic discussion is confirmed by modern genetics (MASSRY et al. 1997 RAABE 2008)--although some later halakhic authorities, notably the Shulhan Arukh, applied or extended this principle to paternal siblings.

      The Talmudic description of hemophilia was two millennia ahead of its time, as the first modern description was recorded in 1803 (INGRAM 1976). Perhaps the Talmudic scholars were in a good position to notice this disorder and its hereditary patterns empirically because the universal Jewish practice of circumcision on the eighth day after birth facilitated the prompt diagnosis of bleeding disorders. Over a few generations the maternal hereditary pattern may have been noticed if after an affected couple divorced, the disorder continued in the maternal line but not in the paternal line. Circumcision may also have been the reason for the widespread impression that classic hemophilia is more frequent among Jews--a notion lacking scientific basis (KRIKLER 1970). Ingram notes that another pre-modern observation of a hemophilia-like condition was made by the Muslim surgeon Abu alQasim Khalaf ibn al-Abbas Al-Zahrawi (936-1013), known in Western literature as Albucasis. Islam also requires universal circumcision, and this might have facilitated Albucasis' observation of excessive bleeding among males of a village. These reports stand in stark contrast to the Western world, where even Renaissance-era European physicians failed to catalogue hemophilia (KERR 1963).

      There is another possible origin to the description in the Talmud of hemorrhage disorders as maternally inherited. The Talmud describes the origin of embryonic development in the following manner:

      The rabbis taught: There are three partners in the creation of a person: the Holy One, Blessed be He, the father, and the mother. The father supplies the white seed from which the bones, sinews, fingernails, brain matter, and white of the eyes [are formed] the mother supplies the red from which the skin, flesh [blood], hair, and black of the eye [are formed] and the Holy One, Blessed be He, contributes the spirit, soul, countenance, vision, audition, speech, mobility, intellect, and discernment (TALMUD Niddah 31a).

      This attribution of "the red from which the flesh [blood]" and therefore the plasma proteins made in the liver as maternally inherited may have been the origin of the Talmudic ruling that coagulation disorders were maternally inherited, and is cited as such by several halakhic commentators (TAZ GRA, Yoreh Deah 263). Yet, there is a significant difficulty in accepting this proposed derivation. The Talmud is comprised of two distinct subject matters: halakhah, judicial discussions and decisions, and aggadah, homiletic discourses and interpretation. The aggadic portions of the Talmud normally are not utilized in deciding halakhah (NODA B'YEHUDAH, Yoreh Deah 2:161). There are two reasons for this distinction. First, aggadah is not generated by the rigorous debate, deliberation, and analysis that define the halakhic process. Second, often it is unclear whether aggadah is referring to physical reality, describing metaphysical ideas, or teaching through analogy (MAHARAL, Beer Ha'Golah 6). Rabbi Shlomo Zalman Auerbach, the twentieth-century authority on medical halakhah in Israel, applies this distinction to the statement in the above Talmudic citation that the woman supplies the blood. Rabbi Auerbach explains that because in this case the Talmud Sages are describing metaphysical concepts, not natural and biological properties, this statement cannot be used to decide halakhic questions (STEINBERG 1994).

      JEWS AND FACTOR XI DEFICIENCY

      The Talmud rules that after two separate occurrences in which brothers hemorrhaged and died at circumcision, the third son should not be circumcised. This exemption applies only to maternally related siblings, and also to maternally related cousins. The Talmud does not consider paternal inheritance a significant factor in the transmission of coagulation disorders, and the majority of subsequent halakhic authorities, including Maimonides, Agudah, and Tor (Bah 263), rule accordingly. The Shulhan Arukh, the Code of Jewish Law compiled by Rabbi Yosef Karo in the sixteenth century, however, rules that paternally related children also can establish a hereditary pattern of hemorrhage, even though such a genetic transmission is implicitly rejected by the Talmud. A chronology of the realities observable to these halakhic authorities in their lifetimes will illuminate the underlying reasons for their differences of opinion.

      Although the overwhelming majority of hemophiliacs suffer from either hemophilia A or B, there is another form of clotting protein deficiency called factor XI deficiency (also known as hemophilia c) caused by mutations of an autosomal gene (i.e., not a gene located on the sex-determining chromosome) that encodes for factor XI. (1) Factor xi deficiency seldom affects non-Jewish populations but is relatively common among Ashkenazi Jews, with a heterozygote frequency of 9 percent (Castaman 2008), and it is present, albeit to a lesser extent, in other Jewish populations. A common mutation associated with factor xi deficiency identified among Ashkenazi and Iraqi Jews is estimated to have occurred more than one hundred generations ago, suggesting that it emerged prior to the date traditionally ascribed to the Babylonian dispersion. This finding provides evidence for the common ancestry of these distinct Jewish populations (Goldstein et al 1999). Subsequent mutations have accounted for the increased rate of factor xi deficiency in Ashkenazi Jews (ASAKAI et al. 1991).

      Interestingly, in contrast to hemophilia a and b, which are associated with mutations on the X chromosome, factor xi deficiency is linked to gene mutations on chromosome 4, an autosome. Autosomal traits are inherited from both sexes equally and do not follow the distinctive inheritance pattern of genes on the X chromosome. Thus, it seems difficult to understand why the Talmud described hemophilia as inherited from the mother only when, according to Goldstein's research, the mutation causing factor XI deficiency had already occurred while the Talmud was being compiled. This is especially challenging considering the high incidence of factor XI deficiency among Jewish populations. For example, the rate for homozygotic factor XI in Israel is one in 190, making it one of the most common genetic disorders among that population (ASAKAI et al. 1991). There are no statistics to show the prevalence of factor XI deficiency among Talmudic-era populations, yet the fact that one of the most prevalent mutations associated with factor XI deficiency among Jews likely occurred prior to the Babylonian exile (GOLDSTEIN et al. 1999) suggests that factor xi deficiency was already present many centuries before the final editing of the Talmud. This suggests that, although not recorded in the Talmud, the non-maternal hereditary pattern of factor XI deficiency could have been observed by Talmudic era decisors.

      There are many enigmas regarding the etiology and treatment of factor xi deficiency. One mystery is that some patients will suffer mild post-traumatic hemorrhage, while others will not, and these variations do not correlate with the plasma level of factor XI (BOLTON-MAGGS 2009). Many patients with factor XI deficiency only suffer severe bleeding following surgery or trauma involving mucosal surfaces due to local fibrinolytic activity involving tissue plasminogen activator in saliva (ASAKAI et al. 1991). Surgical complications to anatomical areas not characterized by high fibrinolytic activity, such as with circumcision, are rare, with a bleeding rate of 6.5 percent (CASTAMAN 2008), although severe bleeding can occur following circumcision of severely deficient infants (BOLTON-MAGGS 2008). This low rate of incidence may have been unperceived by the Talmud Sages, or it may have been recognized as an anomaly, causing the Sages to disregard biparental inheritance of genetic coagulation disorders as a significant halakhic factor. The subsequent recognition of such patterns of inheritance, or the subsequent amplification of factor xi deficiency among the Jewish population due to additional mutations, as documented by Goldstein and colleagues in 1999, may have prompted the Shulhan Arukh to suspend circumcision for paternal relatives of chronic hemorrhagic families. Although hemorrhagic death from factor xi deficiency is uncommon, halakhah is extra-vigilant in protecting life, as Rabbi Moses Isserles confirms in regards to the ruling in the Shulhan Arukh: "In matters of life and death, we are lenient" (Yoreh Deah 263). It should be noted that this ruling in the Shulhan Arukh is derived from the late thirteenth-century Rabbeinu Manoah, one of the Rishonim who lived in Provence, France. This may be significant in identifying the original Jewish population among whom this ruling originated, and in ascertaining the existence of additional mutations causing factor xi deficiency among this population.

      HEMOPHILIA, CIRCUMCISION, AND TWINS

      When the Talmud ruled that if two siblings died of circumcision, the third should not be circumcised, the assumption was that a hereditary condition caused the circumcision to be dangerous. An interesting question was raised by the nineteenth-century adjudicator Rabbi J. S. Nathanson (Shoel UMeishiv 1:238): What is the status of a family in which a set of twins died following circumcision--are these deaths considered as two distinct occurrences, thus prohibiting the circumcision of a later son, or are they considered as a single unit? Without differentiating between monozygotic and dizygotic twins, Rabbi Nathanson ruled that the death of twins established a pattern of hereditary disease (ROSNER 1998). A reevaluation of this question in light of current medical knowledge will help illuminate aspects of the underlying rationale of this ruling.

      If one child died of blood loss following circumcision, a genetic disorder cannot, as yet, be assumed. Perhaps the bleeding disorder was not genetic. Acquired coagulation disorders are more frequent and complex than the genetic varieties, and some of these acquired disorders affect children (HANDIN 1998). One such disorder is vitamin K deficiency bleeding (VKDB). A proper concentration of vitamin k can prevent life-threatening hemorrhage. While extremely rare in adults, VKDB is more common in neonates (LIPPI and FRANCHINI 2011). To rule out VKDB, a second death must occur before a hereditary disease is assumed. Thus, the death of twins, whether identical or fraternal, following circumcision may have resulted from dietary-related VKDB. It would follow that the deaths of the twins should be considered jointly. Lippi and Franchini note that VKDB normally presents either from days one to seven of a neonate's life (classic VKDB) or after two weeks (late vkdb). In studies involving thirty-nine cases of vkdb, the disease never presented between days eight to ten (MCNINCH, BUSFIELD, and TRIPP 2007). An infant circumcised on the Biblically commanded eighth day would therefore be unlikely to be susceptible to lethality due to VKDB.

      Giving birth to a child with hemophilia does not conclusively indicate that the parents carry the defective gene in their body, or somatic cells. Rather, the defective gene may have arisen during gametogenesis in either parent. At least 30 percent of hemophilia cases are due to spontaneous de novo mutations occurring during the processes of spermatogenesis and oogenesis in the parents (KAUSHANSKY and WILLIAMS 2010). Such spontaneous mutations are the suspected cause of hemophilia in individuals with no family history of the disease. Because neonates with a family history of hemophilia are not circumcised, de novo mutations may often be the cause of hemophilia presenting upon circumcision. In a case of twin hemophiliacs, the feasibility of a spontaneous mutation resulting in their disease would depend on whether they are identical or fraternal twins. If the twins are identical, they may have acquired the same mutation from the single gamete from which they originated, and a familial disease would not be conclusively shown. In the case of fraternal twins, two simultaneous mutations would have to be assumed, making it more plausible to assume common inheritance.

      Although knowledge of these possibilities is based on modern medical discoveries, the absence of a hereditary pattern of disease is empirically recognizable. The Talmudic requirement of multiple presentations to establish a hereditary disorder may have been based on the observation that often coagulation disorders are not present in siblings of sufferers.

      In summary, ". we are impressed by the seeming purposefulness of many of the inspired religio-medical laws which so nicely dovetail into our present concepts of the prophylaxis of disease" (MILLER 1937) and the eventual genetic therapy of disease by allelic replacement.

      I would like to thank Dr. Harvey Babich for initiating this project and for guiding me to its completion. I would also like to thank my parents for providing me with a first-rate Jewish education, and the wonderful staff at Touro College for their support and tutelage. My deepest appreciation is reserved for my wife, Leah, for whom words do not suffice.

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      (1.) Editor's note: Factor xi deficiency was discovered by Dr. Nathan Rosenthal, the first hematologist in New York City.

      SAMUEL REISMAN is currently pursuing a degree in biology at Touro College in New York City. He has been involved in research at the New York School of Career and Applied Sciences, studying the effects of green tea polyphenols on the infectivity of coliphages, and, currently, the comparative evaluation of the toxicity of polyphenols in the absence and presence of a reducing agent. He volunteers at Yeshiva Bonim Lamokom, where he teaches literacy skills to children with Down syndrome. Reisman received a Bachelor's of Talmudic Law from Beis Medrash Gavoah in 2012.