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Factor VIII deficiency

Haemophilia A (also spelt Hemophilia A or Hæmophilia A) is a blood clotting disorder caused by a mutation of the factor VIII gene, leading to a deficiency in Factor VIII. It is the most common hemophilia. Inheritance is X-linked; hence, males are affected while females are carriers or very rarely display a mild phenotype. 1 in 10,000 males are affected. more...

Fabry's disease
Factor V Leiden mutation
Factor VIII deficiency
Fallot tetralogy
Familial adenomatous...
Familial Mediterranean fever
Familial periodic paralysis
Familial polyposis
Fanconi syndrome
Fanconi's anemia
Farber's disease
Fatal familial insomnia
Fatty liver
Febrile seizure
Fibrodysplasia ossificans...
Fibrous dysplasia
Fissured tongue
Fitz-Hugh-Curtis syndrome
Flesh eating bacteria
Focal dystonia
Foix-Alajouanine syndrome
Follicular lymphoma
Fountain syndrome
Fragile X syndrome
Fraser syndrome
FRAXA syndrome
Friedreich's ataxia
Frontotemporal dementia
Fructose intolerance

Signs and symptoms

Hemophilia leads to a severely increased risk of bleeding from common injuries. The sites of bleeding are:

  • joints
  • muscles
  • digestive tract
  • brain

The muscle and joint haemorrhages are quite typical of haemophilia, while digestive tract and cerebral haemorrhages are also germane to other coagulation disorders.


The diagnosis may be suspected as coagulation testing reveals an increased PTT in the context of a normal PT and bleeding time. The diagnosis is made in the presence of very low (<10 IU) levels of factor VIII. A family history is frequently present, although not essential. Nowadays, genetic testing may also be performed.

The most important differential diagnosis is that of hemophilia B (also known as Christmas disease) or von Willebrand disease. The former is usually considered if factor VIII levels are normal in a person with a haemophilia phenotype. The latter is excluded on routine testing for that condition.

A very small minority of patients has antibodies against factor VIII that impair its functioning. Management of these patients is more complicated (see below).


Most haemophilia patients require regular supplementation with intravenous recombinant factor VIII. This is highly individually determined. Apart from "routine" supplementation, extra factor concentrate is given around surgical procedures and after trauma. In children, an easily accessible intravenous port (e.g. Port-a-Cath) may have to be inserted to minimise frequent traumatic intravenous cannulation.

Some may manage on desmopressin, if the clotting factor is still partially active.

A particular therapeutic conundrum is the development of "inhibitor" antibodies against factor VIII due to frequent infusions. These probably develop as the body recognises the factor VIII as foreign, as the body does not have its own "copy". The problem is that in these patients, factor VIII infusions are ineffective. Recently activated factor VII (NovoSeven®) has become available as a treatment for haemorrhage in patients with haemophilia and factor inhibitors.


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Hepatitis A among persons with hemophilia who received clotting factor concentrate - United States, September-December 1995
From Morbidity and Mortality Weekly Report, 1/19/96

Hepatitis A outbreaks associated with receipt of clotting factor concentrate previously have been recognized in Europe but not in the United States (1-5). During 9eptember-november 1995, three cases of hepatitis A in recipients of Alphanate[TM](*) factor VIII concentrate Alpha Therapeutic Corporation, Los Angeles, California) from lot number AP5014A were reported to CDC. On December 8, the manufacturer voluntarily withdrew Alphanate[TM] lot number AP5014A from the market. In addition, one case Of hepatitis A in a recipient of AlphaNine S-D[TM] factor IX concentrate (Alpha Therapeutic Corporation) has been reported and is under investigation. On January 11, 1996, the manufacturer voluntarily withheld four lots of AlphaNine S-DTM from further distribution as a precautionary measure. This report describes these four cases, summarizes the status of the investigation of the cases, and provides guidelines for testing and reporting of patients who received these products.

Hepatitis A in Factor VIII Recipients

Case 1. On September 5, 1995, a 13-year-old boy with mild hemophilia A (factor VIII deficiency) became acutely ill with nausea and vomiting after a 2-week period of fatigue, Poor appetite, and low-grade fever. Blood tests revealed elevated liver enzymes and a positive test for immunoglobulin M antibody to hepatitis A virus (IgM anti-HAV). No sources of infection (e.g., close contact with a person with hepatitis A, household contact with a person working in or attending a day-care center, or international travel) were reported. During the 6 weeks preceding illness, the patient had used 68 vials (approximately 34,000 units) from the implicated lot (i.e., lot number AP5014A) of Alphanate[TM] and nine vials from four lots of another brand of factor VIII concentrate.

Case 2. On October 20, during a hospital visit to evaluate vaginal bleeding 1 month postpartum, a 28-year-old woman with type 2 von Willebrand disease was found to have elevated liver enzymes and was IgM anti-HAV positive. She reported that, during September, she had had dinner on two occasions with an international visitor who had appeared jaundiced but not ill. No other potential sources of infection were identified. During 1995, her only exposure to factor concentrate was use of 48 vials (approximately 24,000 units) of Alphanate[TM] from the implicated lot on September 19. (*) Use of trade names and commercial sources is for identification only and does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services.

Case 3. On November 10, the National Hemophilia Foundation faxed a medical bulletin nationwide to 140 hemophilia treatment centers describing the first two cases of hepatitis A and their possible association with Alphanate[TM] lot number AP5014A. in response to this bulletin, two brothers with hemophilia A (aged 6 and 7 years) who had received this clotting factor concentrate were identified and tested for anti-HAV on November 17. The younger boy was IgM anti-HAV positive; the older boy was anti-HAV positive and IgM anti-HAV negative. Three weeks before testing for IgM anti-HAV, the younger brother had had a 5-day illness with nausea, vomiting, and abdominal pain. During the 3 months preceding testing, both boys had received approximately equal amounts of a total of 31 vials (approximately 15,500 units) of Alphanate[TM] from the implicated lot. No other factor products had been used during this interval, and no other sources of infection were identified.

Laboratory studies. One sample each from the implicated lot of Alphanate[TM], acute-phase serum from patient 2, and stool from patient 1 were positive for HAV RNA after amplification by polymerase chain reaction of the amino terminal region of that portion of the HAV genome coding for VP1. Genetic sequencing indicated that the viral nucleic acid isolated from each source was of HAV genotype 1a, Sequence analysis indicated that these isolates were identical and unique from other previously sequenced strains (6).

Hepatitis A in a Factor IX Recipient

On December 7, 1995, a 15-year-old boy with severe hemophilia B (factor IX deficiency) presented to his physician with symptoms of acute hepatitis; diagnostic studies indicated elevated liver enzymes and a positive test for IgM anti-HAV. No sources of infection were identified, and his family members were negative for anti-HAV and IgM anti-HAV. During the 3 months preceding testing, the boy had received 40 vials (approximately 40,000 units) of AlphaNine S-D[TM]; most of the vials had come from four different product lots. Three of these lots originated from source plasma pools common to the implicated lot of Alphanate[TM]. Reported by: FB Ruymann, MD, Div of Pediatric Hematology/Oncology, Children's Hospital, Columbus, CE Krill, Jr, MD, Hemophilia Treatment Center, Children's Hospital Medical Center, Akron; TJ Halpin, MD, State Epidemiologist, Ohio Dept of Health. WH Churchill, Jr MD, Blood Bank, B Ewenstein, MD, Comprehensive Hemophilia Treatment Center Brigham and Women's Hospital, Boston, A DeMaria, Jr MD, State Epidemiologist, Massachusetts Dept of Public Health. MJ Manco-Johnson, MD, Univ of Colorado Health Sciences Center Denver, RE Hoffman, MD, State Epidemiologist Colorado Dept of Public Health and Environment. National Hemophilia Foundation, New York. Office of Blood Research and Review, Center for Biologics and Evaluation Research, Food and Drug Administration. Hematologic Diseases Br, Div of AIDSI, STD, and TB Laboratory Research, and Hepatitis Br Div of Viral and Rickeffsial Diseases, Natiohal Center for Infectious Diseases, CDC.

Editorial Note: This report is the first to document transmission of HAV through clotting factor concentrates in the United States. Most cases of hepatitis A in the United States occur in community-wide outbreaks through person-to-person transmission by the fecal-oral route. However, because viremia occurs during the prodromal phase of the illness, asymptomatic blood donors, on rare occasions, have been the source of HAV infection transmitted by transfusion (7).

Several key findings support the conclusion that clotting factor concentrate was the source of infection in the factor will case-patients. First, the cases occurred in geographically dispersed areas, none of which were having community-wide epidemics of hepatitis A, and no community source of infection was identified. Second, the patients received the same lot of factor VIII concentrate. Third, HAV RNA was identified in that product lot. Finally, the genetic sequence of the HAV RNA from the factor concentrate was identical to that obtained from two of the case-patients.

In Europe, investigations of recent hepatitis A outbreaks among recipients of factor VIII concentrates implicated products prepared by a manufacturing method that included a solvent detergent (S-D) viral inactivation step (1-5). The largest outbreak occurred in Italy, involving 52 patients with hemophilia (5). The only risk factor for hepatitis A infection was receipt of factor VIII concentrate prepared using this method, and HAV RNA was detected in the factor concentrate (8). No hepatitis A outbreaks associated with receipt of factor IX concentrates have been reported previously. The factor concentrates used by the case-patients described in this report also were prepared using the S-D method of viral inactivation. Although this method inactivates enveloped viruses such as hepatitis B virus, hepatitis C virus, and human immunodeficiency virus (9), nonenveloped viruses such as HAV are resistant to inactivation by this method. Other plasma-derived factor Vill and factor IX concentrates manufactured using similar or different viral-reducing steps also may contain HAV, although no documented cases of transmission have been reported. Clotting factor concentrates manufactured by recombinant technology, which are now available for the treatment of factor VIII deficiency, have not been shown to transmit infectious agents. No recombinant factor IX clotting products have been approved by the Food and Drug Administration.

CDC is continuing to investigate these cases and requests assistance in identifying additional cases. Patients who received lot numbers CA5410A, CA5412A, CA5413A, or CA5421A of AlphaNine S-D[TM] since July 1, 1995, should be tested for IgM anti-HAV. Patients receiving any clotting factor who develop symptoms of acute hepatitis should have a complete diagnostic evaluation, including testing for IgM anti-HAV. A positive test for IgM anti-HAV is evidence of HAV infection during the previous 6 months. Persons who are anti-HAV positive and IgM anti-HAV negative had HAV infection >6 months previously and are immune. Patients who are IgM anti-HAV positive should be reported to their local or state health department and directly to CDCS Hematologic Disease Branch, Div of AIDS, STD, and TB Laboratory Research, National Center for Infectious Diseases (NCID), telephone (404) 639-3925.

Inactivated hepatitis A vaccine (HAVRIX[R], Smithkline Beecham, Inc., Pittsburgh, Pennsylvania) was licensed in 1995, and physicians should consider vaccinating susceptible patients who receive clotting factor. Because limited available data suggest a high seroprevalence of anti-HAV among persons with hemophilia, all such patients should undergo prevaccination testing. Persons who are anti-HAV (total) positive are immune to HAV and do not require vaccination. The vaccine provides active immunity against HAV, which is estimated to persist for at least 20 years in healthy adults 10). Information about the vaccine's effectiveness in persons with hemophilia and immunocompromised persons is limited. The vaccine is licensed as a two-dose series of 1440 ELISA units (EL.U.) per dose for adults, with the second dose administered 6-12 months after the first dose, and in a 3-dose series of 360 EL.U. per dose for children aged 2-18 years, with the second dose administered 1 month after the first dose, and the third dose administered 6-12 months after the first dose. The vaccine is not licensed for use in children aged <2 years. The vaccine should be administered by intra-muscular injection in the deltoid. A physician familiar with the patient's risk for bleeding should evaluate whether the vaccine can be given with reasonable safety by this route. No data are available regarding administration of the vaccine by the intradermal or subcutaneous route. If the patient receives clotting factor or other similar therapy, intramuscular vaccination can be scheduled shortly after receipt of such therapy.

Patients should consult their physician or health-care provider for answers to any questions related to their current factor VIII or factor IX replacement product. Additional information about this investigation is available from the Hematologic Diseases Branch and additional information about the hepatitis A vaccine, including preventive measures for children aged <2 years, is available from CDCS Hepatitis Branch, Division of Viral and Rickettsial Diseases, NCID, telephone (404) 639-3048.



(1.) Mannucci PM, Santagostino E, Di Bona E, et al. The outbreak of hepatitis A in italian patients with hemophilia: facts and fancies. Vox Sang 1994;67(suppl 1):31-5. (2.) Brackmann H-H, Oldenburg J, Eis-hubinger AM, Gerritzen A, Hammerstein U, Hanfland P. Hepatitis A virus infection among the hemophilia pokulation at the Bonn Hemophilia Center. Vox Sang 1994;67(suppl 1):3-8. (3.) Lawlor E, Johnson Z, Thornton L, Temperley 1. investigation of an outbreak of hepatitis A in Irish haemophilia A patients. Vox Sang 1994;67(suppl 1):18-20. (4.) Peerlinck K, Goubau P, Coppens G, Desmyter J, Vermylen J. is the apparent outbreak of hepatitis A in Belgian hemophiliacs due to a loss of previous passive immunity? Vox Sang 1994;67(suppl 1):14-7. (5.) Mannucci PM, Gdovin S, Gringeri A, et al. Transmission of hepatitis A to patients with hemophilia by factor VIII concentrates treated with organic solvent and detergent to inactivate viruses. Ann Intern Med 1994;120:1-7. (6.) Robertson BH, Hkanna B, Nainan OV, Margolis HS. Epidemiologic patterns of wild-type hepatitis A virus determined by genetic variation. J Infect Dis 1991;163:286-92. (7.) Lemon SM. The natural history of hepatitis A: the potential for transmission by transfusion of blood or blood products. Vox Sang 1994;67(suppl 4):19-23. (8.) Normann A, Graff J, Gerritzen A, Brackmann H, Flehmig B. Detection of hepatitis A virus RNA in commercially available factor Vill preparation [Letter]. Lancet 1992;340:1232. (9.) Schwinn H, Smith A, Wolter D. Progress in purification of virus-inactivated factor Vill concentrates. Drug Res 1989;39:1302. (10.) Van Domme P, Thoelen S, Cramm M, De Groote K, Safary A, Meheus A. Inactivated hepatitis A vaccine: reactogenicity, immunogenicity, and long-term antibody persistence. J Med Virol 1994;44:446-51.

COPYRIGHT 1996 U.S. Government Printing Office
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