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TREATMENT OF HEMOPHILIA December 2008 · No. 46 SYMPTOMATIC CARRIERS OF HEMOPHILIA Eveline P. Mauser-Bunschoten Van Creveldkliniek and Haematology University Medical Centre, Utrecht Utrecht, The Netherlands Published by the World Federation of Hemophilia (WFH), 2008 © Copyright World Federation of Hemophilia, 2008 The WFH encourages redistribution of its publications for educational purposes by not-for-profit hemophilia organizations. In order to obtain permission to reprint, redistribute, or translate this publication, please contact the Programs and Education Department at the address below. This publication is accessible from the World Federation of Hemophilia’s eLearning Platform at eLearning.wfh.org Additional copies are also available from the WFH at: World Federation of Hemophilia 1425 René Lévesque Boulevard West, Suite 1010 Montréal, Québec H3G 1T7 CANADA Tel. : (514) 875-7944 Fax : (514) 875-8916 E-mail: [email protected] Internet: www.wfh.org The Treatment of Hemophilia series is intended to provide general information on the treatment and management of hemophilia. The World Federation of Hemophilia does not engage in the practice of medicine and under no circumstances recommends particular treatment for specific individuals. Dose schedules and other treatment regimes are continually revised and new side-effects recognized. WFH makes no representation, express or implied, that drug doses or other treatment recommendations in this publication are correct. For these reasons it is strongly recommended that individuals seek the advice of a medical adviser and/or to consult printed instructions provided by the pharmaceutical company before administering any of the drugs referred to in this monograph. Statements and opinions expressed here do not necessarily represent the opinions, policies, or recommendations of the World Federation of Hemophilia, its Executive Committee, or its staff. Treatment of Hemophilia Monographs Series Editor Dr. Sam Schulman Acknowledgement The author would like to thank Dr. Garrett Bergman and Dr. Alison Street for their critical review. Table of Contents Introduction...............................................................................................................................................................1 Carrier Detection ......................................................................................................................................................1 Clotting Factor Levels in Carriers of Hemophilia...............................................................................................3 Bleeding Symptoms in Carriers of Hemophilia ..................................................................................................3 Bleeding after medical intervention .............................................................................................................4 Menorrhagia .....................................................................................................................................................4 Bleeding after delivery....................................................................................................................................5 Prevention of Bleeding in Carriers ........................................................................................................................5 Prevention of bleeding during pregnancy...................................................................................................5 Treatment of Bleeding in Carriers .........................................................................................................................6 Treatment products .........................................................................................................................................6 Management of specific bleeding problems................................................................................................7 Conclusion.................................................................................................................................................................9 Recommendations....................................................................................................................................................9 References..................................................................................................................................................................9 Appendix 1................................................................................................................................................................11 Symptomatic Carriers of Hemophilia Eveline P. Mauser-Bunschoten Introduction carriers of the disease (i.e. they have one abnormal copy and one normal copy of the gene) and are usually Hemophilia occurs in one out of every 5,000 male unaffected or only mildly affected with bleeding births. Hemophilia A, a deficiency in factor VIII (FVIII), symptoms. Carriers generally have adequate levels and hemophilia B, a deficiency in factor IX (FIX) are (> 60%) of clotting FVIII or FIX to control bleeding. most often inherited as sex-linked (X-linked) recessive However, clotting factor levels vary from one carrier disorders. About 30% of mild and moderate cases of to another due to lyonization [2], in which the hemophilia, and 50% of severe cases, however, are expression of one of the two X chromosomes is so-called “sporadic” or “isolated” cases [1]. The randomly suppressed. The average clotting factor abnormal mutation occurs in the developing fetus level in carriers of hemophilia is 50% of normal, and these patients are the first known cases of consistent with exactly 50% suppression of each X hemophilia in their family. chromosome (one affected, the other one normal). Males have only one X chromosome, which they inherit from their mother. If the mother has the Carrier Detection abnormal gene and passes it on to her son, he will have hemophilia (Figure 1). Women, who have two Only females can be carriers; males always have X chromosomes, can only have hemophilia if they hemophilia if they have the affected X chromosome. inherit two abnormal copies of the gene, which is There are two types of carriers: (1) obligatory carriers, extremely rare. They are most often heterozygote who necessarily carry the affected X chromosome; and (2) possible carriers. Figure 1: Inheritance of hemophilia Obligatory carriers are: Non-affected Carrier • All daughters of a man with hemophilia father mother • Mothers of one son with hemophilia and at least one other family member with hemophilia (brother, maternal grandfather, uncle, nephew, or cousin) • Mothers of one son with hemophilia and a family member who is a carrier of the hemophilia gene (mother, sister, maternal grandmother, aunt, niece, or cousin) • Mothers of two or more sons with hemophilia Possible carriers are: • All daughters of a carrier • Mothers of one son with hemophilia who have no other family members who either have or are carriers of hemophilia • Sisters, mothers, maternal grandmothers, aunts, nieces, and female cousins of carriers Carriers have one normal and one abnormal gene. They have a 50% chance of passing the hemophilia gene on to Pedigree analysis is important to detect obligatory each child. Boys who inherit the abnormal gene will have carriers. The family tree of Queen Victoria of hemophilia; girls who inherit it will become carriers. A girl England, for example, illustrates how hemophilia can only have hemophilia if her father has hemophilia and was transmitted through the royal families of her mother is a carrier, which is very uncommon. Europe (Figure 2). 2 Symptomatic Carriers of Hemophilia Figure 2: The family tree of Queen Victoria of England, in which obligatory and possible carriers are clearly shown Edward Victoria Duke of Kent Princess of Saxe-Coburg (1767-1820) (1786-1861) Victoria Albert Queen of England (1819-1861) (1819-1901) Alice Louis of Hesse Alfred Helena Louise Arthur Leopold Helen Beatrice Henry Victoria Frederick Edward VII of Alexandra England Wilhelm II Sophie of George V Irene Henry Fred Alix Nikolas II Alice of Athlone Alfonso XIII Eugenie Leopold Maurice of Spain Greece of Russia ? Waldemar Alfonso Gonzalo George Prince Henry Olga Marie Alexis Lady May Rupert VI Sigmund Tatiana Anastasia Abel Smith of Prussia Juan Carlos Princess Queen Prince Philip of Spain Margaret Elisabeth Normal Male Normal Female Princess Ann Prince Prince Prince Charles Andrew Edward Hemophilic Male Carrier Female ? Male died in infancy, possible hemophilic Symptomatic Carriers of Hemophilia 3 Previously, FVIII and FIX clotting factor levels were some carriers may have low levels of FVIII or FIX, one measured to detect carriers of hemophilia [3]. In the may expect some to have a bleeding tendency [8, 9]. 1980s, it became possible to detect carriers by means of DNA analysis. First conducted with haplotyping, for which linkage markers were used, today diagnosis Bleeding Symptoms in Carriers of is most often made by mutation analysis, which Hemophilia offers 100% certainty of carrier status [4, 5]. Carriers with clotting factor levels of less than 60% of normal may have an increased bleeding tendency. Clotting Factor Levels in Carriers of The occurrence of symptoms correlates very closely Hemophilia with the carrier’s plasma concentration of FVIII or FIX; the lower a patient’s levels of factor, the greater The expected mean clotting factor levels in carriers the likelihood that they will experience bleeding of
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