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Complications Associated with Carrier Status Among People with Blood Disorders

A Commentary
      Advances in human genomics, such as the completion of the human genome project, have sparked the development of new technologies and have enhanced our understanding of the molecular basis of disease. One important consequence of the genomic revolution has been an explosion in the number of genetic tests available to the public that promise to provide information on risk and/or susceptibility to disease. The potential for genomics and genetic testing to be part of a public health toolkit has launched the new field of public health genomics.
      • Brand A.
      • Brand H.
      • Schulte den Baumen T.S.
      The impact of genetics and genomics on public health.
      CDC
      Office of Genomics and Disease Prevention: genomics and population health: U.S..
      • Gwinn M.
      • Khoury M.J.
      Genomics and public health in the U.S.: signposts on the translation highway.
      As described by Gwinn et al.,
      • Gwinn M.
      • Khoury M.J.
      Genomics and public health in the U.S.: signposts on the translation highway.
      an opportunity now exists to initiate a translational program integrating genomics into policies and programs to benefit the public at large.
      Genetic testing at the population level remains an issue of significant debate in public health genomics today. As newborn screening has long been an integral part of public health practice, much of the discussion in the field of public heath related to genetic testing has been driven by lessons learned from and questions related to newborn screening policies and programs.
      • Gwinn M.
      • Khoury M.J.
      Genomics and public health in the U.S.: signposts on the translation highway.
      • Grosse S.D.
      • Rogowski W.H.
      • Ross L.F.
      • Cornel M.C.
      • Dondorp W.J.
      • Khoury M.J.
      Population screening for genetic disorders in the 21st century: evidence, economics, and ethics.
      An early success and lesson learned was that these programs contributed to significant reduction of mortality and morbidity from genetic disorders in children. Now that large-scale genetic testing is technologically possible, the number of molecular tests that could be potentially incorporated into newborn screening with the hope of a broader impact has significantly increased.
      CDC
      Office of Genomics and Disease Prevention: genomics and population health: U.S..
      Because of this array of available tests, there was little agreement initially among the states in the U.S on which tests to include
      • Gwinn M.
      • Khoury M.J.
      Genomics and public health in the U.S.: signposts on the translation highway.
      ; now, with agreement among all states to use the same newborn testing panel, this impact can soon be evaluated.
      • Grosse S.D.
      • Rogowski W.H.
      • Ross L.F.
      • Cornel M.C.
      • Dondorp W.J.
      • Khoury M.J.
      Population screening for genetic disorders in the 21st century: evidence, economics, and ethics.
      Genetic screening at birth, as well as later in life, can identify not only those with an inherited disorder but also individuals who are carriers or have the trait for a disorder.
      • Gwinn M.
      • Khoury M.J.
      Genomics and public health in the U.S.: signposts on the translation highway.
      • Grosse S.D.
      • Rogowski W.H.
      • Ross L.F.
      • Cornel M.C.
      • Dondorp W.J.
      • Khoury M.J.
      Population screening for genetic disorders in the 21st century: evidence, economics, and ethics.
      There has been much interest in carrier detection because of implications for reproductive and family planning, and consequently there is a considerable amount of published information. Much of this information, however, has been limited to the clinical perspective. The objective of this commentary is not to review the issues surrounding carrier testing but rather to increase awareness that the carrier state for some blood disorders may confer significant morbidity. Although long considered within the field of hematology, this fact may be less appreciated within the broad context of public health. Increased awareness of carrier state–associated morbidity in blood disorders, as well as other nonhematologic disorders, will be important to consider for future screening programs and represents another challenge in the translation of genetic tests into clinical public health practice.
      • Rogowski W.H.
      • Grosse S.D.
      • Khoury M.J.
      Challenges of translating genetic tests into clinical and public health practice.
      One of the best-known inherited blood disorder carrier states is that of hemophilia. This bleeding disorder became prominent because of its presence in the descendents of Queen Victoria (herself a carrier) and its impact on the Russian royal family in the early 20th century.
      • Forbes C.D.
      The early history of hemophilia.
      There are two major types of inherited hemophilia, hemophilia A and hemophilia B, both of which are gender or X-linked and affect primarily men/boys. Hemophilia A, which is characterized by the absence or low levels of clotting factor VIII (FVIII), occurs in about 1 in 5000 men/boys, whereas hemophilia B, which occurs in about 1 in 30,000 men/boys, is characterized by the absence or low levels of clotting factor IX (F IX).
      The age-adjusted prevalence per 100,000 has been reported
      • Soucie M.J.
      • Evatt B.L.
      • Jackson D.
      Hemophilia Surveillance System Project Investigators
      Occurrence of hemophilia in the U.S.
      to be 10.5 and 2.9 for hemophilia A and B, respectively. The hemophilia carrier state, which because of X-linked inheritance is confined to women, is not necessarily a benign condition. Hemophilia carriers most typically have about 50% of normal FVIII and F IX clotting activity, which is usually sufficient for normal clotting to occur. However, the level can vary significantly among carrier women/girls, with a greater risk of bleeding events in women with levels falling below the hemostatic range.
      • Plug I.
      • Bunschoten-Mauser E.P.
      • Vriends-Brocker A.H.J.T.
      • et al.
      Bleeding in carriers of hemophilia.
      Some women will develop mild hemophilia because the remaining functional X chromosome is largely inactivated, and very little clotting factor is produced.
      • Plug I.
      • Bunschoten-Mauser E.P.
      • Vriends-Brocker A.H.J.T.
      • et al.
      Bleeding in carriers of hemophilia.
      • Kadir R.A.
      • Economides D.L.
      • Braithwaite J.
      • Goldman E.
      • Lee C.A.
      The obstetric experience of carriers of haemophilia.
      This heterogeneity highlights the importance of evaluating both the genotype and phenotype (clotting activity) in the hemophilia carrier,
      • Plug I.
      • Bunschoten-Mauser E.P.
      • Vriends-Brocker A.H.J.T.
      • et al.
      Bleeding in carriers of hemophilia.
      and it could be argued that this may also extend to certain other carrier states.
      This heterogeneity in FVIII levels is particularly important for the pregnant carrier for at least two major reasons: First, hemophilia carriers have been reported to be at a significantly higher risk for primary and secondary postpartum hemorrhage.
      • Kadir R.A.
      • Economides D.L.
      • Braithwaite J.
      • Goldman E.
      • Lee C.A.
      The obstetric experience of carriers of haemophilia.
      • Cunningham F.G.
      • MacDonald P.C.
      • Grant N.F.
      Abnormalities of the third stage of labor.
      • Lee C.Y.
      • Madrazo B.
      • Drukker B.H.
      Ultrasonic evaluation of postpartum uterus in the management of postpartum bleeding.
      One study described primary postpartum hemorrhage in about 22% of carriers as compared to 5% of noncarriers.
      • Kadir R.A.
      • Economides D.L.
      • Braithwaite J.
      • Goldman E.
      • Lee C.A.
      The obstetric experience of carriers of haemophilia.
      Second, the risk for hemorrhage also extends to a hemophiliac infant born to the carrier, particularly with respect to scalp and intracranial bleeds.
      • Kadir R.A.
      • Economides D.L.
      • Braithwaite J.
      • Goldman E.
      • Lee C.A.
      The obstetric experience of carriers of haemophilia.
      This risk is particularly problematic if healthcare workers are unaware that the mother is a carrier.
      • Kadir R.A.
      • Economides D.L.
      • Braithwaite J.
      • Goldman E.
      • Lee C.A.
      The obstetric experience of carriers of haemophilia.
      Although bleeding issues with respect to the carrier infant have been poorly studied, it is clear that an awareness of the carrier status may be important for the health of both mother and baby.
      In a more recent study, which also acknowledged that bleeding complications in the hemophilia carrier were not well appreciated, Plug et al.
      • Plug I.
      • Bunschoten-Mauser E.P.
      • Vriends-Brocker A.H.J.T.
      • et al.
      Bleeding in carriers of hemophilia.
      reported that carriers exhibited more spontaneous and provoked hemorrhages than noncarriers and had a greater risk of prolonged bleeding after tooth extraction and surgery. In addition, it was found that carriers experience greater blood loss during the menstrual period, and moderately increased number of joint bleeds.
      • Plug I.
      • Bunschoten-Mauser E.P.
      • Vriends-Brocker A.H.J.T.
      • et al.
      Bleeding in carriers of hemophilia.
      Although population screening for hemophilia carriers is currently not practical because of the low frequency and the large number of gene mutations involved, it has been estimated
      • Street A.M.
      • Ljung R.
      • Lavery S.A.
      Management of carriers and babies with haemophilia.
      that there are five carriers for each man/boy with hemophilia. However, the number of women at risk for bleeding can be identified by reviewing family history and offering testing to potential carriers.
      Sickle cell trait (SCT), estimated to be present in about 300 million people worldwide, is another carrier state that is receiving increased attention.
      • Tsaras G.
      • Owusu-Ansah A.
      • Boateng F.O.
      • Amoateng-Adjepong Y.
      Complication associated with sickle cell trait: a brief narrative review.
      Although it has been long known that exercise-induced collapse and sudden death were rare but well-established complications of SCT, there is increasing awareness that other disorders, such as splenic infarction at high altitude, hematuria resulting from papillary necrosis, and exertional rhabdomyolysis, occur with a higher frequency in individuals with SCT.
      • Tsaras G.
      • Owusu-Ansah A.
      • Boateng F.O.
      • Amoateng-Adjepong Y.
      Complication associated with sickle cell trait: a brief narrative review.
      • Makaryus J.N.
      • Catanzaro J.N.
      • Katona K.C.
      Exertional rhabdomyolysis and renal failure in patients with sickle cell trait; is it time to change our approach?.
      There are also emerging data
      • Austin H.
      • Key N.S.
      • Benson J.M.
      • et al.
      Sickle cell trait and the risk of venous thromboembolism among blacks.
      • Taylor M.Y.
      • Wyatt A.
      • Gray J.
      • et al.
      Pregnancy loss after first trimester viability in women with sickle cell trait; a time for reappraisal?.
      suggesting that SCT carriers are at higher risk for other conditions such as venous thromboembolism (VTE)—particularly pulmonary embolism—and adverse pregnancy outcomes. Of special interest is a recent paper
      • Austin H.
      • Lally C.
      • Benson J.M.
      • Whitsett C.
      • Hooper W.C.
      • Key N.S.
      Hormonal contraception, sickle cell trait, and risk for venous thromboembolism.
      reporting an interaction between hormonal contraception and SCT that increases the risk for VTE. Although those with SCT generally enjoy a normal life expectancy, SCT should be considered a risk factor for adverse health outcomes under certain conditions, and therefore appropriate preventive measures should be taken.
      • Tsaras G.
      • Owusu-Ansah A.
      • Boateng F.O.
      • Amoateng-Adjepong Y.
      Complication associated with sickle cell trait: a brief narrative review.
      • Makaryus J.N.
      • Catanzaro J.N.
      • Katona K.C.
      Exertional rhabdomyolysis and renal failure in patients with sickle cell trait; is it time to change our approach?.
      Although testing for sickle cell disease and trait is part of newborn screening programs, there has been variable reporting of carrier status.
      • Parker H.
      • Qureshi N.
      • Ulph F.
      • Kai J.
      Imparting carrier status detected by universal newborn screening for sickle cell and cystic fibrosis in England: a qualitative study of current practice and policy changes.
      Consequently, some adults might not have been tested, as newborn screening did not become widespread until after a 1987 NIH Consensus Conference; in addition, individuals might not be aware of results that had been done earlier in their lives. Rescreening for SCT may occur in other situations in adulthood, including entry into the military, during pregnancy, or in preparation for participation in competitive sporting events at the collegiate level. With respect to the latter, a recent survey
      Consensus Statement: Sickle cell trait and the athlete.
      suggested that about two thirds of colleges screen athletes for SCT in order to identify those at risk of exertional rhabdomyolysis and exercise-related death. This number is likely to increase further (and perhaps extend to high school athletes) as a result of the recently issued “strong recommendation” by the National Collegiate Athletic Association.
      • Hord J.D.
      • Rice S.G.
      NCAA recommends screening all college athletes for sickle cell trait.
      Notification of individuals carrying SCT or mutations for other diseases evaluated by newborn screening panels is currently a topic of discussion among the medical ethics community.
      • Miller F.A.
      • Robert J.S.
      • Hayeems R.Z.
      Questioning the consensus: managing the carrier status results generated by newborn screening.
      • Miller F.A.
      • Hayeems R.Z.
      • Robert J.S.
      Carrier detection and clinical uncertainty: the case for public health ethics.
      Factor V Leiden (FVL) is another carrier state that is perhaps better known to the public health community at large with respect to genetic screening issues. Because there is a wealth of published information discussing the screening issues surrounding this gene, this topic will be briefly discussed only as it relates to oral contraceptives. Factor V Leiden is the most significant genetic risk factor for VTE in Caucasians of northern European descent and is rare in African Americans and Asians.
      • Hooper W.C.
      Venous thromboembolism in African-Americans: a literature-based commentary.
      Perhaps the most notable difference among FVL, SCT, and hemophilia is that the FVL homozygous state does not always result in thrombotic disease, although its presence significantly increases the risk over that seen in the heterozygote.
      Research demonstrating an interaction between FVL and oral contraceptives and increased risk for VTE has lead to a robust debate as to whether screening of women who are considering oral contraceptive use is appropriate, as well as screening for general thrombophilia testing.
      • Vandenbroucke J.P.
      • van der Meer F.J.
      • Helmerhorst F.M.
      • Rosendal F.R.
      Factor V Leiden: should we screen oral contraceptive users and pregnant women.
      • Machin S.J.
      Pros and cons of thrombophilia testing: cons.
      • Martinelli I.
      Pros and cons of thrombophilia testing: pros.
      The current general consensus
      • Vandenbroucke J.P.
      • van der Meer F.J.
      • Helmerhorst F.M.
      • Rosendal F.R.
      Factor V Leiden: should we screen oral contraceptive users and pregnant women.
      • Goddard K.A.B.
      • Robitaille J.
      • Dowling N.F.
      • et al.
      Health-related direct-to-consumer genetic tests: a public health assessment and analysis of practices related to Internet-based tests for risk of thrombosis.
      • Grody W.W.
      • Griffin J.H.
      • Taylor A.K.
      • Korf B.R.
      • Heit J.A.
      American college of medical genetics consensus statement on factor V Leiden mutation testing.
      is that although it is not cost effective to universally screen for FVL, it may be appropriate to consider screening selected individuals based on a personal or family history of VTE. In addition, a recent report from the Agency for Healthcare Research and Quality has found that FVL testing had little clinical impact.
      Outcomes of genetic testing in adults with a history of venous thromboembolism.
      The methods and approaches that were used for FVL may serve as a guide for other carrier states.
      In summary, it is not the intent for this commentary to either advocate for or argue against carrier testing, but rather to increase awareness that carrier status for certain blood disorders may be associated with clinical consequences that have implications for public health. As our knowledge of disease increases in tandem with advances in genomic technology, we will need to consider more carefully the role of the carrier state with respect to unknown morbidities as well as the potential for new opportunities for public health impact.
      The authors would like to acknowledge Dr. Nicole F. Dowling for her review of the manuscript.
      No financial disclosures were reported by the authors of this paper.

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