EDITORIAL Provision of K– (KEL1–) blood to women not more than 50 years of age
E
xposure to red blood cell (RBC) alloantigens through transfusion or pregnancy may induce the production of alloantibodies. This occurrence depends on genetic or acquired patient-related factors such as immune status, dose and route of administration, and immunogenicity of the antigen. The D antigen is the most immunogenic, followed by antibody formation against K (KEL1), c, E, Fya, and Jka.1,2 Alloimmunization to the D antigen has decreased significantly due to the general transfusion of D antigen– matched blood. In pregnancy it has been reduced by approximately 90% by routine postpartum or abortion prophylactic RhIG to D– women. With the introduction of additional antepartum prophylactic RhIG, the frequency of D alloimmunization is below 0.2%.3 As a result of these measures the antibody frequency in pregnant women of European ancestry has been reduced to below 0.083% for anti-D, while it still is 0.317% for antibodies other than anti-D.4 After the successful reduction in D antigen alloimmunization, attention is now focused on clinically significant alloantibodies against non-D antigens in the Rh, Kell, Duffy, Kidd, and MNS blood group systems. These antibodies can differ in time interval between transfusion and detectable alloantibody formation and risk of immunization after transfusion or pregnancy. Anti-Jka and anti-Jkb have predominantly been reported in patients tested within 3 months after transfusion, while anti-K and Fya are more often detected after 14 days and show a gradual increase in frequency of antibodies until 5 years after transfusion.2 A history of RBC transfusion (even in pregnancy) is the most important risk factor for formation of alloantibodies against K, c, and other non-D Rh antibodies. K immunization by transfusion is reported to be more important than having a K1 partner.5 Thus, a substantial fraction of maternal K alloimmunization could be prevented by provision of K– RBC to women aged not more than 50 years. Such policies, introduced in many European countries, but not in the United States, could prevent 82% of women from making anti-K.6 This projected
doi:10.1111/trf.12988 C 2015 AABB V
TRANSFUSION 2015;55;468–469 468 TRANSFUSION Volume 55, March 2015
frequency corresponds well with Dutch findings of transfusion-associated anti-K in 83% of transfused pregnant women.5 In this issue of TRANSFUSION, O’Brien and colleagues7 present a single-institution retrospective review on the provision of K– blood to obstetric patients. The study seeks to determine compliance and impact for prevention of K alloimmunization and hemolytic disease of the fetus and newborn (HDFN). As noted below, the study has several limitations. Costs associated with phenotyping 1 unit of RBCs for K antigen was estimated to be $20.00. All women not more than 50 years of age without anti-K, transfused with RBCs during a 3-year period at an obstetric institution, were identified. Of the 225 females included, 84% were transfused only K– units, while 37 who received a significantly greater number of RBC units had at least one K-untested unit. However, of the latter only nine had a repeat antibody screen 4 or more weeks posttransfusion. None of them demonstrated anti-K. This result is not unexpected with a K antigen frequency of only 9% in the donor and patient population and the relatively low immunization rate of not more than 10% in K– individuals after exposure to a unit of K1 RBCs.8 All women (n = 1125) admitted to nonobstetric services in the same period, transfused with K-untested RBCs and with anti-K detected during pretransfusion evaluation, were included as a control group. Three women admitted to the nonobstetric services, who were transfused Kuntested RBCs during the study period, developed K alloantibodies due to transfusion. The occurrence of possible transfusion-associated anti-K was also analyzed in the 10year period before the current study. The incidence of possible transfusion associated K alloimmunization in both obstetric and nonobstetric patients was found to be slightly over 0.5%. In spite of the ease of implementation and good adherence in the current study, O’Brien and colleagues could not observe clinical benefit of a policy limiting K antigen exposure through provision of K– RBC to women not more than 50 years of age with respect to prevention of alloimmunization or HDFN. However, important caveats include limited availability of posttransfusion antibody screens, relatively few patients, and a study period of only 3 years—all of which reduce the possibility of accurately assessing the impact of providing K– RBCs. O’Brien and colleagues, nevertheless, advise against provision of K– RBCs to women not more than 50 years of age
EDITORIAL
or adoption of this transfusion practice by US transfusion services. In Europe, many countries perform phenotyping for K and other non-D Rh antigens upon blood donor registration and provide K- RBC to women not more than 50 years of age. To assess the current state a survey has recently been performed (B.G. Solheim and O. Flesland, manuscript in preparation). In elleven responding countries nine perform K phenotyping in all new donors. Depending on the method the cost is estimated to be less than $0.20 to $0.80 per blood donor, and typing with Olympus PK7300 is considered most effective. The cost of K phenotyping of blood donors is favorably influenced by the fact that many of the blood donors in the 11 countries are repetitive donors. In Denmark phenotyping is performed for periods of 1 to 11=2 years. When the number of K– donors decreases, typing is repeated. The K typing is performed in connection with standard phenotyping of donors including non-D antigens in the Rh, Duffy, Kidd, and MNS blood group systems. In Sweden all new group A and group O, and some group B donors, are K phenotyped. All 11 countries transfuse only K– RBC to women not more than 45–50 years of age. In some of the countries K– RBCs are also selected for patients anticipated to need multiple transfusions. The use of K– RBCs for women not more than 50 years of age is generally not mandated, but recommended in the countries’ guidelines. Introduction of the practice varies from the early 1980s in Norway to after 2000 in other countries. Adherence to the European policy is easy as almost all blood donors are phenotyped for KEL1 antigen. Hemovigilance reports indicate a decline of at least 50% in K immunization of pregnant women. The decline is currently carefully evaluated in the Netherlands (results expected published in 2015). The European policy is based on the fact that more than 80% of anti-K in pregnant women has been caused by prior blood transfusions,4,6 that anti-K is the second most important cause for HDFN after anti-D, and that the treatment of anti-K HDFN is both challenging and expensive. Based on more than 30 years of experience in Europe, my recommenda-
tions for practice are to perform phenotyping for K upon blood donor registration and to transfuse women not more than 50 years of age with K– blood.
CONFLICT OF INTEREST The author has disclosed no conflict of interest.
Bjarte G. Solheim, MD, PhD, MHA e-mail: [email protected], [email protected] Institute of Immunology Oslo University Hospital - Rikshospitalet and University of Oslo Oslo, Norway
REFERENCES 1. Giblett ER. A critique of the theoretical hazard of inter vs. intra-racial transfusion. Transfusion 1961;1:233-8. 2. Schonewille H, van de Watering LM, Loomans DS, et al. Red blood cell alloantibodies after transfusion: factors influencing incidence and specificity. Transfusion 2006;46:250-6. 3. Crowther VA, Middleton P, McBain RD. Anti-D administration in pregnancy for preventing Rhesus alloimmunisation. Cochrane Database Syst Rev 2013;2:CD000020. 4. Koelewijn JM, Vrijkotte TG, van der Schoot CE, et al. Effect of screening for red cell antibodies, other than anti-D, to detect hemolytic disease of the fetus and newborn: a population study in the Netherlands. Transfusion 2008;48:941-52. 5. Koelewijn JM, Vrijkotte TG, de Haas M, et al. Risk factors for the presence of non-rhesus D red blood cell antibodies in pregnancy. BJOG 2009;116:655-64. 6. Lee E, de Silva M. Unlike anti-C, anti-K in pregnancy is more likely to have been induced by previous transfusion; this can be prevented. Transfusion 2004;44 Suppl:104A 7. O’Brien KL, Kim YA, Haspel RL, et al. Provision of KEL1negative blood to obstetric patients: a three-year single institution retrospective review. Transfusion 2015;55:000-0. 8. Klein HG, Anstee DJ. Other red cell antigens. In: Mollison’s blood transfusion in clinical medicine. 12th ed. Oxford: Wiley-Blackwell; 2014. p. 216.
Volume 55, March 2015 TRANSFUSION 469
E
xposure to red blood cell (RBC) alloantigens through transfusion or pregnancy may induce the production of alloantibodies. This occurrence depends on genetic or acquired patient-related factors such as immune status, dose and route of administration, and immunogenicity of the antigen. The D antigen is the most immunogenic, followed by antibody formation against K (KEL1), c, E, Fya, and Jka.1,2 Alloimmunization to the D antigen has decreased significantly due to the general transfusion of D antigen– matched blood. In pregnancy it has been reduced by approximately 90% by routine postpartum or abortion prophylactic RhIG to D– women. With the introduction of additional antepartum prophylactic RhIG, the frequency of D alloimmunization is below 0.2%.3 As a result of these measures the antibody frequency in pregnant women of European ancestry has been reduced to below 0.083% for anti-D, while it still is 0.317% for antibodies other than anti-D.4 After the successful reduction in D antigen alloimmunization, attention is now focused on clinically significant alloantibodies against non-D antigens in the Rh, Kell, Duffy, Kidd, and MNS blood group systems. These antibodies can differ in time interval between transfusion and detectable alloantibody formation and risk of immunization after transfusion or pregnancy. Anti-Jka and anti-Jkb have predominantly been reported in patients tested within 3 months after transfusion, while anti-K and Fya are more often detected after 14 days and show a gradual increase in frequency of antibodies until 5 years after transfusion.2 A history of RBC transfusion (even in pregnancy) is the most important risk factor for formation of alloantibodies against K, c, and other non-D Rh antibodies. K immunization by transfusion is reported to be more important than having a K1 partner.5 Thus, a substantial fraction of maternal K alloimmunization could be prevented by provision of K– RBC to women aged not more than 50 years. Such policies, introduced in many European countries, but not in the United States, could prevent 82% of women from making anti-K.6 This projected
doi:10.1111/trf.12988 C 2015 AABB V
TRANSFUSION 2015;55;468–469 468 TRANSFUSION Volume 55, March 2015
frequency corresponds well with Dutch findings of transfusion-associated anti-K in 83% of transfused pregnant women.5 In this issue of TRANSFUSION, O’Brien and colleagues7 present a single-institution retrospective review on the provision of K– blood to obstetric patients. The study seeks to determine compliance and impact for prevention of K alloimmunization and hemolytic disease of the fetus and newborn (HDFN). As noted below, the study has several limitations. Costs associated with phenotyping 1 unit of RBCs for K antigen was estimated to be $20.00. All women not more than 50 years of age without anti-K, transfused with RBCs during a 3-year period at an obstetric institution, were identified. Of the 225 females included, 84% were transfused only K– units, while 37 who received a significantly greater number of RBC units had at least one K-untested unit. However, of the latter only nine had a repeat antibody screen 4 or more weeks posttransfusion. None of them demonstrated anti-K. This result is not unexpected with a K antigen frequency of only 9% in the donor and patient population and the relatively low immunization rate of not more than 10% in K– individuals after exposure to a unit of K1 RBCs.8 All women (n = 1125) admitted to nonobstetric services in the same period, transfused with K-untested RBCs and with anti-K detected during pretransfusion evaluation, were included as a control group. Three women admitted to the nonobstetric services, who were transfused Kuntested RBCs during the study period, developed K alloantibodies due to transfusion. The occurrence of possible transfusion-associated anti-K was also analyzed in the 10year period before the current study. The incidence of possible transfusion associated K alloimmunization in both obstetric and nonobstetric patients was found to be slightly over 0.5%. In spite of the ease of implementation and good adherence in the current study, O’Brien and colleagues could not observe clinical benefit of a policy limiting K antigen exposure through provision of K– RBC to women not more than 50 years of age with respect to prevention of alloimmunization or HDFN. However, important caveats include limited availability of posttransfusion antibody screens, relatively few patients, and a study period of only 3 years—all of which reduce the possibility of accurately assessing the impact of providing K– RBCs. O’Brien and colleagues, nevertheless, advise against provision of K– RBCs to women not more than 50 years of age
EDITORIAL
or adoption of this transfusion practice by US transfusion services. In Europe, many countries perform phenotyping for K and other non-D Rh antigens upon blood donor registration and provide K- RBC to women not more than 50 years of age. To assess the current state a survey has recently been performed (B.G. Solheim and O. Flesland, manuscript in preparation). In elleven responding countries nine perform K phenotyping in all new donors. Depending on the method the cost is estimated to be less than $0.20 to $0.80 per blood donor, and typing with Olympus PK7300 is considered most effective. The cost of K phenotyping of blood donors is favorably influenced by the fact that many of the blood donors in the 11 countries are repetitive donors. In Denmark phenotyping is performed for periods of 1 to 11=2 years. When the number of K– donors decreases, typing is repeated. The K typing is performed in connection with standard phenotyping of donors including non-D antigens in the Rh, Duffy, Kidd, and MNS blood group systems. In Sweden all new group A and group O, and some group B donors, are K phenotyped. All 11 countries transfuse only K– RBC to women not more than 45–50 years of age. In some of the countries K– RBCs are also selected for patients anticipated to need multiple transfusions. The use of K– RBCs for women not more than 50 years of age is generally not mandated, but recommended in the countries’ guidelines. Introduction of the practice varies from the early 1980s in Norway to after 2000 in other countries. Adherence to the European policy is easy as almost all blood donors are phenotyped for KEL1 antigen. Hemovigilance reports indicate a decline of at least 50% in K immunization of pregnant women. The decline is currently carefully evaluated in the Netherlands (results expected published in 2015). The European policy is based on the fact that more than 80% of anti-K in pregnant women has been caused by prior blood transfusions,4,6 that anti-K is the second most important cause for HDFN after anti-D, and that the treatment of anti-K HDFN is both challenging and expensive. Based on more than 30 years of experience in Europe, my recommenda-
tions for practice are to perform phenotyping for K upon blood donor registration and to transfuse women not more than 50 years of age with K– blood.
CONFLICT OF INTEREST The author has disclosed no conflict of interest.
Bjarte G. Solheim, MD, PhD, MHA e-mail: [email protected], [email protected] Institute of Immunology Oslo University Hospital - Rikshospitalet and University of Oslo Oslo, Norway
REFERENCES 1. Giblett ER. A critique of the theoretical hazard of inter vs. intra-racial transfusion. Transfusion 1961;1:233-8. 2. Schonewille H, van de Watering LM, Loomans DS, et al. Red blood cell alloantibodies after transfusion: factors influencing incidence and specificity. Transfusion 2006;46:250-6. 3. Crowther VA, Middleton P, McBain RD. Anti-D administration in pregnancy for preventing Rhesus alloimmunisation. Cochrane Database Syst Rev 2013;2:CD000020. 4. Koelewijn JM, Vrijkotte TG, van der Schoot CE, et al. Effect of screening for red cell antibodies, other than anti-D, to detect hemolytic disease of the fetus and newborn: a population study in the Netherlands. Transfusion 2008;48:941-52. 5. Koelewijn JM, Vrijkotte TG, de Haas M, et al. Risk factors for the presence of non-rhesus D red blood cell antibodies in pregnancy. BJOG 2009;116:655-64. 6. Lee E, de Silva M. Unlike anti-C, anti-K in pregnancy is more likely to have been induced by previous transfusion; this can be prevented. Transfusion 2004;44 Suppl:104A 7. O’Brien KL, Kim YA, Haspel RL, et al. Provision of KEL1negative blood to obstetric patients: a three-year single institution retrospective review. Transfusion 2015;55:000-0. 8. Klein HG, Anstee DJ. Other red cell antigens. In: Mollison’s blood transfusion in clinical medicine. 12th ed. Oxford: Wiley-Blackwell; 2014. p. 216.
Volume 55, March 2015 TRANSFUSION 469
