Canellini, Giorgia

Natterer, Julia

Tissot, Jean-Daniel

Truttmann, Anita

Waldvogel, Sophie

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J. Perinat. Med. 37 (2009) 422–424 • Copyright  by Walter de Gruyter • Berlin • New York. DOI 10.1515/JPM.2009.071Article in press - uncorrected proofSevere neonatal hyporegenerative anemia due to anti-Vw(anti-MNS9) alloantibodySophie Waldvogel1,*, Julia Natterer2,Giorgia Canellini1, Anita Truttmann2 andJean-Daniel Tissot11 Blood Transfusion Service of the Swiss Red Cross,University Hospital of Lausanne, 1005 Lausanne,Switzerland2 Department of Pediatrics, Neonatology Unit, UniversityHospital of Lausanne, 1011 Lausanne, SwitzerlandKeywords: Antiglobulin test; hemolytic disease of thenewborn; low incidence antigens; neonatal anemia;verweyst.Sir,Severe hemolytic disease of the fetus and newborn(HDFN) not related to anti-D (anti-RH1) and requiringintrauterine transfusion or postnatal exchange transfu-sion are most commonly caused by anti-Kell (anti-K1)and anti-c (anti-RH4) w6x. However, antibodies directedagainst low incidence antigen (LIA), particularly thoseresulting from MNS polymorphism can also lead to lifethreatening complications w5, 7x. In some fetuses or new-borns presenting with severe anemia, and more partic-ularly in the presence of anti-Kell (anti-K1) antibodies,suppression of erythropoiesis may be observed. Anemiais associated with reduced reticulocytosis, less erythro-blastosis and less severe hyperbilirubinemia when com-pared with similar hemoglobin levels but related to anti-D(anti-RH1) alloimmunization w9x. These observations havebeen supported by in vitro analysis, showing that seracontaining anti-Kell as well as monoclonal anti-Kell anti-bodies suppressed the growth of Kell-positive erythroidprogenitors w8x. Here, we report a case of severe hypo-regenerative anemia, due to an anti-Vw (anti-MNS9), thatwas not detected by routine screening of alloantibodiesduring pregnancy.*Corresponding author:Sophie WaldvogelService Regional Vaudois de transfusion sanguineBugnon 271005 Lausanne,SwitzerlandTel.: q41213146583Fax: q41213146578E-mail: Sophie.Waldvogel@mavietonsang.chA male newborn from a 32-year-old Caucasian woman,gravida 2 para 1 (1 abortion), without history of transfu-sion, was delivered by emergency cesarean section atthe 34th gestational week because of decreasing fetalmovements during the last three days and non-reactivecardiotocogram on admission. The newborn presentedwith extreme pallor, blueberry muffin spots on the trunkand face, respiratory distress, tachycardia and mildhepatosplenomegaly. Laboratory testing demonstratedsevere and isolated hypoproliferative anemia (hemoglo-bin: 33 g/L; reticulocyte count: 9.6=109/L, nucleated redblood cell per 100 white blood cells: 2), a metabolic aci-dosis with a lactate level of 7.6 mmol/L and a moderatelyincreased bilirubin (46 mmol/L). A first transfusion of redblood cell (O Rh negative, non-cross matched) wasimmediately administered (20 mL/kg). The baby’s con-dition improved rapidly and the skin lesions disappearedin the next 12 h. Abdominal ultrasound only revealedmild hepatomegaly without ascites. Echocardiographyshowed good left ventricular function without morpho-logical anomaly. The direct antiglobulin test (DAT) waspositive (IgG) on cord blood cells. Both mother and childwere O Rh positive. Eluate from the newborn red bloodcells was not performed before the first transfusion andDAT became negative thereafter. Indirect antiglobulin test(IAT) of maternal serum was negative with panel cells, butwas clearly positive (3q) with the father’s red blood cells,suggesting that a low incidence antigen (LIA) wasinvolved as the cause of immunization. Blood samples ofthe mother as well as of the father were tested at thereference laboratory of the Blood Transfusion Service(Bern, Switzerland). Anti-Vw (anti-MNS9) was identified inthe serum of the mother. The father was MNS:-1,2,3,4,9(Vw positive). Extensive investigations for infectious dis-eases (Epstein Barr virus, cytomegalovirus, parvovirusB19, toxoplasmosis, rubella, syphilis, enterovirus) werenot contributive. The Kleihauer-Betke test in the motherwas negative. A screening for pyruvate kinase andglucose-6-phosphate dehydrogenase deficiency wasperformed, and yielded normal results. Therefore, thediagnosis of HDFN related to a LIA was confirmed.Because of ongoing hemolysis with increasing levelsof total bilirubin (278 mmol/L on day 4), phototherapy wasperformed until day 11. A second transfusion (20 mL/kg)performed at day 2 was sufficient to bring the hemoglo-bin level up to 140 g/L. Four weeks later, the baby wasagain transfused because of hemoglobin level of 75 g/LWaldvogel et al., Verweyst alloimmunization 423Article in press - uncorrected proofwith a recticulocyte count of 40=109/L. The baby wasdischarged thereafter. On the last follow-up at 10 weeks,he was healthy and well growing, and showed no evi-dence of neurological impairment. Hemoglobin was112 g/L. The parents were informed of the risk in caseof future pregnancies.Vw (Verweyst) belongs to the MNS blood group systemand is secondary to a gene conversion between genesencoding for glycophorin A and glycophorin B (hybrid A-B-A). The insert encoding the Vw gene results in anamino acid polymorphism at position 28 (Threonine™Methionine) leading to the loss of N-glycosylation of theadjoining asparagine at position 26. It is a LIA but itsprevalence has been reported to be as high as 1.43% insoutheastern Switzerland w7x. This antibody has beenassociated with severe HDFN w5, 7x. As expected, in allreported cases, prenatal IAT were negative and, sincepregnancies were clinically uncomplicated, diagnosiswas only made at birth. Newborns were treated withexchange transfusion and/or transfusion and intensivephototherapy. Retrospectively, some older asymptomaticsiblings were also tested Vw positive. In our case,HDFN occurred already in the second pregnancy after aprobable immunization during the first pregnancy(termination).This case report highlights two different aspects thatare severe anemia of the newborn despite negativescreening tests and apparent suppression of hemato-poiesis due to alloantibodies. Alloantibodies against LIAare of little concern in pretransfusion testing, because therisk for a patient to receive incompatible red cell unitsremains very low. In practice, the screening red bloodcells used in antenatal testing are identical to those usedin pretransfusion testing. According to the recommen-dations of the Swiss Transfusion Service, the panel cellsthat are used must include antigens with a frequency ofmore than 8% of the Caucasian population. Thus, it isimportant to remember that routine IAT testing ignoresmost antibodies that are specific for LIA and missingsuch antibodies may be of great concern in some cases,taking into account that the probability of fetal inheri-tance of the incompatible antigen can be as high as100%, if the father carries the antigen. Therefore, if theantibody screen is negative but alloimmune hemolyticdisease is still suspected, testing of the father’s red bloodcells with the maternal serum is of great interest becausereagents for rare antigen are not available in all labora-tories. In presence of ABO incompatibility between themother and the father, the absorption of anti-A and anti-B should be performed.The present case is also relevant because hemolysiswas associated with severe reticulocytopenia andabsence of erythroblastosis at birth, and was quite pro-longed, therefore a transfusion was still necessary at day27 of life. A similar observation was reported in the lit-erature (absence of significant reticulocytosis and latetransfusion requirement) w5x. These findings suggest thata suppression of erythropoiesis at the progenitor-celllevel by anti-Vw, exacerbating anemia, may be involvedin such cases. Inhibition of erythroid progenitors hasalready been demonstrated in vitro for anti-Kell sensiti-zation w8, 9x, and more recently for anti-Gerbich 3, anantigen of glycophorin C and D w1, 3x. Glycophorin Aappears to be present early in maturation stage of redcells (before RhD but after Kell antigens), as demonstrat-ed with assays on erythroid cultures w2x. Nevertheless,pathogenicity of anti-Vw remains unknown and thishypothesis requires further in vitro investigations. Gly-cophorin contributes to most of the carbohydrates on thered blood cell membrane, which have abundant sialicacid, and confers negative charge, but nothing is knownabout a putative role in erythroid differentiation or growth.In this case, the diagnosis of HDFN was only sus-pected after birth because the DAT was positive. DAT isknown to have a limited usefulness to screen HDFN. Aretrospective study of 1724 DAT analyzed on unselectedumbilical cord blood samples showed a positive predic-tive value of 23% and a sensitivity of 86% for the sub-sequent development of hyperbilirubinemia w4x. However,the significance of a positive DAT should not be neglect-ed in the presence of non-regenerative anemia of thenewborn, even if IAT of maternal serum is negative.This case confirms that anti-Vw may be responsible forsevere HDFN, which is certainly always missed duringroutine screening, and may be associated with suppres-sion of erythropoiesis. Unfortunately, no cost-effectiveroutine prenatal testing can be offered to prevent such acomplication. However, we should keep in mind, that iffetal anemia is suspected, crossmatch of the paternal redblood cell with the maternal serum can help to rule outor confirm alloimmunization.In case of subsequent pregnancies (or of a similar sit-uation in another patient), the following recommenda-tions can be proposed. We strongly favor regularscanning of the middle cerebral artery peak velocity todetect fetal anemia early in pregnancy and to proposeintrauterine fetal transfusions, if necessary. Prenatal phe-notyping or genotyping w7x would be of great interest,since homozygous individuals are exceptional. However,the risk of complications of an invasive procedure shouldbe carefully taken into consideration. Finally, PCR analy-sis of free fetal DNA in maternal blood samples shouldbe discussed, taking into account the fact that this testhas not been validated for ‘‘routine’’ MNS polymorphismevaluation. Titration of anti-Verweyst antibodies withpaternal red cells is also possible but is not recommend-ed because of its potentially poor predictive value, as inanti-K titration.In conclusion, this case confirms the clinical and bio-logical heterogeneity of HDFN, and highlights the limitsof routine prenatal IAT. The question is whether theincreasing use of Doppler ultrasound to detect fetal ane-mia will diminish the number of late diagnoses.424 Waldvogel et al., Verweyst alloimmunizationArticle in press - uncorrected proofReferencesw1x Arndt PA, Garratty G, Daniels G, Green CA, Wilkes AM, HuntP, et al. Late onset neonatal anaemia due to maternal anti-Ge: possible association with destruction of eythroid pro-genitors. Transfus Med. 2005;15:125–32.w2x Bony V, Gane P, Bailly P, Cartron JP. Time-course expressionof polypeptides carrying blood group antigens duringhuman erythroid differentiation. Br J Haematol. 1999;107:263–74.w3x Denomme GA, Shahcheraghi A, Blackall DP, Oza KK, Gar-ratty G. Inhibition of erythroid progenitor cell growth by anti-Ge3. Br J Haematol. 2006;133:443–4.w4x Dinesh D. Review of positive direct antiglobulin tests foundon cord blood sampling. J Paediatr Child Health. 2005;41:504–7.w5x Gorlin JB, Beaton M, Poortenga M, Davidson S, Mullane S.Anti-Vw causing a case of clinically significant hemolyticdisease of the newborn. Transfusion. 1996;36:938–9.w6x Koelewijn JM, Vrijkotte TG, van der Schoot CE, Bonsel GJ,de HM. Effect of screening for red cell antibodies, other thananti-D, to detect hemolytic disease of the fetus and new-born: a population study in the Netherlands. Transfusion.2008;48:941–52.w7x Palacajornsuk P, Nathalang O, Tantimavanich S, Bejrachan-dra S, Reid ME. Detection of MNS hybrid molecules in theThai population using PCR-SSP technique. Transfus Med.2007;17:169–74.w8x Vaughan JI, Manning M, Warwick RM, Letsky EA, MurrayNA, Roberts IA. Inhibition of erythroid progenitor cells byanti-Kell antibodies in fetal alloimmune anemia. N Engl JMed. 1998;338:798–803.w9x Vaughan JI, Warwick R, Letsky E, Nicolini U, Rodeck CH,Fisk NM. Erythropoietic suppression in fetal anemiabecause of Kell alloimmunization. Am J Obstet Gynecol.1994;171:247–52.The authors stated that there are no conflicts of interest regard-ing the publication of this article.Received October 27, 2008. Revised December 10, 2008.Accepted January 26, 2009. Previously published online March17, 2009.

Severe neonatal hyporegenerative anemia due to anti-Vw (anti-MNS9) alloantibody

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