Fetomaternal Incompatibility Research Articles

Bases moléculaires et relations structure-fonction des antigènes de groupe sanguin Duffy: récepteur de chimiokines et de Plasmodium vivax

Duffy blood group antigens are of major interest in clinical medicine as they are not only involved in blood transfusion risks and occasionally in neonatal hemolytic disease, but also in the invasion of red blood cells by the hemoparasitic Plasmodium vivax. The FY locus maps to chromosome 1q22-q23, and is composed of 4 alleles: FY*A and FY*B (coding for the Fya and Fyb antigens, respectively), FY*X and FY*Fy. The Duffy antigens are carried by a 336 amino-acid glycoprotein named the Duffy Antigen/Receptor for Chemokines (DARC) that can bind with high affinity selected members of the CXC and CC classes of chemokines. Today, the genetic bases of the Duffy system have been characterized. The identification of the polymorphisms associated with the 4 alleles FY*A, FY*B, FY*Fy and FY*X has led to the development of a complete genotyping of the Duffy system by PCR, which increases the safety and lessens the risk of blood transfusion, and is useful in determining feto-maternal incompatibilities and in genetic filiation analyses. DARC is not solely expressed in erythroid cells: the same polypeptide isoform is found on the surface of endothelial cells of post-capillary venules throughout the body and also on the surface of Purkinje cells in the cerebellum, although it is encoded by different RNA messengers in each case, i.e., 1.35 and 7.5 kb, respectively. The preliminary analyses of receptor-ligand interaction have shown the existence of a chemokine-binding pocket defined by the close proximity of the first and fourth transmembrane domains of the DARC protein, and also by the importance of the N-terminal extracellular region for the binding of Plasmodium vivax merozoites.

The management of alloimmune neonatal thrombocytopenia

Neonatal alloimmune thrombocytopenia (NAITP), defined as thrombocytopenia (platelet count <150×109/l) due to transplacentally acquired maternal platelet alloantibodies, occurs in approximately 1 per 1200 live births in a Caucasian population. In such a population, the majority (>75 percent) of cases are due to fetomaternal incompatibility for the platelet specific alloantigen, HPA-1a (PlA1, Zwa). Incompatibility for the HPA-5b (Bra) alloantigen is the next most frequent cause of NAITP in Caucasians; much less common is NAITP due to incompatibility for HLA, blood group ABO or other platelet-specific antigens. In non-Caucasian populations (e.g. Orientals) HPA-1a incompatibility is a rare cause of NAITP and other alloantigens e.g. HPA-4b (Penb, Yuka) are implicated. The greatest clinical challange relates to the antenatal management of pregnant women alloimmunized to the HPA-1a (PlA1, Zwa) antigen, and particularly the subset of such women who have a history of a previously affected infant with severe thrombocytopenia and/or intracranial hemorrhage (ICH). The risk of antenatal ICH in the fetus of such women is high enough to merit intervention, either weekly infusion of high-dose intravenous immunoglobulin G (IVIG) with or without corticosteroids given to the mother (the preferred approach in North American centres), or repeated in-utero fetal platelet transfusions (the preferred treatment approach in some European centres). Post-natal management of severely affected infants centres on the rapid provision of compatible antigen-negative platelets harvested from the mother or a phenotyped donor. The value of antenatal screening programs to detect ‘at risk’ alloimmunized women during pregnancy continues to be debated.

HLA antibodies and fetomaternal alloimmune thrombocytopenia: myth or meaningful?

~ETOMATERNAL alloimmune thrombocytopenia (FMAIT), also called neonatal alloimmune thrombocytopenia (NAIT) or alloimmune neonatal thrombocytopenia (AINT), was first described in the early 1950s. 1 It is a result of fetomaternal incompatibility and is similar to hemolytic disease of the newborn except that the platelets are the target of the alloantibodies. As a consequence of the inheritance by the fetus of the paternal platelet alloantigen lacking in the mother, maternal alloantibodies are formed against fetal platelet antigens. The mother's alloantibodies pass the placenta and bind to the target platelet alloantigens on fetal platelets, resulting in immunemediated platelet phagocytosis. Sequelae of the thrombocytopenia may be observed in both the fetus and the neonate. However, most cases of FMAIT are diagnosed in the neonatal period. The clinical presentation and course is variable and ranges from asymptomatic thrombocytopenia to intracerebral bleeding and death. The typical picture is a neonate born to a healthy mother, who shows widespread purpura minutes to hours after birth. The thrombocytopenia usually lasts for 1 to 3 weeks after birth but may persist much longer. 2 The incidence of FMAIT is about 1 to 1.5 per 1,000 live births. 3,4 In contrast to hemolytic disease of the newborn, alloimmunization can occur in the first pregnancy in approximately 50% of the cases. 5,6 It is well documented that FMAIT may be caused by maternal alloantibodies against fetal human platelet antigens (HPA).

Production of pigs expressing multiple transgenes for use in xenotransplantation studies

Flow cytometry (FC) has been primarily applied to the diagnosis of hematological malignancies, and thereafter, to detection and quantification of CD34+ cells in bone marrow transplants, and granulocytes in neutropenias and paroxysmal nocturnal hemoglobinuria (PNH). In PNH and hereditary spherocytosis, changes in some of the erythrocyte membrane proteins are tested (CD59, CD55, and band 3). The purpose of this paper is to focus on the use of FC in RBC testing. With anti-D, -HbF, and -CA (carbonic anhydrase), we can detect RhD+, HbF+, and CA- fetal RBCs in the maternal RhD-, HbF-, and CA+ blood sample. Obtained results allow to select the appropriate dose of anti-D Ig in the RhD prophylaxis of feto-maternal incompatibility, or to detect the cause of fetal anemia. Expression of antigens and their weak variants, and concentration of specific antibodies, can also be assessed. It is possible to observe changes in selected CD molecules during storage of RBC units. If RBCs for transfusion are unavailable, due to patient's unusual antibody specificity, some of the available RBCs are opsonised, and then phagocytosis with the recipient monocytes is assessed. The microscopic time-consuming and subjective assay is usually used. Stained CD14+ monocytes and CD235a+ erythrocytes are visible on cytograms as well as their interaction. It makes evaluation of phagocytosis easier and objective. Microparticles of RBCs released during storage are also detected. They are 235a+. In differentiation of hemolysis causes, it is important to measure osmotic fragility, and that can be also achieved using FC. Flow cytometry should be applied to immunohematological testing of red blood cells more often than now.

Maternal DRB1*1501, DQA1*0102, DQB1*0602 haplotype in fetomaternal alloimmunization against human platelet alloantigen HPA-6b (GPIIIa-Gln489).

Fetomaternal incompatibility of platelet alloantigens may lead to alloimmunization and neonatal alloimmune thrombocytopenia (NAIT). Human platelet alloantigen (HPA) 6b, which associates with residue Gln 489 of platelet membrane glycoprotein IIIa, has been described as a cause of NAIT. We have studied the MHC genes of all available family members in the six thus far reported families with a thrombocytopenic newborn and fetomaternal HPA-6b incompatibility. Maternal HPA-6b antibodies could be detected in five mothers to the altogether seven thrombocytopenic male infants. The MHC genes HLA-DRB, -DQA1, -DQB1, -DPB1, TAP1,2 and HSP70-Hom were studied by using polymerase chain reaction (PCR)-based DNA analysis methods. All five mothers with detectable circulating HPA-6b antibodies at the time of delivery shared an identical DRB1*1501, DQA1*0102, DQB1*0602 haplotype. The sixth, HPA antibody negative mother and a HPA-6b-negative mother to a healthy HPA-6b+ child were negative for this haplotype. The frequency of DRB1*15-positive haplotype was increased in immunized mothers (100%) as compared with the general Finnish population (27%), but the association was not statistically significant after correction. We conclude that there is a potential association between the MHC haplotype DRB1*1501, DQA1*0102, DQB1*0602 and alloimmunization to the HPA-6b antigen and that this alloimmunization probably involves different HLA class II molecules from immunization to HPA-1a.

The Le(a) antigen and neonatal hyperbilirubinemia in Taiwan.

Neonatal jaundice is known to be more severe in Taiwanese infants than in Caucasian infants. Although ABO fetomaternal incompatibility and glucose-6-phosphate dehydrogenase deficiency have been shown to play a role in the etiology of neonatal jaundice in some Taiwanese infants, the etiology in the majority of cases is unknown. In this study we found that in Taiwanese newborn infants, the red cell Le(a) antigen appeared later in infants who were jaundiced (peak serum bilirubin levels of > 12 mg/dl during the first week of life) than in infants who were not. However, the Leb antigen, and hence the transferase encoded by the Se and Se(w) genes, did not appear to be similarly involved in the etiology of physiological jaundice. Thus it would appear that the Le gene-specified transferase is less active or has a delayed function, in jaundiced infants. The relationship between the Le gene-specified transferase and bilirubin has yet to be established.

Antenatal screening for fetal alloimmune thrombocytopenia: the results of a pilot study

Feto-maternal incompatibility for the human platelet antigen HPA-1a is an important cause of severe fetal thrombocytopenia. The incidence is 1 in 1000-2000 pregnancies, which is more common than other conditions for which screening is presently carried out. Antenatal diagnosis and management are now available, but only for subsequent siblings following diagnosis of a previously affected infant. This study describes a pilot prospective screening programme for the antenatal detection of fetomaternal alloimmune thrombocytopenia (FMAIT) due to HPA-1a incompatibility. 3473 women were typed for HPA-1a using a method designed for large-scale typing. 71 women found to be HPA-1a negative were further tested for HLA-DR52a as a risk factor for alloimmunization. All women were monitored for the development of anti-HPA-1a throughout pregnancy and a cord full blood count was taken at delivery. Two affected pregnancies were found and treated: a singleton pregnancy was treated antenatally and a twin pregnancy after delivery. The study showed that screening for FMAIT could be established within the pre-existing antenatal red cell serology programme. It was concluded that screening should be based on platelet typing and offered regardless of parity. Further stratification, combining DR52a typing and HPA-1a antibody screening, although focusing on the group of women at greater risk, may not identify all affected pregnancies. Confirmation of the diagnosis and severity of FMAIT continues to depend on fetal blood sampling during pregnancy or cord blood samples after birth.

Neonatal allo-immune thrombocytopenia due to fetomaternal HPA-1 incompatibility of a homozygous HPA-1?a mother and a homozygous HPA-1?b father

Neonatal allo-immune thrombocytopenia due to fetomaternal HPA-1 incompatibility of a homozygous HPA-1?a mother and a homozygous HPA-1?b father

Aetiological pathways to spastic cerebral palsy.

An aetiological pathway is a sequence of interdependent events culminating in disease. Recognition of such pathways can be clinically useful if it suggests more effective methods of disease prevention. Kernicterus arising from feto-maternal Rhesus incompatibility and resulting in choreoathetosis comprises an aetiological pathway to cerebral palsy. The failure to recognise sufficient causes or to intervene effectively when a sufficient cause is suspected in the majority of cerebral palsy cases suggests that there may be other aetiological pathways. Evidence for other pathways was sought in the data from the Western Australian case-control study of 183 children with spastic cerebral palsy. Two or more factors likely to be of aetiological significance were recognised for nearly one-third of cases. As anticipated, the numbers with any specific combination of factors were small, pointing to the need for collaborative studies to obtain larger numbers to confirm their aetiological significance. The implications for the true proportion of cases with multifactorial aetiology and the problems inherent in such an investigation are discussed.

ABO and Rh(D) blood group distribution and their implication for feto-maternal incompatibility among the Palestinian population.

ABO and Rh(D) blood group distribution was evaluated among Palestinian women in the southern area of the West Bank and east Jerusalem. Eleven per cent of women were Rh(D) negative. The review of the last 12,169 deliveries at Makassed Hospital showed that 4.8% of Rh(D)-negative mothers gave birth to Rh(D)-positive infants with haemolytic disease of the newborn. Thirty per cent of A or B infants born to O Rh(D)-positive mothers had a positive direct antiglobulin test with the presence of allo-immune A or B antibody in infant serum. ABO incompatibility was a major reason for phototherapy during the 1st week of life. Results and possibilities for prevention are discussed.

AB0 segregation distortion in Visakhapatnam, India

Distortions in mother-infant, mother-child and father-child segregation for the ABO system as well as in the sex of offspring are described in a sample from a maternity service and from families of Visakhapatnam, India. Some distortions follow the expected fetomaternal incompatibility depression, others the expected feto-maternal induction of tolerance, and some remain unexplained. A differential action of selective factors on male and female fetuses, infants and children was also found, but no hypothesis could be postulated to explain it. The mother-infant matrix was found to be different from the mother-child matrix probably due to the inclusion of the reproductive time only in the mother-infant matrix. Unexpectedly, father-child segregation distortions were also found.

Posttransfusion Purpura Associated with an Anti‐Bakb

We describe a 46-year-old white woman with typical clinical features of posttransfusion purpura (PTP) whose serum held a platelet-specific alloantibody reactive with an antigen antithetical to Baka, i.e. anti-Bakb. The specificity of the antibody was confirmed by family analysis, a population study (expected versus observed gene frequency: 0.3651 versus 0.3984; n = 105) and localization of the antigen on glycoprotein IIb in radioimmunoprecipitation. Typing of family members and blood donors for platelet antigens disclosed that the patient had been preimmunized by two blood transfusions in 1981, while fetomaternal incompatibility for Bakb was ruled out (her three children and their father were Bakb negative). Treatment of PTP with corticosteroids and platelet transfusions was ineffective, but infusion of high-dose intravenous IgG resulted in a rapid increase in the platelet count.

Neonatal Alloimmune Thrombocytopenia due to Fetomaternal Zwb Incompatibility

A case of neonatal alloimmune thrombocytopenia due to fetomaternal incompatibility against the platelet-specific antigen Zw^b (P1^A2) is described. The antibody was of the IgG class and did not fix complement in vitro. Its specificity was established by panel identification and by comparison to a Zw^b antiserum. Gene dosage determinations of Zw^a antigens on platelets of parents and child revealed that the mother was homozygous Zw^a Zw^a, while father and child were heterozygous for this antigen.

Red cell antibodies detected in antenatal tests on rhesus positive women in South and Mid Wales, 1948-1978.

A total of 733 rhesus positive women with antibodies were found during antenatal screening of 380,790 pregnancies in South and Mid Wales, over a 30-year-period. A steady increase was observed in the frequency of antibodies, particularly non-rhesus antibodies and the mothers concerned had a significantly increased history of previous blood transfusion. In 50 per cent of those with non-rhesus antibodies, transfusion was the only stimulus. Conversely, for the majority (61 per cent) of women with rhesus antibodies feto-maternal incompatibility was the sole apparent stimulus. No identifiable stimulus could be found in 25 per cent of women with anti-E and 13 per cent of those with anti-Kell. Compared to rhesus negative mothers with anti-D severe clinical haemolytic disease of the newborn was uncommon, but in 75 per cent of rhesus positive mothers with infants carrying the homologous antigen, there was some evidence of haemolytic disease. Anti-c was much the worst in this respect with 19.4 per cent of infants needing transfusion. The probability of having an incompatible infant was much less for the mothers with non-rhesus antibodies (27.3 per cent) and of these infants only 5.7 per cent needed transfusion.

Feto-maternal histoincompatibility and placental blood flow.

1. We have designed experiments aimed at resolving some of the controversy concerning the effect of histoincompatibility on the development of the fetus and its placenta. 2. Experiments included the generation of pregnancies in which H-2 compatible and H-2 histoincompatible embryos were simultaneously present. Genetic markers (Brachyury and Kink) were used to facilitate determination of the H-2 haplotype. Additional strain combinations were used to analyse the role of non-H-2 differences. 3. In addition to determining fetal and placental weights, blood flow to the placenta was measured by use of radioisotope-labelled microspheres introduced into the arterial circulation. 4. Under the conditions of our experiments we have failed to detect differences in fetal weight, in placental weight, or in placental blood flow. 5. Thus we support the increasingly prevalent view that histo-incompatibility does not necessarily lead to changes in placental or fetal weight, and we add the additional finding that placental blood flow also is not significantly altered as a result of feto-maternal incompatibility.

Fréquence et importance des hémorragies fœto-maternelles par amniocentèse précoce

Amniocentesis is a technic to which it is now made more and more reference, even when feto-maternal incompatibility is not involved, for many various indications and at variable chronology along pregnancy. Our study concerns the risk developing Rh immunization among Rh negative women, undergoing amniocentesis early in pregnancy. 233 women had 243 amniocentesis between 16 and 21 weeks of pregnancy. Fetal cells in the maternal circulation were searched for using the Kleihauer's acid elution technic. In 154 cases, the Kleihauer's method was also used just before the amniocentesis, in order to run out a spontaneous foeto-maternal haemorrhage and to correlate the 25 (16,2%) transplacental haemorrhage reported to amniocentesis. When ever the result was positive, we observed a feto-maternal ratio varying from 1/20 000 to 100/20 000 but it is very difficult at this early period of fetal life to assure a precise volume of blood from this ratio. Placental localization preceeding amniocentesis does not seem minimizing the risk of bleeding. Althrough the occurence of a fetal bleeding seems to be more frequent in cases where blood can be demonstrated in the amniotic fluid (8/25 = 32%) than in cases it is not, the estimated volume of the foeto-maternal haemorrhage is not related to the presence or absence of blood in the amniotic cavity. In 3 cases the intra-amniotic blood was tested by the Kleihauer's method. In two instances there was a mixture of adult and fetal cells. In the 3rd case only fetal cells were present. In this last case, as in 17/25 bloody amniotic fluid (68%) no feto-maternal haemorrhage could be demonstrated. The risk of Rh immunization commands prophylaxis. In such Rh negative women, we inject intravenously a 85 mug dose of anti-D immunoglobulin, soon after performing amniocentesis, what ever the result of Kleihauer test is positive or negative.

Evidence of interaction between the polymorphism of placental alkaline phosphatase and those ofRh and Abo systems

Placental alkaline phosphatase presents electrophoretic polymorphism with 6 common phenotypes determined by 3 alleles (Pls1, Plf1 and Plf1) at an autosomal locus. The electrophoretic pheonotypes of alkaline phosphatase from 2000 consecutively delivered placentas of white and negro subjects were determined. The results were subdivided according to race and to the presence or absence of Rh and/or ABO feto-maternal incompatibility. In the group of ABO incompatible infants, a further subdivision was made according to the presence or absence of a positive direct Coombs test and/or jaundice. Within the compatible groups the frequency of allele Pls1 was significantly higher in “first born” than in “subsequently born” infants. The reverse was true in the incompatible groups. Among infants with ABO incompatibility, allele Pf1 was significantly more frequent in infants without evidence of isoimmunization than in those with a positive Coombs test and/or jaundice. These results suggests that placental alkaline phosphatase may play a role in the maintenance of the fertilized ovum in utero and that in this regard allele Pls1 may be more efficient than allele Plf1. These results also suggest the possibility of an interaction between the polymorphism of placental alkaline phosphatase and those of Rh and ABO systems whereby, in the presence of feto-maternal incompatibility, allel Plf1 seems to provide an advantage when compared to allele Pls1.

NB1, a new neutrophil-specific antigen involved in the pathogenesis of neonatal neutropenia.

A new human antigen is reported which is present only on blood neutrophils. A neutrophil-specific antigen, designated NA1, has previously been identified in two unrelated families, and was shown to be involved in fetomaternal incompatibility and the development of isoimmune neonatal neutropenia in five newborns. In the present paper, a second antigen, designated NB1, is identified in four families with seven affected children. Antibodies that react with this second antigen are shown to produce selective agglutination of neutrophils but not other blood cells. They are neither absorbed by cells prepared from solid tissues nor by non-neutrophilic blood cells. By family and population studies, NB is shown to be distinct from NA, representing an independent genetic locus. 68% of the New York population are homozygous for NB1, 29% heterozygous, and 3% negative. The NB locus is shown to be independent from those of HL-A and other known leukocyte antigens. No evidence for linkage between NA, NB, and red cell antigens was obtained.

Gm Factor Fetomaternal Gamma Globulin Incompatibility

Extract: Sera of 1763 normal pregnant women were screened for antibodies against Gm (a), Gm (b), and Gm (f) factors. Twenty-eight patients (1.59%) possessed specific Gm agglutinators. Incidence of fetal death, synthesis of the incompatible genetic gamma globulin factor, and levels of gamma globulin were determined. Four infants with Gm factor fetomaternal incompatibilities whose mothers possessed isoantibodies were studied over a period of from 8 to 24 months. Serial quantitative gamma globulin determinations from the affected infants produced results which compared favorably with seven control infants and normal values cited in the literature. There appeared to be no impairment of synthesis of the specific incompatible genetic gamma globulin, expressed as a titer of hemagglutination inhibition. The development of specific genetic gamma globulin factors throughout infancy is delineated. In the patients studied, no adverse effects resulted from fetomaternal gamma globulin incompatibility.Speculation: High titers of maternal Gm antibody of the gamma G fraction may traverse the placenta and result in suppression of synthesis of the corresponding gamma globulin of the infant. Low titers cannot reach the fetal circulation in sufficient quantities to produce suppression. Alternatively, despite high levels of maternal antibody, no biological effects may result.

Fetomaternal leukocyte incompatibility

Fetomaternal leukocyte incompatibility