Maternal intravenous immunoglobulin treatment does not prevent intracranial haemorrhage in fetal alloimmune thrombocytopenia

SUMMARY. In fetal alloimmune thrombocytopenia (FAIT) the fetus is threatened by intracranial haemorrhage (ICH); therefore early diagnostic and therapeutic intervention is required. We followed the clinical course of a 30-year-old woman during her fifth pregnancy after she had given birth to a child with alloimmune thrombocytopenia due to anti-Zw^a. The fetus was monitored by 13 fetal blood samplings (FBS) always followed by transfusion of either maternal or compatible donor platelets. Intravenous immunoglobulin (ivIg) treatment of the mother was begun at 20 weeks of gestation when the fetal platelet count was 36 times 10⁹/1. The fetal platelets were typed Zw^a positive by DNA analysis. Despite 11 weeks of maternal ivIg treatment fetal platelet counts progressively declined to 6 times 10/1 and ICH occurred. Subsequently, the fetus was successfully managed by intrauterine platelet transfusions at shorter intervals (3–5 days) and elective Cesarean section was carried out at 35 weeks of gestation. We conclude that maternal ivIg treatment does not prevent ICH in FAIT. The treatment of choice for severely affected cases is serial FBS combined with transfusion of compatible platelets.     

Epidemiology and management of fetal and neonatal alloimmune thrombocytopenia

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a disease in pregnancy characterized by maternal alloantibodies directed against the human platelet antigen (HPA). These antibodies can cause intracranial hemorrhage (ICH) or other major bleeding resulting in lifelong handicaps or death. Optimal fetal care can be provided by timely identification of pregnancies at risk. However, this can only be done by routinely antenatal screening. Whether nationwide screening is cost-effective is still being debated. HPA-1a alloantibodies are estimated to be found in 1 in 400 pregnancies resulting in severe burden and fetal ICH in 1 in 10.000 pregnancies. Antenatal treatment is focused on the prevention of fetal ICH and consists of weekly maternal IVIg administration. In high-risk FNAIT treatment should be initiated at 12–18 weeks gestational age using high dosage and in standard-risk FNAIT at 20–28 weeks gestational age using a lower dosage. Postnatal prophylactic platelet transfusions are often given in case of severe thrombocytopenia to prevent bleedings. The optimal threshold and product for postnatal transfusion is not known and international consensus is lacking. In this review practical guidelines for antenatal and postnatal management are offered to clinicians that face the challenge of reducing the risk of bleeding in fetuses and infants affected by FNAIT.     

Strategies to develop a prophylaxis for the prevention of HPA-1a immunization and fetal and neonatal alloimmune thrombocytopenia

Anti-HPA-1a-antibodies are the main cause of fetal and neonatal alloimmune thrombocytopenia (FNAIT) which may result in intracranial hemorrhage (ICH) and death among fetuses and newborns. Advances in understanding the pathogenesis of FNAIT and proof of concept for prophylaxis to prevent immunization suggest that development of hyperimmune anti-HPA-1a IgG aimed at preventing immunization against HPA-1a and FNAIT is feasible. Anti-HPA-1a IgG can be obtained either by isolating immunoglobulin from already-immunized women or by development of monoclonal anti-HPA-1a antibodies.Here we discuss recent advances that may lead to the development of a prenatal and postnatal prophylactic treatment for the prevention of HPA-1a-associated FNAIT and life-threatening FNAIT-induced complications.     

Prospective epidemiologic study of the outcome and cost-effectiveness of antenatal screening to detect neonatal alloimmune thrombocytopenia due to anti-HPA-1a

BACKGROUND: To assess the value of antenatal screening to detect neonatal alloimmune thrombocytopenia (NAIT) due to anti-HPA-1a, a prospective study was carried out to quantify the potential clinical benefits and determine whether screening would be cost-effective. STUDY DESIGN AND METHODS: An observational prospective controlled study was carried out on 26,506 pregnant women over 2 years. HPA-1a phenotyping was performed in the first trimester and women confirmed HPA-1a-negative were tested for anti-HPA-1a during pregnancy, at delivery, and 10 to 14 days after birth. Babies of HPA-1a-negative women were tested at delivery for thrombocytopenia and examined for signs of bleeding. Economic evaluation was undertaken on the basis of the data collected during the study. RESULTS: Twenty-five of 318 women (7.9%) had anti-HPA-1a detected for the first time. Eight women (43 per 100,000) gave birth to babies with NAIT, and 5 (27 per 100,000) had severe thrombocytopenia. Three babies had mild signs of bleeding, and no cases of intracranial hemorrhage (ICH) or fetal loss were detected. It is estimated that it would cost 60,596 pounds (98,771 US dollars) to detect a case of severe NAIT, where anti-HPA-1a has been identified for the first time, and 1,151,323 pounds (1,876,656 US dollars) to prevent a case of ICH, assuming that detection allowed successful intervention. CONCLUSIONS: Our data suggest that severe HPA-1a NAIT is underdiagnosed in the absence of routine antenatal screening. Serious bleeding complications and ICH, however, occur less frequently in first cases of NAIT than suspected from the literature, and the costs of screening and possible intervention must be balanced against the procedural risks.     

A systematic review and survey of the management of unexpected neonatal alloimmune thrombocytopenia

BACKGROUND: Unexpected neonatal alloimmune thrombocytopenia (NAIT) may have devastating consequences and its management is challenging. To design future trials, evidence from the literature and existing best practice need review. STUDY DESIGN AND METHODS: This study was a cross-sectional survey of neonatal units in Germany and Canada to determine management strategies of NAIT and a systematic search for randomized controlled trials (RCTs). RESULTS: Management of NAIT differs substantially between countries with regard to platelet (PLT) thresholds for screening, initiation of therapy, and treatment. Seventy-seven percent of Canadian physicians versus 68 percent of German physicians screen preterm and term infants, at a PLT threshold of 30 x 10(9) to 100 x 10(9) per L. In preterm infants, 60 percent of Canadian neonatologists commence treatment at a PLT count of between 30 x 10(9) and 50 x 10(9) per L. In Germany 32 percent of the physicians start treatment at this level and 25 percent use a threshold of between 10 x 10(9) and 20 x 10(9) per L. In term infants, 6 percent of the Canadian physicians and 16 percent of the German physicians use even lower treatment triggers of between 5 x 10(9) and 10 x 10(9) per L. In the presence of bleeding, 61 percent of German physicians await the arrival of antigen-negative PLTs, while 64 percent of Canadian neonatologists prefer intravenous immunoglobulin or random-donor PLTs (81%). Maternal PLTs are utilized by 31 percent of physicians in both countries. No RCTs were identified. CONCLUSION: In the absence of RCTs, management of unexpected NAIT differs between countries. Clinicians and transfusion services may use the results of our study to develop collaborative protocols, redefine preferred hospitalwide strategies, and design future controlled trials.     

Implication of antibodies against human leukocyte antigen in simultaneous presentation of fetal and neonatal alloimmune thrombocytopenia and neutropenia

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) and neonatal alloimmune neutropenia (NAN) are two rare complications of newborns caused by antibodies against paternal inherited antigens. Human platelet (HPA) and neutrophil antigens (HNA) are the common targets. Human leukocyte antigen (HLA) class I proteins are also expressed on platelets and neutrophils and anti-HLA antibodies have occasionally been implicated in these complications. We report a premature twin infant who presented with severe thrombocytopenia and neutropenia clinically compatible with FNAIT and NAN, from a mother with no identifiable HPA or HNA antibodies, but with very high levels of complement-fixing antibodies against paternal inherited HLA. These antibodies were also detected in the infant. HLA antibodies are commonly present in multiparous women who deliver healthy infants. They can, however, be cytotoxic and cause clinical complications after blood products transfusion (TRALI and becoming refractory to platelets transfusion) and after organ transplantation (allogeneic organ rejection).     

Plasma exchange and intravenous immunoglobulin treatment of the mother to diminish fetal rhesus hemolytic disease

Three pregnant women with a previous history of and laboratory findings consistent with severe rhesus immunization were treated with high-dose intravenous immunoglobulin (IVIG) after a mean reduction of the antibody concentration of 64% by plasma exchange. Two of the cases were successful as judged by the clinical condition of the newborns, the slow increase in serum anti-D concentrations, and the decrease in amniotic fluid bilirubin levels after the combined treatment. The effect was less pronounced in the third case treated with a different preparation of IVIG. The maternal antibody production rate seems to be decreased by IVIG treatment and the placental transfer of IgG antibodies may also be affected. However, as anti-D antibodies were found at a high concentration in the blood of the newborns, we suggest that a major effect of the treatment is decreased fetal hemolysis, which may be caused by blockade of the fetal reticuloendothelial system.     

A new platelet alloantigen, Swi(a) , located on glycoprotein Ia identified in a family with fetal and neonatal alloimmune thrombocytopenia

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a bleeding disorder caused by transplacental passage of maternal antibodies to fetuses whose platelets (PLTs) express the corresponding human PLT antigen (HPA). STUDY DESIGNS AND METHODS: We observed a fetus with FNAIT who died from a severe intracranial hemorrhage. Analysis of maternal serum in antigen capture assay with paternal PLTs showed reactivity with PLT glycoprotein (GP)IIb/IIIa (α_IIbβ₃) and GPIa/IIa (α₂β₁ integrin), indicating the presence of anti‐HPA‐1a and an additional alloantibody against GPIa (termed anti‐Swi^a). RESULTS: By immunochemical studies, the localization of the Swi^a antigen on GPIa/IIa could be confirmed. Analysis of paternal GPIa full‐length cDNA showed a single‐nucleotide substitution C₃₃₄₇T in Exon 28 resulting in a Thr₁₀₈₇Met amino acid substitution. Testing of family members by polymerase chain reaction‐restriction fragment length polymorphism using MslI endonuclease showed perfect correlation with phenotyping. Extended family and population studies showed that 4 of 10 members of the paternal family but none of 500 unrelated blood donors were Swi^a carriers. Expression studies on allele‐specific transfected Chinese hamster ovary (CHO) cells confirmed that the single‐amino‐acid substitution Thr₁₀₈₇Met was responsible for the formation of the Swi^a epitope. Adhesion of CHO cells expressing the Swi^a alloantigen to immobilized collagens was not impaired compared to the wild‐type control and was not inhibited by anti‐Swi^a alloantibodies. CONCLUSION: In this study we defined a new PLT alloantigen Swi^a that was involved in a case of additional immunization against HPA‐1a. Our observations demonstrate that combinations of PLT‐specific alloantibodies may comprise low‐frequency alloantigens.     

抗HPA-3a抗体所致新生儿同种免疫性血小板减少性紫癜一例并文献复习

目的 探讨抗血小板特异性抗原(HPA)-3a抗体所致新生儿同种免疫性血小板减少性紫癜(NAITP)的诊断和治疗.方法 采用多重PCR及基因测序技术检测1例出血伴血小板减少新生儿及其父母HPA-1~21bw系统基因型,采用流式细胞术(FCM)和血小板抗原单克隆抗体特异性免疫固定检测技术(MAIPA)检测患儿及其母亲血清血小板特异性抗体并进行特异性鉴定.结果 患儿出生后2 h出现全身多发皮下出血点、血尿及咖啡色呕吐物.基因分型显示患儿为HPA-3ab、母亲为HPA-3bb、父亲为HPA-3aa;患儿及母亲血清中均含与患儿父亲血小板反应的特异性抗体,经MAIPA技术鉴定为抗HPA-3a抗体.结论 发现1例抗HPA-3a抗体所致NAITP患者,通过临床特征分析为该病的诊断和治疗提供借鉴与参考.     

Toward a prophylaxis against fetal and neonatal alloimmune thrombocytopenia: induction of antibody-mediated immune suppression and prevention of severe clinical complications in a murine model

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a severe bleeding disorder caused by maternal antibody–mediated destruction of fetal or neonatal platelets (PLTs). Results from our recent large screening study suggest that the pathophysiology of FNAIT is more similar to hemolytic disease of the fetus and newborn (HDFN) than previously thought. Immunization against HPA‐1a might therefore be preventable by a prophylactic regimen of inducing antibody‐mediated immune suppression (AMIS), which has been documented to be a useful prophylaxis against HDFN. This preclinical proof‐of‐concept study investigated whether passive administration of anti‐β3 integrin could induce AMIS and thereby prevent clinical complications of FNAIT. STUDY DESIGN AND METHODS: A murine model of FNAIT using β3 integrin (GPIIIa)‐deficient (β3?/?) mice was employed for this study. AMIS in β3?/? mice was induced by intravenous administration of human anti‐HPA‐1a immunoglobulin G or murine anti‐β3 antisera given as prophylaxis after transfusion of HPA‐1a–positive human PLTs or murine wild‐type PLTs, respectively. RESULTS: AMIS against both human and murine PLT antigens was induced using this prophylactic approach, reducing the amount of maternal PLT antibodies by up to 90%. Neonatal PLT counts were significantly increased and pregnancy outcome was improved in a dose‐dependent manner. The incidence of intracranial hemorrhage, miscarriage, and dead‐born pups in mice receiving high‐dose prophylaxis was reduced to that of normal controls. We also observed that the severity of thrombocytopenia inversely correlated with birth weight. CONCLUSION: This work conceptually proves that prophylactic administration of PLT antibodies induces AMIS and prevents poor pregnancy outcome in FNAIT.     

Pathophysiology and treatment of fetal anemia due to placental chorioangioma.

Placental chorioangiomas occur in 1% of pregnancies. Large chorioangiomas may cause serious complications such as fetal anemia, hydrops and fetal death. In this case report, a pregnancy complicated by a large placental chorioangioma is described. Severe fetal anemia without the occurrence of hydrops fetalis was suspected using ultrasound and Doppler examinations. Successful intrauterine blood transfusion was performed, with an unusually large amount of blood needed to obtain an adequate rise in fetal hematocrit. Two weeks later, at 32 weeks, the infant was born in good condition. In pregnancies with large chorioangiomas, we advise regular ultrasound and Doppler examinations, with the aim of detecting fetal anemia before hydrops develops. When anemia is suspected, fetal blood sampling is indicated and intrauterine transfusion therapy may be beneficial to preserve fetal health until maturity is reached.