Severe thrombocytopenia and intracranial hemorrhage in a newborn with Noonan syndrome and neonatal alloimmune thrombocytopenia

Abstract The study's objective was to identify HPA 1a–negative women and to offer them an intervention program aimed to reduce morbidity and mortality of neonatal alloimmune thrombocytopenia (NAIT). HPA 1 typing was performed in 100 448 pregnant women. The HPA 1a–negative women were screened for anti–HPA 1a. In immunized women, delivery was performed by Cesarean section 2 to 4 weeks prior to term, with platelets from HPA 1a–negative donors reserved for immediate transfusion if petechiae were present and/or if platelet count was less than 35 × 109/L. Of the women screened, 2.1% were HPA 1a negative, and anti–HPA 1a was detected in 10.6% of these. One hundred seventy pregnancies were managed according to the intervention program, resulting in 161 HPA 1a–positive children. Of these, 55 had severe thrombocytopenia (< 50 × 109/L), including 2 with intracranial hemorrhage (ICH). One woman with a twin pregnancy missed the follow-up and had one stillborn and one severely thrombocytopenic live child. In 15 previous prospective studies (136 814 women) there were 51 cases of severe NAIT (3 intrauterine deaths and 7 with ICH). Acknowledging the limitation of comparing with historic controls, implementation of our screening and intervention program seemed to reduce the number of cases of severe NAIT-related complications from 10 of 51 to 3 of 57.

Download Full-text

Maternal Anti-HPA-1a Antibodies Increase Endothelial Cell Apoptosis and Permeability

Journal of Vascular Research ◽

10.1159/000515703 ◽

2021 ◽

pp. 1-9

Author(s):

Rima Dardik ◽

Ophira Salomon

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Intracranial Hemorrhage ◽

Cell Apoptosis ◽

Endothelial Damage ◽

Αvβ3 Integrin ◽

Endothelial Cell Apoptosis ◽

Vascular Beds ◽

Alloimmune Thrombocytopenia

Intracranial hemorrhage (ICH) associated with fetal/neonatal alloimmune thrombocytopenia (FNAIT) is attributed mainly to endothelial damage caused by binding of maternal anti-HPA-1a antibodies to the αvβ3 integrin on endothelial cells (ECs). We examined the effect of anti-HPA-1a antibodies on EC function using 2 EC lines from different vascular beds, HMVEC of dermal origin and hCMEC/D3 of cerebral origin. Anti-HPA-1a sera significantly increased apoptosis in both HMVEC and hCMEC/D3 cells and permeability in hCMEC/D3 cells only. This increase in both apoptosis and permeability was significantly inhibited by a monoclonal anti-β3 antibody (SZ21) binding to the HPA-1a epitope. Our results indicate that (1) maternal anti-HPA-1a antibodies impair EC function by increasing apoptosis and permeability and (2) ECs from different vascular beds vary in their susceptibility to pathological effects elicited by maternal anti-HPA-1a antibodies on EC permeability. Examination of maternal anti-HPA-1a antibodies for their effect on EC permeability may predict potential ICH associated with FNAIT.

Download Full-text

Successful management of neonatal alloimmune thrombocytopenia in the second pregnancy: a case report

Einstein (São Paulo) ◽

10.1590/s1679-45082014rc2729 ◽

2014 ◽

Vol 12 (1) ◽

pp. 96-99 ◽

Cited By ~ 1

Author(s):

Fabiana Mendes Conti ◽

Sergio Hibner ◽

Thiago Henrique Costa ◽

Marcia Regina Dezan ◽

Maria Giselda Aravechia ◽

...

Keyword(s):

Significant Risk ◽

Clinical Importance ◽

Neurological Impairment ◽

Severe Thrombocytopenia ◽

Successful Management ◽

First Child ◽

Neonatal Thrombocytopenia ◽

Serious Disease ◽

Alloimmune Thrombocytopenia ◽

Severe Neurological Impairment

Neonatal alloimmune thrombocytopenia is a serious disease, in which the mother produces antibodies against fetal platelet antigens inherited from the father; it is still an underdiagnosed disease. This disease is considered the platelet counterpart of the RhD hemolytic disease of the fetus and newborn, yet in neonatal alloimmune thrombocytopenia the first child is affected with fetal and/or neonatal thrombocytopenia. There is a significant risk of intracranial hemorrhage and severe neurological impairment, with a tendency for earlier and more severe thrombocytopenia in subsequent pregnancies. This article reports a case of neonatal alloimmune thrombocytopenia in the second pregnancy affected and discusses diagnosis, management and the clinical importance of this disease.

Download Full-text

Prolonged thrombocytopenia in a neonate with Noonan syndrome: a case report

Journal of International Medical Research ◽

10.1177/0300060520936445 ◽

2020 ◽

Vol 48 (8) ◽

pp. 030006052093644

Author(s):

Meng Li ◽

Jinghui Zhang ◽

Nianzheng Sun

Keyword(s):

Platelet Count ◽

Case Report ◽

Noonan Syndrome ◽

Immune Thrombocytopenia ◽

Perinatal Asphyxia ◽

Juvenile Myelomonocytic Leukemia ◽

Normal Range ◽

Ptpn11 Gene ◽

Alloimmune Thrombocytopenia ◽

Myelomonocytic Leukemia

We report a case of a Chinese neonate who was diagnosed with Noonan syndrome and had persistent, self-limited thrombocytopenia. The neonate was admitted to the Neonatology Department 20 minutes after birth because of respiratory distress. From birth until 2 months of age, platelet values fluctuated between approximately 6 and 30 × 109/L. There was no intracranial hemorrhage. However, the child had a transient hypocalcemic seizure and fever. We excluded thrombocytopenia caused by perinatal asphyxia, immune thrombocytopenia, fetomaternal alloimmune thrombocytopenia, juvenile myelomonocytic leukemia, and chromosome 13, 18, and 21 trisomy syndromes. Despite treatment with anti-infective agents and transfusion of platelets and immunoglobulin, the platelet count did not return to the normal range. Genetic testing confirmed a PTPN11 gene mutation, which led to the diagnosis of Noonan syndrome. At 3 months of age, the platelet count gradually increased without intervention and returned to the normal range by 6 months. We speculate that the thrombocytopenia in this case was closely related to Noonan syndrome.

Download Full-text

Massive intracranial hemorrhage caused by neonatal alloimmune thrombocytopenia associated with anti-group A antibody

Journal of Perinatology ◽

10.1038/jp.2011.204 ◽

2012 ◽

Vol 33 (1) ◽

pp. 79-82 ◽

Cited By ~ 12

Author(s):

S Kato ◽

T Sugiura ◽

H Ueda ◽

K Ito ◽

H Kakita ◽

...

Keyword(s):

Intracranial Hemorrhage ◽

Group A ◽

Alloimmune Thrombocytopenia

Download Full-text

The Development of Severe Neonatal Alloimmune Thrombocytopenia due to Anti-HPA-1a Antibodies Is Correlated to MaternalABOGenotypes

Clinical and Developmental Immunology ◽

10.1155/2012/156867 ◽

2012 ◽

Vol 2012 ◽

pp. 1-5 ◽

Cited By ~ 11

Author(s):

Maria Therese Ahlen ◽

Anne Husebekk ◽

Mette Kjær Killie ◽

Jens Kjeldsen-Kragh ◽

Martin L. Olsson ◽

...

Keyword(s):

Relative Risk ◽

Pregnant Women ◽

Blood Group ◽

Lower Risk ◽

Abo Blood Group ◽

Severe Thrombocytopenia ◽

Blood Group A ◽

Group A ◽

Alloimmune Thrombocytopenia ◽

Design And Methods

Background. Maternal alloantibodies against HPA-1a can cross placenta, opsonize foetal platelets, and induce neonatal alloimmune thrombocytopenia (NAIT). In a study of 100, 448 pregnant women in Norway during 1995–2004, 10.6% of HPA-1a negative women had detectable anti-HPA-1a antibodies.Design and Methods. A possible correlation between the maternal ABO blood group phenotype, or underlying genotype, and severe thrombocytopenia in the newborn was investigated.Results. We observed that immunized women with blood group O had a lower risk of having a child with severe NAIT than women with group A; 20% with blood group O gave birth to children with severe NAIT, compared to 47% among the blood group A mothers (relative risk 0.43; 95% CI 0.25–0.75).Conclusion. The risk of severe neonatal alloimmune thrombocytopenia due to anti-HPA-1a antibodies is correlated to maternalABOtypes, and this study indicates that the observation is due to genetic properties on the maternal side.

Download Full-text

A Screening and Intervention Program Reducing Mortality and Serious Morbidity Associated with Neonatal Alloimmune Thrombocytopenia.

Blood ◽

10.1182/blood.v106.11.1232.1232 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1232-1232

Author(s):

Jens Kjeldsen-Kragh ◽

Mette K. Killie ◽

Geir Tomter ◽

Elzbieta Golebiowska ◽

Helene Pedersen ◽

...

Keyword(s):

Platelet Count ◽

Intervention Program ◽

Human Platelet ◽

Fetal Brain ◽

University Hospital ◽

Severe Thrombocytopenia ◽

Platelet Antigen ◽

Human Platelet Antigen ◽

Alloimmune Thrombocytopenia

Abstract Background: Neonatal alloimmune thrombocytopenia (NAIT) is most frequently caused by antibodies against the human platelet antigen (HPA) 1a. The objective of the present study was to identify HPA 1a negative women, and to offer them an intervention program aimed to reduce morbidity and mortality of NAIT. Methods: A total of 100,448 pregnant women were HPA 1 typed. The HPA 1a negative women were screened for anti-HPA 1a, which was quantified when present. Immunized women were referred to a university hospital for clinical follow-up, including ultrasonographic examination of the fetal brain. Caesarean section was performed 2–4 weeks prior to term with platelets from HPA 1bb donors reserved for immediate transfusion if petechiae were present and/or if platelet count was < 35 × 109/L. Results: Of all women typed 2.1% were HPA 1a negative. Anti-HPA 1a was detected in 210 of 1,990 HPA 1a negative women. A total of 170 pregnancies in 154 HPA 1a negative women were managed according to the intervention program. These women gave birth to 161 HPA 1a positive children of whom 55 had severe thrombocytopenia (<50 × 109/L) including two with ICH. There were no intrauterine deaths. In 13 previously published prospective studies comprising 131,465 women of whom 2,290 were HPA 1a negative, there were 10 cases with severe NAIT-related complications (3 intrauterine deaths and 7 neonates with ICH), which are significantly higher than in our study (p < 0.05). Conclusions: The screening and intervention program seems to reduce mortality and serious morbidity associated with NAIT.

Download Full-text

Isolation and Characterization of CD4+ T Cells Specific for the HPA 1a Epitope Associated with Neonatal Alloimmune Thrombocytopenia.

Blood ◽

10.1182/blood.v110.11.2091.2091 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2091-2091

Author(s):

Maria T. Ahlen ◽

Mette K. Killie ◽

Bjorn Skogen ◽

Anne Husebekk ◽

Tor B. Stuge

Keyword(s):

Flow Cytometry ◽

T Cells ◽

T Cell ◽

Cell Lines ◽

Cell Detection ◽

Severe Thrombocytopenia ◽

Isolation And Characterization ◽

T Cell Lines ◽

Alloimmune Thrombocytopenia

Abstract Neonatal alloimmune thrombocytopenia (NAIT) can cause severe complications such as intrauterine death or intracranial hemorrhage (ICH) in the newborn, and is caused by the transfer of platelet-depleting antibodies from the mother to the fetus during pregnancy. These antibodies react with allogeneic epitopes, most commonly human platelet antigen (HPA) 1a, when present on fetal platelets. Although these responses are thought to be a result of a T cell-dependent immune response, HPA 1a specific T cells have not yet been isolated. To examine whether HPA 1a specific T cells could be detected and isolated, we collected PBMC post delivery from an HPA 1a negative mother who gave birth to an HPA 1a positive neonate suffering from severe thrombocytopenia (platelet count <50×109/L). The cells were stimulated with HPA 1a peptides (20aa) in long term cultures supplemented with IL-7 and IL-2, and subsequently, IL-15. After 4 weeks in culture these cells were labeled with CFSE dye and restimulated with HPA 1a or control peptides. After additional 2 weeks in culture supplemented with IL-2 and IL-15, specific proliferative responses were detectable by CFSE dye dilution by flow cytometry. The cells were cloned by fluorescent-activated cell sorting (FACS) and expanded in numbers with anti-CD3 stimulation in the presence of irradiated allogeneic PBMC and IL-2. The resulting clonal T cell lines were characterized in proliferation assays, ELISPOT assays and phenotyped by flow cytometry. All clones were CD3+, CD4+ and CD19−, and the majority of the clones proliferated and secreted cytokines in response to stimulation with HPA 1a peptides, but not control peptides. In ELISPOT assays, peptide-pulsed antigen-presenting cells were required for T cell detection. These clonal HPA 1a specific CD4+ T cell lines represent formal evidence of the existence of HPA 1a specific T cell responses related to NAIT and will serve as important tools for further characterization of maternal immune responses associated with NAIT.

Download Full-text

Intracranial Hemorrhage and Autoimmune Thrombocytopenia in a Neonate

Child Neurology Open ◽

10.1177/2329048x18768693 ◽

2018 ◽

Vol 5 ◽

pp. 2329048X1876869 ◽

Cited By ~ 1

Author(s):

Andrea Becocci ◽

Cristina Felice-Civitillo ◽

Méryle Laurent ◽

Françoise Boehlen ◽

Roberta De Luca ◽

...

Keyword(s):

Platelet Count ◽

Intracranial Hemorrhage ◽

Rare Complication ◽

Preventive Treatment ◽

Perinatal Period ◽

Severe Thrombocytopenia ◽

Cranial Ultrasound ◽

Autoimmune Thrombocytopenia ◽

Neonatal Thrombocytopenia ◽

Maternal Predictors

Neonatal thrombocytopenia is a rare complication of maternal autoimmune thrombocytopenia, and no maternal predictors of its gravity and potential complications have been identified. Neonatal cerebral hemorrhage, a feared event in the setting of autoimmune thrombocytopenia, is fortunately uncommon, but it can occur in utero or in the perinatal period, with potentially serious consequences. The authors report the case of a boy born to a mother affected by autoimmune thrombocytopenia, who presented with severe thrombocytopenia at birth and developed intracranial hemorrhage despite mild maternal thrombocytopenia at delivery and a prompt preventive treatment of the newborn. Platelet count should be tested at birth in all babies born from mothers with autoimmune thrombocytopenia, irrespective of maternal platelets counts during pregnancy or at delivery, and should be closely monitored during the first days of life. Systematic early and serial cranial ultrasound might be advocated in the setting of neonatal thrombocytopenia.

Download Full-text