ABSTRACT
BACKGROUND: Maternal alloantibodies to human platelet antigen-1a can cause severe intracranial hemorrhage in a fetus or newborn. Although never evaluated in placebo-controlled clinical trials, most Western countries use off-label weekly administration of high-dosage intravenous immunoglobulin in all pregnant women with an obstetrical history of fetal and neonatal alloimmune thrombocytopenia. In Norway, antenatal intravenous immunoglobulin is only recommended in pregnancies wherein a previous child had intracranial hemorrhage (high-risk) and is generally not given in other human platelet antigen-1a alloimmunized pregnancies (low-risk). OBJECTIVE: To compare the frequency of anti-human platelet antigen-1a-induced intracranial hemorrhage in pregnancies at risk treated with intravenous immunoglobulin vs pregnancies not receiving this treatment as a part of a different management program. STUDY DESIGN: This was a retrospective comparative study where the neonatal outcomes of 71 untreated human platelet antigen-1a-alloimmunized pregnancies in Norway during a 20-year period was compared with 403 intravenous-immunoglobulin-treated pregnancies identified through a recent systematic review. We stratified analyses on the basis of whether the mothers belonged to high- or low-risk pregnancies. Therefore, only women who previously had a child with fetal and neonatal alloimmune thrombocytopenia were included. RESULTS: Two neonates with brain bleeds were identified from 313 treated low-risk pregnancies (0.6%; 95% confidence interval, 0.2-2.3). There were no neonates born with intracranial hemorrhage of 64 nontreated, low-risk mothers (0.0%; 95% confidence interval, 0.0-5.7). Thus, no significant difference was observed in the neonatal outcome between immunoglobulin-treated and untreated low-risk pregnancies. Among high-risk mothers, 5 of 90 neonates from treated pregnancies were diagnosed with intracranial hemorrhage (5.6%; 95% confidence interval, 2.4-12.4) compared with 2 of 7 neonates from nontreated pregnancies (29%; 95% confidence interval, 8.2-64.1; P=.08). CONCLUSION: The most reliable data hitherto for the evaluation of intravenous immunoglobulins treatment in low-risk pregnancies is shown herein. We did not find evidence that omitting antenatal intravenous immunoglobulin treatment in low-risk pregnancies increases the risk of neonatal intracranial hemorrhage.
Subject(s)
Fetal Diseases , Thrombocytopenia, Neonatal Alloimmune , Female , Fetal Diseases/chemically induced , Fetal Diseases/diagnosis , Fetus , Hemorrhage , Humans , Immunoglobulins, Intravenous/therapeutic use , Infant, Newborn , Intracranial Hemorrhages/chemically induced , Intracranial Hemorrhages/epidemiology , Pregnancy , Retrospective Studies , Thrombocytopenia, Neonatal Alloimmune/diagnosisABSTRACT
Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening bleeding disorder caused by maternal antibodies directed against paternally inherited antigens present on the surface of fetal platelets. The human platelet alloantigen HPA-1a (formerly known as the PlA1 alloantigen), is the most frequently implicated HPA for causing FNAIT in Whites. A single Leu33Pro amino acid polymorphism residing within the â¼50-amino-acid plexin-semaphorin-integrin domain near the N-terminus of the integrin ß3 subunit (platelet membrane glycoprotein IIIa [GPIIIa]) is responsible for generating the HPA-1a and HPA-1b epitopes in human GPIIIa and serves as the central target for alloantibody-mediated platelet destruction. To simulate the etiology of human FNAIT, wild-type female mice were pre-immunized with platelets derived from transgenic mice engineered to express the human HPA-1a epitope on a murine GPIIIa backbone. These mice developed a strong alloimmune response specific for HPA-1a, and when bred with HPA-1a+ males, gave birth to severely thrombocytopenic pups that exhibited an accompanying bleeding phenotype. Administering either polyclonal intravenous immunoglobulin G or a human monoclonal blocking antibody specific for the HPA-1a epitope into pregnant female mice resulted in significant elevation of the neonatal platelet count, normalized hemostasis, and prevented bleeding. The establishment of an alloantigen-specific murine model that recapitulates many of the clinically important features of FNAIT should pave the way for the preclinical development and testing of novel therapeutic and prophylactic modalities to treat or prevent FNAIT in humans.
Subject(s)
Antigens, Human Platelet , Thrombocytopenia, Neonatal Alloimmune , Animals , Antigens, Human Platelet/genetics , Female , Fetus , Immunotherapy , Isoantibodies , Male , Mice , Pregnancy , Thrombocytopenia, Neonatal Alloimmune/genetics , Thrombocytopenia, Neonatal Alloimmune/therapyABSTRACT
We report findings in five patients who presented with venous thrombosis and thrombocytopenia 7 to 10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against coronavirus disease 2019 (Covid-19). The patients were health care workers who were 32 to 54 years of age. All the patients had high levels of antibodies to platelet factor 4-polyanion complexes; however, they had had no previous exposure to heparin. Because the five cases occurred in a population of more than 130,000 vaccinated persons, we propose that they represent a rare vaccine-related variant of spontaneous heparin-induced thrombocytopenia that we refer to as vaccine-induced immune thrombotic thrombocytopenia.