© Borgis - Postępy Nauk Medycznych 6/2016, s. 397-403
Joanna Wójtowicz1, 2, *Teresa Jackowska1, 2, Ewa Wagiel2, Agnieszka Obitko-Płudowska3
Alloimmune thrombocytopenia associated with neutropenia in a 8-week old boy – a case report**
Alloimmunologiczna małopłytkowość z towarzyszącą neutropenią u 8-tygodniowego chłopca – opis przypadku
1Department of Pediatrics, Centre of Postgraduate Medical Education, Warsaw
Head of Department: prof. Teresa Jackowska, MD, PhD
2Department of Pediatrics, Father Jerzy Popiełuszko "Bielański" Hospital, Independent Public Health Care Institution in Warsaw
Head of Department: prof. Teresa Jackowska, MD, PhD
3Ambulatory Hematological Care for Children, Father Jerzy Popiełuszko “Bielański” Hospital, Independent Public Health Care Institution in Warsaw
Head of Ambulatory: Włodzimierz Borowski, MD
Najczęstszą przyczyną małopłytkowości u niemowląt w pierwszych miesiącach życia są infekcje, rzadziej niszczenie płytek w przebiegu reakcji immunologicznych. W przypadku reakcji alloimmunologicznych objawy mogą pojawić się już u płodu bądź wkrótce po urodzeniu i są spowodowane przechodzącymi przez łożysko przeciwciałami matczynymi. Przeciwciała te najczęściej są skierowane przeciwko antygenom płytkowym (ang. anti-human platelet antigens – anty-HPA) dziecka, odziedziczonym po ojcu. Znacznie rzadziej przyczyną małopłytkowości są przeciwciała przeciwleukocytane (ang. anti-human leukocyte antigens – anty-HLA). Można je wykryć w surowicy krwi u 7-39% ciężarnych, ale rzadko wywołują noworodkowe alloimmunologiczne cytopenie. W literaturze opisano przypadki małopłytkowości u noworodków, u matek których wykryto w surowicy jedynie przeciwciała anty-HLA, bez obecności anty-HPA. Jednakże sporadyczne są doniesienia o równoczesnej trombocytopenii i neutropenii u tych dzieci.
W pracy przedstawiamy przypadek chłopca, u którego ciężka małopłytkowość i neutropenia pojawiły się w 8. tygodniu życia. W leczeniu zastosowano wlew immunoglobulin z dobrym efektem. Zaburzenia hematologiczne ustąpiły całkowicie po 3. miesiącu życia. Na podstawie przebiegu choroby i po wykluczeniu innych przyczyn wysunięto podejrzenie alloimmunologicznej cytopenii. Nie stwierdzono niezgodności antygenów płytek krwi rodziców. W surowicy krwi matki były natomiast obecne przeciwciała antyleukocytarne (anty-HLA), które zapewne były przyczyną choroby.
The most common cause of thrombocytopenia in infants in the first months of life are infections, while destruction of platelets in the course of immunological reactions occurs less frequently. In the case of the alloimmune reactions symptoms may appear as early as in the fetal life or shortly after birth and are caused by maternal antibodies passing through the placenta. The antibodies are most often directed against platelet antigens (anti-human platelet antigens – anti-HPA) of the child, inherited from the father. Much less likely to cause thrombocytopenia are leukocyte antibodies (anti-human leukocyte antigens – anti--HLA). They are, however, detected in 7-39% of pregnant women in serum, but they rarely cause neonatal alloimmune cytopenias. A few cases of thrombocytopenia in neonates of mothers with anti-HLA antibodies, but not anti-HPA, present in serum have been described in the literature. However, there are occasional reports of simultaneous thrombocytopenia and neutropenia in these children.
The paper presents a case of a boy in whom severe thrombocytopenia and neutropenia occurred in the 8th week of postnatal life. The patient was treated with infusion of immunoglobulins with a good effect. The hematologic abnormalities resolved completely after 3 months of age. Taking into account the course of the disease and the exclusion of other reasons of cytopenia, alloimmune thrombocytopenia and neutropenia was suspected. There was no incompatibility in platelet antigens of the parents. However, anti-HLA were detected in maternal serum, which most probably was the reason of the thrombocytopenia and neutropenia in the child.
Thrombocytopenia in infants, defined as a platelet count below 150 000/μl, requires a rapid diagnosis and a targeted treatment. The greatest danger is a bleeding into the central nervous system, which may be fatal (1). The differential diagnosis includes two main reasons for thrombocytopenia, which are a condition associated with: (A) insufficient platelet production and (B) an excessive destruction or loss of platelets. Two or, less often, more causes of thrombocytopenia may potentially co-exist in a particular patient (2).
A. An insufficient production of platelets may be caused by various factors. In infants, the most common cause is an ongoing infection. Other causes of thrombocytopenia include nutritional deficiencies, bone marrow failure (as a result of aplastic anemia, myelodysplastic syndromes or drug toxicity), tumor cell infiltrates that dominate over megacariocytosis in bone marrow. Thrombocytopenia is also one of the symptoms of genetic syndromes, e.g. the Fanconi syndrome, Wiskott-Aldrich syndrome, Thrombocytopenia-absent radius syndrome (TAR syndrome).
B. Excessive destruction of platelets leading to thrombocytopenia may have two main causes: non--immunological and, on the other hand, antibody-induced. The destruction of platelets that is independent of immune mechanisms is characteristic for disseminated intravascular coagulation (DIC), the hemolytic uremic syndrome, heart defects, hypersplenism, large hemangiomas and other conditions (2).
The most frequent cause of thrombocytopenia in children is platelet consumption in the course of immune reactions caused by auto- or alloantibodies directed against platelet antigens. Autoantibodies lead to the destruction of platelets in the course of the immune thrombocytopenia (ITP) and autoimmune diseases (e.g. lupus erythematosus). Thrombocytopenia may also be drug-induced. Alloantibodies, which are antibodies derived from another person, initiate the destruction of the donor platelets after blood transfusions. The particular case when alloantibodies may possibly be present in the child’s serum is pregnancy, when maternal antibodies get into the bloodstream of the fetus through the placenta.
Neonatal alloimmune thrombocytopenia (NAIT) is caused by maternal IgG antibodies directed against platelet antigens of the child, inherited from his father. The pathomechanism of NAIT is analogous to the hemolytic disease of the newborn caused by the Rh incompatibility. In contrast to that condition, the symptoms of NAIT may appear in the fetus or neonate already in the first pregnancy, however, in the following child they are much more severe (3). What is more, in NAIT the serum antibodies titers are not associated with the incidence or severity of the thrombocytopenia (4). The child may present varying degrees of disease severity, from a mild thrombocytopenia to a severe one, leading to spontaneous intracranial bleeding, which may affect up to 25% of the infants (1, 5). The symptoms disappear within a few weeks. In principle, the mother presents no abnormalities. An accurate diagnosis of a possible platelet incompatibility in the child is essential for the safety of the parents’ next child.
The criteria for the diagnosis of neonatal alloimmune thrombocytopenia include a statement of thrombocytopenia in the newborn or fetus, identification of a platelet antigen in the father, fetus or the newborn not found in the mother, and detection of maternal antibodies against that antigen (tab. 1) (5).
The most common platelet incompatibility in Caucasians is caused by the HPA-1a (6), followed by the HPA-5b and the HPA-15 (5, 7). Alloimmunity in the HPA-1a induces the most severe symptoms (8). Individual cases of neonatal alloimmune thrombocytopenia were associated with the presence of alloantibodies directed against human leukocyte antigens (anti-human leukocyte antigens – anti-HLA) (9, 10). These antigens are in fact also present in platelet cell membranes (11). Hardly ever was the presence of anti-HLA antibodies in the mother associated with the occurrence of neonatal thrombocytopenia and neutropenia at the same time (7, 12-14). In the study we present a case of a 8-week old boy with thrombocytopenia co-occurring with neutropenia, caused by gamma globulins present in his mother’s serum that were directed against the HLA class I antigens.
Tab. 1. Criteria for neonatal alloimmune thrombocytopenia diagnosis. Data from (8)
|Criteria for the diagnosis of neonatal alloimmune thrombocytopenia|
|– fetal or neonatal thrombocytopenia|
– identification of a parental, fetal or neonatal platelet antigen that the mother lacks
– identification of maternal antibodies to that antygen
An 8-week old boy was sent to hospital because of numerous petechiae and bruises, which, according to the mother, appeared due to child’s restlessness and crying caused by a stomachache. Single skin lesions similar to petechiae were possibly observed by her since his birth, but she linked it with food allergy. The mother did not notice any signs of infection, including fever. Two weeks before admission he was vaccinated with DTaP + Hib and against hepatitis B, without any complications. Until admission he had only received prophylactic doses of vitamins K and D.
The boy was born from the first pregnancy; the childbirth took place vaginally at 41 weeks, with a body weight of 3710 g, length of 55 cm, 10 points of the Apgar scale. The parents were young and healthy. No autoimmune diseases were diagnosed in the mother and all the complete blood counts performed during pregnancy were normal. Assays for the cytomegalovirus (CMV IgG positive, IgM negative), rubella (IgG positive, IgM negative) and toxoplasmosis (IgG and IgM negative) did not confirm acute infections with these pathogens during pregnancy. Further assays also excluded human immunodeficiency virus (HIV), syphilis, hepatitis type C (HCV) and group B streptococci (GBS, Streptococcus agalactiae) infections. The prenatal ultrasound examinations were normal and showed no signs of possible bleeding. The neonatal period of the boy was uneventful. The child was breastfed on demand, normal weight gain was observed. There was neither bleeding from the umbilical cord stump nor bruises after intramuscular administration of vitamin K or after vaccinations. No blood counts were performed in the child until the admission.
On admission to our ward, the boy was in a relatively good general condition, but anxious. In the physical examination jaundice was not noticed, but the skin was covered by many petechiae and small bruises on the face, especially around the eyes, on the neck, the trunk and on the limbs (fig. 1 and 2). The petechiae and ecchymoses were found on the soft palate. The left axillary lymph node was 1-1.5 cm in diameter, shifting, seemed painful; the skin over it was unchanged. The other peripheral lymph nodes were not detected. The abdomen was soft, painless, the liver palpable to 2.5 cm, the spleen palpable to 0.5 cm below the costal margins. No other abnormalities were found in the physical examination. Laboratory tests at admission indicated low markers of inflammation, i.e. acute phase protein (C-reactive protein – CRP) – 0.35 mg/L and procalcitonin (PCT) – 0.08 ng/μl. The red and white blood cell counts were appropriate to the patient’s age (Hb – 11.5 g%, RBC – 3.7 million/μl, MCV – 90 fl, WBC – 11 000/μl, granulocytes – 2310/μl and lymphocytes – 7230/μl). Only the number of platelets was significantly reduced to 5000/μl. The biochemical assays: electrolytes, renal and liver function parameters, coagulation – were correct. The urinalysis was without any deviation. Table 2 presents the results of the complete blood counts of the boy performed during hospitalization and the subsequent visits at the hematology ambulatory care.
Fig. 1. Massive petechiae and bruises on the boy’s arm
Fig. 2. Massive petechiae and bruises on the boy’s face, especially around the eyes
Tab. 2. The results of complete blood counts of the boy obtained during hospital stay and ambulatory hematological care. The age of the boy, day of the hospital stay and doses of intravenous immunoglobulins (IVIG) are provided
|Complete blood count parameters||Data obtained during hospitalization (day of the hospital stay)||Data from Hematological Ambulatory Care|
|Age of the boy||8 wk (0)||8 wk (1) after 1. dose of IVIG||8 wk (2) after 2. dose of IVIG||8 wk (4)||2.5/12||3/12||5/12||15/12|
|RBC (x 109/μl)||3.7||3.2||3.1||3.0||3.6||4.3||5.1||5.07|
|WBC (x 103/μl)||11.7||4.8||6.3||4.5||5.7||6.7||5.8||5.3|
|Neutrophils (x 103/μl)||2.31||0.48||0.61||0.58||0.37||0.94||1.16||1.70|
|Platelets (x 103/μl)||5||27||119||263||668||512||381||213|
Based on the history, the physical examination and the results of the additional assays, thrombocytopenia was diagnosed. Taking into account the fact that the cause of the disease was immunological, the patient received human immunoglobulin intravenously (IVIG). A dose of 5 g IVIG in total, i.e. 0.8 g/kg body weight, was administered.
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