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Fetal alloimmune thrombocytopenia is caused by maternal sensitization to paternally-derived antigens on fetal platelets, most commonly HPA-1a.1 It occurs in approximately 1 in 1000 live births and is the commonest cause of severe fetal and neonatal thrombocytopenia, and of intracranial hemorrhage in neonates born at term.2 Since there is currently no routine screening, first-time cases of fetal alloimmune thrombocytopenia are generally identified following the birth of a markedly thrombocytopenic neonate. Antenatal management is thus only possible in subsequent pregnancies. Intracranial hemorrhage is the most devastating complication of fetal alloimmune thrombocytopenia and often occurs antenatally. Assessment of projected clinical severity is thus based on the development of intracranial hemorrhage in a previous sibling. If there is such a history of intracranial hemorrhage, the chance of this complication occurring again in the next pregnancy is extremely high in an untreated, antigen-positive sibling.3 Administration of intravenous immunoglobulin (IVIG) to the mother, initially given in conjunction with dexamethasone, was first used to prevent recurrence of antenatal intracranial hemorrhage in 1988.4 This approach of providing IVIG-based medical therapy administered to the mother to increase the fetal platelet count has since been extensively investigated in hundreds of maternal-fetal pairs.5 The efficacy of IVIG-based therapy has been supported by numerous studies6–16 (Table 1A) but not by others17–19 (Table 1B). The studies presented in Tables 1A and 1B surprisingly report virtually identical percentages of cases of intracranial hemorrhage: 2.7% versus 2.9%, respectively. However, overall mean birth platelet counts differed markedly between the two groups. While platelet counts are considered to be surrogate markers of intracranial hemorrhage, fortunately, the likelihood of fetal and neonatal intracranial hemorrhage, in the absence of this complication having occurred in a previous sibling, is relatively low.

Udgivelsesdato: 2008-Apr

Salama et al. [1] noticed that in patients with autoimmune thrombocytopenia (AITP) treated with high-dose i.v. Ig, the red cells became weakly sensitized with IgG antibodies, present in the i.v. Ig preparation. They concluded that the effect of i.v. Ig on the platelet count is due to a competition between sensitized red cells and platelets sensitized with auto-antibodies, for Fc-receptors (FcR) on splenic macrophages. This observation was the basis of their treatment of patients with AITP with i.v. anti-D IgG. Since the first publication of Salama et al. [2] on the subject, many patients have been treated in several centres. There is controversy concerning the question whether the effect of i.v. anti-D IgG is indeed due to a competition between sensitized red cells and sensitized platelets for FcR and therefore to the RhD antibodies themselves, or to other factors, also present in the anti-D preparation. This question is interesting from a theoretical but also from a practical point of view. There is a general shortage of anti-D Ig for immunoprophylaxis in D-negative women. If not the anti-D but other factors are responsible for the effect in AITP, anti-D Ig should not be used to treat patients with this disease. These considerations led us to devote an International Forum to this subject. The questions listed below were sent to 18 experts of whom 7 have contributed to the Forum. Questions (1) Do you, or your colleagues, treat patients with AITP with i.v. anti-D Ig or have you done so in the past? (2) If so, what have the results of this treatment been? (3) If treatment with anti-D causes an increase in the platelet count (a) do you think that this effect is due to a competition between anti-D IgG sensitized red cells and auto-antibody-sensitized platelets for FcR on macrophages? If so, how do you explain the simultaneous, often severe, destruction of red cells by IgG warm auto-antibodies and of platelets by auto-antibodies in Evans’ syndrome? (b) do you think that any effect on the platelet count is not due to anti-D but, e.g, to other antibodies present in the anti-D preparation? (c) do you have experience with anti-D treatment of Rh-D-negative patients with AITP? (d) do you have experience with anti-D treatment of patients with IgA platelet autoantibodies?

We describe 2 patients with thrombocytopenia and autoantibodies in the blood against platelet membrane glycoprotein (GP) IIb/IIIa, in whom reactivity of the antibodies with their antigen was greatly diminished in the presence of sodium EDTA. One patient also showed a marked thrombocytopathy, suggesting a functional blocking of GP IIb/IIIa by these autoantibodies. These observations show that some immunologically important autoantibodies can easily be missed in routine serological investigations in which EDTA blood is used, obscuring the autoimmune nature of a thrombocytopenia and possibly of a thrombopathy as well.

An extended family is described in which three members had thrombocytopenia. These affected members had chromosomal changes resembling those found in Fanconi's anaemia, though they lacked the development defects associated with that syndrome. One had bone-marrow hypoplasia and died of squamous cell carcinoma of the mouth at the age of 27. In addition, all three had platelet autoantibodies not found in any other family members tested. There was no linkage between the thrombocytopenia and HLA groups. The nature of the association of thrombocytopenia, platelet autoantibodies and chromosomal abnormalities in this family remains doubtful.

Sera of 22 patients with Felty's syndrome and 14 patients with rheumatoid arthritis were tested in assays routinely used for the detection of neutrophil antibodies (i.e. immunofluorescence, agglutination and cytotoxicity tests) as well as in the antibody-dependent lymphocyte-mediated granulocytotoxicity test. One or more of the routinely used assays were positive in a high percentage of the sera (77% and 64%, respectively). The antibody-dependent lymphocyte-mediated granulocytotoxicity test was only positive with sera of three patients with Felty's syndrome. Positive results in the immunofluorescence and agglutination tests could be attributed to the presence of immune complexes in the sera, whereas positive antibody-dependent lymphocyte-mediated granulocytotoxicity tests were probably due to the presence of HLA alloantibodies. It is concluded that serological tests routinely used for the detection of neutrophil autoantibodies should be interpreted with caution in patients with Felty's syndrome. Our results also indicate that the neutropenia in Felty's syndrome is rarely, if ever, due to neutrophil-specific autoantibodies.