Antiphospholipid antibody-associated haemophagocytic syndrome
K. Ikeda,
M. Nawata,
S. Ando,
M. Koike,
I. Sekigawa,
N. Iida,
H. Hashimoto1 and
S. Hirose
Department of Medicine, Juntendo University Izu-Nagaoka Hospital, 1129 Nagaoka, Izu-Nagaoka-cho, Tagata-gun, Shizuoka 410-2295 and
1 Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113, Japan
SIR, Reactive haemophagocytic syndrome (HPS) has been reported to be associated with various disorders, particularly infection and lymphoma [1, 2]. Furthermore, autoimmune diseases such as systemic lupus erythematosus (SLE) are known to be causative disorders of this syndrome [3, 4]. We recently encountered a case of HPS associated with primary antiphospholipid syndrome (APS). This patient was a 27-yr-old woman who was admitted to our hospital with thrombocytopenia observed by accident. On hospitalization, her blood cell count showed anaemia and severe thrombocytopenia (white cells, 7.0 x 103/mm3, red cells, 379 x 104/mm3; haemoglobin, 7.6 g/dl; platelets, 0.2 x 104/mm3). Antiphospholipid antibodies (aPL) were detected in the immunological examination [lupus anticoagulant (LAC), 55.1 s, n < 55.5; and anticardiolipin antibodies, IgG, 4.0, n < 1.0; IgM, 4.4, n < 1.0; ß2-glycoprotein 1, 25.2 U/ml, n < 3.5]. Other immunological findings apart from aPL were as follows: antinuclear antibody, x320, n < x 40; anti-DNA antibody, negative; Coombs test, negative; platelet-associated IgG, 148.2, n = 9.025.0; cold haemagglutinin, negative; CH50, 30.8 U/ml, n = 3040. Proper clinical and laboratory examinations allowed us to exclude connective tissue diseases such as SLE, Sjögren's syndrome, and autoimmune haemolytic anaemia. Viral infections and malignancies were also not observed as underlying disorders and her serum levels of several cytokines including tumour necrosis factor-
(TNF-
), TNF-ß, and interferon-
(IFN-
) were not elevated. She had not shown any thrombotic symptoms. Bone marrow smears showed normal to increased cellularity and an increase in mature-looking histiocytes scattered among the haematopoietic cells, which accounted for approximately 3% of all nucleated cells and were distributed unevenly. These cells showed marked phagocytosis of haematopoietic cells, including megakaryocytes, erythroblasts, and a few neutrophils (Fig. 1
). Based on these findings, she was diagnosed as having HPS associated with primary APS. In addition, iron deficiency was thought to play some part in her anaemia (serum Fe, 16 µg/dl, n = 43172). Thrombocytopenia in the patient was dramatically improved by steroid treatment (500 mg/day methylprednisolone for 3 days, followed by 40 mg/day prednisolone), and the platelet count increased to 27.0 x 104/mm3 1 week after the treatment. An amelioration of her anaemia was also observed with these treatments and replacement therapy of iron. Haemophagocytic phenomena almost disappeared in the second bone marrow aspiration 3 weeks after starting steroid treatment.

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FIG. 1. Area of haemophagocytosis of erythroblasts [arrow in (A)] and megakaryocytes [arrow in (B)] in the bone marrow of the patient (MayGiemsa staining, x500).
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HPS associated with autoimmune disorders, including SLE, mixed connective tissue disease (MCTD), and progressive systemic sclerosis (PSS), has been reported [24]. In these patients, phagocytic effects through binding between Fc receptors of histiocytes and the Fc portion of antibodies to platelets and erythrocytes or immune complexes are suggested to be important as mechanisms of the disorder since IgG coated haematopoietic cells are phagocytosed by macrophages and other cells through their expression of Fc
receptors [5]. Several cytokines, such as TNF-
and IFN-
, are reported to be favoured pathogenic agents in HPS associated with infections or malignancies, because these cytokines can activate histiocytes [6]. However, there have been no previously reported cases describing the relationship between primary APS and HPS. Thrombocytopenia in APS is mainly thought to result from the consumption of platelets via thrombi formations [7]. There is no evidence of direct binding of aPL to intact native platelets [8]. However, aPL have been reported to bind freeze-thawed platelets and to regulate the binding of endothelial cells to platelets or monocytes [911]. Although binding effects of aPL to haematopoietic cells are as yet unknown, binding of aPL-bound haematopoietic cells to the Fc receptor of phagocytes via the Fc portion of aPL may play a significant role in aPL-associated HPS, as in our patient. In our case, there was no possible causative factor of HPS except the presence of aPL. In addition, we recently also had another primary APS patient with thrombocytopenia and anaemia with bone marrow haemophagocytosis similar to the presented case, although the frequency of the haemophagocytosis in this patient bone marrow was not sufficient to verify the diagnosis of HPS. These cases indicate that attention should be given to the possibility that certain patients with APS-associated cytopenia may display accompanying intramedullary haemophagocytic phenomena.
Notes
Correspondence to: I. Sekigawa 
References
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Accepted 19 November 1999