METHODS AND PATIENTS

We reviewed patients attending our immunodeficiency service who had required anti-D treatment for the management of refractory ITP. Patient characteristics are shown in table 1.

The diagnosis of ITP was made on the basis of thrombocytopenia, blood film, and bone marrow features, and the exclusion of other diagnoses. The diagnosis of primary antibody deficiency was on the basis of a history of repeated bacterial infections (before immunosuppressive treatment), low antibody concentrations (assessed when off immunomodulatory treatment), and the absence of factors known to be associated with secondary immunodeficiency. All patients had thrombocytopenia refractory to steroids and high dose IVIG (1 g/kg for at least two doses). Two patients had relapsed after splenectomy. At the time of the anti-D infusion, three patients were on replacement doses (0.4 g/kg/3 weeks) of IVIG to prevent infection. One patient (patient 4) was taking cyclosporin (100 mg twice daily) at the time of her first set of anti-D treatments and vincristine (2 mg weekly for four doses) and dexamethasone (40 mg daily for four days, monthly) at the time of her second set of anti-D treatments, having failed to respond to dexamethasone alone. Anti-D immunoglobulin was given intravenously over 30 minutes. If the initial dose produced inadequate response, a higher dose was given subsequently. To minimise the risk of viral transmission, we used a detergent treated anti-D product (Win-Rho; Octapharma, Vienna, Austria) and saw no evidence of hepatitis C transmission.

RESULTS

All patients responded to anti-D (fig 1). Three of our patients had a biphasic response with an early small peak and a later prolonged peak. The duration of the response was 125–390 days, and this was not reduced by previous splenectomy. Repeat infusions have also been effective. All patients are currently in remission and off immunosuppressive treatment.

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Figure 1

Platelet response to anti-D immunoglobulin. Anti-D infusions are indicated by the shaded squares along the x axis. Patient 1 has responded repeatedly to anti-D infusions (50 μg/kg). Patient 2 had a suboptimal response to 40 μg/kg anti-D immunoglobulin. This reduced dose was chosen because of previous haemolytic anaemia. She was re-treated nine months later with 50 μg/kg. Patient 3 had a transient response to 50 μg/kg anti-D immunoglobulin and was re-treated after 18 days with 100 μg/kg. Patient 4 had a transient response to doses of 50 and 100 μg/kg anti-D immunoglobulin three days apart. She was re-treated 21 days later with doses of 100, 100 and 150 μg/kg at 10 and five day intervals, respectively. Relapse one year later was treated with two doses of 150 μg/kg at an eight day interval.

All patients had a fall in haemoglobin (of 13–62 g/litre); one required red blood cell transfusion. Transient neutropenia occurred in two patients (nadirs 0.6 and 0.8 × 10⁹/litre, respectively).

Headache, fever, and malaise were treated symptomatically and could be prevented by premedication with an antihistamine and paracetamol.

DISCUSSION

Anti-D immunoglobulin is a well established treatment for ITP in a variety of settings, including HIV associated secondary immunodeficiency.³ Most series report that anti-D immunoglobulin is ineffective after splenectomy.^3,5 Our experience suggests that anti-D immunoglobulin may be effective in primary antibody deficiency, even after splenectomy.

Although anti-D immunoglobulin is generally well tolerated, a mean fall in haemoglobin of 8 g/litre is expected and severe haemolysis may occur.^3,6 All our patients had a fall in haemoglobin of greater than 10 g/litre and one required red blood cell transfusion. Neutropenia, which occurred in two of our patients, has not been described previously. This limited experience suggests that adverse events may be more common in antibody deficient patients. Whether the presence of pre-existing CVID associated autoimmune haemolytic anaemia and neutropenia increases the risk of cytopenia after anti-D immunoglobulin is unknown.¹

The duration of response in our patients with immunodeficiency was longer than that reported in other series, where the median duration of response was 21 days.³

These observations suggest underlying differences in pathogenesis and are not compatible with the proposed mechanism of action of anti-D immunoglobulin. It is possible that, in our patients, the initial competitive saturation is followed by longer lasting changes in phagocyte Fc receptor expression. There have been isolated cases of responses to anti-D immunoglobulin even after splenectomy in immunocompetent patients. These have been attributed to increased platelet uptake by hepatic macrophages after splenectomy.^7,8 The granulomatous variant of CVID is associated with thrombocytopenia, probably as a result of increased platelet destruction by activated phagocytes.^9,10 Two of our patients (patients 1 and 2) had persistently raised alkaline phosphatase concentrations, although no granulomata were seen on splenic histology of the two patients (patients 2 and 4) who underwent splenectomy. We speculate that our patients may have had activated hepatic macrophages or granulomata, resulting in relapse of thrombocytopenia after splenectomy and explaining the unexpectedly high success rate of anti-D immunoglobulin.

Thus, anti-D immunoglobulin should be administered with caution because of the risk of neutropenia and red blood cell destruction. However, it is a valuable non-immunosuppressive, long acting alternative to conventional ITP treatments in primary antibody deficiency, even after splenectomy.