Lupus Research Unit, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK
Correspondence to:
M. A. Khamashta.
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Abstract |
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Methods. Fifty-five APS patients with a platelet count of <100x109 /l at least twice were analysed retrospectively. Therapeutic response or remission was considered when the platelet count was >100x109 /l after 1 month and with no relapse on stopping or tapering the steroid dose. No response or refractory disease was defined as an absence of increase in platelet count, a total count that never exceeded 50x109 /l during treatment or when the dose requirements were such that the patient developed serious side-effects.
Results. Fifty patients were classified as having secondary APS associated with systemic lupus erythematosus (SLE) and five were identified as primary APS (PAPS). Splenectomy was performed in 11 cases (20%), two PAPS and nine SLE-APS, with an average time of 28±9 months after the development of thrombocytopenia. Eight patients were initially characterized as ITP (six SLE-APS; two PAPS) with an average time of 4.4±1.1 yr until the APS diagnosis. All but two were responsive to splenectomy.
Conclusion. Splenectomy was required in 11 (20%) of the patients with APS-associated thrombocytopenia. There was a high rate of good and long-term response.
KEY WORDS: Autoimmune thrombocytopenia, Antiplatelet antibodies, Antiphospholipid antibodies, Antiphospholipid syndrome, Splenectomy, Systemic lupus erythematosus.
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Introduction |
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This entity, first described by Hughes in 1983 [1] in patients with systemic lupus erythematosus (SLE), may appear in patients with no underlying disease, i.e. the `primary' antiphospholipid syndrome (PAPS) [2, 3].
Thrombocytopenia in APS is usually mild and benign (70120x109 /l), rarely associated with bleeding complications and, generally, does not require treatment. The estimate prevalence in the literature ranges from 20 to 40% with no significant difference between primary and secondary cases [4]. Recently, Cuadrado et al. [5] reported a prevalence of 23.4% in a series of 171 APS patients, being severe (<50x109 /l) only in six of them (17.6%). Love and Santoro [6] found this prevalence three times greater in SLE patients with aPL than in those without these antibodies, suggesting that aPL might play a role in its pathogenesis.
The mechanism of thrombocytopenia in APS is still unknown. Occasionally, it is the first and only manifestation in APS patients, being then diagnosed as `idiopathic' thrombocytopenic purpura (ITP). Owing to the shared features with ITP, Galli [7] and others have suggested similar treatment regimes.
In this paper, we report our experience in patients with APS-associated thrombocytopenia who required splenectomy after being refractory to steroids and/or immunosuppressive therapy.
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Patients and methods |
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All patients fulfilled the proposed criteria for APS [8]. The classification of SLE was made according to the 1982 American College of Rheumatology criteria and the latest revision [9, 10]. Thrombocytopenia was considered a clinical feature of APS when a platelet count of <100x109 /l was found at least twice, separated by at least 2 months. ITP was diagnosed by exclusion with thrombocytopenia, a normal bone marrow biopsy or with a mildly increased megakaryocyte count (only performed in one case), in the absence of other associated disorders. Therapeutic response or remission was considered when the platelet count was >100x109 /l after 1 month and with no relapse on stopping or tapering the steroid dose. No response or refractory disease was defined as an absence of increase in platelet count, a rise that never reached a level of 50x109 /l during treatment or when the dose requirements were such that the patient developed serious side-effects.
Antiphospholipid antibodies and LA were detected by standard methods [11, 12]. Serum samples were tested for antinuclear antibodies (ANA), double-stranded DNA antibodies (anti-ds DNA) and antibodies against extractable nuclear antigen (ENA) according to standard methods.
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Results |
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Splenectomy was performed in 11 cases (11/55, 20%) due to the lack of a long-term response to high doses of steroids and, in four patients, to immunosuppressive therapy with an average time of 28±9 months (range 196) after the development of thrombocytopenia. Bleeding complications forced splenectomy in three cases (patients 6, 7 and 9). Clinical and laboratory findings are summarized in Tables 1 and 2.
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Bone marrow biopsy data were only available in one ITP patient and were consistent with this diagnosis. Haemolytic anaemia was present in two cases. Prothrombin levels were normal in all but one patient who developed severe haemolytic anaemia and thrombocytopenia at the same time (patient 6).
All patients had positive ANA, two of them were primary and nine secondary APS. The results of aPL were a positive LA alone in three, a positive aCL alone in three and both in five.
Before undergoing splenectomy, all 11 patients were treated with steroids at least for 1 month (range 196 months) with a mean dose between 0.5 and 1 mg/kg/day. Four patients were also unresponsive to immunosuppressive therapy (cyclophosphamide, azathioprine, vinblastine), i.v. immunoglobulin (IVIG) and plasmapheresis.
Post-operative complications were not reported in any patient, and all but two were responsive to splenectomy. Among patients who were previously treated with IVIG, splenectomy was successful only in those with a good but transient response to this therapy (patients 7 and 9). Platelet counts on their last visit ranged between 180 and >400x109 /l.
Splenectomy was unsuccessful in two patients. The first was a 47-yr-old Indian man diagnosed as having ITP in 1988 after spontaneous mouth and nose bleeding. A bone marrow biopsy performed at that time was consistent with this entity. The diagnosis of PAPS was made when a strong positive result for LA was found, although he did not develop any thrombotic event. After being treated for 5 yr with high doses of steroids (>30 mg daily), azathioprine (150 mg daily) and subsequently IVIG, he underwent splenectomy because of bleeding complications and platelet counts below 20x109 /l. Low-molecular-weight heparin (10000 U/day) and aspirin were used during the surgical procedure. Twenty-four hours after surgery, the platelet count was 9x109 /l and i.v. pulses of methylprednisolone and IVIG were given. The platelet count during the post-splenectomy follow-up has never been >40x109 /l despite treatment with steroids, azathioprine, danazol, cyclosporin and interferon alpha. Although he has been asymptomatic since splenectomy, he has remained on treatment with low doses of prednisolone because of the low platelet count.
The second case was a 52-yr-old Caucasian woman diagnosed as having SLE with secondary APS in 1991. After being treated for 1 yr with steroids (0.5 mg/ kg/day), splenectomy was required in 1992 due to platelet counts below 30x109 /l. Since then, she has remained asymptomatic with hydroxychloroquine (HCQ), but, at her last visit, the platelet count had fallen to 23x109 /l again with no bleeding complications.
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Discussion |
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Before the description of APS, thrombocytopenia was thought to be secondary to peripheral platelet destruction induced by the binding of autoantibodies to the platelet membrane or by increasing uptake of immune complexes added to the platelet surface. In 1985, our group found a strong correlation between thrombocytopenia and raised levels of aCL (IgG, 72%; IgM, 44%) in 116 patients with different autoimmune diseases and in 30% of patients with ITP [13, 14]. It is not known whether they are responsible for peripheral platelet destruction [15, 16], and different antibodies directed against platelet glycoproteins (GP) have also been described and related to the pathogenesis of ITP [17]. These antiplatelet antibodies detected as platelet-associated (PAIg) or as free serum antibodies are non-specific [18] and appear to bear no correlation with the degree of clinical severity or therapy failure [19, 20].
Antiphospholipid antibodies bind to phospholipids in vitro when they are exposed on the outer surface of the cytoplasmic membrane after platelet activation and by shedding of procoagulant platelet microvesicles [2124]. However, activated circulating platelets have not been positively identified yet in vivo [25, 26] and results in experimental assays in mice have been controversial [27, 28].
Increased plasma levels of anti-GP antibodies against GP IIb/IIIa and Ib/IX have been found in 40% of aPL-positive patients [2931], a prevalence similar to that described for ITP [19]. The presence of this antibody was significantly associated with the presence of thrombocytopenia, but did not correlate with demographic or clinical conditions, the history of thrombosis, the degree of thrombocytopenia, aCL titre or the presence of LA. However, `natural' IgG antibodies with specificity to different internal platelet proteins have been described in healthy individuals with titres that, in some cases, approach those of antibodies with pathological significance [30]. Stasi et al. [32] found a positive result for aPL in nearly half of 149 ITP patients (LA or aCL: 46.3%; LA and aCL: 16.1%), and the majority of them (83%) had positive PAIg. However, there was no correlation between antibodies or clinical parameters. Patients with a therapeutic response did not show any change in aPL levels, while a significant decrease in PAIgG was detected.
We should point out that, among our patients, two had haemolytic anaemia. One of them (patient 9), with SLE, developed severe haematological involvement, mild articular affection and serositis without serological data. This suggests that this patient could belong to a different subgroup of SLE patients, as has been previously described [33].
Therefore, it is likely that, in the presence of antiplatelet antibodies, enhanced platelet sequestration by the mononuclear phagocyte system is mainly involved in the pathogenesis of the APS-associated thrombocytopenia, rather than local cytotoxic effects subsequent to aCL deposition on platelet membrane. According to this, when treatment is necessary, ITP rules are followed. High doses of steroids (0.51 mg/kg/day) are the conventional initial therapy for patients who have more severe thrombocytopenia [34]. About two-thirds of ITP patients have a good response [35], but <25% maintain a persistent complete or partial response [36]. Equally mixed results have been obtained with i.v. pulses of methylprednisolone or dexamethasone with a short-lived response that tends to diminish with each dose [37, 38]. When steroids are unsuccessful, splenectomy is usually performed on the basis of the removal of the major site of platelet destruction and antibody production [34]. There is improvement in 7090% of patients after splenectomy and platelets are permanently restored to normal levels in at least two-thirds [35, 36]. Plasma and platelet-associated autoantibodies usually become undetectable after splenectomy [39, 40]. Unfortunately, there are no clinical or analytical parameters that adequately predict the response to splenectomy [41]. Only the response to IVIG in ITP patients seems to have a relationship to the outcome of splenectomy [42].
Other therapeutic options have been anecdotally reported, without long remission despite early encouraging results [34, 43]. They include aspirin, antimalarial drugs or warfarin [4347], and immunomodulating agents such as danazol and dapsone [4850].
No controlled studies have been reported and the experience in APS-associated thrombocytopenia is very limited [5154]. Our experience supports the value of splenectomy when steroids have failed with a high rate of response after 1 yr of follow-up. However, two of our patients did not respond to this procedure. Possible reasons include a different pathogenic mechanism than that suggested for ITP, different aCL and PAIg subtypes or different patterns of platelet sequestration such as splenic, hepatic or hepatosplenic. We should also point out that all patients from our series with a good response remained on different therapies after splenectomy for several reasons (Table 1). Thus, we cannot conclude that this option is definitely followed by a complete and persistent remission.
Summarizing, APS-associated thrombocytopenia appears in about one-third of the patients and can be misdiagnosed as ITP in about one-third of them. Its pathogenesis remains unknown and several hypotheses, related to aPL and antiplatelet antibodies, have been suggested. Rarely, this disorder requires treatment and, due to the shared characteristics with ITP, a similar therapeutic sequence is followed. Splenectomy was required in 20% of our cases after a poor response to steroids or immunosuppressive therapy. Our experience shows that this procedure has a high rate of good and long-term response. However, two patients were unresponsive to splenectomy.
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Acknowledgments |
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References |
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