Splenectomy for refractory thrombocytopenia in the antiphospholipid syndrome

M. Galindo, M. A. Khamashta and G. R. V. Hughes

Lupus Research Unit, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK

Correspondence to: M. A. Khamashta.


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. Thrombocytopenia, usually mild, is one of the clinical criteria of the antiphospholipid syndrome (APS). Rarely, this disorder requires treatment and, due to the shared characteristics with idiopathic thrombocytopenic purpura (ITP), similar rules are followed. We report our experience in patients who required splenectomy after being refractory to steroids and immunosuppressive therapy.

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.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The antiphospholipid syndrome (APS) is characterized by arterial/venous thrombosis, recurrent pregnancy loss or thrombocytopenia in the presence of antiphospholipid antibodies (aPL). These antibodies are usually identified as lupus anticoagulant (LA) which prolongs phospholipid-dependent coagulation tests, or as anticardiolipin antibodies (aCL) detected by immunoassays.

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 (70–120x109 /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.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A retrospective analysis was performed in 55 APS patients with thrombocytopenia, attending the Lupus Clinic at St Thomas' Hospital in London. All of them were referred patients and their charts were carefully reviewed.

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.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Among 55 APS patients with thrombocytopenia, 50 were classified as having secondary APS associated with SLE and five were identified as PAPS. ITP was the first diagnosis in 16 patients (16/55, 29%).

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 1–96) 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 2GoGo.


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TABLE 1.  Characteristics of splenectomized patients
 

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TABLE 2.  Characteristics of SLE patients
 
Among splenectomized patients, all but one were female and the mean age was 39 yr (range 22–58). Eight patients were initially characterized as ITP (six SLE-APS; two PAPS) with an average time of 4.4±1.1 yr (range 1–10) until APS diagnosis.

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 1–96 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.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Thrombocytopenia, usually mild, is one of the clinical criteria for the diagnosis of APS [1]. Although our experience supports the value of splenectomy in severe and drug-resistant thrombocytopenia in APS patients, there are some unresponsive cases.

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 (0.5–1 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 70–90% 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 1Go). 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.


    Acknowledgments
 
This work was supported by Lupus UK. We wish to thank Dr F. Romero for critical review of the manuscript.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1.  Hughes GRV. Thrombosis, abortion, cerebral disease and the lupus anticoagulant. Br Med J 1983;287:1088–9.[ISI][Medline]
  2.  Asherson RA, Khamashta MA, Ordi-Ros J et al. The `primary' antiphospholipid syndrome: major clinical and serological features. Medicine 1989;68:366–74.[ISI][Medline]
  3.  Alarcon-Segovia D, Delezé M, Oria C et al. Antiphospholipid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus: a review of 500 consecutive cases. Medicine 1989;68:353–65.[ISI][Medline]
  4.  Vianna J, Khamashta MA, Ordi-Ros J et al. Comparison of the primary and secondary antiphospholipid syndrome: a European multicenter study of 114 patients. Am J Med 1994;96:3–9.[ISI][Medline]
  5.  Cuadrado MJ, Mujic F, Muñoz E, Khamashta MA, Hughes GRV. Thrombocytopenia in the antiphospholipid syndrome. Ann Rheum Dis 1997;56:194–6.[Abstract/Free Full Text]
  6.  Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Ann Intern Med 1990;112:682–8.[ISI][Medline]
  7.  Galli M. Annotation. Thrombocytopenia in the antiphospholipid syndrome. Br J Haematol 1996;93:1–5.[ISI][Medline]
  8.  Harris EN. Annotation. Antiphospholipid antibodies. Br J Haematol 1990;74:1–9.[ISI][Medline]
  9.  Tan EM, Cohen AS, Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982;25:1271–7.[ISI][Medline]
  10. Hochberg MC. Updating the American College of Rheumatology Revised Criteria for the Classification of Systemic Lupus Erythematosus. Arthritis Rheum 1997; 40:1725.[ISI][Medline]
  11. Exner T, Triplett DA, Taberner D, Machin SJ. Guidelines for testing and revised criteria for lupus anticoagulants. SSC Subcommittee for the standardization of lupus anticoagulants. Thromb Haemostasis 1991;65:320–2.[ISI][Medline]
  12. Harris EN, Gharavi AE, Patel S et al. Evaluation of the anticardiolipin test: Report of an international workshop held 4 April 1986. Clin Exp Immunol 1987;68:215–22.[ISI][Medline]
  13. Harris EN, Asherson RA, Gharavi AE, Morgan SH, Derue G, Hughes GRV. Thrombocytopenia in SLE and related autoimmune disorders: association with anticardiolipin antibody. Br J Haematol 1985;59:227–30.[ISI][Medline]
  14. Harris EN, Gharavi AE, Hegde U et al. Anticardiolipin antibodies in autoimmune thrombocytopenic purpura. Br J Haematol 1985;59:231–4.[ISI][Medline]
  15. Deleze M, Oria CV, Alarcon-Segovia D. Occurrence of both haemolytic anemia and thrombocytopenic purpura (Evan's syndrome) in systemic lupus erythematosus. Relationship with antiphospholipid antibodies. J Rheumatol 1988;15:611–5.[ISI][Medline]
  16. Deleze M, Alarcon-Segovia D, Oria CV et al. Hemocytopenia in systemic lupus erythematosus. Relationship to antiphospholipid antibodies. J Rheumatol 1989;16:926–30.[ISI][Medline]
  17. Von dem Borne AEG, Helmerhorst FM, Van Leeuwen EF, Pegels HG, Von Riesz E, Engelfriet CP. Autoimmune thrombocytopenia: detection of platelet antibodies with the suspension immunofluorescence test. Br J Haematol 1980;45:319–27.[ISI][Medline]
  18. Hegde UM, Ball S, Zuiable A, Roter T. Platelet associated immunoglobulins (PAIgG and PAIgM) in autoimmune thrombocytopenia. Br J Haematol 1985;59:221–6.[ISI][Medline]
  19. Ruyi He, Reid D, Jones Ch, Shulman R. Spectrum of Ig classes, specificities, and titers of serum antiglycoproteins in chronic idiopathic thrombocytopenic purpura. Blood 1994;83:1024–32.[Abstract/Free Full Text]
  20. Kieffel V, Santoso S, Kauffmann E, Mueller-Eckhardt C. Autoantibodies against platelet glycoprotein Ib/IX: a frequent finding in autoimmune thrombocytopenic purpura. Br J Haematol 1991;79:256–62.[ISI][Medline]
  21. Pfueller SL, Logan D, Tran T, Bilston RA. Naturally occurring human IgG antibodies to intracellular and cytoskeletal components of human platelets. Clin Exp Immunol 1990;79:367–73.[ISI][Medline]
  22. Khamashta MA, Harris EN, Gharavi AE et al. Immune mediated mechanism for thrombosis: antiphospholipid antibody binding to platelet membranes. Ann Rheum Dis 1988;47:849–55.[Abstract]
  23. Galli M, Bevers M, Comfurius P, Barbui T, Zwaal RF. Effect of antiphospholipid antibodies on procoagulant activity of activated platelets and platelet-derived microvesicles. Br J Haematol 1993;83:466–72.[ISI][Medline]
  24. Out HJ, de Groot G, Van Vliet M, de Gast GC, Nieuwenhuis HK, Derksen R. Antibodies to platelets in patients with antiphospholipid antibodies. Blood 1991; 77:2655–9.[Abstract]
  25. Martinuzzo ME, Maclouf J, Carreras LO, Levy-Toledano S. Antiphospholipid antibodies enhance thrombin-induced platelet activation and thromboxane formation. Thromb Haemostasis 1993;70:667–71.[ISI][Medline]
  26. Galli M, Cortelazzo S, Viero P, Finazzi G, Barbui T. Interaction between platelets and lupus anticoagulant. Eur J Haematol 1988;41:88–94.[ISI][Medline]
  27. Blank M, Cohen J, Toder V, Shoenfeld Y. Induction of antiphospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anticardiolipin antibodies. Proc Natl Acad Sci USA 1991;88:3069–73.[Abstract]
  28. Bakimer R, Fishman P, Blank M, Sredni B, Djaldetti M, Shoenfeld Y. Induction of primary antiphospholipid syndrome in mice by immunization with a human monoclonal anticardiolipin antibody (H-3). J Clin Invest 1992; 89:1558–63.[ISI][Medline]
  29. Galli M, Daldossi M, Barbui T. Anti-glycoprotein Ib/IX and IIb/IIIa antibodies in patients with antiphospholipid antibodies. Thromb Haemostasis 1994;71:571–5.[ISI][Medline]
  30. Fabris F, Steffan A, Cordiano I et al. Specific antiplatelet autoantibodies in patients with antiphospholipid antibodies and thrombocytopenia. Eur J Haematol 1994;53:232–6.[ISI][Medline]
  31. Macchi L, Rispal P, Clofent-Sánchez G et al. Antiplatelet antibodies in patients with systemic lupus erythematosus and the primary antiphospholipid syndrome: their relationship with the observed thrombocytopenia. Br J Haematol 1997;98:336–41.[ISI][Medline]
  32. Stasi R, Stipa E, Masi M, Oliva F et al. Prevalence and clinical significance of elevated antiphospholipid antibodies in patients with idiopathic thrombocytopenic purpura. Blood 1994;84:4203–8.[Abstract/Free Full Text]
  33. Lang B, Straub RH, Weber S, Rother E, Fleck M, Peter HH. Elevated anticardiolipin antibodies in autoimmune haemolytic anaemia irrespective of underlying systemic lupus erythematosus. Lupus 1997;6:652–5.[ISI][Medline]
  34. George J, Woolf S, Raskob G et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood 1996;88:3–40.[Free Full Text]
  35. Stasi R, Stipa E, Masi M, Cecconi M et al. Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura. Am J Med 1995;98:436–42.[ISI][Medline]
  36. Berchtold P, Mcmillan R. Therapy of chronic idiopathic thrombocytopenic purpura in adults. Blood 1989;74: 2309–17.[Abstract]
  37. Mackworth-Young CG, Walport MJ, Hughes GRV. Thrombocytopenia in a case of systemic lupus erythematosus: repeated administration of `pulse' methylprednisolone. Br J Rheumatol 1984;23:298–300.[ISI][Medline]
  38. Andersen JC. Response of resistant idiopathic thrombocytopenic purpura to pulsed high-dose dexamethasone therapy. N Engl J Med 1994;330:1560–4.[Abstract/Free Full Text]
  39. Berchtold P, Wenger M. Autoantibodies against platelet glycoproteins in autoimmune thrombocytopenic purpura: their clinical significance and response to treatment. Blood 1993;81:1246–50.[Abstract]
  40. Fujisawa K, Tani P, Piro L, McMillan R. The effect of therapy on platelet-associated autoantibody in chronic immune thrombocytopenic purpura. Blood 1993;81: 2872–7.[Abstract]
  41. Juliá A, Araguás C, Rosselló J et al. Lack of useful clinical predictors of response to splenectomy in patients with chronic idiopathic thrombocytopenic purpura. Br J Haematol 1990;76:250–2.[ISI][Medline]
  42. Law C, Marcaccio M, Tam P et al. High-dose intravenous immune globulin and the response to splenectomy in patients with idiopathic thrombocytopenic purpura. N Engl J Med 1997;336:1494–8.[Abstract/Free Full Text]
  43. Alarcón-Segovia D, Sánchez-Guerrero J. Correction of thrombocytopenia with small dose aspirin in the primary antiphospholipid syndrome. J Rheumatol 1989;16:1359–61.[ISI][Medline]
  44. Suarez MI, Díaz RA, Aguayo Canela D, Pujol de la Llave E. Correction of severe thrombocytopenia with chloroquine in the primary antiphospholipid syndrome. Lupus 1996;5:81–3.[ISI][Medline]
  45. Ames PRJ, Orefice G, Brancaccio V. Reversal of thrombocytopenia following oral anticoagulation in two patients with primary antiphospholipid. Lupus 1995;4:491–3.[ISI][Medline]
  46. Kuwana M, Kaburaki J, Hirakata M, Tojo T, Handa M, Ikeda Y. Thrombocytopenia responsive to warfarin in a patient with systemic sclerosis-systemic lupus erythematosus overlap. Clin Exp Rheumatol 1995;13:103–6.[ISI][Medline]
  47. Wisbey H, Klestov AC. Thrombocytopenia corrected by warfarin in antiphospholipid syndrome. J Rheumatol 1996;23:769–71.[ISI][Medline]
  48. Kavanaugh A. Danazol therapy in thrombocytopenia associated with the antiphospholipid antibody syndrome. Ann Intern Med 1994;121:767–8.[Free Full Text]
  49. West SG, Johnson SC. Danazol for the treatment of refractory autoimmune thrombocytopenia in systemic lupus erythematosus. Ann Intern Med 1988;108:703–6.[ISI][Medline]
  50. Durand JM, Lefevre P, Kaplanski G, Cretel E, Mongin M, Soubeyrand J. Correction of thrombocytopenia with dapsone in the primary antiphospholipid syndrome. J Rheumatol 1993;20:1777–8.[ISI][Medline]
  51. Pallarés JA, Caba F. Anesthetic implications of antiphospholipid syndrome. Two cases report. Rev Esp Anestesiol Reanim 1995;42:182–5.[Medline]
  52. Ballerini G, Gemmati D, Moratelli S, Morelli P, Serino ML. Anticardiolipin antibody-related thrombocytopenia: persistent remission after splenectomy. Haematologica 1995;80:248–51.[ISI][Medline]
  53. Leuzzi RA, Davis GH, Cowchock FS, Murphy S, Vernick JJ. Management of immune thrombocytopenic purpura associated with the antiphospholipid antibody syndrome. Clin Exp Rheumatol 1997;15:197–200.[ISI][Medline]
  54. Hakim AJ, Machin SJ, Isenberg DA. Autoimmune thrombocytopenia in primary antiphospholipid syndrome and systemic lupus erythematosus: the response to splenectomy. Semin Arthritis Rheum 1998;28:20–5.[ISI][Medline]
Submitted 30 September 1998; revised version accepted 6 April 1999.