Thrombotic thrombocytopenic purpura in autoimmune hepatitis

Received: July 17, 2000 / Accepted: August 25, 2000     

Treatment advances in adult immune thrombocytopenic purpura

Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by autoantibody-mediated destruction of platelets. The disease generally runs a mild clinical course, though significant morbidity and mortality can occur. Steroids and/or splenectomy are effective in treating the disease in approximately 70% of patients. These treatments have been well established with approximately 50 years of clinical experience. While open splenectomy is the traditional surgical procedure, laparoscopic splenectomy, splenic artery embolization, and splenic irradiation are viable alternatives. For patients who relapse after the above therapies, treatment is more difficult and seldom results in a cure. The goals of therapy involve maintaining a safe platelet count while minimizing toxicities from the treatment. Multiple treatment options exist including corticosteroids, androgens, immunomodulatory drugs, cytotoxic chemotherapy, immunoglobulin preparations, bone marrow transplantation, Helicobacter pylori eradication, and others. While the standard treatment of steroids and splenectomy has changed little over the past decades, a number of promising new therapies on the horizon may soon join the armamentarium upon which the clinician can draw to fight the disease. In this review, we will examine treatment for chronic ITP in adults in the pre-splenectomy, splenectomy, and post-splenectomy settings.     

Antiphospholipid antibodies in adults with immune thrombocytopenic purpura

To determine the clinical significance of antiphospholipid antibodies (aPL) in patients with immune thrombocytopenic purpura (ITP), anticardiolipin (aCL) (IgG and IgM) and lupus anticoagulant (LA) were sought at diagnosis in 215 ITP adults with platelets <50 × 10⁹/l. aPL (aCL and/or LA) were detected in 55 patients (26%): aCL alone in 39 (18%), aCL and LA in 15 (7%) and LA alone in one (0·5%). LA was significantly associated with high IgG-aCL levels ( P  =   0·001). Among age, sex, initial platelet count, bleeding score, acute or chronic ITP outcome, only younger age was significantly associated with LA-positivity (mean age 29 ± 14 years vs. 45 ± 20 years, P  =   0·002). After a median follow-up of 31 months, 14/215 (7%) patients developed thrombosis (four arterial, 10 venous and/or pulmonary embolism); four of them (29%) had high aCL levels and LA. Multivariate analysis significantly associated thrombosis events only with age [hazard ratio (HR)   =   1·6; 95% confidence interval (CI): 1·2–2·4], LA (HR: 9·9; 95% CI: 2·3–43·4) or high IgG-aCL level (HR: 7·5; 95% CI; 1·8–31·5). Although the thrombosis rate was low, the significant associations between thrombosis and LA or high aCL level suggest that aPL should be tested at ITP diagnosis.     

Immune thrombocytopenic purpura in patients with ulcerative colitis

Extraintestinal manifestations of ulcerative colitis (UC) are well known, but immunologically mediated hematological diseases are relatively rare. We describe two cases of immune thrombocytopenic purpura (ITP) associated with preexisting UC. Our patients had typical symptoms of UC, and endoscopy showed pancolitis. During treatment with 5-aminosalicylic acid and steroids, severe thrombocytopenia was noted. ITP was diagnosed based on a normal to high number of megakaryocytes in the bone marrow, positive autoantibody to platelet membrane antigen, and absence of splenomegaly. Medical treatment, including increased dosage of steroids, failed to control UC and ITP in both patients. In the first patient, the platelet count recovered after colectomy, while the second patient died of a cerebral hemorrhage. We stress that a diagnosis of ITP should be considered for thrombocytopenia in patients with UC, especially those showing extensive and significant colonic inflammation, and that colectomy of UC might resolve resistant ITP.     

Rituximab in recalcitrant thrombotic thrombocytopenic purpura secondary to systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a typical autoimmune disease with manifestations due to unopposed production of autoantibodies against the patient's own cells. The clinical features are diverse, ranging from musculoskeletal involvement, lupus nephritis to cerebral and even haematological involvement. We report a case of a young woman with known SLE who developed thrombotic thrombocytopenic purpura (TTP) secondary to SLE resistant to conventional treatment with plasma exchange. She was then treated with rituximab (MabThera®), a CD20 monoclonal antibody, and showed remarkable improvement. To our best knowledge this is the first case reporting the use of rituximab in acute resistant TTP secondary to SLE.     

Prevalence and clinical significance of elevated antinuclear antibody test in children and adult patients with idiopathic thrombocytopenic purpura

Background To determine the clinical significance of the antinuclear antibody (ANA) test in children and adult patients with idiopathic thrombocytopenic purpura (ITP). Method We conducted a retrospective analysis of 365 children and 108 adult patients with ITP. Patients found to have positive ANA were regularly followed-up by an experienced hematologist until December 2006 for development of symptoms indicative of autoimmune disorder. Mean follow-up 3.6 years (range: 2.1–7 years) for all patients. At the time of diagnosis of ITP, patients with connective tissue diseases (CTD) were excluded. Out of 365 childhood ITP; 301 (82.4%) patients were acute, 64 (17.6%) patients were chronic ITP. ANA titer ≥1:80 were positive in 33 (9.04%) of 365 patients with childhood ITP; 21 patients (6.9%) were in acute, and 12 patients (18.7%) were in chronic group. Out of 108 adult patients with ITP; 31 (28.7%) patients were acute and 77 (71.3%) patients were chronic ITP cases. ANA titer ≥1:80 were positive in 36 (33.3%) of 108 patients with adult ITP; 12 patients (38.8%) were in acute, and 24 patients (31.2%) were in chronic group. At the end of follow-up period Sjogren’s syndrome (SS) was diagnosed in only one adult chronic ITP cases. None of the other ANA positive patients developed SLE or other CTD. Conclusions Our data demonstrated that ANA positivity is often found in adult and children patients with ITP, and indicate that the detection of ANA positivity is not enough to identify those patients with ITP who are at risk of developing SLE or other CTD. There is a statistically significant difference in terms of ANA positivity between childhood acute and chronic ITP patients. We think that ANA positivity may be an indicator in terms of chronicity for childhood ITP. However, large-scale studies should be considered to determine the significance of ANA positivity and their utility in differentiating acute from chronic ITP.     

Dapsone for immune thrombocytopenic purpura in children and adults

Dapsone is one of the second line treatments of immune thrombocytopenic purpura (ITP). Dapsone is cheap and has response rates comparable to other second line treatment options like azathioprine, danazol, cyclophosphamide, cyclosporine, and vincristine. This retrospective analysis includes 38 patients (out of total 313 patients) of ITP treated with dapsone from 2004 to 2012. All male patients were screened for G6PD deficiency before starting dapsone. Out of 38 patients (12 children and 26 adults), one was newly diagnosed ITP, seven were persistent ITP, and 30 were chronic ITP. Five patients had side effects of dapsone; two required discontinuation due to skin rashes. The average dose of dapsone was 1.57?mg/kg/day and time to response was 57 days (19–108 days). The response was irrespective of previous treatments and response to them. The response rate was 48.6% (complete response?=?40.5%). Only two adult patients had sustained response (> 6 months) after dapsone discontinuation. There were no predictors identified for dapsone response. Dapsone is a safe and cheap second-line therapy for ITP with a response rate of about 50% (majority being CR). A response to dapsone is slow, sustained, and relapses are uncommon on therapy. Dapsone withdrawal leads to relapse in most of the patients.     

Rituximab-induced serum sickness in refractory immune thrombocytopenic purpura

Serum sickness may occur in patients treated with chimeric monoclonal antibody. Rituximab, an anti-CD20 chimeric monoclonal antibody, is used with increasing frequency in chronic immune thrombocytopenic purpura (ITP). Rituximab is relatively safe; however, serum sickness is reported in 1-20% of patients, more commonly among those with autoimmune conditions. We describe a case of serum sickness in a patient with ITP and review the literature of rituximab-induced serum sickness.     

Rituximab therapy in adult patients with relapsed or refractory immune thrombocytopenic purpura: long-term follow-up results

Objective:  To evaluate the long-term activity and toxicity profile of rituximab in adult patients with idiopathic immune thrombocytopenic purpura (ITP).
Patients and methods:  Twenty-six patients with active and symptomatic ITP relapsed or refractory received weekly infusions of rituximab 375 mg/m² for 4 wk. Median time from diagnosis to rituximab was 34.5 months . The following parameters of efficacy and toxicity were considered: complete response (CR) and partial response (PR), relapse rate, relapse-free survival (RFS), therapy-free survival (TFS), short- and long-term toxicity.
Results:  CR and PR were 14/26 (54%) and 4/26 (15%), respectively. Median time of observation was 56.5 months (range 39–77). Nine of the 18 responding patients relapsed after a median of 21 months (range 8–66); 9/26 patients (35%) maintained the response, with a median follow-up of 57 months (range 39–69), and 11/26 (42%) did not necessitate further therapy; estimated 5 yr RFS and TFS were 61% and 72%, respectively. Younger age and shorter interval from diagnosis to rituximab appeared indicators of better outcome. Rituximab administration was associated with two episodes of short-term toxicity, with one case of serum sickness syndrome; no infectious or other significant long-term complications were documented.
Conclusion:  Rituximab therapy may achieve long-lasting remission in nearly one-third of patients with relapsed or refractory ITP, with a good safety profile.     

rhTPO在系统性红斑狼疮合并难治性血小板减少性紫癜治疗中的应用

目的评价国产重组人血小板生成素（rhTPO）用于系统性红斑狼疮（SLE）合并难治性血小板减少性紫癜的可行性及安全性。方法对12例SLE并难治性血小板减少性紫癜患者行国产rhTPO皮下注射,15000U／d,疗程14d。检测用药前、用药后7、10、14d及停药3个月后的血小板数,判定疗效及不良反应情况。结果用药前血小板计数为（14．3±5．2）×10^9／L,用药后7、10、14d分别为（37．8±9．3）×10^9／L、（64．2±15．6）×10^9／L、（84．3±25．7）×10^9／L,与用药前相比,P均〈0．01。停药后3个月血小板计数为（53．2±15．6）×10^9／L,与治疗前比较,P〈0．01。总有效率为83．33％,仅2例出现轻微不良反应。结论rhTPO治疗SLE合并难治性血小板减少性紫癜疗效确切,且较为安全。     

Complement activation on platelets correlates with a decrease in circulating immature platelets in patients with immune thrombocytopenic purpura

The role of the complement system in immune thrombocytopenic purpura (ITP) is not well defined. We examined plasma from 79 patients with ITP, 50 healthy volunteers, and 25 patients with non‐immune mediated thrombocytopenia, to investigate their complement activation/fixation capacity (CAC) on immobilized heterologous platelets. Enhanced CAC was found in 46 plasma samples (59%) from patients with ITP, but no samples from patients with non‐immune mediated thrombocytopenia. Plasma from healthy volunteers was used for comparison. In patients with ITP, an enhanced plasma CAC was associated with a decreased circulating absolute immature platelet fraction (A‐IPF) (<15 × 10⁹/l) (P = 0·027) and thrombocytopenia (platelet count < 100 × 10⁹/l) (P = 0·024). The positive predictive value of an enhanced CAC for a low A‐IPF was 93%, with a specificity of 77%. The specificity and positive predictive values increased to 100% when plasma CAC was defined strictly by enhanced C1q and/or C4d deposition on test platelets. Although no statistically significant correlation emerged between CAC and response to different pharmacological therapies, an enhanced response to splenectomy was noted (P < 0·063). Thus, complement fixation may contribute to the thrombocytopenia of ITP by enhancing clearance of opsonized platelets from the circulation, and/or directly damaging platelets and megakaryocytes.     

Very long-term remission induced by short-term rituximab monotherapy in a patient with heavily pretreated, chronic immune thrombocytopenic purpura

The management of patients with refractory immune thrombocytopenic purpura (ITP) may be difficult. We describe a rapid-onset very long-term remission (9 years) induced by short-term rituximab monotherapy in a 62-year-old man with treatment-refractory chronic ITP. Over a 30-year period from the original diagnosis to last follow-up, the patient needed renewed treatment twelve times within the first two decades and was subsequently brought in continuous complete remission for the last decade by a single course of rituximab. The effect of rituximab in ITP has previously been described. However, in chronic, treatment-refractory ITP occurring in elderly patients, remission rates tend to be low and of short duration.     

Successful treatment of thrombotic thrombocytopenic purpura with plasmapheresis and anti-CD20 antibodies in a patient with immune thrombocytopenia and systemic lupus erythematosus: Case report

Rationale:Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology with diverse clinical and laboratory manifestations, including thrombocytopenia. About 25% of patients with SLE may be affected by thrombocytopenia, many of whom are asymptomatic. Some patients, however, experience platelet counts that drop quite low and predispose them to bleeding. Thrombotic thrombocytopenic purpura (TTP) is defined with a classic pentad of clinical features, such as thrombocytopenia, microangiopathic hemolytic anemia, neurological symptoms and signs, renal symptoms and signs, and fever. The association of TTP and SLE has been sporadically reported in the literature.Patient concerns and diagnosis:We describe a 16-year-old girl with SLE and immune thrombocytopenia, in whom TTP was diagnosed.Interventions and outcomes:She was treated with pulse methylprednisolone, whose platelet counts normalized after therapy with plasmapheresis and an anti-CD20 monoclonal antibody (rituximab).Conclusion:A pediatric patient with SLE and immune thrombocytopenia in whom TTP developed was treated with plasmapheresis and rituximab therapy successfully, though the patient experienced a disease relapsed after 18 months, which was controlled by the same management.     

Biomarkers for predicting response to corticosteroid therapy for immune thrombocytopenic purpura

Patients with immune thrombocytopenic purpura (ITP) often receive corticosteroids as a first-line treatment strategy. The ability to predict the therapeutic response to corticosteroids before initiating treatment would reduce the risk of adverse events, but biomarkers of this parameter have not yet been established. Here, in a single-centre, retrospective, cohort study of 127 ITP patients who received corticosteroids as first-line treatment, we compared several characteristics and test results between those patients with a favourable response to corticosteroids (responder cohort, n = 68) and those with a poor response to corticosteroids (non-responder cohort, n = 59) to identify potential biomarkers that were predictive of corticosteroid response. We extracted six factors as indicative of poor response to corticosteroid therapy for ITP: old age (≥81 years) (odds ratio [OR], 2.44; p = 0.02); low platelet count (<9 × 10⁹/L) (OR, 2.25; p = 0.02); high level of platelet-associated IgG (≥445 ng/10⁷cells) (OR, 3.95; p < 0.01), high platelet distribution width (≥ 14.0 g/dL) (OR, 2.00; p = 0.03), high lymphocyte-to-monocyte ratio (≥ 3.52) (OR, 1.40, p = 0.04), and low megakaryocyte count in bone marrow (< 85.5/μl) (OR, 1.72; p = 0.04). Thus, our present data support the fact that these six factors are useful biomarkers for predicting corticosteroid response in patients with ITP.     

Acute renal failure after intravenous anti-D immune globulin in an adult with immune thrombocytopenic purpura

Intravenous anti-D immune globulin (anti-D IGIV) is indicated for the treatment of immune thrombocytopenic purpura (ITP) in nonsplenectomized patients who are Rh(D)-positive. Recent reports have described episodes of intravascular hemolysis (IVH) and acute renal failure (ARF) after anti-D IGIV. We report the first adult patient with ITP who required and received dialysis after IVH and ARF complicating treatment with anti-D IGIV. Whether the transfusion of 2 units of Rh(D)-positive red cells, indicated for the resulting anemia, exacerbated the IVH and renal failure is unclear. Three weeks after the administration of anti-D IGIV (13 days after two hemodialysis treatments), the patient's renal function had returned to normal. This case highlights the infrequent but potentially serious side effects of anti-D IGIV and the need to monitor a patient's renal function closely if there is evidence of IVH after infusion of anti-D IGIV. If red cell transfusion is indicated, we recommend the use of Rh(D)-negative red cell products.     

Complete recovery from refractory immune thrombocytopenic purpura in three patients treated with etanercept

Management of patients with immune thrombocytopenic purpura (ITP) who have persistent, severe, and symptomatic thrombocytopenia following splenectomy is difficult and empirical. No single agent or regimen provides long-term success for most patients, and for most treatments it is difficult to assess whether benefits outweigh risks. We report three consecutive patients with critical chronic refractory ITP, who responded promptly and completely following treatment with etanercept, an inhibitor of tumor necrosis factor-alpha. These patients had failed 6-11 previous treatments. In the first patient, etanercept was given for its approved indication: a flare of co-existing rheumatoid arthritis. The next two patients were treated with etanercept because of successful outcomes in the previous patients. Although etanercept appeared to be effective treatment for ITP in these 3 patients, the experimental nature of this treatment and the potential risks must be emphasized. On the basis of these case reports, a clinical trial has been initiated to systematically evaluate the efficacy and risks of etanercept in the management of children and adults with chronic ITP.     

Accessory spleen in recurrent chronic immune thrombocytopenic purpura.

From 1969 to 1985 we discovered accessory spleens in 8 patients with chronic immune thrombocytopenic purpura (ITP) who relapsed or failed after splenectomy. Imaging of accessory spleen used a liver spleen scintigraphy with heat-treated RBC labeled with Tc-99m. Platelet kinetic studies with 51Cr or 111In, including sequestration index, were performed. Five patients had accessory splenectomy. Disappearance of bleeding symptoms was achieved in the 5 splenectomized patients but with only partial response of platelet counts. These results are discussed in the context of diagnosis and therapeutic management of accessory spleens in patients with chronic immune thrombocytopenic purpura who relapsed or failed after splenectomy.