Rituximab for the treatment of refractory idiopathic thrombocytopenic purpura (ITP) and thrombotic thrombocytopenic purpura (TTP): report of three cases

Three patients (one with idiopathic thrombocytopenic purpura [ITP] and two with thrombotic thrombocytopenic purpura [TTP]) were treated with rituximab (anti-CD20 chimeric antibody) at a dose of 325 mg/m2 administered weekly after they failed standard therapies. The patient with ITP who did not respond to steroids and anti-D antibody administration achieved augmentation of her platelet counts up to 180 x 10(3)/microL after four doses of rituximab. Six months later, when her counts started to decrease, she received maintenance therapy with an additional course of 4 standard doses of antibody that resulted in consolidation of her platelet counts around 100 x 10(3)/microL. One patient with TTP and concurrent idiopathic nephropathy who was previously treated with plasmapheresis, steroids, and vincristine improved only after 4 weekly administrations of the antibody. Moreover, his nephrotic-range proteinuria resolved after he received rituximab. The other patient with chronic TTP who still relapsed after splenectomy received 5 doses of rituximab with concomitant plasmapheresis. His thrombocytopenia improved slowly, and his platelet count stabilized at 300 x 10(3)/microL. All three patients showed evidence of response to anti-CD20 antibody with improvement in clinical outcome as well as augmentation of platelet counts to normal levels. We conclude that rituximab is a useful immunomodulating adjunct in the treatment of refractory ITP and TTP.     

Refractory chronic immune thrombocytopenic purpura in a child with acute lymphoblastic leukemia

Immune thrombocytopenic purpura (ITP) has been associated with several hematologic malignancies such as Hodgkin and non-Hodgkin lymphomas and chronic lymphocytic leukemia, but it is rare in children with acute lymphoblastic leukemia (ALL). Here, we report a 7-year-old girl with chronic ITP during early intensive phase of chemotherapy for ALL. She underwent splenectomy because thrombocytopenia had persisted even after treatment with intravenous immunoglobulin (IVIG), steroids, vincristine, rituximab, and anti-D antibody. After splenectomy, her platelet count had recovered, and maintenance therapy could be resumed with a support of IVIG. To our knowledge, this is the first child case of chronic ITP during chemotherapy for ALL and splenectomy was effective in this patient.     

The effect of therapy on platelet-associated autoantibody in chronic immune thrombocytopenic purpura

Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disorder due to autoantibody-induced destruction of platelets. Several forms of therapy have been used, including corticosteroids, splenectomy, danazol, and a variety of immunosuppressants. We studied the mechanism of action of some of these treatments by evaluating patients' platelet- associated autoantibodies (PAAb) and platelet count before and serially following therapy. Treatment with corticosteroids, splenectomy, cyclophosphamide, and combination chemotherapy resulted in a progressive decrease in PAAb associated with an improvement in the platelet count, and appeared to act by primarily affecting autoantibody production. Conversely, PAAb levels either remained stable or increased during vincristine or danazol therapy despite improvement in the platelet count, suggesting that the major effect of these agents was decreased platelet removal by the reticuloendothelial (RE) system.     

Combination chemotherapy with CHOP for recurrent thrombotic thrombocytopenic purpura

We report the case of a 42-year-old woman with chronic recurrent thrombotic thrombocytopenic purpura. Therapy with corticosteroids, high-dose immunoglobulins, plasma exchange and cyclophosphamide only induced short-lasting remissions during a course of almost 3 months. Following a severe relapse on day 90 after the start of symptoms, polychemotherapy with cyclophosphamide, adriamycin, vincristine and prednisolone (CHOP) was begun. After two cycles of CHOP the patient has stayed in complete remission, with normal platelet counts for more than 9 months to date.     

Rituximab treatment of refractory fludarabine-associated immune thrombocytopenia in chronic lymphocytic leukemia

Fludarabine can exacerbate idiopathic thrombocytopenia (ITP) in chronic lymphocytic leukemia (CLL). We report 3 CLL patients with refractory fludarabine-associated ITP who responded to rituximab. The patients had Rai stages III, III, and IV disease. Before fludarabine treatment, the platelet counts were 141 000/microL, 118 000/microL, and 70 000/microL. ITP developed within week 1 of cycle 3 in 2 patients and within week 2 of cycle 1 in 1 patient. Platelet count nadirs were 4000/microL, 1000/microL, and 2000/microL, respectively, and did not respond to treatment with steroids or intravenous immunoglobulin. Rituximab therapy (375 mg/m(2) per week for 4 weeks) was begun on days 18, 23, and 20 of ITP. Patient 1 achieved a platelet count of more than 50 000/microL at day 21 and more than 133 000/microL at day 28, patient 2 achieved a platelet count of more than 50 000/microL at day 4 and more than 150 000/microL at day 10, and patient 3 achieved a platelet count of more than 50 000/microL at day 5 and 72 000/microL at day 28 of rituximab therapy, with platelet response durations of 17+, 6+, and 6 months. These results suggest rituximab can rapidly reverse refractory fludarabine-associated ITP.     

Intravenous cyclophosphamide therapy in a case with refractory thrombotic microangiopathic hemolytic anemia and SLE

The case of a 27-year-old woman who simultaneously presented with SLE and severe refractory thrombotic microangiopathic hemolytic anemia (TMHA) is reported. She had extremely high levels of platelet-associated IgG (PAIgG), and her TMHA was refractory to plasma exchange and corticosteroid therapy. However, the TMHA was effectively controlled by i.v. cyclophosphamide therapy. ITP and TTP are generally considered distinct diseases; however, TMHA may occur secondary to platelet aggregation via autoimmune mechanisms in certain cases. Immunosuppressive therapy at an early stage of the disease may be beneficial in refractory cases of TMHA with autoimmune features.     

Hemorrhagic sequelae of immune thrombocytopenic purpura in human immunodeficiency virus-infected hemophiliacs

Clinical bleeding tendency and tests of immune function were studied prospectively in 11 human immunodeficiency virus (HIV)-infected hemophiliacs with immune thrombocytopenic purpura (ITP) and a platelet count less than 50,000/microL. These 11 patients represented 13% of a well-characterized cohort of 87 HIV + hemophiliacs. ITP developed a mean 3.5 years after seroconversion, mean platelet count at presentation was 36,000/microL (range 15,000 to 49,000/microL), and the mean age at seroconversion was 37.1 years. Nine patients (82%) suffered bleeding complications, including four with intracranial hemorrhage, which was fatal in three. At the onset of ITP, five had AIDS and six were asymptomatic. Mean T4 lymphocyte count at onset of ITP was 126 +/- 32/microL (range 5 to 267/microL). Sustained treatment responses occurred with intravenous gammaglobulin (2 of 2), one of whom spontaneously remitted, and with zidovudine (1 of 2), but not with steroids (0 of 6) or danazol (0 of 3). In conclusion, 13% of a cohort of HIV + hemophiliacs has developed ITP with platelets less than 50,000/microL, a significant proportion of whom (82%) have experienced bleeding complications. It is recommended that treatment for ITP in HIV + hemophiliacs be instituted once the platelet count falls below 50,000/microL in order to avoid serious hemorrhagic sequelae.     

Life-threatening hypercoagulable state following splenectomy in ITP: successful management with aggressive antithrombotic therapy and danazol.

A life-threatening hypercoagulable state (HCS) is reported that developed after splenectomy in idiopathic thrombocytopenic purpura (ITP). A 50-year-old active male was rejected for blood donation because of an incidental finding of low platelet counts, 40,000/uL. The diagnosis was ITP. Although asymptomatic, he underwent splenectomy because of poor response to steroids and intravenous (IV) gamma globulin. One month after splenectomy, he suffered pulmonary emboli without deep venous embolism (DVT), followed by bilateral DVT, threatening amputation of the legs. Emergency thrombolysis, insertion of stent, and IV heparin saved his legs. Extensive workup for HCS was negative. IV heparin was withheld for colonoscopy for possible gastrointestinal neoplasm, at which time DVT recurred, necessitating another thrombolysis and heparin infusion. He was discharged on enoxaparin, antiplatelet therapy, and danazol. Platelet hyperactivation, characterized by high platelet microparticles (PMP) and CD62P, was present throughout his course of active ITP, resolving when ITP went into remission with danazol therapy. ITP has remained in remission for 4 years after stopping enoxaparin and danazol. In vitro, his plasma in active ITP induced activation of normal platelets, generating PMP and inducing CD62p-positive platelets and platelet aggregates; his plasma from remission had no effect. This indicates the presence of a platelet activating factor, possibly anti-platelet antibodies. Splenectomy may have allowed procoagulant PMP to accumulate to high levels resulting in HCS. We advise awareness of thrombotic complications post-splenectomy in the subset of ITP patients who are largely asymptomatic and exhibit persisting platelet activation.     

High-dose gammaglobulin therapy for idiopathic thrombocytopenic purpura in adults

High-dose gammaglobulin therapy for patients with idiopathic thrombocytopenic purpura (ITP), introduced by Imbach et al., was applied to 5 adults with chronic refractory ITP to investigate the mechanism of the increase in platelet counts. In 4 of the 5 cases, transient increase in platelet count was observed. Platelet-associated IgG was decreased in 3 cases, increased in 1 case and unchanged in 1 case after treatment. In 4 cases having a variety of autoantibodies, the antibody titers decreased after treatment. No significant changes in antiplatelet antibody titers in serum, or in circulating immune complexes were observed during or after these treatments. No side effects were noted in any of the cases. These results indicate that the treatment is suitable for the treatment of patients prior to surgery and of patients at high risk of intense bleeding and death. It can be reasonably assumed that the increased platelet count is mainly due to a defective removal of antibody-coated platelets.     

Successful treatment with vincristine for an elderly patient with idiopathic thrombocytopenic purpura]

A 77-year-old female was referred to our hospital in March 1991 because of a severe bleeding tendency. Her blood count on admission was as follows: Hb 7.5 g/dl, WBC 4.6 x 10(9)/l with normal differentiation and platelet 2 x 10(9)/l. One month prior to admission, her blood count was normal. Initially, acute idiopathic thrombocytopenic purpura (ITP) was suspected, because of the acute onset of the bleeding tendency and thrombocytopenia. High dose intravenous immunoglobulin (400 mg/kg/day for 5 days) and bolus methylprednisolone (1 g/day for 3 days then tapered) were administered, starting March 13. Her platelet count had increased immediately on March 20 to 40 x 10(9)/l. However, platelet count decreased to 4 x 10(9)/l in the following two weeks. Her clinical course differed from that of typical acute ITP. Because the treatment with prednisolone was not effective, it was changed to intravenous infusion of vincristine (VCR) at a weekly dose of 1 mg for 6 weeks. The treatment was extremely effective, and her platelet count reached over 200 x 10(9)/l. The treatment was discontinued. Three weeks later, her platelet count decreased to 15 x 10(9)/l, the administration of VCR was resumed, and her platelet count recovered again. Throughout her clinical course, no side effect of VCR was noticed except for mild hypesthesia of the fingertips. VCR therapy was considered to be an useful treatment in elderly patients with ITP.     

Thrombotic thrombocytopenic purpura: Prolonged coma with recovery of neurologic function with intensive plasma exchange

A 45-year-old-woman was presented with fever, microangiopathic hemolytic anemia, thrombocytopenia, purpura, and mental status changes. She was diagnosed as having thrombotic thrombocytopenic purpura (TPP). She was treated with daily plasma exchange and antiplatelet drugs, steroids, and vincristine. This patient had a remarkable course with 18 days of coma on full therapy followed by essentially complete recovery coincident with an increase of the plasma exchange dose to two plasma volumes processed per procedure. The patient has remained well with discontinuation of plasma exchange. We conclude that prolonged coma without evidence of major central nervous system structural lesions in TTP should be treated vigorously and continuously with plasma exchange.     

Qualitative Platelet Abnormalities in a Patient with Chronic Idiopathic Thrombocytopenic Purpura (ITP)††

A patient is described with active, chronic idiopathic thrombocytopenic purpura (ITP) and qualitative platelet abnormalities. An antiplatelet factor was demonstrated by the reduced survival of both autologous and isolo-gous platelets, and its identification as antibody suggested by positive tests for antiplatelet antibody. The major abnormalities of platelet function were reduced platelet adhesion in vivo and to glass, and reduced platelet aggregation with ADP, Ristocetin and collagen. ADP-induced aggregation of normal platelets was reduced by prior incubation of the normal platelets with the patient's platelet-poor plasma (PPP). It is suggested that abnormal platelet function in ITP may be an index of antibody activity, a determinant of premature platelet removal by the reticulo-endothelial system (RES) and a contributing factor to impaired haemostasis.     

Life-threatening severe immune thrombocytopenia during alpha-interferon therapy for chronic hepatitis C

Although mild thrombocytopenia is a common adverse effect of interferon therapy, severe life-threatening thrombocytopenia is extremely rare. Here, we report a case of chronic hepatitis C patient that developed severe thrombocytopenia during alpha-interferon therapy, possibly due to an autoimmune mechanism. A 24-year-old female presented chronic hepatitis C in May, 1998. Based on the clinicopathological findings including a liver biopsy, administration of alpha-interferon was begun. In the fourth week of therapy, she experienced mild dyspnea and general fatigue. Complete blood count demonstrated thrombocytopenia (48,000/microL). Despite the immediate withdrawal of interferon, her platelet count further decreased to 1,100/microL. Bone marrow aspirate and elevated platelet-associated IgG antibodies were suggestive of immune thrombocytopenia. She was treated with intravenous and oral administration of steroids. Her platelet count returned to normal level 5 days later. Response to steroid treatment was consistent with the diagnosis of alpha-interferon-induced immune thrombocytopenia in this patient.     

A case of rheumatoid arthritis complicated with idiopathic thrombocytopenic purpura and Hashimoto's disease

A 37 year old nurse with the rare combination of idiopathic thrombocytopenic purpura (ITP), Hashimoto's thyroiditis and rheumatoid arthritis (RA) was reported. In 1983, six years before her final diagnosis was made, she presented with purpura over her extremities and swelling of the cervical lymph nodes. Laboratory findings showed the following: platelet count 15 x 10(3)/microliters, the number of megakaryocyte without platelet production in bone marrow was increased, platelet life span (T1/2) 11 min. A diagnosis of ITP was made. In 1984 goiter was noticed. Laboratory data were as follows: T3 502ng/ml, T4 27.0 micrograms/dl, thyroid test x 1,600, microsome test x 409,600. She was diagnosed as having ITP and Hashimotoxicosis. She had been uneventful except temporary hyperthyroidism until 1989 when she developed morning stiffness, polyarthralgia, swelling of PIP joints, contracture of elbow joints and hallux valgus. Laboratory investigation were reported as follows. ESR 111mm/h, platelet count 31 x 10(3)/microliters, platelet associated IgG 800ng/10(7) pl, antinuclear antibody x 2,560, rheumatoid factor 1+, microsome test x 1,600, anti-DNA antibody 3U/ml. Anti-Sm antibody and anti-RNP antibody were not detected. The LE cell test was negative. Schirmer test and sialography were interpreted as normal. These findings confirmed the diagnosis of RA in addition to ITP and Hashimoto's thyroiditis. The combination of RA, ITP and Hashimoto's thyroiditis is extremely rare although these three disorders are classified as autoimmune disease.     

Danazol therapy in refractory chronic immune thrombocytopenic purpura

We report our experience with danazol in the treatment of patients with refractory immune thrombocytopenic purpura (ITP). The effects of this drug were investigated in 10 patients, 6 males and 4 females, aged from 40 to 85 years, (median 58 years), with a platelet count below 50 X 10(9)/l. The patients had previously been treated with steroids; one of them had also been unsuccessfully splenectomized. Danazol was administered at a dosage of 600 mg/day for 3 months. Before and after treatment, detection of antiplatelet antibodies was performed. Seven patients were treated for 3 months. One of them showed a transient increase of platelet count, in the others, no significant rise was noted. Six patients experienced side effects during treatment. We think that danazol does not appear to be an alternative therapeutical approach in refractory ITP.     

High-dose dexamethasone as a first- and second-line treatment of idiopathic thrombocytopenic purpura in adults

The current first-line choice of treatment of idiopathic thrombocytopenic purpura (ITP) in adults, prednisone, is effective but has many side effects. Furthermore, reduction of the dose leads to a relapse of ITP in a majority of cases. Courses of high-dose dexamethasone (HD) aim to avoid these problems. We treated 36 patients with newly diagnosed or recurrent ITP with an 8-day course of HD, with a peak dose of 40 mg/day. The courses were repeated up to a maximum of six courses, with a 28-day interval. Acute and chronic effects of HD on platelet counts were observed, as well as side effects. HD led to an acute response (rise of platelet count to a level above 50×10⁹/l) in 83%. When HD was given as a first-line treatment, 59% of patients were still in remission after 31 months. When HD was given as a second-line treatment, 50% of patients were in remission after 5 months, declining to 25% after 54 months. Side effects were frequent but rarely dangerous. In conclusion, acute effects of HD were excellent. Long-term effects of HD as a first-line therapy of ITP were good, but its long-term effects as a second-line therapy were much poorer.     

Specific antiplatelet autoantibodies in patients with antiphospholipid antibodies and thrombocytopenia

By means of immunoblotting and monoclonal antibody immobilization of platelet antigens (MAIPA) we have studied the specificity of antiplatelet antibodies in patients with antiphospholipid antibodies and thrombocytopenia defined as presence of anticardiolipin IgG and a platelet count below 100 × 10⁹/l. The study group consisted of 10 patients with systemic lupus erythematosus (SLE), 8 patients with primary anti-phospholipid syndrome (PAPS) and 16 patients with idiopathic thrombocytopenic purpura (ITP). The comparison group was formed by 17 patients with classical chronic ITP without anticardiolipin IgG. We identified the 80–100, 130–150 and 150–170 KD surface proteins that comigrate with GPIIIa, GPIIb and GPIb and a 50–70 KD cytoplasm band by immunoblot. In patients with classical chronic ITP, the prevalence of the antiplatelet antibodies against GPIIIa was 53% on immunoblot assay and 47% on MAIPA. In ITP patients who had also anti-phospholipid antibodies in serum, the percentage of reactivity to GPIIIa declined to 37% on immunoblot and 21 % on MAIPA but it was not statistically different from the percentage observed in patients with classical ITP. Autoantibodies to platelet surface glycoproteins were almost absent in SLE and PAPS patients, who showed a significant prevalence (78%) of IgG reactivity to the 50–70 KD internal platelet protein which was frequently encountered also in patients with ITP and aPL (56%). Our study provides additional evidence that platelet antigens in patients with phospholipid-associated secondary immune thrombocytopenia are different from those of primary ITP, and that surface glycoproteins were not involved.     

THROMBOCYTOPENIA IN A CASE OF SYSTEMIC LUPUS ERYTHEMATOSUS: REPEATED ADMINISTRATION OF 'PULSE' METHYL PREDNISOLONE

The case of a young woman with systemic lupus erythematosus(SLE) is reported in whom thrombocytopenia was a major featureof her disease. She was given three courses of ‘pulse’intravenous methyl prednisolone (IVMP) on separate occasionsas treatment for profound thrombo-cytopenia. A diminishing responsein platelet count was obtained following each course. She receiveda further course of IVMP for treatment of a nephritis, witha moderate platelet response: this may have been related inpart to concomitant oral cyclophosphamide. IVMP may be an effective treatment for SLE-associated thrombocytopeniabut repeated courses may result in a reduced platelet response. KEY WORDS: Systemic lupus erythematosus, Thrombocytopenia, Pulse steroid therapy     

Antiplatelet antibodies and their correlation with clinical findings in childhood immune thrombocytopenic purpura

The demonstration of antiplatelet antibodies (PAIgG, PAIgM) and decreased detection of platelet surface antigens (CD41, CD61, CD42b) in children with immune thrombocytopenic purpura (ITP) have a diagnostic role. This study was conducted to determine whether these parameters differed in acute and chronic ITP. Chronic ITP was defined as thrombocytopenia persisting for more than 6 months from the onset of illness. A total of 80 subjects were divided into three groups: group 1 included 39 patients with acute ITP; group 2 included 31 patients with chronic ITP, and group 3 included 10 healthy children. At diagnosis, blood samples were obtained for platelet count, mean platelet volume, plateletcrit and platelet distribution width along with platelet surface antigens and antiplatelet immunoglobulins. We found that platelet surface antigens were significantly decreased in both acute and chronic ITP when compared to the control group (p = 0.001). In contrast, PAIgG was increased in acute and chronic ITP patients compared to the control group. PAIgM was significantly higher in acute ITP. We conclude that decreased platelet surface antigens and increased antiplatelet antibodies are observed in both acute and chronic ITP. In patients with chronic progress, a relatively lower level of PAIgM can be identified.     

Splenectomy for immune thrombocytopenic purpura: long-term results and treatment of postsplenectomy relapses

Information regarding prognostic determinants of outcome after splenectomy for adult immune thrombocytopenic purpura (ITP) and the management of postsplenectomy relapse is limited. Among 140 adult patients with ITP who had therapeutic splenectomy at our institution, 88% achieved either a complete (platelets > 150 x 10(9)/l) or a partial (platelets > or = 50 x 10(9)/l) response that was sustained for at least 1 month. At 3, 6, and 12 months after splenectomy, time-adjusted complete response rates were 77%, 71%, and 74%, respectively. The 5-year relapse-free survival was 75%; all but three relapses occurred within 2 years of splenectomy. In multivariate analysis, younger age and higher peak postsplenectomy platelet counts were significantly associated with a favorable response to splenectomy. None of several preoperative or perioperative variables was predictive of a relapse after an initial response to splenectomy. Corticosteroids, danazol, vincristine, and cyclophosphamide were often effective in the treatment of patients who were either refractory to or had a relapse after splenectomy. One patient responded to rituximab after not responding to corticosteroids, azathioprine, and vincristine. After a median follow-up of 37.5 months (range: 0-183) from splenectomy, there were 25 deaths, including 2 from postoperative complications, 1 from gastrointestinal bleeding related to thrombocytopenia, and 1 from overwhelming sepsis related to the splenectomized state. The current study provides additional data on both the long-term outcome of splenectomy in adults with ITP and the management of postsplenectomy relapse.