SummaryIdiopathic thrombocytopenic purpura (ITP) is characterized by a low platelet count, which is the result of both increased platelet destruction and insufficient platelet production. Although the development of autoantibodies against platelet glycoproteins remains central in the pathophysiology of ITP, several abnormalities involving the cellular mechanisms of immune modulation have been identified. Conventional treatments for ITP aim at reducing platelet destruction, either by immunosuppression or splenectomy. Two new thrombopoietic agents, AMG 531 and eltrombopag, have been used in clinical trials to stimulate platelet production in ITP patients not responsive to standard treatments. These new molecules bear no structural resemblance to thrombopoietin, but still bind and activate the thrombopoietin receptor. This review will focus on the pathophysiology and treatment of ITP in adults, highlighting recent advances in both fields.

The effects of B-cell depletion with rituximab on regulatory T cells (Tregs) have not been determined. We investigated Tregs in patients receiving rituximab for chronic idiopathic thrombocytopenic purpura (ITP). The peripheral blood Tregs, identified as CD4+FOXP3+ T cells, were measured by flow cytometry prior to and after the immunotherapy. In addition, Tregs were analyzed for their usage of the T-cell receptor (TCR) beta-variable (VB) region gene as well as their regulatory function as assessed by cell proliferation assays. Pretreatment data revealed a reduced number and a defective suppressive capacity of Tregs in ITP patients compared with control individuals. In addition, Tregs showed a polyclonal spectratype. Patients, particularly responders, showed restored numbers of Tregs as well as a restored regulatory function upon treatment with rituximab. These results indicate that patients with active ITP have a defective T regulatory cell compartment that can be modulated by a B cell-targeted therapy.

Rituximab, an anti-CD20 monoclonal antibody, has been used to treat autoimmune disorders such as idiopathic thrombocytopenic purpura (ITP). However, its mechanisms of action as well as the effects on cellular immunity remain poorly defined. We investigated the changes of different peripheral blood T-cell subsets, the apoptosis profile, as well as the changes of T-cell receptor (TCR) beta-variable (VB) region gene usage of CD4+ and CD8+ T-cell subpopulations following rituximab therapy. The study involved 30 patients with chronic ITP who received rituximab, of whom 14 achieved a durable (> 6 months) response. Compared with the control group, pretreatment abnormalities of T cells in ITP patients included an increase of the Th1/Th2 ratio and of the Tc1/Tc2 ratios (P < .001), increased expression of Fas ligand on Th1 and Th2 cells (P < .001), increased expression of Bcl-2 mRNA (P = .003) and decreased expression of bax mRNA (P = .025) in Th cells, and expansion of oligoclonal T cells with no preferential use of any TCR VB subfamily. These abnormalities were reverted in responders at 3 and 6 months after treatment, whereas they remained unchanged in nonresponders. Our findings indicate that in patients with ITP, response to B-cell depletion induced by rituximab is associated with significant changes of the T-cell compartment.

In a recent article we indicated that rituximab is an active and safe drug in patients with chronic ITP. We report now the updated results of this study. Twenty-five individuals with chronic ITP were treated with intravenous rituximab at the dose of 375 mg/m2 once weekly for 4 weeks. Rituximab infusion-related side effects were observed in 18 patients, but they were of modest intensity and did not require discontinuation of treatment. Long-term side effects included a decreased B-cell count of several months duration in most patients which, however, did not translate into a significant rate of infections. The overall response rate was 52%, with 7 cases showing a sustained response (6 months or longer). In 2 patients with relapsed disease, repeat challenge with rituximab induced a new response. In responders a significant rise in platelet concentrations was observed early during the course of treatment, usually 1 week after the first rituximab infusion. No clinical or laboratory parameter was found to predict treatment outcome. In conclusion, we confirm that rituximab can induce long-lasting responses in patients with chronic ITP and has a favorable side effect profile. Therefore, we suggest its use in refractory ITP cases.

Antiphospholid antibodies are associated with fetal distress and fetal death. Although different therapeutic regimens have been used, the incidence of fetal growth retardation varies between 30 and 60 per cent of reported cases. We report the evolution of fetal growth in patients with antiphospholipid antibody syndrome treated with high‐dose intravenous immunoglobulins (IVIG). Fourteen patients with a history of recurrent spontaneous abortion and immunological diagnosis of antiphospholipid syndrome were followed longitudinally. Intravenous immunoglobulin at a dose of 0.5 g/kg body weight for two consecutive days was started from the fifth week of pregnancy and repeated every 4 weeks until the 33rd week of gestation. Fetal biometry was evaluated longitudinally from the appearance of the gestational sac at 4 weekly intervals. In the period between 26 and 34 weeks, the frequency of evaluation was increased to every 14 days. Data obtained were compared with a control group of 70 fetuses with uneventful pregnancies matched for gestational age. Neonatal weight is shown in relation to the centiles for the normal population. One patient out of 14 (7.1 per cent) developed gestational hypertension and abruptio placentae. No other pregnancy complications were seen. No proteinuria was found. The mean maternal age was 31.2±3.8 years. Median birth weight was 3433 g±287. The median centile of the birth weight was 65.3±18.6. Mean gestational age at delivery was 1.3 weeks. No fetal or neonatal growth retardation was seen. No significant differences were found in the biometrical parameters investigated in the various gestational ages vs. the control group (Student's t‐test not significant); a significant increase in head circumference (P< 0.001) and abdominal circumference (P< 0.05) was found at 36–37 weeks gestational age in the IVIG‐treated fetuses. The presence of antiphospholipid antibodies is considered detrimental for pregnancy outcome because of their negative effects on placental vascular perfusion and fetal transfer of metabolites. The use of IVIG seems to avoid or inhibit the reduced availability of nutrients for the fetal anabolic functions, as the expected reduction in fetal growth was not seen in our series.

Thirty vasculopathic subjects with hyperlipoproteinemia (18) and/or diabetes (22) underwent a clinical double-blind study in order to evaluate the effect of sulodexide on lipid and hemorheologic parameters. The experimental design consisted of a first 20-day i.m. therapeutic period with either sulodexide (300 Lipasemic Units twice daily via intramuscular route) or placebo and the following 70 days with the active compound for both groups at the same posology. Results obtained demonstrated that sulodexide yields a hypotriglyceridemic effect on type IV hyperlipoproteinemia and hypofibrinogenic effect, as well. Moreover, this compound exerted a beneficial effect on HDL Cholesterol levels and on the antithrombin III activity by increasing both parameters significantly. Signs and symptoms were alleviated, particularly in the most severe cases of peripheral vascular disease. Insignificant and slight changes were observed at the end of treatments as regards the efficacy of the two administration routes, the i.m. one being more efficacious on lipid parameters and faster acting. No side effects or intolerance were observed during the different periods of the trial.