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Although outstanding progress has been made in understanding the pathophysiology of thrombotic thrombocytopenic purpura (TTP), knowledge of the immunopathogenesis of the disease is only at an early stage. Anti-ADAMTS13 auto-antibodies were shown to block proteolysis of von Willebrand factor and/or induce ADAMTS13 clearance from the circulation. However, it still remains to identify which immune cells are involved in the production of anti-ADAMTS13 autoantibodies, and therefore account for the remarkable efficacy of the B-cell depleting agents in this disease. The mechanisms leading to the loss of tolerance of the immune system towards ADAMTS13 involve the predisposing genetic factors of the human leukocyte antigen class II locus DRB1*11 and DQB1*03 alleles as well as the protective allele DRB1*04, and modifying factors such as ethnicity, sex and obesity. Future studies have to identify why these identified genetic risk factors are also frequently to be found in the healthy population although the incidence of immune-mediated thrombotic thrombocytopenic purpura (iTTP) is extremely low. Moreover, the development of recombinant ADAMTS13 opens a new therapeutic era in the field. Interactions of recombinant ADAMTS13 with the immune system of iTTP patients will require intensive investigation, especially for its potential immunogenicity. Better understanding of iTTP immunopathogenesis should, therefore, provide a basis for the development of novel therapeutic approaches to restore immune tolerance towards ADAMTS13 and thereby better prevent refractoriness and relapses in patients with iTTP. In this review, we address these issues and the related challenges in this field., (Copyright© 2018 Ferrata Storti Foundation.)

Background: The assay for ADAMTS13 activity helps clinicians to confirm the clinical diagnosis of idiopathic thrombotic thrombocytopenic purpura. The clinical value of testing for the antigen level of ADAMTS13 protein is, however, less clear., Design and Methods: In this study, both ADAMTS13 antigen and activity levels were measured in 835 sequential samples from 40 consecutive patients who were followed for an average of 29 months throughout the course of acute episode plasma exchange treatment and clinical remission., Results: During acute episodes, ADAMTS13 activity was severely deficient while ADAMTS13 antigen levels were more variable, ranging from severely deficient to as high as within the reference range. A severe depletion of ADAMTS13 antigen level during acute disease was, however, statistically associated with disease mortality (P=0.0322). For patients who achieved initial clinical responses, ADAMTS13 antigen levels appeared to be restored faster than ADAMTS13 activity to the normal range. Further analysis demonstrated that the ADAMTS13 antigen level at the time of initial clinical recovery was significantly higher in the patients who subsequently achieved a sustained clinical remission than in the group who soon after had an exacerbation (P=0.0187)., Conclusions: Our data suggest that evaluation of ADAMTS13 antigen levels during the course of therapy and follow-up may offer additional useful information for the management of patients with thrombotic thrombocytopenic purpura.

Background and Objective: For several decades clinicians worldwide considered TTP a severe and frustrating therapeutic problem. Fortunately, however, the prognosis of TTP patients has greatly benefited from the use of plasma manipulation techniques, particularly plasma-exchange (PE), so that the overall rate of complete responses currently ranges between 70-85% and may even exceed these figures. Despite this dramatic improvement, a number of questions remain concerning the best treatment for TTP patients. Analyzing acquired data and discussing future perspectives, this review will address the following key issues: is PE really the treatment of choice for TTP and what is the role of PE with cryosupernatant? what is the role of all the drugs which are commonly combined with PE, antiplatelet drugs and steroids in particular? what, if any, is the role of cytotoxic agents, especially vincristine? is there a treatment for PE-resistant patients? does secondary TTP need different treatments?, Design and Methods: The authors have been involved in the study and treatment of TTP for years; furthermore, they extensively searched the PubMed database of the National Library of Congress through the Internet., Interpretation and Conclusions: PE remains the treatment of choice for TTP. A large randomized trial now in progress will assess whether exchange with cryosupernatant plasma can improve treatment efficacy. The administration of antiplatelet drugs in combination with PE was fiercely debated over the past years but seems indicated both in acute TTP and as a prophylactic treatment to prevent relapses. It appears that steroids cannot be avoided, especially in light of the latest findings on TTP pathogenesis, but only specific trials will assess the optimal cortisone type and dose. Presently, different treatments can be suggested only to patients failing to respond to PE, while no specific therapy can be indicated for secondary TTP, which usually has a very poor prognosis. Finally, we would like to stress that only international co-operative (multicenter) trials on large series of patients will be able to shed light on a still obscure, if fascinating, disease. Our hope and wish is that the new century will see TTP among the diseases defeated by man's clever mind and heart.

Background and Objective: The key pathogenic feature of TTP is the formation of platelet aggregates within the microcirculation; however, the etiology of such aggregates has been elusive for years. A large amount of evidence points to an abnormal interaction between damaged vascular endothelium and platelets, although the cause of the primary microvascular endothelial cell injury is seldom clear. The autoimmune hypothesis often recurs, and this is based on a number of observations: the claimed superiority of plasma-exchange over plasma infusion, the anecdotal report of the presence of immunocomplexes and autoantibodies in TTP patients, the efficacy of the administration of corticosteroids and other immunosuppressant agents, and the concomitant occurrence of TTP in association with autoimmune diseases, especially systemic lupus erythematosus (SLE). This review will focus on the complex relationships between TTP and humoral autoimmunity; in particular, similarities and differences between TTP, SLE and antiphospholipid (aPL) antibodies syndrome, as well as the putative role of several other antibodies directed towards endothelial cells and/or platelets, including the recently discovered anti-CD36 antibodies and antivWF-cleaving metalloprotease, will be discussed., Design and Methods: The authors have been involved in the study and treatment of TTP and autoimmune diseases for years; furthermore, the PubMed data base of the National Library of Congress has been extensively searched using the Internet., Conclusions: Although over the years evidence has increased in favor of the autoimmune hypothesis for TTP etiopathogenesis, TTP should not yet be considered an autoimmune disease. Autoantibodies should be regarded as only one of the many different insults which can trigger microvascular thrombosis even though the autoimmune theory of the pathogenesis of TTP is gaining more and more strength. As far as concerns the relationship between TTP, SLE and aPL antibodies-related disorders, these diseases should be distinguished on the basis of both different clinical presentations and accurate antibody screening, although this approach should definitely not delay the prompt start of treatment.

Background and Objective: Antiplatelet agents are often included in plasma exchange-based regimens for thrombotic thrombocytopenic purpura (TTP) patients; however, the opportuneness of their use in TTP is still controversial. The italian Cooperative Group for TTP carried out a randomized trial to investigate their actual effectiveness, both in acute TTP and as maintenance treatment., Methods: Seventy-two TTP patients were randomized to receive plasma exchange and steroids with (group B) or without (group A) aspirin and dipyridamole. Treatment efficacy was evaluated after 15 days and salvage treatments were also considered for non-responders. Upon disease remission, the patients already treated with antiplatelet agents received ticlopidine for one year., Results: Regarding the treatment of acute phase TTP, similar overall response rates were observed in the two groups (91.4% in group B vs. 75.6% in group A), but lower mortality rates were observed at 15 days in the patients treated with antiplatelet agents; as a matter of fact, 5 patients from arm A died in the first 15 days (13.5%) versus only one in arm B (2.8%). These figures, while not statistically significant, seem to suggest that antiplatelet agents might be useful in preventing deaths in acute TTP; moreover, bleeding did not worsen in antiplatelet agent-treated patients. As for the role of maintenance treatment, our results support the efficacy and safety of one-year ticlopidine therapy since the current relapse rate is significantly higher in non-treated patients; as a matter of fact, 6 patients (21.4%) in the non-ticlopidine group and only 2 (6.25%) in the ticlopidine group relapsed (P = .0182 in favor of maintenance treatment)., Interpretation and Conclusions: Our results suggest the usefulness of antiplatelet agents in the treatment of acute phase TTP patients. Moreover, one-year ticlopidine maintenance therapy appears to be beneficial in preventing TTP relapses; however, only the completion of an adequate follow-up for all patients will definitively confirm this observation.

Treatment of thrombotic thrombocytopenic purpura (TTP) with cryoprecipitate-poor plasma (cryosupernatant) as substitution liquid has brought a portion of the relapsing forms of this syndrome under control. We experimented the use of plasma exchange (PE) with CPP as plasma substitute in the initial treatment of four patients with TTP at onset, in an attempt to elicit a faster response to therapy. We observed a clinical response in the four patients treated; however, laboratory indices of complete and stable response (platelet count, serum lactate dehydrogenase level) did not normalize in concert with clinical improvement.

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare vascular disorder of unknown etiology. There is evidence to support the hypothesis that platelets and endothelium play a pivotal pathogenetic role. Immunological assays for plasma thrombomodulin and P-selectin levels have recently been made available and they allow simple evaluation of endothelial damage and endothelial/platelet activation, respectively. In this study, we measured the plasma levels of thrombomodulin, P-selectin and von Willebrand factor in 9 TTP patients during active disease and at the time of complete remission (CR)., Methods: Thrombomodulin, P-selectin and von Willebrand factor were measured by enzyme immunoassay., Results: Mean thrombomodulin and von Willebrand factor plasma values were always within the normal range. P-selectin plasma levels, both in the active phase of the disease and in CR (median 312 and 185 ng/mL, respectively), were significantly higher than in normal controls (mean 96 +/- 35 ng/mL, mean 88 ng/mL; p < 0.05). However, the mean value of P-selectin in CR (median 185 ng/mL) was significantly lower than that observed at diagnosis (p < 0.05). In addition, an inverse relationship between P-selectin plasma levels and platelet count (r = -0.526; p = 0.03) was observed., Conclusions: These findings suggest that activation of platelets and/or endothelium may play a relevant role in the pathogenesis of TTP.

We report two cases of thrombotic thrombocytopenic purpura (TTP) in advanced stage HIV-positive patients (CD4+ < 0.05 x 10(9)/L). Clinical symptoms were relevant, but their course was not fulminant; the two patients responded to different therapies (plasma or plasma plus plasmapheresis, and steroids), showing rapid improvement in symptoms. One patient remained asymptomatic with zidovudine only, while the other relapsed (probably due to an intercurrent infection). This second person is now asymptomatic on zidovudine plus low doses of steroids.

Background: Plasma exchange (PE) with reinfusion of fresh frozen plasma (FFP) is the therapy of choice for thrombotic thrombocytopenic purpura (TTP) in the acute phase. About 20% of patients do not respond fully to this treatment and can suffer relapse. The plasma cryosupernatant (PCS) fraction depleted of the largest von Willebrand factor (vWF) multimers, considered to be among the possible causes of relapse, has recently been suggested as an alternative to FFP., Methods: We submitted three patients in TTP relapse to plasma exchange with reinfusion of PCS. This treatment was associated with anti-platelet agents in two of the patients., Results: Infusion of PCS led to a rapid improvement of the clinical picture in all three patients, with a return to normal of the reference parameters (platelet count' serum LDH). A few days after suspending PE, the patient not receiving anti-platelet treatment suffered another relapse which was definitively resolved with resumption of PE and administration of anti-platelet agents., Conclusions: We consider PCS to be a valid alternative treatment for TTP relapses, and we have found that the best results are obtained when it is associated with anti-platelet agents.

Long-lasting remission after high-dose intravenous immunoglobulins in a case of relapsing thrombotic thrombocytopenic purpura (TTP) is reported. The patient had two early relapses after intensive plasma-exchange therapy. Serum platelet aggregating factor was absent. High-dose intravenous immunoglobulins (i.v. Ig) (0.4 g/Kg/day for 5 days) were infused. Platelet count promptly rose and 7 days after the completion of immunoglobulins complete response was obtained. The patient is still in complete remission, without further Ig infusion, 19 months later. This case adds to the anecdotal reports on the effectiveness of Ig, even when not associated with other treatments, in TTP. High-dose i.v. Ig could be successfully used in relapsing or unresponsive patients with TTP.

We report on the cases of two women with acute thrombotic thrombocytopenic purpura (TTP) whose clinical courses were characterized by the onset of a coma state. Prompt commencement of plasma-exchange (PE) treatment led to complete hematological and neurological remission, which can still be observed without any maintenance therapy. No CNS abnormalities were observed in either patient using brain CT and NMR scans.

The clinical characteristics, treatment and outcome are reported in 7 patients with 8 episodes of thrombotic thrombocytopenic purpura (TTP). In all episodes a complete remission was reached. Plasma exchange therapy was successful as single treatment in two episodes. Combination with other treatment modalities, however, was necessary in six episodes, in which a complete hematologic and clinical remission was obtained with antiplatelet therapy (4 X), and with antiplatelet therapy and corticosteroids (2 X).