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The paradigm for managing primary immune thrombocytopenia (ITP) in adults has changed with the advent of rituximab and thrombopoietin receptor agonists (TPO-RAs) as options for second-line therapy. Splenectomy continues to provide the highest cure rate (60%-70% at 5+ years). Nonetheless, splenectomy is invasive, irreversible, associated with postoperative complications, and its outcome is currently unpredictable, leading some physicians and patients toward postponement and use of alternative approaches. An important predicament is the lack of studies comparing second-line options to splenectomy and to each other. Furthermore, some adults will improve spontaneously within 1-2 years. Rituximab has been given to more than 1 million patients worldwide, is generally well tolerated, and its short-term toxicity is acceptable. In adults with ITP, 40% of patients are complete responders at one year and 20% remain responders at 3-5 years. Newer approaches to using rituximab are under study. TPO-RAs induce platelet counts > 50 000/μL in 60%-90% of adults with ITP, are well-tolerated, and show relatively little short-term toxicity. The fraction of TPO-RA-treated patients who will be treatment-free after 12-24 months of therapy is unknown but likely to be low. As each approach has advantages and disadvantages, treatment needs to be individualized, and patient participation in decision-making is paramount.

Background: Conventional anticoagulant treatment for acute deep vein thrombosis (DVT) effectively prevents thrombus extension and recurrence, but does not dissolve the clot, and many patients develop post-thrombotic syndrome (PTS). We aimed to examine whether additional treatment with catheter-directed thrombolysis (CDT) using alteplase reduced development of PTS., Methods: Participants in this open-label, randomised controlled trial were recruited from 20 hospitals in the Norwegian southeastern health region. Patients aged 18-75 years with a first-time iliofemoral DVT were included within 21 days from symptom onset. Patients were randomly assigned (1:1) by picking lowest number of sealed envelopes to conventional treatment alone or additional CDT. Randomisation was stratified for involvement of the pelvic veins with blocks of six. We assessed two co-primary outcomes: frequency of PTS as assessed by Villalta score at 24 months, and iliofemoral patency after 6 months. Analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00251771., Findings: 209 patients were randomly assigned to treatment groups (108 control, 101 CDT). At completion of 24 months' follow-up, data for clinical status were available for 189 patients (90%; 99 control, 90 CDT). At 24 months, 37 (41·1%, 95% CI 31·5-51·4) patients allocated additional CDT presented with PTS compared with 55 (55·6%, 95% CI 45·7-65·0) in the control group (p=0·047). The difference in PTS corresponds to an absolute risk reduction of 14·4% (95% CI 0·2-27·9), and the number needed to treat was 7 (95% CI 4-502). Iliofemoral patency after 6 months was reported in 58 patients (65·9%, 95% CI 55·5-75·0) on CDT versus 45 (47·4%, 37·6-57·3) on control (p=0·012). 20 bleeding complications related to CDT included three major and five clinically relevant bleeds., Interpretation: Additional CDT should be considered in patients with a high proximal DVT and low risk of bleeding., Funding: South-Eastern Norway Regional Health Authority; Research Council of Norway; University of Oslo; Oslo University Hospital., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Primary immune thrombocytopenia is an acquired autoimmune disorder characterized by platelet count of <100 × 10(9)/l in the absence of other causes of thrombocytopenia. Primary immune thrombocytopenia is defined as 'chronic' when it has been present for more than 12 months without spontaneous remission or maintenance of complete response to therapy. Recently, thrombopoietin receptor agonists became available for treatment of chronic primary immune thrombocytopenia. Anecdotal reports have raised concerns about a possible association between therapy with thrombopoietin receptor agonists and an increase in bone marrow fibrosis. To investigate this association we studied eight patients with primary immune thrombocytopenia in detail comparing fibrosis and other morphological features in pre-therapy and on-therapy bone marrow biopsies, with the longest follow-up reported to date. A slight but significant increase to MF-1 in reticulin fibrosis was observed during therapy, but collagen was never present. On-therapy bone marrows were hypercellular due to panmyelosis with increased trilineage hematopoiesis. Megakaryocytes were increased in number, with acquisition of evident pleomorphism, nuclear hyperlobulation and tendency in some cases to form clusters. The overall picture of the on-therapy marrows was characterized by myeloproliferative neoplasm-like features, resembling essential thrombocythemia or occasionally early primary myelofibrosis. As thrombopoietin receptor agonists are becoming a mainstream treatment for primary immune thrombocytopenia, general pathologists and especially hematopathologists need to be aware of the characteristic morphological changes associated with use of these therapeutic agents, in order to avoid misdiagnosis of a myeloid neoplasm.

This study assessed the grade of bone marrow (BM) fibrosis and its association with a seromarker for collagen-III formation and fibrosis-related cytokines in 25 immune thrombocytopenia (ITP) patients treated with thrombopoietin receptor agonists (Tpo-RA) who had at least one BM biopsy. Assessment of 8 pre- and on-treatment BM biopsies revealed statistically significant increases in reticulin. Reticulin in biopsies performed after a median of 1·4 years of treatment was graded: MF-0 in 3 (12%), MF-1 in 19 (76%), MF-2 in 2 (8%) and MF-3 in 1 (4%). No cytogenetic or flow-cytometric abnormalities were detected. Median pretreatment Procollagen III N-propeptide (PIIINP) (6·6 μg/l) was significantly higher than on-treatment levels (5·6 μg/l); both were higher than controls (3·4 μg/l; P < 0·001). PIIINP was negatively correlated with treatment duration (r = -0·49) suggesting a decelerated reticulin production over time. There was a trend towards an association between grade of reticulin and PIIINP. Transforming growth factor (GF)-beta and basic-Fibroblast GF were not different between patients and controls but Hepatocyte GF (HGF), an anti-fibrotic cytokine, was significantly elevated in patients. In conclusion, low-grade BM reticulin fibrosis is seen in most ITP patients on Tpo-RA. The novel findings of decreasing PIIINP and elevated HGF need further investigation to explore their significance in BM fibrogenesis., (© 2011 Blackwell Publishing Ltd.)

Background: Immune thrombocytopenia (ITP) is caused by immune-mediated platelet destruction and reduced platelet production. The aim of this review article is to provide an updated overview of pathophysiology and new therapeutic modalities in ITP., Material and Methods: The article is based on literature identified through a non-systematic search in PubMed and our own clinical experience., Results: ITP is diagnosed in patients with platelet count < 100 × 10(9)/l after excluding other causes of thrombocytopenia. Anti-platelet autoantibodies are important in the platelet destruction mechanism, but other important mechanisms have been identified in recent years. Patients with very low platelet count < 30 × 10(9)/l are particularly susceptible to bleeding complications. The goal of treatment so far has been to increase the platelet count to a level that reduces the risk of serious bleeding. Thrombopoietin receptor agonists are new therapeutic agents that target the thrombopoietin receptor to increase platelet production. These drugs are shown to be effective in treatment of ITP., Interpretation: New knowledge about pathophysiological mechanisms, such as sub-optimal platelet production in ITP, has led to the development of new therapeutic options which focus on stimulation of platelet production.

Immune thrombocytopenia (ITP) is a disease characterized by accelerated platelet destruction and suboptimal platelet production. The latter concept has led to the exploration of new therapeutic options by focusing on the stimulation of platelet production as opposed to the traditional approach of immune suppression. Thrombopoietic agents act by stimulating the thrombopoietin receptor on the hematopoietic cells leading to stem cell differentiation, megakaryocyte proliferation, and platelet production. The last decade has witnessed the birth of second-generation thrombopoietic agents. Romiplostim and eltrombopag are the two agents that have been recently licensed. In randomized controlled trials, these agents have demonstrated unequivocal superiority over placebo in the treatment of ITP in splenectomized and in nonsplenectomized patients-an effect that seems to be durable while treatment continues and at an acceptable short-/intermediate-term safety profile. These agents represent a new therapeutic option in refractory ITP and in chronic ITP when splenectomy is contraindicated or needs to be deferred. However, the scope of therapeutic indications is expected to expand should long-term safety be confirmed in the ongoing studies. Several other agents are currently being investigated and are in preclinical and clinical development programs.

Background: The conventional treatment of acute deep vein thrombosis (DVT) is anticoagulation and compression therapy, as recommended in the international guidelines. Anticoagulation prevents recurrent venous thrombosis, pulmonary embolism, and death. Compression therapy reduces the risk of developing long-term sequelae, that is, postthrombotic syndrome (PTS). Evaluation of systemic thrombolysis has shown effective thrombolysis and a likely reduction in PTS but at the cost of increased risk of bleeding complications. Catheter-directed thrombolysis (CDT) was introduced for rapid removal of thrombi and salvage of venous valves with less systemic thrombolytic effect, and is being offered to selected patients with iliofemoral DVT to prevent development of PTS. Case series have shown technical and thrombolytic success; however, no randomized studies have evaluated the long-term clinical effects of venous CDT. The aim of the CaVenT study is to investigate the role of adjunctive CDT by evaluating its clinical efficacy and safety compared with conventional treatment alone in patients with acute iliofemoral DVT., Methods: The CaVenT study is an open, randomized, controlled, clinical trial. We plan to include 200 patients who will receive either CDT, in addition to conventional treatment, or conventional treatment alone. The primary outcome measures are patency at 6 months and prevalence of PTS at 2 years., Conclusion: Implementation of the CaVenT study will be a contribution toward evidence-based medicine in the treatment of acute proximal DVT of the leg. Any documentation of improved functional outcome will have a significant impact on clinical practice for this patient group and may lead to a modification of existing international guidelines.

Background and Objectives: Our knowledge of primary chronic cold agglutinin disease (CAD) is incomplete. The aim of this study was to collect comprehensive and precise data the on epidemiology, clinical and pathological features, course, and therapy of CAD., Design and Methods: We performed a population-based retrospective follow-up study of as many as possible of all CAD patients in Norway. Eighty-six patients were studied., Results: The prevalence of primary CAD was 16 cases per million inhabitants. The incidence rate was 1 per million per year. The median age at onset was 67 years (range, 30-92) and the male to female ratio was 0.55. The median survival was 12.5 years from onset. Autoimmune diseases other than CAD were reported in 8% of patients, cold-induced circulatory symptoms in 91%, and exacerbation of hemolytic anemia during febrile illness in 74%. At least 51% had received red blood cell transfusions. The mean initial hemoglobin level was 9.2 g/dL (range, 4.5-15.6) and the median monoclonal immunoglobulin level 4.0 g/L (range, 0.0-47.3). Most laboratory findings did not change significantly during a median follow-up of 5 years. Monoclonal IgM was detected in 90%; IgG and IgA in 3.5% each; with kappa light chains in 94%. An abnormal kappa/lambda ratio in bone marrow was found in 90%, lymphoma in 76%, and lymphoplasmacytic lymphoma in 50%. Transformation to aggressive lymphoma occurred in 3.5% during 10 years. Rituximab therapy was the only treatment showing acceptable response rates (60%)., Interpretation and Conclusions: Primary CAD represents a spectrum of clonal lymphoproliferative bone marrow disorders, in most cases with morphological signs of lymphoma. Despite a favorable prognosis for survival, the disease is not indolent in terms of clinical manifestations.

A 58-yr-old woman was diagnosed with Ph(+) chronic myeloid leukaemia in May 2001. She was initially treated with hydroxyurea and subsequently with interferon-alpha (IFN-alpha). Imatinib mesylate was started in April 2002 after failure of IFN-alpha to induce a cytogenetic response. The patient remained on treatment with imatinib mesylate for 3 months during which she suffered daily fever resulting in discontinuation of the treatment. Response evaluation performed shortly after discontinuing imatinib mesylate revealed a complete cytogenetic remission and a substantial molecular response. Fifteen months later, she was still enjoying a major cytogenetic response. This case illustrates that a short course of imatinib mesylate may result in a sustained haematological and cytogenetic response.

Conventional therapies for primary chronic cold agglutinin disease (CAD) are ineffective, but remissions after treatment with the anti-CD20 antibody rituximab have been described in a small, prospective trial and in some case reports. In this study we report on 37 courses of rituximab administered prospectively to 27 patients. Fourteen of 27 patients responded to their first course of rituximab, and 6 of 10 responded to re-treatment. In both groups combined, responses were achieved after 20 of 37 courses, giving an overall response rate of 54%. We observed 1 complete and 19 partial responses. Two nonresponders and 3 patients who experienced relapse received second-line therapy with interferon-alpha combined with a new course of rituximab, and 1 nonresponder and 2 patients who experienced relapse achieved partial responses. Responders achieved a median increase in hemoglobin levels of 40 g/L (4 g/dL). Median time to response was 1.5 months, and median observed response duration was 11 months. We conclude that rituximab is an effective and well-tolerated therapy for CAD. Histologic and flow cytometric findings suggest that some of the effect may be mediated by mechanisms other than the elimination of clonal lymphocytes. We were unable to predict responses from the hematologic, immunologic, or histologic parameters before therapy.

Background: Hairy cell leukaemia is a chronic B-cell disorder that follows an indolent course. Cladribine has in the last decade emerged as the drug of choice for treating hairy cell leukaemia., Material: We report on the long-term follow-up of 26 patients treated from January 1992 to June 1993 with cladribine administered subcutaneously., Results: 25 patients were evaluable for response. 21 patients (84%) achieved complete remission, three patients (12%) achieved partial remission, and one patient had no response. At a median follow-up of 6.8 years, 24 patients (92%) were still alive. One patient died from infections four months after treatment, while the other patient died from a malignant melanoma 4.4 years after treatment. Relapse assessed by flow cytometry was diagnosed in 95% of the patients. 38% of those in complete and 67% of those in partial remission were treated by a second course of cladribine during the follow-up. Retreatment led to normalisation of peripheral blood count in all patients., Interpretation: Cladribine is not a curative treatment in hairy cell leukaemia, but it induces long lasting remission.