Vincenzo Fontana

Increased procoagulant cell-derived microparticles (C-MP) in splenectomized patients with ITP ☆

BACKGROUND Splenectomy is frequently employed for therapeutic and diagnostic purposes in various clinical disorders. However its long-term safety is not well elucidated. Although risk of infection by encapsulated organisms is widely recognized, less well-known are risks of thrombosis and cardiovascular disease. METHODS We investigated levels of cell-derived microparticles (C-MP) in 23 splenectomized ITP (ITP-S) and 53 unsplenectomized ITP patients (ITP-nS). Assay of C-MP derived from platelets (PMP), leukocytes (LMP), red cells (RMP) and endothelial cells (EMP) were performed by flow cytometry. Coagulation parameters included PT, aPTT and activities of FVIII, IX and XI. Results of all measures were compared between the two groups, ITP-S vs ITP-nS. RESULTS Levels of all C-MP were higher in ITP-S than ITP-nS but only RMP and LMP reached statistical significance (p = 0.0035 and p < 0.0001, respectively). The aPTT was significantly shorter in ITP-S (p = 0.029). Interestingly, correlation analysis revealed that RMP, but not other C-MP, were associated with shortening of aPTT (p = 0.024) as well as with increased activities of factors VIII (p = 0.023), IX (p = 0.021) and XI (p = 0.0089). CONCLUSIONS RMP and LMP were significantly elevated in splenectomized compared to non-splenectomized ITP patients. This suggests that the spleen functions to clear procoagulant C-MP, and that elevation of C-MP might contribute to increased risk of thrombosis, progression of atherosclerosis and cardiovascular disease following splenectomy.

Platelet Activation in Helicobacter pylori-Associated Idiopathic Thrombocytopenic Purpura: Eradication Reduces Platelet Activation but Seldom Improves Platelet Counts

Introduction: It has been suggested that Helicobacter pylori eradication often increases platelet counts in patients with chronic idiopathic thrombocytopenic purpura (ITP). In addition, H. pylori has been shown to induce platelet activation (CD62p or P-selectin expression) in previous studies. We assessed the response of platelet count and CD62p expression after eradication therapy in patients with ITP and H. pylori infection. Methods and Results: We prospectively studied 15 ITP patients diagnosed with H. pylori infection by serology and breath test. A follow-up breath test was used to document eradication. Two out of 15 patients showed improvement in platelet counts after 6 months, 1 of which may have had drug-induced thrombocytopenia. Overall, certain platelet response rate in our series was 6.7% (1/15). We found that platelet CD62p expression by flow cytometry was elevated in 10/15 (66.7%) H. pylori-infected patients, which is a statistically significant difference when compared with 3/33 (9.1%) control ITP patients seronegative for H. pylori (p = 0.002). In addition, eradication therapy decreased CD62p expression (p = 0.04). However, reduction in platelet activation was not associated with an increase in platelet counts (mean 72.4 × 109/l before and 68.7 after therapy; p = 0.4). Conclusion: In our series, platelet activation was common in ITP patients with H. pylori, and eradication therapy decreased platelet activation but seldom increased platelet counts. Increased platelet CD62p expression is a putative link between chronic infections and atherosclerosis, but further study is needed to clarify the implications of our observation.

Antiphospholipid antibodies and platelet activation as risk factors for thrombosis in thrombocythaemia

Abstract Introduction: Risk factors for thrombosis (TB) in thrombocythaemia (TC) associated with myeloproliferative disorder (MPD) are not well defined. Methods: We measured antiphospholipid antibodies (APLA) in 35 patients with TC associated with MPD. Fourteen had TB and 21 did not. We assayed IgG and IgM APLA by ELISA for 6 antigens: β2GP1, cardiolipin (CL), phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylethanolamine (PE) and FVII/VIIa, together with markers of activation of platelets (CD62P) and endothelium [endothelial microparticles (EMP)]. Results: At least one positive APLA was detected in 66% of TC patients overall. The incidence was significantly higher in the TB subgroup (92.8%) than non-TB (47.6%, p < 0.05). Multiple APLA (positive for more than one antigen) were also more frequent in TB, for both IgG and IgM, for all 6 antigens tested (p < 0.05). However, IgM APLA predominated, being about 2-fold more frequently positive than IgG for all 6 antigens. Platelet CD62P was significantly higher in the TB group (p < 0.05). EMP did not differ between TB and non-TB. The most frequent thrombotic complication was recurring ischemic cerebral vascular accidents (ICVA), leading to progressive cognitive impairment. Venous TB often developed at unusual sites. Recurring and reversible TB were common features in TC. Summary: This study suggests that APLA and platelet activation are risk factors for TB in TC. APLA are prevalent in TC, and IgM APLA predominated over IgG. Activation of platelets but not of endothelium may be consistent with the reversible and recurrent features of TB in TC.

Interleukin-11 for treatment of hepatitis C-associated ITP

Background: Immune thrombocytopenic purpura (ITP) is frequently associated with chronic hepatitis C (HpC-ITP). Methods: Recombinant interleukin-11 (rIL-11), which has both thrombopoietic and anti-inflammatory properties, was evaluated in 12 patients with HpC-ITP in this pilot study. Group 1 (7 patients) was treated at high dose (50 µg/kg daily) while group 2 (5 patients) at low dose (15–35 µg/kg three/week). Results: In group 1, mean platelet counts rose from initial 54 × 109/l to 103 × 109/l (p = 0.02) and in group 2, from an initial 51 × 109/l to 74 × 109/l (p = 0.04). Antiplatelet antibody (aPlt-Ab) decreased in group 1. LFT improved in both groups. The mean HCV-RNA decreased in group 1 (p = 0.04), not in group 2. Side effects were common and troublesome, but were minimized with individualized dosing. One patient achieved good remission of both ITP and HpC lasting >2 years with low-dose maintenance. Conclusion: When used based on individual tolerance, rIL-11 appears useful in HpC-ITP.

Danazol therapy combined with intermittent application of chemotherapy induces lasting remission in myeloproliferative disorder (MPD): an alternative for the elderly with advanced MPD

Abstract There is no good alternative therapy available for elderly patients with advanced myeloproliferative disorders (MPD) who failed on conventional therapies and are not candidates for bone marrow transplant. We report here an effective therapy that induced exceptionally long‐lasting remissions and improved quality of life. Eighteen elderly patients (mean age: 70·6 years) (16 myelofibrosis and 2 thrombocythemia) who had failed on conventional therapies were treated. Danazol was administered daily at 200–800 mg throughout the study. Chemotherapy was applied intermittently as needed to reduce spleen size and blood counts. Busulfan (2–4 mg/day) was used most often and 6‐mercaptopurine (6‐MP) (50–100 mg/day) and/or cytarabine (100–200 mg/m2) if the white blood cell (WBC) count rose rapidly. When MPD stabilized, chemotherapy was discontinued and dosage of danazol was reduced. Therapy was well tolerated. Overall, 61% of patients responded with unexpectedly long‐lasting remissions and improved quality of life. Three (17%) had excellent (E) response, defined by normalization of blood counts and non‐palpable spleen, while eight (44%) had good (G) response, defined by rise of Hct by ⩾7% and ⩾50% reduction of spleen. Mean duration of remission was 45 months (10–78 months) in E responders and 11 months in G responders (2–22 months). This regimen offers a safe and effective alternative for advanced MPD in the elderly.

Interstitial lung disease (ILD) and severe ITP

Abstract Introduction: Platelets play an important role in inflammatory and immune responses. We report interstitial lung disease (ILD) developing during the acute phase of severe thrombocytopenia in 3 patients with severe refractory ITP. Methods and Results: We identified 3 cases with severe ITP who developed ILD in the course of refractory chronic ITP. The thrombocytopenia was severe in all cases. ILD was an incidental finding at the presentation and often misdiagnosed as lung infections. ILD was documented by lung biopsy in cases 1 and 2, supplemented by serial chest X-rays and/or CAT scan. As the ITP improved, ILD regressed in case 1, persisted in case 2, and progressed to advanced pulmonary fibrosis in case 3. Conclusion: We report an association of ILD with severe refractory ITP. ILD was detected in acute phase of platelet destruction, suggesting that platelet destruction may have triggered inflammation in the lung, leading to ILD.

Atypical chronic myeloid leukemia following organ transplants

Abstract:  Secondary malignancy frequently develops among recipients of organ transplants, most commonly malignancies of the lymphoid system and skin. However, chronic myeloid leukemia (CML) is rare following transplant, with only a handful of cases reported, all of whom had kidney transplant and received azathioprine for immunosuppression. We report three cases of post‐transplant CML seen at a single institution within a two‐yr period. Two had received liver and one a kidney transplant. None were on azathioprine but all had tacrolimus. CML is a rare hematological malignancy, usually presenting with high white counts and splenomegaly. In all three of our subjects, presentation of CML post‐transplant was so atypical that their diagnosis could easily be missed. All had rapid and excellent response to imatinib, and underwent clinical remission. This is the first report of CML developing in the course of tacrolimus therapy among liver transplant recipients. Presentations of CML were highly atypical and easy to miss in early stage. Awareness of atypical CML developing post‐transplant is important since early and timely therapeutic intervention with imatinib is critical for improving quality of life and overall prognosis.

Very poor performance status elderly patients with aggressive B cell lymphomas can benefit from intensive chemotherapy

Elderly patients tolerate chemotherapy less well than younger ones, especially when they have a poor performance status (PS) and comorbidities (Lichtman, 2006). Aggressive B cell lymphomas are potentially curable, yet elderly patients are not always offered treatment, often because of presumed risk of toxicity (Thieblemont & Coiffier, 2007). Patient surveys suggest they would choose to try curative chemotherapy at much lower chances of success than would doctors (Slevin et al, 1990). Some predictors of toxicity enable toxicity to be avoided in a dying patient (Tirelli et al, 2001; Pfreundschuh, 2010), but data are sparse regarding intensively treated aggressive B cell lymphoma in elderly patients with very poor PS. We aim to offer intensive chemotherapy to all such patients, and present our retrospective 10-year analysis. We asked:

Primary sclerosing cholangitis complicating plasma cell dyscrasia (PCD): remission of PCD following liver transplant

Abstract:  We report the first case of primary sclerosing cholangitis (PSC) complicated with plasma cell dyscrasia (PCD) in which liver transplant resulted in unexpected therapeutic benefit of PCD. A 61‐year‐old man with 12 yr history of PSC presented with a monoclonal gammopathy of undetermined significance (MGUS) with an IgG level of 3400 mg/dL. It was stable initially for 3 yr but progressed to features consistent with multiple myeloma (MM): IgG rose to 5290 mg/dL along with development of terminal stage of liver failure. Liver transplant was performed in desperation. Unexpectedly, MM underwent clinical remission following transplant. At 3 and 14 months following transplant, IgG stayed below 2080 mg/dL and he was able to return to full‐time employment. This case may suggest that chronic antigenic stimulation from cirrhotic liver contributed to MGUS and subsequent transformation to MM. Liver transplant eliminated chronic antigenic stimulation, apparently leading to remission of MM. Since PCD is often associated with other chronic liver diseases, similar benefit may accrue to a range of patients with chronic liver diseases complicating PCD.