Pinhas Stark

Thrombotic complications in essential thrombocythemia with relatively low platelet counts

Essential thrombocythemia (ET) is often associated with thrombotic and hemorrhagic complications, mostly at platelet counts exceeding 600 × 109/L. There are, however, a few reports of such complications in ET at considerably lower platelet levels and the therapeutic approach to affected patients with relatively low platelet counts is still controversial. In the present study, the first to directly address the issue of hemostatic manifestations at relatively low platelet counts, we have determined the lowest platelet counts associated with such manifestations in 56 consecutive ET patients. Clinical manifestations related to ET were recorded in 46 (82%) patients. Of the symptomatic patients, 32 (70%) had symptoms at platelet counts lower than 600 × 109/L, 23 (50%) at counts lower than 500 × 109/L, 10 (22%) at counts lower than 400 × 109/L, and 6 patients (13%) at platelet counts as low as 300–350 × 109/L. Severe complications occurred at platelet counts lower than 600 × 109/L in 10 patients (22%), lower than 500 × 109/L in 7 (15%), and at lower than 400 × 109/L in 2 (4%). Thrombotic neurologic symptoms were the most common (31 patients, 67%), followed by peripheral vascular symptoms (17 patients, 37%); hemorrhagic complications were relatively rare (3 patients, 7%). In most cases, cessation or improvement of clinical manifestations was observed only after further reduction in platelet counts. In conclusion, thrombotic manifestations, including severe ones, are not uncommon in ET at relatively low platelet counts. We recommend that symptomatic patients with relatively low platelet counts be treated and the platelet counts further reduced well into the lower normal range. Am. J. Hematol. 56:168–172, 1997.

Acquired proximal renal tubular dysfunction in β-thalassemia patients treated with deferasirox.

Deferasirox is a recently approved oral iron chelator for treatment of patients with transfusion-related iron overload. Although renal function disturbances were recognized, proximal renal tubulopathy was not addressed in published safety reports for deferasirox. Although subclinical proximal tubulopathy was described in β-thalassemia homozygotes, overt Fanconi kidney is not an established disease complication. We describe 4 cases out of 50 children and adults with transfusion-dependent β-thalassemia, treated with deferasirox for iron overload, who developed clinically significant Fanconi syndrome. Three had concomitant infectious events; the fourth case was entirely spontaneous. In addition, all 4 patients were moderately to well chelated. Cessation of deferasirox resulted in prompt recovery. We propose the necessity for diligent monitoring for proximal tubule nephropathy, possibly related to infectious events, during treatment with deferasirox.

Sublingual therapy for cobalamin deficiency as an alternative to oral and parenteral cobalamin supplementation

Effectiveness of sublingual cobalamin-replacement therapy was studied in 18 people with cobalamin deficiency. Administration was efficacious and convenient, and compliance was high.

Antiphospholipid antibodies may be a new prognostic parameter in aggressive non‐Hodgkin's lymphoma

Abstract:  Objectives: Patients with malignancies have an increased prevalence of antiphospholipid antibodies (APA). The aim of this study was to determine the prevalence of IgG, IgM, and IgA anticardiolipin antibodies (aCL) and anti‐beta‐2 glycoprotein I antibodies (anti‐β2‐GPI) in patients with non‐Hodgkins lymphoma (NHL), and to investigate their clinical and prognostic significance. Methods: The study group included 86 patients with NHL. Enzyme‐linked immunosorbent assay kits were used to measure the concentrations of aCL and anti‐β2‐GPI, and coagulation tests, to measure lupus anticoagulant (LAC) activity. Blood was collected at diagnosis in all patients and at follow‐up in 15. Median follow‐up time was 1.9 yr. Results: Elevated APA levels were found in 35 patients (41%) at diagnosis: one patient aCL IgG, five patients aCL IgM, five aCL IgA, one anti‐β2‐GPI IgG, 14 anti‐β2‐GPI IgM, and 19 anti‐β2‐GPI IgA; LAC activity was found in three of 67 patients (4.5%). There was no significant correlation between elevated APA levels and patients age or sex, disease stage or grade, bone marrow involvement, B symptoms, serum lactate dehydrogenase levels, serum β2 microglobulin levels, International Prognostic Index (IPI) score, performance status, type of treatment, or response to treatment. There was a correlation between elevated APA and absence of extranodal disease (P = 0.045). A strong negative correlation was found between elevated APA at diagnosis and survival time. Two‐year survival was 90 ± 5% for patients without APA at diagnosis compared with 63 ± 11% for patients with an elevated APA levels (P = 0.0025). APA added to the predictive value of IPI for event‐free and overall survival. Conclusions: APA are elevated in 41% of NHL patients at diagnosis and are correlated with shortened survival. Their level may serve as an independent prognostic variable in aggressive NHL.

High incidence of silent cerebral infarcts in adult patients with beta thalassemia major

OBJECTIVES Survival of beta thalassemia major (TM) patients has improved significantly over the past few decades. Consequently, less commonly reported complications are now being recognized. An incidence as high as 60% of silent cerebral infarcts (SCI) has been demonstrated by brain Magnetic Resonance Imaging (MRI) studies in beta thalassemia intermedia (TI). The aim of this study was to determine whether regularly transfused TM adult patients experience less SCI, as compared to the incidence described in TI. METHODS In this observational study, 28 transfusion dependent TM patients, >18years of age underwent brain MRI studies. RESULTS Focal bright foci in the cerebral white matter were demonstrated in 17 (60.7%) patients; most of them had multiple lesions. Elevated serum ferritin (SF), primarily 5years Area Under the Curve, was found to have a significant association with the presence of SCI (p<0.031). Similar results were found when 4 patients with intact spleen and 2 patients with splenules were excluded (p=0.027). There was no significant association between number of SCI and clinical or other laboratory parameter evaluated. CONCLUSIONS The present study demonstrates a high rate of SCI in regularly transfused TM adult patients. Effective continuous iron chelation, preventive low dose aspirin and routine periodical brain MRI are recommended.

Lactose intolerance is not the cause of gastrointestinal adverse effects in beta thalassemia patients treated with deferasirox

patients were able to proceed to HSCT. We also used sorafenib in patients whose leukemia with FLT3-ITD relapsed after HSCT and observed meaningful clinical outcomes in this extremely poor prognostic situation. Metzelder et al. demonstrated high activity of sorafenib in FLT3-ITD AML post-HSCT possibly secondary to synergizing allo-immune effects leading to sustained regression in this specific population [9]. We also used sorafenib as maintenance therapy preand post-HSCT with durable complete response. Sorafenib was tolerated well with occasional dose reductions due to adverse events including elevated liver enzymes. Further prospective clinical trials are needed to evaluate the use of sorafenib in FLT3-ITD AML as single and/or adjunctive therapy.

GFR in Patients with β-Thalassemia Major

BACKGROUND AND OBJECTIVES Patients with β-thalassemia major (TM) may have tubular dysfunction and glomerular dysfunction, primarily hyperfiltration, based on eGFR. Assessment of GFR based on serum creatinine concentration may overestimate GFR in these patients. This study sought to determine GFR by using inulin clearance and compare it with measured creatinine clearance (Ccr) and eGFR. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS Patients followed up in an Israeli thalassemia clinic who had been regularly transfused for years and treated with deferasirox were included in the study. They were studied by inulin clearance, Ccr, the CKD Epidemiology Collaboration and the Modification of Diet in Renal Disease equations for eGFR, and the Cockcroft-Gault estimation for Ccr. Expected creatinine excretion rate and tubular creatinine secretion rate were calculated. RESULTS Nine white patients were studied. Results, given as medians, were as follows: serum creatinine was 0.59 mg/dl (below normal limits); GFR was low (76.6 ml/min per 1.73 m(2)) and reached the level of CKD; Ccr was 134.9 ml/min per 1.73 m(2), higher than the GFR because of a tubular creatinine secretion rate of 30.3 ml/min per 1.73 m(2) (this accounted for 40% of the Ccr); and eGFR calculated by the CKD Epidemiology Collaboration and Modification of Diet in Renal Disease equations and Cockcroft-Gault-estimated Ccr were 133, 141, and 168 ml/min per 1.73 m(2), respectively. These latter values were significantly higher than the GFR, reaching the hyperfiltration range, and indicated that the estimation techniques were clinically unacceptable as a method for measuring kidney function compared with the GFR according to Bland and Altman analyses. CONCLUSIONS Contrary to previous reports, patients in this study with TM had normal or reduced GFR. The estimating methods showed erroneous overestimation of GFR and were clinically unacceptable for GFR measurements in patients with TM by Bland and Altman analysis. Therefore, more accurate methods should be used for early detection of reduced GFR and prevention of its further decline toward CKD in these patients.

Human T lymphotropic virus type 1 in a seronegative B chronic lymphocytic leukemia patient.

Human T lymphotropic virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. HTLV-1 infection in patients with B cell-type chronic lymphocytic leukemia (B-CLL) is rare and has been reported only in areas in which HTLV-1 is endemic. In the present study, we detected HTLV-1 proviral DNA by polymerase chain reaction, using tax primers, in peripheral blood lymphocytes from a B-CLL patient, an immigrant to Israel, where HTLV-1 infection is not endemic. F344 rats injected intravenously with peripheral blood lymphocytes obtained from the patient developed HTLV-1 antibodies. Titers of antibody to HTLV-1 in the rat blood were 1:512 by particle agglutination; enzyme-linked immunosorbent assay and Western blotting were also positive. No antibody against HTLV-1 was demonstrated in the animal model after inoculation of either purified B lymphocytes from the B-CLL patient or peripheral blood mononuclear cells from healthy donors. This is one of the few studies showing the presence of HTLV-1 provirus in T lymphocytes of a B-CLL patient who had multiple infections, and died of salmonella sepsis, and the first report of HTLV-1 antibody induction in an animal model by inoculation of lymphocytes obtained from an HTLV-1-infected B-CLL patient.