Comparison of low fixed dose versus standard-dose rituximab to treat thrombotic thrombocytopenic purpura in the acute phase and preemptively during remission.

The standard dose of rituximab used in B-cell hematological malignancies, 375 mg/m2 weekly, may be excessive for autoimmune conditions. Successful use of a low, fixed dose of 100-200 mg of rituximab, weekly for 4 weeks, has been reported in the literature in the treatment of autoimmune thrombotic thrombocytopenic purpura (aTTP). We retrospectively analyzed our rituximab data in aTTP over a 13-year-period for 39 patients, with the aim of comparing response and outcomes with a standard lymphoma-dose course versus a low fixed 100 mg-dose course. Compared to the standard dose (17 patients, 17 courses of 4 infusions), our patients who received a low dose (8 patients, 9 courses of 4 infusions) had a possibly lower baseline risk but did achieve a similar time to remission and number of plasma exchange procedures to remission. Preemptive low-dose courses for ADAMTS13 activity <50 % during remission (6 patients, 10 courses of 4 infusions) achieved a median peak ADAMTS13 activity of 99 %, in a median of 1 month, with no clinical relapses. Our results provide additional evidence for the efficacy of low-dose rituximab, with the benefit of much lower cost, less infusion time, and theoretically lower risk of toxicity.

Resolution of acute hepatitis B-associated aplastic anaemia with antiviral therapy.

A previously healthy 44-year-old woman presented with 3 days of worsening petechial rash, epistaxis and fatigue. Admission labs revealed pancytopenia, low reticulocyte index and elevated liver enzymes. Bone marrow biopsy demonstrated a profoundly hypocellular bone marrow without dysplasia and additional testing demonstrated an acute hepatitis B infection. In the context of an acute hepatitis B infection, elevated liver enzymes and aplastic anaemia, our patient was diagnosed with severe hepatitis-associated aplastic anaemia due to an acute hepatitis B infection. She was initiated on antiviral therapy with tenofovir and briefly received immunosuppressive therapy with a robust sustained improvement in her blood counts. Acute hepatitis B-associated aplastic anaemia is an exceptionally rare presentation of aplastic anaemia. We present acute hepatitis B-associated aplastic anaemia that resolved with antiviral therapy, which to our knowledge is the second such case reported in the literature and the first using tenofovir.

Ischemic stroke in a patient with moderate to severe inherited factor VII deficiency.

Thrombosis is known to occur in patients with rare inherited bleeding disorders, usually in the presence of a thrombotic risk factor such as surgery and/or factor replacement therapy, but sometimes spontaneously. We present the case of a 72-year-old African American male diagnosed with congenital factor VII (FVII) deficiency after presenting with ischemic stroke, presumably embolic, in the setting of atherosclerotic carotid artery stenosis. The patient had an international normalized ratio (INR) of 2.0 at presentation, with FVII activity of 6% and normal Extem clotting time in rotational thromboelastometry. He was treated with aspirin (325 mg daily) and clopidogrel (75 mg daily) with no additional bleeding or thrombotic complications throughout his admission. This case provides further evidence that moderate to severe FVII deficiency does not protect against thrombosis.

Treatment of refractory thrombotic thrombocytopenic purpura with N-acetylcysteine: a case report.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease resulting in systemic microvascular thrombosis. The disease is caused by excessive platelet (PLT) adhesion to ultra-large (UL) von Willebrand factor (VWF) multimers inadequately cleaved by the processing enzyme ADAMTS-13. While many cases respond to plasma exchange performed with or without concurrent corticosteroids, treatment of the 10% to 20% of patients with refractory disease is difficult. Experimental studies demonstrating that N-acetylcysteine (NAC) inhibits PLT binding to endothelial cell-secreted and anchored UL VWF multimers suggest that NAC may be useful in the treatment of TTP. CASE REPORT: A 44-year-old woman presented with malaise, confusion, chest and abdominal pain, and transient visual loss. Laboratory results and peripheral blood smear were consistent with TTP. The patient was begun on plasma exchange and corticosteroid treatment, but after 10 days the PLT count was still less than 10.0 × 10(9) /L and she developed a fever. Rituximab was initiated, but the patient's condition worsened and she became comatose. Antibiotics were initiated, but cultures remained sterile. After 3 days of coma and further clinical deterioration, treatment with NAC was begun. The patient received a loading dose of 150 mg/kg NAC intravenously (IV) over 1 hour. Within 18 hours the patient awakened abruptly and began communicating with medical personnel. Plasma exchange, corticosteroids, rituximab, and NAC infusion (150 mg/kg IV over 17 hr daily × 10 days) were continued and by Day 17 the PLT count was more than 50 × 10(9) /L. The patient fully recovered and was discharged on Day 31. CONCLUSION: This is the first complete report of a TTP patient treated with NAC. NAC was a safe and effective supplementary treatment for refractory TTP in this patient.

Biochemical factors governing the steady-state estrone/estradiol ratios catalyzed by human 17beta-hydroxysteroid dehydrogenases types 1 and 2 in HEK-293 cells.

Human 17beta-hydroxysteroid dehydrogenase types 1 and 2 (17betaHSD1 and 17betaHSD2) regulate estrogen potency by catalyzing the interconversion of estrone (E1) and estradiol (E2) using nicotinamide adenine dinucleotide (phosphate) cofactors NAD(P)(H). In intact cells, 17betaHSD1 and 17betaHSD2 establish pseudo-equilibria favoring E1 reduction or E2 oxidation, respectively. The vulnerability of these equilibrium steroid distributions to mutations and to altered intracellular cofactor abundance and redox state, however, is not known. We demonstrate that the equilibrium E2/E1 ratio achieved by 17betaHSD1 in intact HEK-293 cell lines is progressively reduced from 94:6 to 10:90 after mutagenesis of R38, which interacts with the 2'-phosphate of NADP(H), and by glucose deprivation, which lowers the NADPH/NADP(+) ratio. The shift to E2 oxidation parallels changes in apparent K(m) values for purified 17betaHSD1 proteins to favor NAD(H) over NADP(H). In contrast, mutagenesis of E116 (corresponding to R38 in 17betaHSD1) and changes in intracellular cofactor ratios do not alter the greater than 90:10 E1/E2 ratio catalyzed by 17betaHSD2, and these mutations lower the apparent K(m) of recombinant 17betaHSD2 for NADP(H) only less than 3-fold. We conclude that the equilibrium E1/E2 ratio maintained by human 17betaHSD1 in intact cells is governed by NADPH saturation, which is strongly dependent on both R38 and high intracellular NADPH/NADP(+) ratios. In contrast, the preference of 17betaHSD2 for E2 oxidation strongly resists alteration by genetic and metabolic manipulations. These findings suggest that additional structural features, beyond the lack of a specific arginine residue, disfavor NADPH binding and thus support E2 oxidation by 17betaHSD2 in intact cells.