Life-threatening delayed hyperhemolytic transfusion reaction in a patient with sickle cell disease: effective treatment with eculizumab followed by rituximab.

BACKGROUND: Hyperhemolysis in sickle cell disease is a rare and potentially life-threatening complication of transfusion. STUDY DESIGN AND METHODS: In this article we report a case of delayed hemolytic transfusion reaction with resultant hyperhemolysis triggered by an anti-IH autoantibody with alloantibody behavior. RESULTS: The anti-IH was reactive at room temperature as well as 37 °C, but only weakly reactive with autologous red blood cells. Initial cold agglutinin titer was 512. The profound, life-threatening, intravascular hemolysis was rapidly and dramatically reduced with the Complement 5 (C5) inhibitory antibody, eculizumab. The auto/allo cold agglutinin was subsequently suppressed with rituximab treatment. CONCLUSIONS: Eculizumab, a potent C5 inhibitory antibody, can be a rapid and effective therapy for hyperhemolytic transfusion reactions when given in a sufficient dose to fully block the activation of complement C5.

Partial opening and subconductance gating of mechanosensitive ion channels in dystrophic skeletal muscle.

We recorded the activity of single mechanosensitive (MS) ion channels in skeletal muscle from the mdx mouse, a deletion mutant that lacks the cytoskeletal protein, dystrophin. Experiments were designed to examine the influence of dystrophin, a major component of skeletal muscle costameres, on the behaviour of single MS channels. In the majority of recordings from cell-attached patches, MS channels have a conductance of ∼23 pS. Recordings from some patches, however, showed a smaller conductance channel of ∼7-14 pS. Large and small conductance channels were detected in a single patch and showed serial, non-random gating, suggesting different opening levels of a single channel. Analysis of the distribution of current amplitudes within the open channel showed MS channels fluctuate between subconductance levels. MS channels in dystrophic muscle spend ∼60% of the time at smaller subconductance levels, often failing to reach the fully open level. Applying pressure to the membrane of mdx fibres increases in a graded manner occupancy of the fully open state, while reducing occupancy of subconductance levels. Recordings also show partial openings of MS channels in both wild-type and mdx muscle that fail to reach the fully open state. Partial openings occur at a higher frequency in mdx muscle and reflect occupancy of subconductance levels seen during complete activations. In muscle from mdx/utrn(-/-) double knockout mice, MS channels also spend more time at subconductance levels than the fully open state. Conductance variability of MS channels may represent gating of a heteromeric protein composed of different channel subunits. The results also show that partial opening and prolonged burst duration are distinct mechanisms that contribute to excess Ca(2+) entry in dystrophic muscle.