Hemolysis

Drug-Induced Oxidative Hemolysis

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A 57-year-old woman with a history of depression and insomnia presented to the emergency department with a 3-day history of shortness of breath and dizziness. The physical examination was notable for pallor. Laboratory studies showed a hemoglobin level of 4.4 g per deciliter (reference range, 11.6 to 15.5), an elevated reticulocyte count, an elevated lactate dehydrogenase level, and a low haptoglobin level. The results of hemoglobin electrophoresis and glucose-6-phosphate dehydrogenase testing were normal, and methemoglobin and direct antiglobulin tests were negative. A peripheral-blood smear (Panel A, Giemsa staining) showed poikilocytosis, nucleated red cells (black arrows), and polychromatic cells (white arrows). The findings were also consistent with oxidative hemolysis, including the presence of bite cells (Panel A, red arrows), blister cells (Panel A, asterisks), and erythrocyte inclusions (Panel B, Giemsa staining). The erythrocyte inclusions were identified as Heinz bodies on the basis of positive staining with methyl violet (Panel C). Blood transfusions were administered. After a prolonged toxicologic investigation that involved multiple readmissions over the course of the next 7 months, the patient eventually reported having taken 10 times the recommended daily dose of zopiclone (a nonbenzodiazepine hypnotic) every night to treat insomnia since 1 month before the first presentation. Urine drug testing was positive for zopiclone. A diagnosis of drug-induced oxidative hemolysis was made. The patient was counseled to cease zopiclone use and was referred to psychiatry for treatment.

Terminal Complement Inhibitor Eculizumab in Atypical Hemolytic–Uremic Syndrome.

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BACKGROUND

Atypical hemolytic–uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease.

METHODS

We conducted two prospective phase 2 trials in which patients with atypical hemolytic–uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event–free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2).

RESULTS

A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×109 per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event–free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period.

CONCLUSIONS

Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic–uremic syndrome.

 

Source: NEJM