Lawrence C. Wolfe

Prevention of Cardiac Disease by Subcutaneous Deferoxamine in Patients with Thalassemia Major

We examined the efficacy of long-term subcutaneous deferoxamine therapy in the prevention of iron-related cardiac disease in patients with thalassemia major who began treatment after the age of 10 years. Of 36 such patients without preexisting cardiac disease, 19 did not comply with the program of chelation therapy. Over the course of treatment (1977 to 1983) serum ferritin and aspartate aminotransferase levels fell in the compliant group, from mean values (+/- S.D.) of 4765 +/- 2610 to 2950 +/- 1850 ng per milliliter and 58.1 +/- 22 IU to 30 +/- 20 IU per liter, respectively (P less than 0.05), but rose in the noncompliant group, from 5000 +/- 2316 to 6040 +/- 2550 ng per milliliter and 56.6 +/- 20 to 90 +/- 35 IU per liter, respectively. Only one patient in the compliant group acquired cardiac disease and died of fulminant congestive heart failure. In contrast, 12 noncompliant patients acquired cardiac disease, and 7 died. In addition, the mean age of the compliant population (18.9 +/- 4.5 years) now approaches the mean age of acquisition of cardiac disease in the noncompliant group (19 +/- 4.3). These data demonstrate that compliance with treatment with deferoxamine may protect patients from cardiac disease induced by iron overload.

A Genetic Defect in the Binding of Protein 4.1 to Spectrin in a Kindred with Hereditary Spherocytosis

Indirect evidence suggests that the genetic defect in hereditary spherocytosis lies in the erythrocyte membrane skeleton, a submembranous meshwork of proteins (principally spectrin, actin, and protein 4.1) responsible for membrane shape and structural stability. To test this premise we systematically assayed the interactions of spectrin, the major skeletal protein, in six kindreds with autosomal dominant hereditary spherocytosis. In one these kindreds, enhancement of spectrin-actin binding by protein 4.1 was reduced, owing to a 39 +/- 4 per cent decrease (mean +/- S.D) in the binding of normal protein 4.1 by spectrin, in all of four members with the disorder. The defective spectrin was separated into two populations by affinity chromatography on immobilized normal protein 4.1. One population (41 +/- 2 per cent) lacked the ability to bind 4.1, but the other functioned normally. Presumable, the nonfunctional spectrin was the product of the autosomal dominant gene responsible for the hereditary spherocytosis in this kindred.

Molecular defect in the membrane skeleton of blood bank-stored red cells. Abnormal spectrin-protein 4.1-actin complex formation.

During liquid preservation under blood bank conditions, red cell membranes inexorably undergo damage that decreases erythrocyte survival after transfusion. Accordingly, we have surveyed membrane skeletal protein interactions during storage. We uncovered a decrease in the in vitro formation of spectrin-actin complex in the absence (50%) or presence (60%) of protein 4.1. Actual formation of the spectrin-actin-protein 4.1 complex fell in a linear fashion during the storage period. This fall in spectrin-actin interaction tightly correlated with the decline in total red cell phospholipid (R = 0.9932) measured simultaneously. This decrement of spectrin-actin association could be restored to greater than 70% of normal values by preincubation of stored spectrin with 50 mM dithiothreitol. This storage injury to spectrin-actin interaction might weaken the membrane skeleton and lead to decreased red cell survival. In vitro reversibility of the damage by reducing agents suggests a possible new direction for prolonging the shelf life of stored blood.

Inherited Disorders of the Red Cell Membrane Skeleton

Current knowledge of red cell membrane structure and function are briefly presented, and the pathophysiology, diagnosis, and treatment of hereditary spherocytosis, hereditary elliptocytosis, and hereditary pyropoikilocytosis are discussed.

High yield purification of protein 4.1 from human erythrocyte membranes.

Protein 4.1 has been purified from human erythrocyte membranes by a simple method employing the nonionic detergent Tween 20 and anion exchange chromatography. The procedure results in the production of large quantities of protein 4.1, which retains immunoreactivity and the functional properties of binding to spectrin and enhancing the interaction of spectrin and actin.

CHELATION THERAPY IN OLDER PATIENTS WITH THALASSEMIA MAJOR

To determine the utility of chronic subcutaneous Desferal (SCDF) therapy (Rx) in the prevention of cardiac disease in patients with thalassemia major who began treatment after the age of 10, we evaluated 36 patients; all of whom were started on SCDF when they were 10 years of age or older and had no pre-existing cardiac disease (defined as clinical congestive heart failure or abnormal left ventricular function). There were 17 compliant patients (mean age 12.3 years at onset of Rx) who used SCDF at least 5 days a week; 8-12 hours each day. Nineteen patients were noncompliant (mean age 16.6 years), they used SCDF periodically. In the group of compliant patients, the mean number of years on Desferal Rx was 4.8 years, in the noncompliant group, 4.0 years. All patients have been on a hypertransfusion regimen (maintaining a hemoglobin of 11%), at least since they began SCDF. Only one patient in the compliant group developed cardiac disease (at age 11) and she died of congestive heart failure at age 18. In contrast, 12 in the noncompliant group developed cardiac disease. Two of these patients have died. The mean age of development of cardiac disease in the noncompliant patients was 20.3 years ± 4.2 years. Therefore, the lack of cardiac complications in the compliant group suggests that compliance with SCDF Rx may reduce the risk of cardiac disease in older patients.

Blood transfusion for the neonatal patient

The authors discuss issues of neonatal transfusion, including assessment of laboratory values; clinical evaluation of gestational age and birthweight, cardiopulmonary conditions, sepsis, immunologic status, and bleeding; and the collection of blood and blood components. The handling of specimens and the performance of exchange transfusions are discussed, and both immediate and delayed adverse reactions are reviewed.