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The Effect of Methemoglobin Formation in Sickle Cell Disease

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The Effect of Methemoglobin Formation in Sickle Cell Disease THE EFFECT OF METHEMOGLOBIN FORMATION IN SICKLE CELL DISEASE Ernest Beutler J Clin Invest. 1961;40(10):1856-1871. https://doi.org/10.1172/JCI104410. Research Article Find the latest version: https://jci.me/104410/pdf THE EFFECT OF METHEMOGLOBIN FORMATION IN SICKLE CELL DISEASE * By ERNEST BEUTLER WITH THE TECHNICAL ASSISTANCE OF BARBARA J. MIKUS (From the Department of Medicine, City of Hope Medical Center, Duarte, Calif.) (Submitted for publication January 18, 1961; accepted June 15, 1961) On a biochemical level, sickle cell disease is A recent review (6) stimulated us to approach perhaps the most completely understood disease this problem from a different point of view. of man. In spite of this, no satisfactory treatment Itano (7) had demonstrated that complete con- is available to patients afflicted with this disorder. version of sickle hemoglobin to the methemoglobin The clinical manifestations of sickle cell anemia derivative prevented the sickling process. It are varied. Some of the complaints of patients seemed probable that conversion of only a part with this disease can be ascribed directly to the of the hemoglobin of sickle cells to methemoglobin lack of oxygen-carrying capacity of the blood. would result in partial inhibition of the sickling Other symptoms, however, such as the painful process. The studies of Greenberg, Kass and crises, the leg ulcers and bone infarcts, are not Castle (8) have demonstrated that the mean due to anemia alone. They do not occur in other corpuscular sickle hemoglobin concentration anemias of equal severity and must thus be as- (MCSHC) was important in determining whether cribed to additional factors. One such factor pronounced clinical symptoms of sickle cell dis- might be the distortion which sickle cells undergo ease were present. Those patients whose when the oxygen tension is lowered. Any means MCSHC values were less than 15 g per cent were by which the shape change of red cells could be not anemic and had no painful crises. Hemoglobin inhibited might, therefore, benefit patients with converted to methemoglobin would be removed this disorder. Reports of attempts to modify the from the oxyhemoglobin-reduced hemoglobin equi- sickling process by changing the pH of the en- librium. In this way the MCSHC of sickle cells vironment of red cells through the administra- would in effect be diminished when methemoglobin tion of sodium bicarbonate (1) or by poisoning red was formed. Thus, inhibition of sickling might cell carbonic anhydrase with acetazolamide (Dia- take place in patients treated with methemoglobin- mox) have been published (2). Clinical results forming agents. of acetazolamide treatment have been disappoint- Furthermore, it has been shown that the lowest ing (3). We are not aware of published confir- gelling point of mixtures of S hemoglobin with mation of the effect of alkali therapy on the clini- other hemoglobins depends not only on the ab- cal course of sickle crises, although a recent study solute concentration of sickle hemoglobin in the (4) showed that it was not possible to influence solution, but also on the type of the other hemo- in vivo sickling by intravenous administration of globins (9). In addition, sickling of red blood bicarbonate. The effect of older therapies on cells of infants with sickle cell trait has been found sickle cell disease has recently been reviewed by to correlate not with the absolute quantity of sickle Dacie (5). None is considered effective. To our hemoglobin in the red cells, but rather with the knowledge, studies of the effect of any drug ther- reciprocal of the amount of fetal hemoglobin pres- apy on in vivo red cell survival have not been ent (10). Therefore, it appeared at least theo- published. retically possible that methemoglobin might inter- fere with the sickling process to a greater extent * Supported in part by USPHS Grant no. H-5313. A than would be expected from its effect in remov- portion of this work was carried out in the Department ing hemoglobin from the Hb z HbO2 equilibrium, of Medicine and the Argonne Cancer Research Hospital, alone. operated by the University of Chicago for the U. S. Proceeding on the premise that it may be pos- Atomic Energy Commission. Presented in part at the 1960 Annual Meeting of the American Society of He- sible to benefit patients with sickle cell anemia by matology, November 30, 1960, Montreal, Canada (46). inhibiting the sickling process, even if they are at 1856 EFFECT OF METHEMOGLOBIN FORMATION IN SICKLE CELL DISEASE 1857 TABLE I Laboratory data on five patients with sickle cell anemia * Alkali- Bilirubin Appearance of resistant Patient Hb Hct RBC Retic. RBC on smear Hb Direct Total g % % 106/mm3 % RBC % total mg % L.A. 7.3 27.5 2.80 11.5 Sickling, Howell-Jolly bodies, normo- blasts, target cells B.W. 10.0 27 3.24 6.1 Sickling, 4.52 0.30 0.60 many target cells T.P. 7.37 23.5 2.65 14.3 Sickling 4.64 J.G. 6.2 19 1.97 Sickling 3.90 2.22 3.34 J.R. 8.0 24 2.53 10.0 Sickling 3.44 0.80 3.80 * All 5 patients had SS hemoglobin shown by paper electrophoresis, and the glutathione stability test was normal in each. the same time deprived of a certain quantity of case 1 (except for the 1 per cent 02 mixture): 0, 1, 3, 5, oxygen-carrying capacity, we have undertaken an 10 and 20 per cent 02. The CO2 content varied from 8.1 to 10.0 per cent. The balance of gas was N2. The ac- investigation of the effect of such chemical modi- tual O, content has been used in calculating the PO2 fication of sickle hemoglobin in patients with sickle throughout, except in the case of 1 per cent 02. Each cell disease. After these studies had been under- gas mixture was passed through a gas-washing bottle taken and a preliminary communication had been filled with distilled water. published (11), we learned that in his thesis It was found in preliminary experiments that con- sistently satisfactory results relating oxygen tension to Itano (7) had suggested that clinical investiga- percentage sickling could not be obtained on washed, tions of the treatment of sickle cell disease with resuspended red cells, so that it was necessary to carry sodium nitrite might be carried out. At his sug- out studies on whole blood samples. Accordingly, hepari- gestion, preliminary trials were carried out by nized blood was obtained from each subject and 1 ml was Dr. J. C. S. Paterson. In long-term experi- introduced into a 500 ml separatory funnel (total vol- in ume, 650 ml) which was employed as a tonometer. In ments, 300 to 500 mg sodium nitrite divided studies done on Subject T.P., 2.5 ml was used. The daily doses was well tolerated and, although sub- space in the separatory funnel was flushed with the ap- jective improvement was noted, there was little propriate gas mixture at a rate of 6 L per minute; it was evidence of hematological improvement. In acute stoppered and the stopcock closed. The funnel was then experiments the side effects of sodium nitrite ad- rotated at room temperature (22 to 250 C) in such a manner as to spread the blood in a thin film on the sur- ministration by infusion in anemic patients were face of the glass. After 5 minutes, the gas inside the found to be sufficiently troublesome to necessitate funnel was again flushed out for 30 seconds at a flow interrupting his studies. These observations have rate of approximately 6 L per minute and the rotating not been published (12). process repeated. After a third flushing and period of rotation, the funnel was flushed with gas a fourth time for 30 seconds and a drop of blood was introduced un- MATERIALS AND METHODS der oil from the stem of the funnel into a fixative con- taining 5.0 per cent formalin,2 0.010 M NaHPO, and A. Patients. Five Negro women between the ages of 0.138 M NaCl which had been saturated with the gas 21 and 33 volunteered for these studies. The pertinent with which the blood sample had been equilibrated. This admission laboratory data are given in Table I. No blood fixative was designed to give a final pH of from 6.6 to transfusions were given to any of the patients during the course of the studies. 1 Courtesy of Mr. John Barr, chief technician, Cardiac B. Determination of oxygen tension sickling curves. Physiology Laboratory, City of Hope Medical Center. The following gas mixtures were obtained from a com- 2 Solution of formaldehyde, 37 per cent by weight, mercial source and the exact gas content assayed in each USP, Merck. 1858 ERNEST BEUTLER 6.8. After 15 to 30 minutes' fixation, a droplet of blood of Premarin (Ayerst) and 200 mg progesterone (Pfizer) was introduced into a counting chamber and approxi- daily for a period of 10 days. mately 200 cells were enumerated; the percentage of dis- E. Oxygen dissociation curves. Oxygen dissociation torted cells was recorded. The blood of patients with- curves were determined on aliquots of blood equilibrated out sickle hemoglobin but with a similar degree of ane- in a separatory funnel as indicated above, collected under mia was studied to determine the control level of red cell oil, and introduced into the Van Slyke apparatus (17), distortion. after hemoglobin and methemoglobin determinations had In most studies a red cell which deviated in any ap- been carried out. preciable manner from a regular discoid shape was con- F. Serial osmotic hemolysis.
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