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Histochemical Studies on Leukocyte Alkaline Phosphatase Activity with Special Reference to Various Types of Hemolytic Disorders

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Histochemical Studies on Leukocyte Alkaline Phosphatase Activity with Special Reference to Various Types of Hemolytic Disorders Tohoku J. exp. Med ., 1966, 89, 387-399 Histochemical Studies on Leukocyte Alkaline Phosphatase Activity with Special Reference to Various Types of Hemolytic Disorders Shinobu Sakamoto Departmentof Internal Medicine(Prof. T. Torikai), TohokuUniversity School of Medicine,Sendai Alkaline phosphatase activity of neutrophils was estimated histochemically with special reference to various types of hemolytic disorders. Enzyme activity tended to be lower than normal in all but one of the cases studied . Leukocytes incubated for one hour at 37•Ž in plasma obtained from a patient with paroxysmal nocturnal hemoglobinuria and from a patient with congenital spherocytosis showed a decrease in enzyme activity. When leukocytes were incubated in normal plasma containing bovine hemoglobin, enzyme activity also decreased . Plasma obtained from patients with hyperbilirubinemia caused by bile duct obstruction did not affect enzyme activity in vitro at all. It was concluded from these observations that the low enzyme activity seen in various hemolytic disorders was due to the inhibitory effect of hemoglobin in plasma and not due to indirect bilirubin. Differences in enzyme activity in these hemolytic states were considered to be due to differences in plasma hemoglobin concentration. It was Kaplow1 who first devised a fairly satisfactory, clinically applicable cytochemical staining method for the demonstration of leukocyte alkaline phosphatase activity in blood smears. This method, however, had disadvantages of low sensitivity and ill-defined localization of enzymatic activity. With this method, it is difficult to detect low levels of activity of this enzyme in leukocytes and it is impossible to determine minute differences in enzyme activity. Recently it was disclosed that certain substituted naphthol AS phosphate derivatives2-5 offered most satisfactory staining results because of their sensitivity, specificity and sharp topographical localization of enzymatic activity in cells. Its diagnostic value in certain hematological disorders is well established.5-12 However, little is known about what influence the strength of the activity of this enzyme has on the leukocyte and in what way this enzyme activity is regulated in leukocytes. It is a well known fact that enzyme activity is very low in paroxysmal nocturnal hemoglobinuria.6,10,13-16 However, only a few studies have been presented concerning this enzyme in hemolytic disorders other than paroxysmal nocturnal hemoglobinuria. Tanaka et al.13 reported depressed activity of the Received for publication, April 27, 1966. 387 388 S. Sakamoto enzyme in some cases of acquired hemolytic anemia and sickle-cell anemia. Martinez-Maldonado et al.8 found the same tendency in a case of sickle-cell anemia. On the other hand, Hayhoe and Quaglino7 reported normal or high enzymatic activity in four cases of idiopathic acquired hemolytic anemia. Mitus et al.10 reported normal activity in a case of acquired hemolytic anemia. Hashimoto10 observed normal activity in four cases of congenital spherocytosis and in a case of congenital non-spherocytic hemolytic anemia; and slightly elevated activity in a case of acquired hemolytic anemia with leukemoid reaction. The same observations were made by Leonard et al.9 in acquired auto-immune hemolytic anemia with leukemoid reactions. As cited above, quite different findings have been reported by different investigators. This led the present author to examine leukocyte alkaline phosphatase activity in various types of hemolytic disorders including paroxysmal nocturnal hemoglobinuria and to determine whether any influence of hemolysis on this enzyme activity in leukocytes can be seen. MATERIALS AND METHODS Sources: Thin blood films on glass slides were obtained from 40 healthy subjects (20 males and 20 females), consisting of doctors, nurses and others, ranging from 18 to 53 years in age. The various hemolytic diseases studied in this report are as follows: a) 2 cases of acquired auto-immune hemolytic anemia, b) 3 cases of congenital spherocytosis, c) I case of congenital non-spherocytic hemolytic anemia, d) 3 cases of paroxysmal nocturnal hemoglobinuria, e) 1 case of methemoglobinemia, and f) 1 case of sulfhemoglobinemia. Histochemical demonstration of leukocyte alkaline phosphatase activity: Leu kocyte alkaline phosphatase activity was demonstrated histochemically by Tomonaga's method in which naphthol AS-MX phosphate was used as the substrate and fast blue RR salt as the azo dye.5 Scoring was done according to Tomonaga's modified criteria and the sum of the ratings of 100 successive neutrophils was designated as the alkaline phos phatase score, "AP" scores, for a given blood smear. Examination of in vitro effect of plasma obtained from patients with hemolytic disorders on leukocyte alkaline phosphatase activity: By venipuncture with a heparinized syringe, 10 ml of blood were obtained respectively from a patient with paroxysmal nocturnal hemoglobinuria and from a patient with congenital spherocytosis and with a low "AP" score. These blood samples were placed separately in test tubes and centrifuged at 1,500 r.p.m . for 5 minutes. Three milliliters of plasma were taken from each of these samples and kept aside for a while. Leukocyte Alkaline Phosphatase in Hemolytic Disorders 389 In the same way 10 ml of blood were drawn from healthy persons with the same blood type as the above-mentioned patients and poured into test tubes. After standing one hour at room temperature, these samples were centrifuged at 1,500 r.p.m. for 5 minutes. The buffy coat was collected by capillary pipette and poured into the test tubes containing previously prepared plasma. The contents were then mixed gently, but well. The rest of the blood, from which the buffy coat was taken, was used as control during incubation. After incubation of these mixtures and control samples for one hour at 37•Ž, the buffy coat was collected into Wintrobe tubes by capillary pipette and centrifuged at 1,000 r.p.m. for 3 minutes. This last procedure was omitted when white cells proved to be sedimented sufficiently as a white layer after incubation. The in vitro effect on leukocyte alkaline phosphatase of plasma from a patient with chronic myelogenous leukemia was also examined in a similar way. Examination of in vitro effect of hemoglobin on leukocyte alkaline phosphatase activity: As described previously, 2 ml of normal plasma were prepared in a test tube. The rest of the blood from which plasma was taken was used as a leukocyte source and as control during incubation. Eight milligrams of bovine hemoglobin (Tokyo Kasei, commercially available) were dissolved in this plasma. The huffy coat of the same blood sample was placed into this hemoglobin dissolved plasma and mixed gently and well. Blood films were made in exactly the same way from the leukocyte layer after one hour incubation at 37•Ž. Examination of in vitro effect of plasma obtained from patients with hyper bilirubinemia on leukocyte alkaline phosphatase activity: Plasma obtained from two patients with obstructive jaundice was used in this experiment. The procedure was the same as described above. RESULTS 1. Normal subjects The results obtained from normal subjects are summarized in Table 1. "AP" scores for healthy men were distributed in the range from 156 to 271 and those for healthy women ranged from 183 to 334. "AP" scores were higher for women than for men. The mean and standard deviation for both sexes were 233.9 •} 60.4. Women were all premenopausal and were not menorrheic when examined. 2. Hemolytic diseases It is obvious from Fig. 1 that all but one case among the hemolytic disorders showed lower values than normal. In acquired auto-immune hemolytic anemia, one case showed a remarkably low value which approximates the value seen in chronic myelogenous leukemia, while the other showed a subnormal value. The course of this case with low 390 S. Sakamoto TABLE 1. Neutrophil alkaline phosphatase scores in healthy subjects * Standard deviation Fig. 1. Neutrophil alkaline phosphatase activity in hemolytic disorders. enzyme activity is illustrated in Fig. 2. This case was the so-called "Lederer type" with leukemoid reaction. When first studied at the time of admission, its "AP" score was found to be near the upper limits of the normal range, and leukocytosis was observed. As leukocyte counts returned to normal and anemia improved by the administration of steroid hormone, its "AP" score became remarkably low. The "AP" score remained low until the second leukemoid reaction and marked anemia occurred. Unfortunately, leukocyte alkaline phosphatase activity was not determined at the time of the highest leukocyte count, but the "AP" score rose to normal when leukocyte counts became normal. Afterwards, contrary to the increase in erythrocytes and leukocytes, the "AP" score fell below normal. The probable implication of this phenomenon will be discussed later. Relatively low values were obtained in two of three cases of congenital apherocytosis; the other case showed normal values. A case of congenital non spherocytic hemolytic anemia which showed no hitherto known erythrocyte Leukocyte Alkaline Phosphatase in Hemolytic Disorders 391 Fig. 2. Acquired auto-immune hemolytic anemia (male, 40 y.). Fig. 3. Paroxysmal nocturnal hemoglobinuria following aplastic anemia (male 28 y.). Note gradual fall of "AP" score and its return to normal after disappearance of hemoglobinuria. 392 S. Sakamoto Fig. 4. Relationship between serum indirect bilirubin and neutrophil "AP" score. enzyme
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