The parenchyma of the human spleen divides into the white pulp as the lymphatic tissue, and the red pulp composed the splenic cord and the venous sinus. The marginal zone consisted of two layers in the human spleen is seen between the white and red pulp. The lymph follicle abuts at the periphery of the periarterial lymphatic sheath in many place. It is thought that the white pulp and the inner layer of the marginal zone composed of medium-sized lymphocytes having a B-cell nature take part in the immunological mechanism in vivo mainly.
In the splenic cord of the red pulp as well as the outer layer of the marginal zone, reticular cells and fibers form the reticular meshwork. Macrophages and blood cells are found in these reticular meshwork, in which arterial capillaries terminate open. Namely, direct communication between the arterial capillary and the venous sinus can not be found in the human spleen so far as examined (Open circulation).
It seems that the width of the slit between sinus endothelial cells is influenced by the gradient pressure between the splenic cord and the venous sinus, abundant filaments as well as intermediate junction of sinus endothelial cells and the tension of the basement membrane surrounding the sinus wall. Blood cells losing deformability as well as foreign particles which are detained in the reticular meshwork, undergo trapping, phagocytosis, degradation and removal by macrophages. Namely, it is considered that the red pulp and the outer layer of the marginal zone are the filtration bed.
It seems that the sheath of the capillary in the human spleen has some filtrating action, although it does not so well develop.
The parenchyma of the human spleen is supported by reticular cells. Their cytoplasm had many filaments 40∼60 Å in diameter which were tightly organized as dense bands. It is suggested that these reticular cells may participate in the regulation of blood flow of the human spleen in addition to the cytoskeletal role themselves by these filaments as well as the capsule, trabecula, sheathed capillary and sinus endothelial cell.

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Histological observation of the spleen which had been removed surgically was performed in 39 cases of hereditary spherocytosis, 4 of autoimmune hemolytic anemia and 3 of pyruvate kinase deficiency, comparing with that of gastric carcinoma, ITP, Banti's syndrome and liver cirrhosis.
The spleen in hereditary spherocytosis revealed enlargement of about 5 times with marked expansion of the medullary cord by accumulation of spherocytes, no increase of reticulin and collagen fibers and a mild increase of macrophages. The histology seemed to be functionally well adapted state of the spleen with activated reticuloendothelial cells for increased red cell destruction. In autoimmune hemolytic anemia an increase of IgG positive cells suggested immunological participation of the spleen as ITP in which nearly the same increase of IgG positive cells was present. Non specific congestive changes, moderate erythrophagia of macrophages and hemosiderin deposit were observable in pyruvate kinase deficiency.

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Based on the electron microscopic observations of the red pulp of the spleens from the patients with hemolytic anemias, such as hereditary spherocytosis, pyruvate kinase deficiency, pyrimidine 5¹-nucleotidase deficiency, unstable hemoglobin hemolytic anemia and autoimmune hemolytic anemia, the mechanism of hemolysis was tudied. Morphologically, stagnation of red cells in the cord, erythrophagocytosis by the cordal macrophages and occasinally by the sinus endothelial cells, intravascular hemolysis as evidenced by the red cell ghosts, and removal of rigid inclusions at the sinus wall were noted. All these findings were related directly or indirectly to the mechanism of hemolysis. Both congenital and acquired abnormalities of red cellls (abnormalities of membrane, metabolic process and hemoglobin molecule) are exaggerated during the passage through the spleen, finally leading to the reduced deformability and/or increased osmotic fragility of defective red cells. This function of the spleen is accomplished by the combination of anatomical structure, metabolic conditions and immunologic ability of of the red pulp. Thus, the spleen is not a simple filter, but works as the apparatus to scrutinize the circulating red cells and destroys only the defective ones.

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Splenic hemodynamics was measured and analysed in detail for better understanding of its role in red cell destruction.
In the first step of this study, hemodynamics character through the spleen was determined by perfusion experiments of isolated dog spleens with radiotracers of red cell and the plasma. Analysis of radiograms of the spleen and its out-put revealed the dynamics character which was composed of the fast and slow phase and was represented by sum of corresponding exponential components.
Clinical study was designed to measure the dynamics in vivo under physiological condition in 10 controls, 15 hereditary sperocytosis with autogeneous cell and normal cell, 16 studies in autoimmune hemolytic anemias and 44 studies in portal congestive splenomegalies. The dynamics study was carried out separately in the fast phase and in the slow phase applying appropriate method and analysis technique to each dynamic phase. With these results, a over-all hemodynamics chracter was constructed for each blood tracer in each spleen. Three compartments with different dynamic character, i.e., the fast, intermediate and slow ones, were allotted to red cell flow, while two were allotted to the plasma as the fast and intermediate ones.
Average value in hereditary spherocytosis exhibited that 77.5% of red cells of splenic arterial inflow passed the fast compartment with mean transit time of 11 seconds, only 2% of them entered the slow one with the transit time of 19 minutes and the residual participated in the intermediate one. There was no significant differnce in partition ratio of red cell into the fast compartment among control and disease groups and the dynamics in this compartment was supposed to be under a control to maintain a certain flow rate.
With the parameters which represent red cell and plasma dynamics, multiple regression analysis was performed agaist red cell destruction rate to elucidate the relationship between the spleen hemodynamics character and red cell destruction. A close relationship was manifested in hereditary sherocytosis by a multiple correlation coefficient of 0.956 with cotributors of plasma flow, red cell dynamics in the slow compartment and the spleen size. In autoimmunehemolytic anemias, a poor relationship was yielded as a whole but a closely resembled pattern was displayed in some cases to that observed in hereditary spherocytosis and splenectomy yielded a excellent effect in these cases.
In some cases of portal congestive splenomegaly, accelerated red cell destruction developed following the shunt operation in spite of reduction in the spleen size. This hemolysis was closely related to postoperative alteration in the splenic hemodynamics, i.e., acceleration of plasma flow, stagnation of red cell in the slow compartment and change in the dynamics in intermediate one accompanying the spleen size reduction. The multiple correlation coefficient was 0.880.
Red cells obtained in delayed phase of perfusion of surgecally removed human spleen demostrated increased fragility by coil planet centrifuge as well as stomato-echinocyte alteration by scanning electron microscopy. Splenic dynamics and extraction of artificially denaturated red cells was determined. These cells had been treated with NEM or heating and demonstrated increased fragility and morphological changes and displayed the shift to slower dynamics, which was accompanied by a proportional increase in their extraction rate.

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The clinical and experimental studies of the role of the spleen for red cell destruction were performed in hereditary spherocytosis (HS) and autoimmune hemolytic anemia (AIHA). Splenomegaly was evident in patients with HS and AIHA. The spleen size was well correlated with effective red cell destruction evaluated from daily hemoglobin degradation rate. Splenic surface counting in ⁵¹Cr labeled red cell survival studies showed an immediate rapid destruction followed by a gradual destruction in HS. In AIHA, labeled red cells were destructed in constant rate.
Splenectomy is often considered in HS with good results. In AIHA, however, number of cases with good results was 50%. These clinical results suggest the spleen has a different role in hemolysis of spherocytes and antibody coated cells.
In C3H mice, the red cell destruction of spherocytes and antibody coated cells was examined by using ⁵⁹Fe labeled heat damaged red cells and cells treated with anti-C3H-erythrocyte-sera. Heat damaged cell destruction was depressed in splenectomized mice, which were treated by the previous intra-venous injection of heat damaged, nonlabeled red cells as the blockade of RES, but the antibody coated red cells were not depressed. These experiments suggest spherocytes were predominantly destructed into the spleen and antibody coated cells were broken down in spleen, liver or other RES organs.

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Nineteen cases of splenectomy for ITP were analyzed.
Cases were divided into three groups according to the last platelet count of the hospital records: group A with over 100,000 per mm³, group B with less than 100,000 per mm³ (increment >20,000 per mm³), and group C with no postoperative increment.
The number of patients was 13 (68%) in group A, 4 (22%) in group B, and 2 (10%) in group C.
The spleen/liver sequestration ratio of the Cr⁵¹ labeled platelets were not different in the groups A and B.
One patient who had normal platelet survival had a very poor postoperative result.
The number of megakaryocytes in preoperative bone marrow were not significantly different in three groups. However, two patients who had lower normal number of megakaryocytes were found: one in the group B and another in the group C.
Above results reveal that the organic sequestration pattern of C⁵¹ labeled platelets may not be a useful way for predicting the postoperative results. On the other hand, the low normal number of megakaryocytes in marrow may give contraindication for splenectomy.

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Subcutaneous cerebrospinal-fluid (Ommaya) reservoirs were used in 3 adult patients with acute leukemia.
In two patients reservoirs were inserted for the treatment of meningeal leukemia and the other for drainage of cerebrospinal fluid to decrease intracranial hypertention. In the formers CNS-leukemia was successfully controlled by low dose of MTX injected via reservoir twice a week, but they died from relapse of their systemic disease without any clinical signs of meningeal leukemia. The concentration of MTX and ACNU in intraventricular fluid after intravenous infusion were also studied.
Although the principle complications of subcutaneous reservoir such as infection, obstruction, misplacement of Ommaya reservoir and leukemic cell growing around the canula were reported before, there was no side effect in our cases.
We consider that with adequate supervision, the reservoirs are valuable aids to intrathecal therapy in adult patients with meningeal leukemia.

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This report is concerned with studies on the disorder of hemostasis in 54 patients with chronic myelogenous leukemia (CML) and the developing of stairway phenomenon in thrombelastgram.
Hemorrhagic episodes were noted in 32 patients (59.3%). In the group of spontaneous hemorrhage, the mature neutrophil count was grately elevated to 25,000/cmm or more, and the platelet count was higher than 700,000/cmm. On the other hand, mechanical hemorrhages were often observed in cases with total mature neutrophil count of more than 25,000/cmm. There was no exaggerated bleeding during surgical procedures of patients whose mature neutrophil count controlled under 21,000/cmm. The stairway phenomena of thrombelastgraphic patterns were reported with many cases of CML. In this report, these phenomena were classified into two types, I and II, with or without impairment of maximum amplitude (ma), respectively. It was significant that the mature neutrophil count was higher in patients of type I with statistical evaluation of P<0.001, whereas the platelet count was higher in type II with P<0.05. Hemorrhagic episodes were often invited when the stairway phenomenon was detected and the mature neutrophil or the platelet count elevated. Therefore, it was postulated that patients should not be operated when type I was showed in thrombelastgram.
Experimentally it could be demonstrated that the developing mechanism of stairway phenomenon seemed to be attributable to the coagulative, fibrinolytic and biological activities of the marked increased mature neutrophils in blood samples. The disorder of hemostasis in CML would be increased by proteases of mature neutrophils in addition to the same mechanism, because the vascular connective tissues would be destroyed by these proteases in a hemostatic site in vivo.

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Hepatic dysfunction was analyzed in 35 adult patients with acute non-lympocytic leukemia with particular relation to the anti-leukemia treatment. Hepatic dysfunction was defined as the combined elevation of GOT, GPT or serum total bilirubin concentration. This complication was encountered in 26 patients (74%). Five patients showed hepatic dysfunction at the initial presentation and prior to anti-leukemic chemotherapy. In these cases, peripheral leukocyte count was greater than 10,000/μl, and their hepatic dysfunction improved by the remission induction chemotherapy, thus suggesting that the dysfunction was possibly related to the hepatic infiltration of leukemic cells in these cases.
Blood transfusion was given in all patients and the amount transfused was 7,600±12,900 ml (Mean±S. D.). HB-Ag and HB-Ab was positive in 17.1% and 25.7% of patients respectively, and both were negative in 62.8%. The number of courses of chemotherapy required for remission induction did not correlate with the extent of either GOT, GPT or bilirubin abnormalities. It was noted that GPT continued to aggravate after chemotherapy courses in 17 of 41 courses (41%) where the GPT values had been increasing in the preceding week of chemotherapy, whereas it remained unchanged or decreased in 80 of 90 courses (89%) in which the value had been either stable or improving during the preceding week. Two patients died of fulminant hepatitis. Both were positive for HB-Ag and showed marked rise in GPT immediately before the last course. Duration of survival after diagnosis for 16 patients complicated with hepatic dysfunction was 361±270 days and that for 7 patients without hepatic dysfunction was 294±113 days. The difference between these two groups, however, was not statistically significant.

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A 43-year-old woman was diagnosed as having CML in May, 1978, and she responded well to Busulfan. She was readmitted on June 7, 1979 because of peripheral lymphadenopathy of one month's duration, and hepatosplenomegaly. Hematologic studies showed moderate anemia, and a white cell count of 55,900/mm³ with 17% myloblasts.
Neutrophil alkaline phosphatase score was 88 by the method of Tomonaga. The section of the cervical lymphnode obtained by biopsy revealed myloblastic infiltration and myeloid metaplasia with numerous megakaryocytes. Peroxidase reaction of the myeloblasts was positive. The bone marrow biopsy showed myelofibrosis and proliferation of granulocytic series.
The karyotype of lymphnode cells as peripheral blood cells was 50, XX, Ph¹ t (9q+: 22q-), +8, +19, +20, +Ph¹ t (9q+: 22q-), and 46, XX, Ph¹ t (9q+22q-), 17P+. Various chemotherapeutic agents were given without effect. The patient died of septicemia due to E. Coli on November 22, 1979.
At autopsy, there was generalized enlargement of lymphnodes which showed myeloblastic infiltration. Myeloid metaplasia was found in the spleen and kidneys. There was Candida infection in the esophagus, bowels, and vagina.

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A 40 year old female was admitted to our hospital with general malaise and weight loss on Jan. 1975. A diagnosis of chronic myelogenous leukemia (CML) was made from the hematological findings of peripheral blood, bone marrow, and positive Philadelphia chromosome (Ph¹ chromosome). The patient responded excellently to the treatment with carboquone and dibromomannitol for 5 years.
On Nov. 1979, she complained of a mild pain in the upper part of the right thigh. Three months later, she developed an increasing pain followed by fever of unexplained origin and enlarged hepatosplenomegaly. On March 7, 1980, she suffered from a fracture of the right femur and then admitted to our hospital.
Increase of myeloblasts in peripheral blood and bone marrow were strongly suggested of the blastic crisis of CML.
She made no response to the therapy and died although immediately DCP combination therapy was performed.
An autopsy showed a pathological fracture due to myeloblastoma and tumor formation in the liver, spleen and kidney.
In preparation for various complication of leukemic tumor, this case was considered to worth reporting.

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A 14 year-old-boy with acute myeloblastic leukemia developed diabetes mellitus while receiving therapeutic L-asparaginase. The insulin binding determined as the percentage of ¹²⁵I-insulin bound to his erythrocytes was found markedly decreased at the time of being diabetic and then gradually returned to normal with recovery.
By using erythrocytes from 3 more patients with acute leukemia, ¹²⁵I-insulin binding was also assayed before and after L-asparaginase treatment. Decrease of insulin binding induced by L-asparaginase was confirmed in these studies.
It is suggested that hyperglycemia induced by L-asparaginase could be caused by changes in the quantity of insulin receptor or in the affinity of these receptors for insulin.

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A 50-year-old woman with atypical acute myeloblastic leukemia after ¹³¹I therapy for hyperthyroidism is described. She had been treated with 12 mCi of ¹³¹I because of hyperthyroidism three years before admission to the hospital on February 12, 1975. On admission, hematologic examination showed marked anemia and a white cell count of 1,300 with 1% myeloblasts and 34% monocytes. Peroxidase reaction of myeloblasts was negative.
Bone marrow aspirate revealed 16.8% myeloblasts and 9.0% promyelocytes. Platelet count was normal. Blood transfusion, prednisolone and 6 MP were effective to her.
But monocytosis and mild myeloblastosis continued for 20 months after admission. Following the atypical leukemic stage, marked myeloblastosis abruptly developed one month prior to death. She died on September 17, 1976.

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The second case of thrombotic thrombocytopenic purpura (TTP) treated successfully by warfarin, dipyridamole and aspirin is reported. A 38 years old housewife with the pentad of hemolytic anemia, thrombocytopenic purpura, fever, renal dysfunction and complicated neurologic symptoms did not respond to dipyridamol and aspirin initially. However, when the value of thrombotest decreased less than 20% after the administration of warfarin and prednisolon, the improvement of her various symptoms and laboratory findings was observed.
The level of circulating immune complex had been always within normal range in the clinical course.
The effectiveness of the oral anti-coaqulant, warfarin to TTP combined with antiplatelet agents and the evaluation of other therapies including exchange transfusion, antiplatelet agents, heparin and corticosteroid were discussed on our cases refering with literatures.

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The patient (67 years M) suffered from leukopenia on 60 and anemia with splenomegaly since. 62. Splenectomy was done on 67 to be followed by the change of hematological features with what to be the steady increase of monocytes (maximum caluculation, WBC 99,900/cmm including atypical monocytoid cells 29,000/cmm). The excised spleen was congested to weigh 870 gr consisting of fibroadenia together with Gandy-Gamna bodies without any leukemic infiltration. Monocytoid cells showed positive Peroxidase reaction, positive non-specific esterase activity and positive specific esterase activity. Leukemic organ involvement was seen in bone marrow, liver and lymph nodes with the spares leukemic cell infiltration. This case was diagnosed as subacute myelomonocytic leukemia after the onset and course as well as the leukemic cell features of maturating monocytoid cells and of cytochemical reactions. The case is compatible with cases of subacute or chronic myelomonocytic leukemia in the literature.

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In 1966 Albrecht first reported Gaucher-like cells in bone marrow smears of chronic myelocytic leukemia patients. Additional informations have been reported by Smith, Kattlove, and Sawitsky. Although a considerable number of publicatons have appeared in recent years, little is known about the mechanism of development of Gaucher-like cells or sea-blue histiocytes in the bone marrow of patients with acute or chronic myelocytic leukemia, or idiopathic thrombocytopenic purpura.
This study was designed to elucidate the mechanism of sea-blue histiocyte formation in the bone marrow. Histochemical, ultrastructural, and leukokinetic studies were performed on a patient with chronic myelocytic leukemia in order to find the relationship between the appearance of sea-blue histiocytes in the bone marrow and the granulocyte turnover rate. The high incidence of sea-blue histiocytes was considered to be resulted from the increased granulocyte turnover rate, which was thought to run in parallel with the glycolipid turnover rate. It was concluded that the excess glycolipid was accumulated and stored in reticuloendothelial cells.

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A case of new G6PD variant with congenital nonspherocytic anemia is reported.
The patient is a 3-year-old boy who was admitted to National Sapporo Hospital in February 1978 because of hemolytic crisis after having Phenacetin and Pyramidon as antipyretics.
On physical examination, the patient was anemia and icteric. Laboratory findings showed RBC 288×10⁴/cmm, Hb 8.6 g/dl, reticulocyte count 20.0%, serum bilirubin 1.8 mg/dl (indirect bilirubin 1.1 mg/dl) and ⁵¹Cr-labeled red cell half-life 13 days.
The red cells of the patient contained an extremely low level of G6PD activity (3.6% of normal mean). Biochemical characteristics of the affected enzyme were disclosed to have normal electrophoretic mobility, normal Km for G6P, normal Km for NADP, high Ki for NADPH, normal utilization of 2-deoxy -G6P and deamino-NADP, heat instability and a normal pH optimum curve.
The patient has been followed up to date and has been slightly icteric. So this case can be classified as Class 1 G6PD variant.
This variant is a newly identified variant with unique characteristics which was designated G6PD Sapporo.

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A case of 51-year-old female with chronic erythremic myelosis is described. The patient was admitted to our hospital on August 7, 1975, because of general malaise and anemia.
On admission, the laboratory study showed a macrocytic hyperchromic anemia with anisocytosis, poikilocytosis and anisochromia. Bone marrow study revieled erythroid hyperplasia, abnormal polynuclear erythroblasts and megaloblastoid cells. Chromosome abnormality and ineffective erythropoiesis were also present.
Any therapy except blood transfusion was ineffective and she survived for 9 years, She died of sepsis on September 17, 1976. Hemosiderosis and slight extramedullary hematopoiesis in the spleen were recongnized at necropsy.
From these findings we diagnosed her as chronic erythremic myelosis. Congenital dyserythropoietic anemia and sideroblastic anemia were excluded.

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