Acute erythremic myelosis (DiGuglielmo) following atypical aplastic anemia.

A patient presented with acute erythromyelosis (DiGuglielmo) which was developed after 3 yr of aplastic anemia. Aplastic anemia differed from the classical form, since erythroid cells and megakaryocytes were relatively preserved in the bone marrow. Treatment with androgens induced the increase of hematocrit and reticulocyte as well as general improvement. The sudden appearance of hemorrhagic syndrome due to thrombocytopenia was associated with aggravation of anemia and granulocytopenia. In the bone marrow, giant multinuclear proerythroblasts with bizarre nuclear morphology and PAS positivity with coarse granules was found. Serum erythropoietin (Ep) level was high. Bone marrow cells culture in vitro revealed two types of erythroid colonies: typical and giant multinuclear cells, both benzidine-positive. The number of colonies was irrespective to the Ep dose. "Autonomous" Ep independent growth of these colonies was also demonstrated. The number of colonies was more than 3 times higher per number of cells seeded when compared to normals, which indicated malignant proliferation and Ep independent growth. Treatment with 6-mercaptopurine and transfusions was without effect and the patient died after 15 days with signs of cerebral bleeding.

Drug-induced agranulocytosis: bone marrow granulocytic progenitor cells.

Bone marrow CFU-GM and cluster forming cells were studied in ten patients in different stages of drug-induced agranulocytosis using a methylcellulose cell culture technique in vitro. In the aplastic phase of the disease (A), the number of both CFU-GM and cluster forming cells was decreased in comparison to normal values. In the regenerative phase of the disease (R), the number of both granulocytic progenitors increased but did not reach normal values. In patients considered to be recovered from acute agranulocytosis (Rec), a decreased number of progenitors persisted indicating residual damage at this granulocytic cell level. It is suggested that agranulocytosis is due to isolated damage of granulocytic cells and predictable cascade of events within different cell compartments could be used as an in vivo model for investigation of the regulation of granulopoiesis.

[Chronic lymphocytic leukemia complicated by pernicious anemia during long-term remission]. / Hronicna limfocitna leukemija komplikovana pojavom perniciozne anemije u toku dugotrajne remisije.

Chronic lymphocytic leukaemia was diagnosed in 1957 in a 29-year-old male patient who lived 31 years after that time. At the time of diagnosis he was in good general condition with the enlarged liver (4 cm) and spleen (5 cm). In peripheral blood the leukocyte count was 47 x 10(9)/1 with 80% lymphocytes (38 x 10(9)/1), Hb 106 g/1; the bone marrow showed hypercellularity with predominance of lymphocytes. Treatment with corticosteroids was during 1958-1966. In 1967 Chlorambucil was given for 3 months, in 1972 for one month, inducing normalization of leukocyte count, 5.7 x 10(9)/1 with 40-50% of lymphocytes (3 x 10(9)/1). In 1977 the bone marrow showed slight lymphocytosis (38%). Numerous infections were recorded. Splenomegaly disappeared in 1980. In 1982 macrocytic anaemia was observed. Diagnosis of pernicious anaemia was established based on megaloblastic bone marrow and positive Schilling test. Vitamin B12 treatment resulted in reticulocyte response (crisis) and normalization of haemoglobin level. In 1988 light anaemia and melena appeared. Gastroscopy revealed lesions in the fornix histologically identified as ventricular carcinoma. It can be presumed that the appearance of pernicious anaemia as an autoimmune disease is analogous to other autoimmune complications in chronic lymphocytic leukaemia (haemolytic anaemia, thrombocytopenia).

[Results in the treatment of acute leukemias at the Internal Clinic B in the period 1970-1975]. / Rezultati lecenja akutne leukemije na internoj klinici B u periodu 1970-1975. Godine

Results of the treatment of 102 acute leukemia patients are presented. The diagnosis in 61 patients was acute myeloid leukemia (AML) and in 41 patients acute lymphoid leukemia (ALL). In the treatment of AML were used Daunorubicyne (DNR), Cytosine arabinoside (ARA-C) or combination of both drugs, some elder patients being treated with 6-mercapropurine. Number of patients were made aplastic and died during the initial phase of therapy. Nine of 24 patients treated with DNR, ARA-C or combined developed complete remission, 6 patients lived for one year and 4 patients two years. ALL patients were treated with Prednisone-Vincristine, Prednisone-Vincristine-DNR and some of them with Prednisone-Vincristine-DNR-Cyclophosphamide-L-Asparaginase combinations of drugs. Complete remission was obtained in 22 out of 32 patients (69%) and 6 patients lived for 2 years.

[Postpartum hemorrhage syndrome caused by factor VIII inhibitor in the blood]. / Postpartalni hemoragijski sindrom prouzrokovan inhibitorom VIII faktora koagulacije krvi

The appearance of Factor VIII inhibitor in women after childbirth is a very rare occurence. However the hemorrhagic syndrome which results from such condition can be very serious and difficult to treat. In this paper a case of young women is described who developed after childbirth a severe bleeding disorder. Clinical feature was very similar to those seen in haemophilia. The patient was investigated in the local hospital but the diagnosis was not made. The bleeding disorder lasted with various extension for six months and patient finally developed a severe sublingual and laringeal bleeding. She was transfered to the Clinic "B" of Internal Medicine in a very serious condition. On examination there was marked prolongation of the clotting time and no detectable Factor VIII. On the basis of these findings and the clinical expression of bleeding disorders, the tentative diagnosis of Factor VIII inhibitor was made. The treatment was not possible to institute because the patient expired within hours. Autopsy showed that bleeding into deep laringeal tissue was the sole cause of her death. Additional examination of the of the patient's plasma specimen using the antibody assay (Biggs-Bidwell-1959) showed the presence of the antibody to the Factor Viii which were active in 1:100 dilution.

Erythropoietin in patients with anaemia in rheumatoid arthritis.

Iron status and erythropoietin (Ep) level in serum and urine were determined in 30 patients with anaemia in rheumatoid arthritis. The anaemia in these patients was mild and fulfilled the criteria for anaemia of chronic disorders. The iron status of these patients differed from the iron status in patients with sideropenic anaemia. Serum Ep, level, measured indirectly by the polycythaemic mouse bioassay, was either not detected or when detected it did not correspond to the degree of anaemia. The data suggest that the failure to produce sufficient amount of Ep, among other causes, could be important in the pathogenesis of anaemia in rheumatoid arthritis.

A study of disturbances in granulocytopoiesis in humans using a diffusion chamber system.

Data are presented demonstrating that bone marrow granulocytic cells from normal persons continuously proliferate and mature during 5 d of cultivation in a diffusion chamber system (DC). Bone marrow granulocytopoiesis in 3 patients with different granulocytopoietic disorders was investigated using DC. In patient 1, with drug-induced agranulocytosis, bone marrow aspirated on the "day of recovery" revealed intensive proliferation in DC resulting in a highly significant increase of mature granulocytes. Patient 2 suffered from chronic neutropenia of unknown aetiology. After 5 d cultivation of bone marrow in DC an increase of metamyelocytes was observed, indicating delayed maturation of granulocytic cells. Patient 3 had neutropenia probably due to the splenic sequestration. Data obtained with DC suggest stimulated granulocytopoiesis in this patient. The results obtained using DC reflect the particular phase of the disease in which bone marrow was aspirated. It may be concluded that this method could provide additional data in quantitative and functional disorders of granulocytes.

Endogenous BFU-E in peripheral blood in diagnosis of polycythemia vera.

Erythroid progenitors (CFU-E and BFU-E) growth in vitro from bone marrow and peripheral blood of patients with polycythemia vera (PV) was studied using a methylcellulose culture technique. The aim of the study was to find out whether the in vitro colony formation of peripheral blood could be used in the differential diagnosis of PV. In all 25 patients studied, endogenous colonies were found in the bone marrow and peripheral blood. The parallel study of both bone marrow and peripheral blood erythroid progenitors indicates that the presence of endogenous BFU-E in peripheral blood is a dependable test for PV. The results presented here showed that the abnormalities in PV erythroid progenitors are expressed at the level of both CFU-E and BFU-E, suggesting multiple changes in the erythroid progenitors. Our finding indicate that peripheral blood BFU-E differ from bone marrow BFU-E with regard to their dependence for further differentiation on BPA, the activity present in PHA-LCM.

Cell cycle time of erythroid cells in mice with normal and stimulated erythropoiesis.

The cell cycle time of erythroid cells was determined in normal mice and in polycythaemic mice after stimulation of erythropoiesis by exogenous erythropoietin. The method employed was 3HTdR autoradiography of bone marrow cells. After 21 or 38 hours of administratering the erythropoietin 3HTdR was injected into the animals. The cell cycle time was calculated from the curves of changes in the labelling indices of proerythroblasts and basophilic erythroblasts at one hour intervals. The cell cycle time in normal animals was 8.5 hours. Twenty-two to twenty-five hours after stimulation with 1.5 units of erythropoietin, the cell cycle was 7.8 hours. Thirty-nine to forty-two hours after injection, at the time when the number of nucleated erythroid cells was within normal limits, the cell cycle time was 7.7 hours. Under the used experimental conditions, the cell cycle time of early erythroid cells was not significantly changed in comparison with the values obtained in non-treated animals. This is in contrast to the results reported when extreme stimulation of erythropoiesis with endogenous erythropoietin was used.

[Immunoneutropenia]. / Imunoneutropenija.

A patient with two episodes of acute agranulocytosis was described. Recovery was followed by an unusually slow increase in the number of peripheral blood granulocytes in spite of the presence of granulocyte precursors in the bone marrow. High level of circulating immune complexes as well as an increased number of immunoglobulins on the surface of granulocyte membrane was demonstrated throughout the course of the disease. When the level of CIC and the number of Ig-NG decreased and attained normal values, the number of granulocytes increased rapidly. The possibility that immune complexes were responsible for this neutropenia was suggested.

Myelopoiesis and erythropoiesis of bone marrow cells cultured in vitro in patients recovered from aplastic anaemia.

Methylcellulose culture assay was used to detect committed haemopoietic stem cells, CFU-C and CFU-E, in aplastic anaemia patients with autologous haemopoietic reconstitution. Severe diminution of CFU-C was found in all the patients studied and the absence of a dose-response to colony stimulating factor (CSF) was demonstrated. A reduced number of CFU-E and lower erythropoietin (Ep) sensitivity of those progenitors was detected as well. Autologous serum added to the bone marrow cultures of these patients enhanced the growth of CFU-C but inhibited CFU-E growth. According to the results presented, some residual damage at the stem cell level is suggested.

Erythropoiesis in paroxysmal nocturnal hemoglobinuria.

Ten patients with paroxysmal nocturnal hemoglobinuria were studied. The diagnosis was made on the basis of hemolytic anemia, a positive Ham test and hemosiderinuria. Six patients had primary paroxysmal nocturnal hemoglobinuria evolved from aplastic anemia. These four patients also had a milder form of the disease, Over long periods of the follow-up, large variations of hemoglobin values and red blood cell counts were observed. Both absolute and percent reticulocyte counts were increased. Erythroblast counts in the bone marrow were 3-5 times higher than normal. Reticulocyte counts in the bone marrow were 3-5 times higher than normal. Reticulocyte counts showed wide variations but substantially smaller than those in autoimmune hemolytic anemias. Serum iron was either normal or increased, while the bone marrow iron store was high or low. However, the finding of urinary hemosiderin in all cases spoke against depletion of iron stores. The red blood cell life span was moderately shortened. Kinetic studies with 59Fe showed a high red blood cell iron incorporation, while the curves frequently had irregular shapes (broken curve) or an early, abrupt fall. Studies of late erythroid progenitors (CFU-E) indicated that this compartment was preserved. Even after long observation periods was no stem cell pool depletion due to an increased red blood cell demand observed.

Hemoglobin Beograd (alpha2beta2 121 Glu leads to Val) interacting with beta-thalassemia.

Hematological and biochemical findings in a family with hemoglobin (Hb) Beograd interacting with beta-thalassemia are presented. Hb Beograd (alpha2beta2 121 Gul leads to Val) was found in 3 members. In two members it interacted with beta-thalassemia. These two double heterozygotes had anemia of intermediate severity and splenomegaly. Studies with 51Cr and 59Fe showed a shortened life span of red cells and ineffective erythropoiesis. The abnormal Hb amounted to 86-87%, and Hb F to 5-7%. No Hb A was present. One subject of the family was heterozygous for Hb Beograd. He showed normal clinical and hematological findings. The abnormal hemoglobin was 38%. Four members of the family were heterozygotes for beta-thalassemia. The interaction between beta-thalassemia and beta-chain variants is discussed.

Erythropoietin in aplastic anemia.

The level of erythropoietin (Ep) was measured in sera and urine from aplastic anemia patients. Increased levels of Ep were demonstrated in sera from all 25 patients studied. An elevated level of Ep was found in the urine of 17 of 23 patients in whom the urine was tested. No correlation between blood hemoglobin and Ep level was observed. A higher serum Ep level was noted in patients with aplastic anemia than in patients with sideropenic anemia of the same severity. To explain the discrepancy diminished Ep consumption in bone marrow of aplastic anemia patients is discussed.

[Erythropoietin in sideropenic anemias]. / Eritropoetin u sideropenijskim anemijama.

The erythropoietic activity in the sera of 18 patients with sideropenic anemia was investigated. The ex-hypoxic mouse bioassay was used and the 48 hour incorporation of radioiron into the peripheral blood was measured. The level of erythropoietin found was compared to the hemoglobin concentration and the PCV values in those patients. The statistically significant correlation was found between erythropoietin in the patients sera and the degree of anemia. Higher erythropoietin values were found in men as compared to women with the same severity of anemia. It was concluded that the results obtained in this study can be used as control values when erythropoietic activity in the sera of patients with different hematological disorders is measured.