A case of 'auto-immune thrombocytopenic purpura' serologically similar to post-transfusion purpura.

The report describes a HPA-1a (Zwa)-negative woman with thrombocytopenia and antibodies in serum and eluate from autologous platelets with an operational anti-HPA-1a specificity. The results of the serological investigations were similar to the findings in most patients suffering from post-transfusion purpura. However, the present patient had no history of blood transfusion prior to the unset of purpura and the thrombocytopenia had persisted 6 months before splenectomy.

Acute leukaemia: development, remission/relapse pattern, relationship between normal and leukaemic haemopoiesis, and the 'sleeper-to-feeder' stem cell hypothesis.

Attention has been focused on two problems of acute leukaemia: (1) the origin of normal-appearing haemopoietic cells during relapse, and (2) the inverse relationship between leukaemic blast cell proliferation and useful haemopoietic cell production. The available evidence suggests that the normal-appearing cells during relapse may not all be remnants of normal haemopoiesis but may at least in part be derived from leukaemic cells. Although a differentiation defect is a major characteristic of acute leukaemia, it seems as if this defect is not absolute: some cells may succeed in differentiating more or less normally in spite of their descent from a leukaemic stem cell. Acute leukaemia is usually considered to be a primary white cell disorder which indirectly affects the other haemopoietic cell lines. It appears more likely, however, that acute leukaemia, at least the myeloid type, is a disorder of a stem cell common to granulocytopoiesis, erythropoiesis, and probably thrombocytopoiesis. Most descendants from the diseased stem cell fail to differentiate and remain at the blast cell level where they proliferate for some time; however, at a certain point proliferation ceases and the cells ultimately die. Another fraction of the progeny of the leukaemic stem cells may differentiate to some extent and may give rise to functionally useful cells. This is analogous to chronic myeloid leukaemia. The mechanism by which useful haemopoiesis apparently is suppressed in the presence of leukaemic blast cells has remained enigmatic so far. Previously suggested explanations which all assume some kind of cell-cell interaction by which normal haemopoietic cells succumb have neither been proved nor disproved. In this chapter, a new hypothesis is presented. It is assumed that some normal haemopoietic stem cells enter a dormant state at various distances in lineage from the fertilized ovum ('sleepers'). Another fraction of haemopoietic stem cells ('feeders') are actively proliferating and serve to feed the differentiating haemopoietic cell lines and to maintain the 'feeder' pool. When the 'feeder' pool is exhausted, a 'sleeper' cell is activated and sets up a new 'feeder' clone. Otherwise, 'sleepers' are protected against acting as 'feeders' in order to keep 'sleeper' divisions at a minimum and thus preserve their genetic information as intact as possible. It is suggested that the leukaemic event initially takes place in one or a few 'sleepers'. If the leukaemic 'sleeper' never succeeds in setting up a 'feeder' clone, clinical leukaemia will not develop. Clinical leukaemia will result if a leukaemic 'sleeper' establishes a leukaemic 'feeder' pool.(ABSTRACT TRUNCATED AT 400 WORDS)

Post-transfusion purpura (PTP) due to anti-Zwb (-PlA2): the significance of IgG3 antibodies in PTP.

The first two patients with post-transfusion purpura (PTP) due to platelet antibodies against the Zwb antigen are reported. The anti-Zwb specificity could be demonstrated only with an enzyme-linked immunosorbent assay (ELISA) but not with the immunofluorescence or the complement fixation test due to coexistent potent multispecific HLA antibodies. One of the patients had never received blood transfusion until 24 d before the development of thrombocytopenic purpura. In both patients, anti-Zwb of IgG1 and IgG3 subclasses defined by monoclonal antibodies were present during the thrombocytopenic period but the antibodies of IgG3 subclass disappeared concomitantly with clinical improvement. The association between the IgG3 subclass of anti-Zw antibodies and the destruction of autologous platelets in Zw-immunized individuals was investigated further. All of four PTP patients had anti-Zw antibodies of the IgG1 and IgG3 subclasses during the thrombocytopenic period while all of 20 mothers of children affected with alloimmune neonatal thrombocytopenia (AINT) had anti-Zwa of only the IgG1 and not IgG3 subclass at the time of delivery of thrombocytopenic children (P less than 10(-4). Thus, the destruction of autologous platelets in PTP is associated with the presence of anti-Zw of the IgG3 subclass which may be of importance in the pathogenesis of PTP.

Acute lymphocytic leukaemia with t(4;11): a clinical subentity.

5 cases of ALL are reported with a t(4;11) chromosomal rearrangement, and 31 cases, investigated before therapy, are reviewed. The (4;11) translocation characterizes a subentity of ALL having the following main features, as compared with ALL in general: 1) Excessively poor prognosis, with a median survival of 6 months despite high remission rates. 2) Low median age of 10 months in children. 3) CNS involvement apparently occurs more frequently. 4) Median WBC is 12 times higher in adults and children, median per cent of blasts in blood 1.5 times higher in adults and 1.8 times higher in children. 5) Splenomegaly is present more frequently. 6) Surface markers are non-B, non-T. The incidence of t(4;11) in ALL varies greatly in the series published so far, from 0.04% to 12%.

A monoclonal antibody (NAT-9 II:3F-6F) that identifies a differentiation antigen on human myeloid cells.

A monoclonal antibody, designated NAT-9 II:3F-6F (IgM), was generated by hybridization of mouse myeloma cells with spleen cell from mice immunized with normal human bone marrow cells. The antibody reacted with 40-60% of bone marrow cells as analysed on samples from 40 normal individuals and only with a subpopulation of human acute myeloid leukemia (AML) cells of the M2 class (20/20 tested) and M4 class (12/12 tested) (subclasses of the French-American-British (FAB) classification), but not with leukemic cells of the M1 (0/12 tested) and M5 (0/12 tested) FAB subclasses. This is in contrast to many other myeloid-specific monoclonal antibodies. Fluorescence-activated cell sorter (FACS) analyses and morphological examination of cells stained with peroxidase as based on the NAT-9 II:3F-6F monoclonal antibody showed that this antibody reacted with a distant differentiation antigen which is absent on myeloblasts, but expressed on promyelocytes, myelocytes, metamyelocytes, band neutrophils, and on a minority of mature granulocytes. NAT-9 II:3F-6F did not bind to circulating monocytes, T and B cells, erythrocytes and a variety of different human cell culture lines. Immunoblotting demonstrated that the antibody bind to a cellular component with a Mr approximately 97.400 dalton. The antibody may be useful in immunological subclassification of non-lymphoid leukemias and in studies on hematopoiesis.

Urinary excretion of beta-aminoisobutyrate and pseudouridine in acute and chronic myeloid leukemia.

End products of nucleic acid metabolism including beta-aminoisobutyrate (beta-AIB) and pseudouridine (psi-Urd) have been considered as potential biochemical markers for cancer. The urinary excretion of both metabolites was investigated in abnormal hematopoietic conditions including 26 patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) and was compared to that of 25 healthy controls. beta-AIB excretion in CML was directly correlated to the leukocyte count, the indicator of tumor cell mass. beta-AIB excretion was elevated in 27 and 75% of untreated AML and CML cases, respectively. Marrow blast cell content tended to correlate positively with psi-Urd excretion in AML. psi-Urd excretion was elevated in 82 and 87% of untreated AML and CML, respectively. Turnover of hematopoietic cells seemed to be a determinant for beta-AIB excretion, indicating higher cell turnover in CML patients compared to that in AML patients and in controls. With cytostatic treatment, excretion levels of beta-AIB and/or psi-Urd decreased after a transient rise.

Cytoplasmic labelling of eosinophils with tritiated thymidine triphosphate.

A new technique which detects the presence of DNA polymerase and primer-template DNA by measuring the incorporation of 3H-thymidine-5-triphosphate (3H-TTP) showed cytoplasmic labelling of eosinophilic granulocytes and eosinophilic myelocytes in normals, in acute leukaemia, in chronic myeloid leukaemia and in patients with eosinophilia of unknown origin.

Successful nonsibling bone marrow transplantation in severe combined immunodeficiency.

Severe combined immunodeficiency (SCID) was diagnosed in a girl immediately after birth; her older brother had SCID and was successfully reconstituted by bone marrow transplantation from his uncle. She was isolated in a laminar air flow bench and decontaminated. The father differed by one HLA-A antigen but was HLA-Dw2 homozygous like the patient; his lymphocytes showed a slight response to the patient's cells in mixed lymphocyte culture (MLC). At the age of 2 1/2 months and again at 5 months, she was given a bone marrow transplant from the father. During the entire course the patient had no infections, and apart from a transient eosinophilia she had no signs of graft-versus-host reaction. Immunological reconstitution was nearly complete at 9 months of age, when she was recontaminated. One year later plasma immunoglobulin concentrations are in the low normal range (IgG and IgM) or decreased (IgA); tests of cell-mediated immunity are normal. Apart from slight upper respiratory infections, the patient has been healthy. Physical and psychological development have been normal.

Nuclear DNA-polymerase estimation in human leukaemic myeloblasts.

A technique which detects the presence of DNA-polymerase in cell nuclei by measuring the incorporation of 3H-thymidine-5-triphosphate (3H-TTP) has been used to estimate the proportion of leukaemic myeloblasts which contains DNA-polymerase and DNA capable of acting as primer-template. In six cases of previously untreated acute myeloid leukaemia the 3H-TTP labelling index (3H-TTP LI) was much larger than the fraction in DNA synthesis. After a single 'flash' injection of cytosine arabinoside a pronounced decline was observed in the 3H-TTP LI, which can be explained by a direct inhibition of NDA-polymerase. No change was observed in the fraction of cells labelled with 3H-thymidine. A decrease in 3H-TTP LI was also observed after a single i.v. dose of methotrexate.

Arabinosyl cytosine in chronic myeloid leukaemia: evidence for high cytokinetic sensitivity of myeloblasts.

The effect of a single and of repeated i.v. push dose(s) of Arabinosyl Cytosine (ARA-C) has been investigated in 9 chronic myeloid leukaemia (CML) patients in non-blastic phase. This was done by determining separately the relative compartment size, the mitotic index (IM), and the in vitro 3H-TdR labelling index (IL) of marrow and blood myeloblasts (MB) and promyelocytes plus myelocytes (PMC + MC), before and at intervals after the drug. After a single dose of ARA-C, the IL of marrow MB declines rapidly, and recovers thereafter, often with an overshoot at 15 h. After 2 to 4 doses of ARA-C, the IL of marrow and blood MB rises by a factor of 2 to 3, and is maintained at a plateau during further treatment. The behaviour of the IL of blood MB is not always the same as that of marrow MB. The IM of marrow MB does not rise proportionally to the IL, and sometimes is even found to be decreased. It is suggested that these kinetic perturbations reflect an accumulation of MB in S-phase where many but not all of them are trapped and sooner or later die off. With a few exceptions, ARA-C induces only milder kinetic perturbations in marrow and blood PMC+MC. The overall results of this study are in agreement with the generally accepted mechanism of action of ARA-C (S-phase specific effector agent), and with studies that indicate that the effect of ARA-C depends on the growth pattern and on the degree of maturation of the target cells. It is suggested that a proper evaluation of ARA-C on a cell population should take into account the existence of different cell pools, provided with different proliferative activity and potential, and with variable degrees of maturation.