Gerald L. Logue

Sudden death during doxorubicin administration.

Three patients are described who either died suddenly or had severe, lifethreatening arrhythmias during or immediately after doxorubicin administration. Since doxorubicin and daunorubicin administration is known to be associated with acute EKG abnormalities, the acute decompensation in these patients appeared to be caused by the administration of these agents. The importance of careful observation of patients receiving doxorubicin, because of the possibility of acute cardiac arrhythmias, is stressed.

The Use of in Vitro Technics to Study Drug-Induced Pancytopenia

The confirmation of drug-induced marrow aplasia is difficult since rechallenging the patient can lead to serious morbidity. We used marrow-culture technics to challenge in vitro the bone marrow of a patient with marrow aplasia after ingestion of quinidine. There was no clinical or laboratory evidence of quinidine-mediated destruction of erythrocytes, leukocytes or platelets. By contrast, use of quinidine in combination with the patients serum substantially inhibited in vitro growth of allogeneic marrow granulocytic and erythroid series. Furthermore, use of quinidine in combination with acute-phase serum (but not acute-phase serum alone or quinidine in combination with recovery-phase serum) inhibited growth of the patients marrow. This observation suggests that both a transient serum factor and quinidine were responsible for the marrow aplasia. These technics could be applied with minimal risk to similar patients and would permit in vitro rechallenge with the suspected drug.

Quantitative influence of antibody and complement coating of red cells on monocyte-mediated cell lysis.

Monocyte-mediated lysis in vitro of human red cells coated with measured amounts of immunoglobulin G (IgG) or complement were studied. 1,000-1,500 molecules of IgG anti-D are necessary to effect measurable lysis, and lysis increases linearly with increasing levels of antibody sensitization. 100 microgram/ml of IgG1 abolished lysis even at maximal levels of anti-D sensitization (15,000 molecules/cell). Two isoimmune IgG anti-A or anti-B antisera were 5 to 10-fold less efficient in promoting phagocytosis or lysis per molecule of IgG bound; however, because of the greater antigen density of A or B, more than 100,000 molecules IgG/cell could be bound, producing equivalent lysis to anti-D-coated cells. Although inhibition by IgG1 was similar at equivalent levels of sensitization with anti-A, anti-B, or anti-D at high levels of coating with anti-A or anti-B (not attainable with anti-D), lysis was not inhibited by IgG1. Cells coated with human complement components alone were not lysed by monocytes; however, complement coating augmented IgG-mediated lysis and reduced the quantity of anti-D necessary to produce lysis to less than 1,000 molecules/cell. After thorough degradation of C3b by serum to C3d, complement augmentation persisted.

Mechanisms of Immune Lysis of Red Blood Cells In Vitro I. PAROXYSMAL NOCTURNAL HEMOGLOBINURIA CELLS

The effect of five different reactions which activate complement (antibody activation, reduction in ionic strength, acidification, cobra venom factor (CoF) activation, and inulin activation) upon normal and PNH cells was investigated, using normal serum and serum devoid of the fourth component of complement (C4) activity from patients with hereditary angioneurotic edema (HANE) as a source of complement. Both normal and HANE serum lysed paroxysmal nocturnal hemoglobinuria (PNH) cells when complement was activated by acidification, CoF and inulin, indicating that the terminal steps of complement were activated in the absence of C4, presumably by the alternate or properdin pathway. Normal but not HANE serum lysed cells coated with anti-I, indicating that complement was activated by the C1-dependent classic pathway. HANE serum partially supported lysis by serum at reduced ionic strength, indicating that the activation of terminal complement components had occurred through both of the pathways of activation. The amount of the third component of human complement (C3) which was bound to the membrane of lysed and unlysed cells by these procedures was determined by anti-C3 absorption and was found to differ for each method of complement activation. In general, more C3 was bound to lysed cells than to unlysed cells. For given conditions, more was bound to PNH cells than to normal cells. However, very much less bound C3 was required for lysis of the PNH cells than for lysis of normal cells. These two phenomena, especially the latter, account for the marked lysis of PNH cells when complement is activated. Normal cells treated with AET (aminoethylisothiouronium bromide) did not bind more C3 than untreated cells and the lysed cells had less bound C3 than lysed PNH cells.

Mechanisms of Immune Lysis of the Red Cells in Hereditary Erythroblastic Multinuclearity with a Positive Acidified Serum Test and Paroxysmal Nocturnal Hemoglobinuria

The red cells of patients with hereditary erythroblastic multinuclearity with a positive acidified serum test (HEMPAS), a form of congenital dyserythropoietic anemia, and the cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) are lysed more readily than normal cells by certain antibodies, notably cold agglutinins (anti-I) and complement. With some but not other examples of anti-I, HEMPAS and PNH cells adsorbed more antibody than normal cells. Equal quantities of adsorbed antibody bound equal quantities of the first component of complement (C1) to normal, PNH, and HEMPAS cells. However, for a given quantity of bound antibody and C1, much more of the fourth component of complement (C4) was bound to HEMPAS cells than to normal cells. This resulted in the binding of proportionately larger quantities of the third component of complement (C3) to these cells. The same amount of bound C3 was found on the membranes of normal and HEMPAS cells for a given degree of lysis. Hence, the marked increase in lysis of HEMPAS cells is due to the increased adsorption of antibody and/or increased binding of C4.PNH cells bound the same amount of C4 per bound C1 as normal cells but bound more C3 than normal cells. However, the mean concentration of C3 on the membrane of PNH cells was one-third to one-fifth that on normal cells for a given degree of lysis. Hence, the increased lysis of PNH cells is due to the increased binding of C3 and increased hemolytic effectiveness of the bound C3.

Complement-mediated autoimmune thrombocytopenia. Monoclonal IgM antiplatelet antibody associated with lymphoreticular malignant disease.

CHRONIC or adult autoimmune thrombocytopenia usually occurs with high levels of platelet-associated IgG antibodies,1 2 3 platelet-associated IgM antibodies,4 5 6 or both. The role of complement-med...

Two Biochemical Markers in Lymphocyte Subpopulations

Summary. Human blood lymphocytes can be separated into two populations according to the presence of surface complement receptors. Lymphocytes containing complement receptors (CR+) were found to have a high rate of RNA synthesis or turnover accompanied by increased protein synthesis. Lymphocytes not containing complement receptors (CR—) while maintaining a low profile in RNA synthesis, had a 10–12‐fold greater activity in adenosine deaminase enzyme which is believed to be related to lymphocyte‐immune responses and cell‐mediated immunity. These two biochemical characteristics can be useful tools for future studies in lymphocyte functions. By using these two biochemical markers, we found that CLL lymphocytes were predominantly of the CR+ type, had high active RNA synthesis, and very low adenosine deaminase level. Lymphocytes from two patients with X‐linked agammaglobulinaemia showed a picture opposite to that of CLL.

Alpha-Interferon for Severe Cold Agglutinin Disease

Excerpt Cold agglutinin disease may be classified as primary or secondary. Monoclonal IgM (occasionally IgG or IgA) proteins with the ability to bind to erythrocytes below body core temperature are...

Measurement of the Third Component of Complement Bound to Red Blood Cells in Patients with the Cold Agglutinin Syndrome

The amount of the third component of complement (C3) bound to red cells of patients with the cold agglutinin syndrome was determined by a quantitative assay, measuring the fixation of the first component of complement by anti-C3. Abrupt reduction in the serum concentration of cold agglutinin by plasmapheresis markedly decreased the hemolytic rate, but the amount of C3 bound to circulating cells did not change appreciably. When this patient was transfused with normal cells. C3 accumulated on the transfused cells within 48 h to the level present on his own cells, but selective destruction of the transfused cells did not occur. When patients were subjected to acute cold stress, cell-bound C3 rose abruptly and intravascular hemolysis occurred. These studies suggest that most of the C3 detected on the circulating red cells of cold agglutinin patients is in an inactive form, and that the rate of attachment of C3 to the membrane is important in determining hemolysis.

Felty's Syndrome: Effects of Splenectomy Upon Granulocyte Count and Granulocyte-Associated IgG

Clinical parameters and laboratory studies including granulocyte-associated IgG were documented in 15 patients with Feltys syndrome treated by splenectomy. Five patients did not benefit from splenectomy, six responded partially, and four completely. Response to splenectomy could not be predicted from age, sex, splenomegaly, preoperative granulocyte count, platelet count, lymphocyte count, bone marrow lymphocytosis, or granulocyte bound IgG. In contrast, marked elevation in preoperative serum granulocyte binding IgG predicted response to splenectomy. Furthermore, a postoperative fall in serum granulocyte binding IgG was associated with response. Thus, one beneficial effect of splenectomy in some Feltys syndrome patients is reduction of serum granulocyte binding immunoglobulin.