Autoimmune neutropenia [see comments]

There have been several new developments in the field of autoimmune neutropenia over the past decade. Neutropenia caused by antibodies directed against granulocyte precursor cells, the oligoclonal nature of antineutrophil antibodies, and the expanding knowledge of neutrophil antigens, particularly in relationship to autoantibodies, are exciting new areas of investigation. Knowledge has also been advanced in the effector mechanisms of neutrophil autoantibodies and the effect of autoantibodies on the neutrophil function. In addition, some clinical syndromes of immune neutropenia have been better defined over the past decade, such as autoimmune neutropenia of infancy and chronic idiopathic neutropenia in adults. The past decade also saw interesting developments in the treatment of immune neutropenia, particularly in the use of gammaglobulin preparations and more recently in the advent of hematopoietic growth factors. This review focuses on these newer aspects of autoimmune neutropenia.     

Graft-v-host disease is associated with autoimmune-like thrombocytopenia [see comments]

Persistent thrombocytopenia after allogeneic marrow transplantation is associated with poor patient survival. To identify the mechanisms of the thrombocytopenia, we studied platelet and fibrinogen kinetics and antiplatelet antibodies in 20 patients between 60 and 649 days (median 90) after transplantation. Seventeen patients had isolated thrombocytopenia (less than 100 X 10(9) platelets/L): the marrow cellularity was normal in five patients and slightly reduced in 12, and there was no discrepancy between thrombopoiesis and myeloerythropoiesis. Three patients had pancytopenia following marrow graft rejection (two) and relapse of leukemia (one). Only three patients had evidence of increased platelet production, indicating that in most cases there is a poor marrow response to thrombocytopenia early after marrow grafting. There was no correlation between platelet count and splenic pooling, suggesting that hypersplenism was an unlikely mechanism of the thrombocytopenia. Although there was a direct relationship between platelet count and platelet survival, the reduction in platelet survival was greater than what could be explained by the fixed platelet removal found in thrombocytopenic patients; this suggests increased platelet destruction. Seven patients had intercurrent infections that reduced both platelet and fibrinogen survivals. In addition, platelet antibodies bound to autologous or marrow donor platelets were present in five of the 12 patients studied. Patients with antiplatelet antibodies had lower platelet counts (30 +/- 10 X 10(9)/L v. 49.1 +/- 28.7 X 10(9)/L, P less than 0.05) and platelet survivals (1.32 +/- 0.92 days v. 3.58 +/- 2.02 days, P less than 0.05) than patients without antiplatelet antibodies. Furthermore, platelet- bound autoantibodies were present in five of six patients with grade II- IV acute or chronic graft-versus-host disease (GVHD), but were not present in six patients free of GVHD (P less than 0.01). We conclude that persistent thrombocytopenia after marrow transplantation is most often secondary to increased platelet destruction mediated by multiple mechanisms and that platelet autoantibodies are found in patients with acute or chronic GVHD.     

Histiocytes and histiocytosis [see comments]

The term histiocyte refers to cells of either the macrophage or Langerhans cell lineages. The histiocytic disorders are characterized by the proliferation of cells of these lineages. With recent advances in knowledge of the developmental biology of histiocytic cells, it is now possible to formulate a reasonable catalogue of histiocytic diseases based on ultra-structural and phenotypic markers of cellular origins and molecular or chromosomal markers of malignancy. The catalogue includes the following groups of diseases. Nonmalignant reactive macrophage disorders include (1) macrophage storage diseases, (2) several benign proliferative macrophage disorders that predominantly involve skin and bone, and (3) several hemophagocytic syndromes that vary from indolent and benign to fulminant and fatal. In some of the latter disorders, viruses have been identified as the inciting stimulus. The malignant macrophage disorders include (1) acute monocytic leukemia and (2) chronic myelomonocytic leukemia. A rare disorder that gave rise to a permanent cell line with an anomaly of chromosomal segment 5q35 may also be an example of a histiocytic malignancy. The existence of a separate category of true histiocytic lymphoma of macrophage type is uncertain. Reactive Langerhans cell disorders include (1) congenital self-healing histiocytosis, (2) the many variants of eosinophilic granuloma, and (3) a related disorder designated as relapsing Langerhans cell histiocytosis that is characterized by a relapsing course and infiltration of bone and soft tissues by Langerhans cells. Presumptively neoplastic diseases of Langerhans and dendritic cells include (1) progressive Langerhans cell histiocytosis, a disease with prominent involvement of blood and BM as well as skin and viscera; (2) Langerhans cell lymphoma, and (3) dendritic cell lymphoma. However, clonality as a marker of malignancy has not been proven in these disorders.     

Studies of the activation of factor VII bound to tissue factor [see comments]

Experiments were performed to evaluate activation of factor VII bound to relipidated tissue factor (TF) in suspension and to TF constitutively expressed on the surface of an ovarian carcinoma cell line (OC-2008). Activation was assessed by measuring cleavage of 125I- factor VII and by the ability of unlabeled factor VII to catalyze activation of a variant factor IX molecule that, after activation, cannot back-activate factor VII. Factor Xa was found to effectively activate factor VII bound to TF relipidated in either acidic or neutral phospholipid vesicles. Autoactivation of factor VII bound to TF in suspension was dependent on the preparation of TF apoprotein used and the technique of its relipidation. This highlights the need for caution in extrapolating data from TF in suspension to the activation of factor VII bound to cell surfaces during hemostasis. A relatively slow activation of factor VII bound to OC-2008 monolayers in the absence of added protease was observed consistently. Antithrombin in the presence or absence of heparin prevented this basal activation, whereas TF pathway inhibitor (TFPI/factor Xa complexes had only a limited inhibitory effect. Adding a substrate concentration of factor X markedly enhanced basal activation of factor VII, but both TFPI/factor Xa and antithrombin/heparin abolished this enhancement. Overall, our data are compatible with the hypothesis that not all factor VII/TF complexes formed at a site of tissue injury are readily activated to factor VIIa (VIIa)/TF complexes during hemostasis. The clinical significance of this is discussed.     

Interleukin-10 is an autocrine growth factor for acquired immunodeficiency syndrome-related B-cell lymphoma [see comments]

Interleukin-10 (IL-10) is an acid-sensitive protein of 35 kD that has pleiotropic effects including inhibition of cytotoxic T-cell response, induction of major histocompatibility complex type II in B lymphocytes, induction of B-cell growth and differentiation, and autocrine growth factor activity in monocytes. We and others have shown that IL-10 is produced spontaneously by blood mononuclear cells from human immunodeficiency virus-seropositive patients. In an attempt to ascertain the potential role of IL-10 in acquired immunodeficiency syndrome (AIDS)-related B-cell lymphoma, we evaluated the expression of human IL-10 in both tumor-derived B-cell lines and primary tumor cells. Expression of human IL-10 (hIL-10) mRNA and protein was detected in four of five cell lines examined. An IL-10 antisense oligonucleotide inhibited IL-10 mRNA expression and IL-10 protein production. The proliferation of all B-cell lines was inhibited by an antisense oligonucleotide in a dose-dependent manner that was abrogated by the addition of recombinant hIL-10 protein. No effect of antisense oligonucleotide was observed in the B-cell line not producing hIL-10. Evaluation of primary tumor cells from patients with AIDS-lymphoma cells showed similar production and response to IL-10. These data suggest an autocrine growth mechanism for IL-10 in AIDS-related lymphoma cells and that IL-10 may be important in its pathogenesis.     

Wegener's granulomatosis autoantigen is a novel neutrophil serine proteinase [see comments]

Circulating IgG autoantibodies that produce cytoplasmic immunofluorescence staining of ethanol-fixed normal neutrophils have recently been found in a large percentage of patients with active Wegener's granulomatosis. Such autoantibodies are rarely found in other diseases and are therefore virtually diagnostic of Wegener's granulomatosis. The nature of the neutrophil antigen defined by these autoantibodies is controversial and the roles of the antigen and/or autoantibodies in the pathogenesis of Wegener's granulomatosis are unknown. We studied serum samples that produce the cytoplasmic pattern of staining from 10 patients with a diagnosis of Wegener's granulomatosis. By Western blot analysis, all 10 sera reacted with a 29- Kd neutrophil protein (p29). We generated a mouse monoclonal antibody directed against this antigen. The monoclonal antibody produced the same immunofluorescence staining pattern as the serum autoantibodies and was used to affinity-purify p29. The purified antigen had a novel N- terminal sequence homologous to members of the serine proteinase family and bound to radiolabeled diisopropyl fluorophosphate (DFP). We conclude that the neutrophil antigen responsible for the cytoplasmic staining pattern produced by autoantibodies in patients with active Wegener's granulomatosis is a distinctive serine proteinase.     

The site of the breakpoint within the bcr is a prognostic factor in Philadelphia-positive CML patients [see comments]

The Philadelphia (Ph1) chromosome, characteristic of chronic myelogenous leukemia (CML), arises from a reciprocal translocation between chromosomes 9 and 22. The site of the breakpoint on chromosome 22 is within a small region called the breakpoint cluster region (bcr). We have mapped the breakpoint within the bcr in peripheral blood leukocyte DNA from 22 Ph1-positive CML patients. No correlation between the site of the breakpoint and the clinical phase of the disease was found. However, a striking correlation between the site of the breakpoint and the length of time between presentation and onset of acute phase was observed: on average, patients with a 5' break-point had a fourfold longer chronic phase (median, 203 weeks) than those with a 3' breakpoint (median, 52 weeks).     

Initiation of contact system activation in plasma is dependent on factor XII autoactivation and not on enhanced susceptibility of factor XII for kallikrein cleavage

Various mechanisms have been hypothesized to explain the initiation of contact system activation in plasma. We investigated the capability of dextran sulphate (DS) of different molecular weights to initiate contact system activation in normal human plasma, and compared this with their capability to support factor XII autoactivation and to enhance factor XII susceptibility for cleavage by kallikrein.
Dextran sulphate of M_r 500 000 (DS500) and 50 000 (DS50) was able to initiate contact system activation in plasma (determined by measuring the amount of factor XIIa–C1-inhibitor, kallikrein–C1-inhibitor and factor XIa–C1-inhibitor complexes generated) as well as to support factor XII autoactivation and to enhance factor XII susceptibility for cleavage by kallikrein (as measured with amidolytic assays using purified proteins). In contrast, dextran sulphate of M_r 15 000 (DS15) and 5000 (DS5) neither induced contact system activation in plasma, nor supported autoactivation of factor XII, although both of these DS species enhanced the rate of activation of factor XII by kallikrein in the purified system. Based on these properties (i.e. binding of factor XII without inducing autoactivation), DS15 and DS5 were predicted to be inhibitors of contact system activation induced in plasma by DS500, which indeed was observed.
We conclude that enhanced factor XII susceptibility for kallikrein activation and factor XII autoactivation are distinct phenomena, the latter being necessary to support activation of the contact system in plasma.     

Clonal diseases of large granular lymphocytes [see comments]

Three distinct clinical syndromes occur in patients with increased numbers of circulating LGL. Patients with T-LGL leukemia have clonal proliferations of CD3+ LGL typically associated with chronic neutropenia and autoimmune features. NK-LGL leukemia is characterized by clonal CD3- LGL proliferation with an acute clinical presentation marked by massive hepatosplenomegaly and systemic illness. However, most patients with increased numbers of CD3- LGL do not have clinical features of NK-LGL leukemia and have a chronic clinical course. X- linked gene analyses have supported a polyclonal LGL lymphocytosis in this syndrome. Further studies are needed to determine whether clonal progression can occur in these patients.     

Splenectomy is safe and effective in human immunodeficiency virus- related immune thrombocytopenia [see comments]

Sixty-eight patients, followed in a prospective cohort study of 185 human immunodeficiency virus (HIV)-infected patients with severe immune thrombocytopenia (platelets < 50 x 10(9)/L), underwent splenectomy, 2 to 41 months (median: 10 months) after immune thrombocytopenic purpura (ITP) was diagnosed. The mean platelet count increased from 18 x 10(9)/L to 223 x 10(9)/L with a persistent increase in 56 (82%). It also led to a significant increase of the mean CD4 cell count from 475 x 10(6)/L to 725 x 10(6)/L within a mean delay of 10 months. In the whole cohort, with a mean follow-up of 63 months (range, 6 to 126), the 5-year estimated rate for progression to acquired immunodeficiency syndrome (AIDS) was 23% (95% confidence interval [CI], 15% to 31%) and the AIDS-free survival was 69% (95% CI, 61% to 77%). To investigate the potential impact of splenectomy, a Cox's multiple regression model was used; as splenectomy was not randomly assigned, it was incorporated as a time-dependent covariate. After adjustment on the CD4 cell count, no statistically significant differences were observed between the splenectomized and the nonsplenectomized patients: AIDS progression rate (P = 0.23), survival (P = 0.64) and AIDS-free survival (P = 0.72) were not influenced by splenectomy. Splenectomy is both effective and safe in the treatment of severe, refractory ITP associated with HIV infection.     

Therapy of chronic idiopathic thrombocytopenic purpura in adults [see comments]

Chronic ITP is a common hematologic illness. Approximately three fourths of the patients respond to corticosteroids or splenectomy and need no further treatment. Patients refractory to these two therapeutic approaches are relatively resistant to present forms of treatment and are at much greater risk for morbidity and mortality. Future clinical studies evaluating therapy in this refractory group would be best performed in a cooperative group setting in which large numbers of patients could be treated in a prospective randomized manner.     

The platelet function defect of cardiopulmonary bypass [see comments]

The use of cardiopulmonary bypass (CPB) during cardiac surgery is associated with a hemostatic defect, the hallmark of which is a markedly prolonged bleeding time. However, the nature of the putative platelet function defect is controversial. In this study, blood was analyzed at 10 time points before, during, and after CPB. We used a whole-blood flow cytometric assay to study platelet surface glycoproteins in (1) peripheral blood, (2) peripheral blood activated in vitro by either phorbol myristate acetate, the thromboxane (TX)A2 analog U46619, or a combination of adenosine diphosphate and epinephrine, and (3) the blood emerging from a bleeding-time wound (shed blood). Activation-dependent changes were detected by monoclonal antibodies directed against the glycoprotein (GP)Ib-IX and GPIIb-IIIa complexes and P-selectin. In addition, we measured plasma glycocalicin (a proteolytic fragment of GPIb) and shed-blood TXB2 (a stable breakdown product of TXA2). In shed blood emerging from a bleeding-time wound, the usual time-dependent increase in platelet surface P-selectin was absent during CPB, but returned to normal within 2 hours. This abnormality paralleled both the CPB-induced prolongation of the bleeding time and a CPB-induced marked reduction in shed-blood TXB2 generation. In contrast, there was no loss of platelet reactivity to in vitro agonists during or after CPB. In peripheral blood, platelet surface P-selectin was negligible at every time point, demonstrating that CPB resulted in a minimal number of circulating degranulated platelets. CPB did not change the platelet surface expression of GPIb in peripheral blood, as determined by the platelet binding of a panel of monoclonal antibodies, ristocetin-induced binding of von Willebrand factor, and a lack of increase in plasma glycocalicin. CPB did not change the platelet surface expression of the GPIIb-IIIa complex in peripheral blood, as determined by the platelet binding of fibrinogen and a panel of monoclonal antibodies. In summary, CPB resulted in (1) markedly deficient platelet reactivity in response to an in vivo wound, (2) normal platelet reactivity in vitro, (3) no loss of the platelet surface GPIb-IX and GPIIb-IIIa complexes, and (4) a minimal number of circulating degranulated platelets. These data suggest that the "platelet function defect" of CPB is not a defect intrinsic to the platelet, but is an extrinsic defect such as an in vivo lack of availability of platelet agonists. The near universal use of heparin during CPB is likely to contribute substantially to this defect via its inhibition of thrombin, the preeminent platelet activator.     

Increased platelet-fibrinogen affinity in patients with myeloproliferative disorders [see comments]

Patients with myeloproliferative disorders (MPD) are known to have some abnormalities of platelet glycoproteins (Gp). Quantitative changes of the Gp Ib, IIb-IIIa, and/or their glucidic content have been reported. Since the Gp IIb-IIIa complex plays a major role in fibrinogen binding by activated platelets, we measured the platelet fibrinogen affinity in nine patients with polycythemia vera (PV) and one subject with chronic myeloid leukemia (CML) by the aggregometric method of Marguerie. In all patients the Kd of the platelet fibrinogen reaction was significantly decreased as compared to controls, with evidence in two cases with PV of a heterogeneity of platelet-fibrinogen receptor sites. The measurement of 125I-labeled fibrinogen-platelet binding, performed in seven patients (five PV and two CML), showed receptor populations with increased (Kd1 = 0.58 + 0.3 X 10(7) mol/L) and normal affinity (Kd2 = 5.12 + 3.1 X 10(7) mol/L). These results demonstrate a heterogeneity of platelet-fibrinogen receptors in these patients and may explain the thrombotic diathesis of MPD subjects.     

Leg ulcers in patients with sickle cell disease [see comments]

During the entry examination, leg ulcers were present in 2.5% of 2,075 patients 10 years of age and older with sickle cell disease who entered into the Cooperative Study of Sickle Cell Disease (CSSCD) between 1979 and 1986. Prevalence rates were highest among patients with sickle cell anemia and sickle cell anemia with thalassemia genotypes. Among sickle cell anemia patients free of ulcers at entry, the overall incidence was 5.73 per 100 person years in those having associated alpha-thalassemia and 9.97 for those without. Among sickle cell anemia patients with two alpha genes, the estimated incidence of leg ulcers is 2.38 per 100 person years and 6.12 per 100 person years among sickle cell anemia patients with three alpha genes (P less than .05). In both groups, the incidence was highest among those patients over 20 years of age and considerably higher among males than females (P less than .001). Leg ulcers were nonexistent in patients with sickle beta plus thalassemia and sickle hemoglobin C disease. Low steady-state hemoglobin is associated with a higher incidence of ulcer formation (P less than .0001) in sickle cell anemia patients. The protective effect of hemoglobin F is apparent at all levels of total hemoglobin among sickle cell anemia patients and those with associated alpha-thalassemia.     

Exogenous tat protein activates human endothelial cells [see comments]

tat protein, a human immunodeficiency virus (HIV) gene product that functions as a transactivator for HIV replication, is known to be secreted extracellularly by infected cells. To determine the potential role of tat in the dissemination of HIV into extravascular tissue, this protein was examined for its ability to activate human endothelial cells. The results show that tat does indeed stimulate endothelial cells. This is evidenced by their expression of the endothelial- leukocyte adhesion molecules, E-selectin, critical for the initial binding of leukocytes to the blood vessel wall, and their increased synthesis of interleukin-6 (IL-6), a cytokine known to enhance endothelial cell permeability. Furthermore, tat acts synergistically with low concentrations of tumor necrosis factor-alpha to enhance IL-6 secretion. These data suggest that extracellular tat protein secreted or released into the microenvironment may contribute significantly to the determination of specific sites of leukocyte binding to blood vessels, to transmigration into tissue, and to eventual dissemination of HIV-infected cells or free virions into tissue.     

Monoclonal antibodies reactive with hairy cell leukemia [see comments]

Monoclonal antibodies reactive with hairy cell leukemia were developed to aid in the diagnosis of this subtype of B cell chronic lymphocytic leukemia and to gain better insight into the origin of hairy cells. Three antibodies were found to be of value in the diagnosis of hairy cell leukemia. Antibody B-ly 2 can be considered a pan-B cell reagent and generally reacts similar to CD22 antibodies. Antibody B-ly 6 is reactive with the same antigen as CD11c (p150/95), an antigen that is present on hairy cell leukemia, macrophages, and a minor subpopulation of lymphocytes. Antibody B-ly 7 is a unique antibody reactive with 144 Kd antigen present only on hairy cell leukemia and a very small population of normal B lymphocytes. This subpopulation may be the counterpart of hairy cells.     

Production of granulocyte colony-stimulating factor in vitro by monocytes from preterm and term neonates [see comments]

We postulated that defective generation of granulocyte colony- stimulating factor (G-CSF) by cells of newborn infants might underlie their deficiencies in upregulating neutrophil production and function during bacterial infection. To test this, we isolated monocytes from the blood of preterm neonates, term neonates, and adults and, after stimulation with various concentrations of interleukin-1 alpha (IL-1 alpha) or lipopolysaccharide (LPS), quantified G-CSF concentrations in cell supernatants and G-CSF mRNA in cell lysates. When stimulated with plateau concentrations of IL-1 alpha for 24 hours, G-CSF concentrations were higher in supernatants of adult cells (8,699 +/- 5,529 pg/10(6) monocytes) than in those from term infants (2,557 +/- 442 pg, P < .05) or from preterm infants (879 +/- 348 pg, P < .05 v adults). When stimulated with plateau concentrations of LPS, supernatants of monocytes from preterm neonates had less G-CSF than did those from term neonates or adults. G-CSF mRNA content was low in cells from preterm infants, higher in those from term infants, and highest in those from adults. On the basis of the in vitro studies, we speculated that serum G-CSF concentrations might be less elevated in neutropenic neonates than in neutropenic adults. Indeed, serum concentrations were relatively low in all nonneutropenic subjects; 92 +/- 34 pg/mL (mean +/- SEM) in 10 preterm neonates, 114 +/- 21 pg/mL in 16 term neonates, and 45 +/- 13 pg/mL in 11 healthy adults. Serum concentrations were not elevated in 7 neutropenic neonates (39 +/- 17 pg/mL) but were in 8 neutropenic adults (2101 +/- 942 pg/mL, P < .05 v healthy adults). Other studies suggested that the lower G-CSF production in neonates is not counterbalanced by a heightened sensitivity of G-CSF--responsive progenitors to G-CSF. Therefore, we speculate that newborn infants, particularly those delivered prematurely, generate comparatively low quantities of G-CSF after inflammatory stimulation, and that this might constitute part of the explanation for their defective upregulation of neutrophil production and function during infection.     

Effective stimulation of donors for granulocyte transfusions with recombinant methionyl granulocyte colony-stimulating factor [see comments]

Effective granulocyte transfusion (GT) therapy has been hampered by the low yield of neutrophil granulocytes (PMN) obtainable from normal donors even by use of corticosteroid prestimulation, hydroxyethyl starch (HES), and modern leukapheresis (LA) techniques. To increase the PMN yield we performed LA in 22 healthy volunteer donors after a single subcutaneous administration of 300 micrograms of granulocyte colony- stimulating factor (G-CSF) 12 to 16 hours before LA. Five to 7 L of blood was processed within 1.9 to 3 hours using the standard CS- 3000Plus (Baxter, Deerfield, IL) LA protocol including HES. The mean number of PMN harvested was 44.32 +/- 15.5 x 10(9), corresponding to 6.88 +/- 2.1 x 10(9)/L of blood processed. In the final product PMN functions (in vitro: chemotaxis, phagocytosis, chemiluminescence, superoxide anion production; in vivo: chemiluminescence, half-life) were at least normal. In all donors G-CSF induced a consistent increase of white blood cell (mean 16.46 +/- 3.8 x 10(9)/L) and PMN counts (15.94 +/- 3.6 x 10(9)/L). No G-CSF-related side effects were observed and LA was well tolerated. G-CSF prestimulation allows to harvest three to five times higher numbers of functionally normal PMN by LA compared with corticosteroid pretreatment. This may help to overcome one of the major limitations of an effective PMN support.     

Specific sensitivity of CD43 to neutrophil elastase [see comments]

CD43 (sialophorin, leukosialin), an O-glycosylated and sialylated membrane protein (surface sialomucin) with antiadhesive properties, is thought to protect circulating leukocytes by preventing cell surface interactions. Although it is resistant to several proteases, the granule enzyme elastase was recently implicated in loss of extracellular CD43 regions from incubated neutrophils. Flow cytometry showed that neutrophil CD43 is cleaved by low levels of neutrophil elastase with half-maximal cleavage at 5 micrograms/mL; pancreatic elastase, in contrast, did not cleave CD43. Related neutrophil granule proteases proteinase-3 and cathepsin-G did not cleave CD43 or required greater than 10-fold higher enzyme levels, respectively. The 115-kD CD43 isoform on T-lymphoid cells, which differs in glycosylation from 135-kD neutrophil CD43, was equally sensitive to neutrophil elastase, suggesting that cleavage susceptibility extends to various leukocytes. Enzymatic removal of sialic acid did not facilitate CD43 cleavage by neutrophil elastase, a feature that distinguishes the action of neutrophil elastase from other proteases. Western blots of elastase- treated neutrophils detected an 83-kD CD43 fragment that, together with the released 52-kD fragment and 40-kD subfragment, accounts for the entire molecule and indicates that CD43 is cleaved at two sites only, releasing the distal approximately 40% of the sialomucin region. The specificity of the CD43 cleaving reaction was shown by the insensitivity of other neutrophil and lymphoid surface proteins to elastase levels that deplete CD43. Exceptions were P-selectin glycoprotein ligand-1 on neutrophils, also a surface mucin, and CD16 (Fc gamma RIII), which was previously characterized as elastase sensitive. The sensitivity and specificity of CD43 cleavage by neutrophil elastase, the very high levels of elastase in human neutrophils and its ready release by stimulating conditions suggest important physiologic/pathologic roles for this CD43 cleaving reaction.     

Peripheral blood monoclonal plasma cells as a predictor of survival in patients with multiple myeloma [see comments]

The purpose of this study was to quantitate the number and labeling index of monoclonal plasma cells in the blood of patients with newly diagnosed multiple myeloma (MM) to learn if these values were independent prognostic factors for survival. Patients were candidates for this study if they had untreated myeloma requiring therapy, were evaluated at our institution between 1984 and 1993, and had a sample of blood analyzed with a sensitive immunofluorescence technique for monoclonal plasma cells and the blood B-cell labelling index (BLI). The % blood monoclonal plasma cells (%BPC) and the BLI were analyzed along with stage, marrow plasma cell LI, % marrow plasma cells, calcium, creatinine, albumin, beta-2-microglobulin, and C-reactive protein as univariate and multivariate factors for survival. Eighty percent of the 254 patients accrued to this study had monoclonal BPC detected. The median % BPC was 6% and 57% (144 of 254) of patients had a high number (> or = 4%). Patients with > or = 4% BPC had a median survival of 2.4 years vs 4.4 years for those with < 4% BPC (P < .001). The BLI was also prognostic (P = .008). In a multivariate analysis, the % BPC, age, albumin, stage, marrow plasma cell LI, and the BLI were independent factors for survival. The %BPC and the marrow plasma cell LI best separated the group into low, intermediate, and high risk myeloma with median survivals of 52, 35, and 26 months, respectively. Patients with high %BPC were less likely to have lytic bone disease from their MM (P = .002). The %BPC and the BLI are independent prognostic factors for survival and are useful in identifying patients as low, intermediate, and high risk. Clonal cells in the blood should be quantified in future clinical trials for myeloma.