Wendell F. Rosse

Mortality In Sickle Cell Disease -- Life Expectancy and Risk Factors for Early Death

BACKGROUND Information on life expectancy and risk factors for early death among patients with sickle cell disease (sickle cell anemia, sickle cell-hemoglobin C disease, and the sickle cell-beta-thalassemias) is needed to counsel patients, target therapy, and design clinical trials. METHODS We followed 3764 patients who ranged from birth to 66 years of age at enrollment to determine the life expectancy and calculate the median age at death. In addition, we investigated the circumstances of death for all 209 adult patients who died during the study, and used proportional-hazards regression analysis to identify risk factors for early death among 964 adults with sickle cell anemia who were followed for at least two years. RESULTS Among children and adults with sickle cell anemia (homozygous for sickle hemoglobin), the median age at death was 42 years for males and 48 years for females. Among those with sickle cell-hemoglobin C disease, the median age at death was 60 years for males and 68 years for females. Among adults with sickle cell disease, 18 percent of the deaths occurred in patients with overt organ failure, predominantly renal. Thirty-three percent were clinically free of organ failure but died during an acute sickle crisis (78 percent had pain, the chest syndrome, or both; 22 percent had stroke). Modeling revealed that in patients with sickle cell anemia, the acute chest syndrome, renal failure, seizures, a base-line white-cell count above 15,000 cells per cubic millimeter, and a low level of fetal hemoglobin were associated with an increased risk of early death. CONCLUSIONS Fifty percent of patients with sickle cell anemia survived beyond the fifth decade. A large proportion of those who died had no overt chronic organ failure but died during an acute episode of pain, chest syndrome, or stroke. Early mortality was highest among patients whose disease was symptomatic. A high level of fetal hemoglobin predicted improved survival and is probably a reliable childhood forecaster of adult life expectancy.

Quantitative determination of antibody in idiopathic thrombocytopenic purpura. Correlation of serum and platelet-bound antibody with clinical response.

We studied the clinical applicability of a recently developed technic that determines antiplatelet antibody directly on the platelet surface or in serum. The technic is a quantitative complement lysis-inhibition assay. Normal platelets have less than 0.4 pg of surface IgG. All patients with idiopathic thrombocytopenic purpura who were studied had greater than that value. Surface IgG was increased in inverse proportion to the platelet count. Surface levels of greater than 1.1 pg correlated with failure to respond to prednisone therapy. Incubation of normal serums with normal platelets did not increase surface IgG of such platelets, but the incubation with thrombocytopenic serums increased their surface IgG 0.5 to 100 times. The degree of increase did not predict response to treatment. However, quantitation of surface IgG of thrombocytopenic platelets was useful in predicting response to treatment.

Immune lysis of normal human and paroxysmal nocturnal hemoglobinuria (PNH) red blood cells. I. The sensitivity of PNH red cells to lysis by complement and specific antibody.

time that the red cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) are unusually susceptible to lysis by hetero- and isoantibodies and complement. These observations have since been confirmed by many other studies using a variety of antibodies (2). The susceptibility of these cells to lysis by antibody and complement has been utilized in the detection of hemolytic antibodies in human serum (3) and in the analysis of the kinetics of hemolysis of human cells by specific antibody and complement (4). The red cells of patients with PNH are also lysed by fresh normal serum, especially when the pH is reduced to 6.5 to 7.0 (5, 6). This reaction, the acidified serum test or Hams test, is of major importance in the diagnosis of the disease. Lysis by acidified normal serum is abolished when the serum is treated with ammonia or heated to 56° C

Pulmonary hypertension and nitric oxide depletion in sickle cell disease.

During the past decade a large body of experimental and clinical studies has focused on the hypothesis that nitric oxide (NO) depletion by plasma hemoglobin in the microcirculation plays a central role in the pathogenesis of many manifestations of sickle cell disease (SCD), particularly pulmonary hypertension. We have carefully examined those studies and believe that the conclusions drawn from them are not adequately supported by the data. We agree that NO depletion may well play a role in the pathophysiology of other hemolytic states such as paroxysmal nocturnal hemoglobinuria, in which plasma hemoglobin concentrations are often at least an order of magnitude greater than in SCD. Accordingly, we conclude that clinical trials in SCD designed to increase the bioavailability of NO or association studies in which SCD clinical manifestations are related to plasma hemoglobin via its surrogates should be viewed with caution.

Clinical Course and Flow Cytometric Analysis of Paroxysmal Nocturnal Hemoglobinuria in the United States and Japan

Abstract: To determine and directly compare the clinical course of white and Asian patients with paroxysmal nocturnal hemoglobinuria (PNH), data were collected for epidemiologic analysis on 176 patients from Duke University and 209 patients from Japan. White patients were younger with significantly more classical symptoms of PNH including thrombosis, hemoglobinuria, and infection, while Asian patients were older with more marrow aplasia. The mean fraction of CD59-negative polymorphonuclear cells (PMN) at initial analysis was higher among Duke patients than Japanese patients. In both cohorts, however, a larger PNH clone was associated with classical PNH symptoms, while a smaller PNH clone was associated with marrow aplasia. Thrombosis was significantly more prevalent in white patients than Asian patients, and was associated with a significantly higher proportion of CD59-negative PMN. For individual patients, CD59-negative populations varied considerably over time, but a decreasing PNH clone portended hematopoietic failure. Survival analysis revealed a similar death rate in each group, although causes of death were different and significantly more Duke patients died from thrombosis. Japanese patients had a longer mean survival time (32.1 yr vs. 19.4 yr), although Kaplan-Meier survival curves were not significantly different. Poor survival in both groups was associated with age over 50 years, severe leukopenia/neutropenia at diagnosis, and severe infection as a complication; additionally, thrombosis at diagnosis or follow-up for Duke patients and renal failure for Japanese patients were poor prognostic factors. These data identify important differences between white and Asian patients with PNH. Identification of prognostic factors will help the design of prospective clinical trials for PNH. Abbreviations: BMT = bone marrow transplantation, GPI = glycosylphosphatidylinositol, GPI-AP = glycosylphosphatidylinositol-anchored protein, Hb = hemoglobin, PMN = polymorphonuclear cells, PNH = paroxysmal nocturnal hemoglobinuria, RBC = red blood cells, WBC = white blood cells

Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell disorder characterized by a somatic mutation in the PIGA gene, leading to a deficiency of proteins linked to the cell membrane via glycophosphatidylinositol (GPI) anchors. While flow cytometry is the method of choice for identifying cells deficient in GPI‐linked proteins and is, therefore, necessary for the diagnosis of PNH, to date there has not been an attempt to standardize the methodology used to identify these cells.

Paroxysmal Nocturnal Hemoglobinuria with Onset in Childhood and Adolescence

BACKGROUND Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematologic disorder characterized by hemoglobinuria, thrombosis, infection, and a tendency toward bone marrow aplasia. Onset usually occurs in adulthood. Few children and adolescents with PNH have been described, and data on diagnosis, clinical course, and survival in young patients are unavailable. METHODS We retrospectively reviewed clinical and laboratory data on all patients 21 years old or younger in whom PNH had been diagnosed at Duke University Medical Center from 1966 to 1991. RESULTS Medical records and clinical follow-up data were available for 26 young patients. Although 50 percent of adult patients present with hemoglobinuria, only four of our patients (15 percent) presented with this feature. In contrast, 15 of our patients (58 percent) had moderate or severe bone marrow failure at presentation, as compared with about 25 percent of adults in cases from the literature; all 26 patients eventually had evidence of bone marrow dysfunction. Eight patients (31 percent) have died, with a median survival of 13.5 years since their initial symptoms. CONCLUSIONS Children and adolescents with PNH have a greater prevalence of bone marrow failure than do adults with this disorder, and their morbidity and mortality are high. Bone marrow transplantation should be considered for selected young patients with PNH.

Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria†‡

Paroxysmal nocturnal hemoglobinuria (PNH) is a debilitating and life‐threatening disease in which lysis of PNH red blood cells frequently manifests with chronic hemolysis, anemia, and thrombosis. Renal damage in PNH is associated with chronic hemosiderosis and/or microvascular thrombosis. We determined the incidence of renal dysfunction or damage, defined by stages of chronic kidney disease (CKD), in a large cohort of PNH patients and evaluated the safety and efficacy of the complement inhibitor eculizumab in altering its progression. Renal dysfunction or damage was observed in 65% of the study population at baseline with 21% of patients with later stage CKD or kidney failure (glomerular filtration rate [GFR] ≤60 ml/min/1.73 m2; Stage 3, 4, or 5). Eculizumab treatment was safe and well‐tolerated in patients with renal dysfunction or damage and resulted in the likelihood of improvement as defined as categorical reduction in CKD stage (P < 0.001) compared with baseline and to placebo (P = 0.04). Improvement in renal function was more commonly seen in patients with baseline CKD Stages 1–2 (67.1% improvement, P < 0.001) although improvement was also observed in patients with CKD Stages 3–4 (P = 0.05). Improvements occurred quickly and were sustained for at least 18 months of treatment. Patients categorized at CKD Stages 3–5 did not worsen during treatment with eculizumab. Overall, 40 (21%) of 195 patients who demonstrated renal dysfunction or damage at baseline were no longer classified as such after 18 months of treatment. Administration of eculizumab to patients with renal dysfunction or damage was well tolerated and was usually associated with clinical improvement. Am. J. Hematol. 85:553–559, 2010.

Quantitative immunology of immune hemolytic anemia: II. The relationship of cell-bound antibody to hemolysis and the effect of treatment

The concentration of cell-bound and serum antibody was determined in a series of patients with warm antibody immune hemolytic anemia by determining the amount of C[unk]1 fixed to the cells by anti-IgG. This was compared to the rate of hemolysis as determined by hemoglobin concentration and reticulocyte count, or the endogenous production of carbon monoxide. The rate of hemolysis was, in general, proportional to the concentration of cell-bound antibody. In splenectomized patients, the rate of hemolysis was very much less than in unsplenectomized patients for a given concentration of cell-bound antibody. When prednisone was given, three effects were noted: (a) at high doses of drug, the concentration of cell-bound antibody decreased rapidly and the concentration of serum antibody increased, suggesting that the affinity of antibody for antigen had been altered; (b) in patients achieving remission, the concentration of serum antibody fell to low levels but rose again if the dose of prednisone was insufficient; (c) in one patient, prednisone appeared to inhibit sequestration of highly sensitized cells.

PLATELET ANTIBODY IN AUTOIMMUNE THROMBOCYTOPENIA

Despite early studies which provided evidence for an immune mechanism for platelet destruction in idiopathic thrombocytopenia (ITP) (Harrington et al, 1956; Shulman et al, 1965), only recent information has established the disease as autoimmune. In contrast to the erythrocyte, the platelet has been a difficult blood component to study because of its inherent tendency to aggregate. Therefore, techniques for quantitation of immune injury to platelets have only recently been developed. Also the antiplatelet factor, although originally shown to be a gamma G immunoglobulin, has proven difficult to study for several reasons. Large amounts of this immunoglobulin stick non-specifically to the platelet surface (Nachman, 1968), antigenic specificity for the immunoglobulin has not been demonstrated, and in contrast to other known platelet antibodies, the ITP antibody does not have complement-fixing properties. The diagnosis of ITP had been one of exclusion, suggested by increased numbers of megakaryocytes in a bone marrow aspirate, absence of splenic enlargement, absence of other conditions known to produce thrombocytopenia such as drug ingestion or intravascular coagulation. Several recent investigations have provided techniques for the direct detection of antibody in this disease. As a result of data derived from these studies a positive diagnosis of immune purpura is possible, and this disorder may be considered as autoimmune rather than idiopathic. However, despite identification of the antibody we still have little information as to its origin or specificity of action.