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CAP Home > CAP Reference Resources and Publications > CAP TODAY > CAP TODAY 2006 Archive > January 2005 Clinical Abstracts
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  Clinical Abstracts






January 2005

Michael Bissell, MD, PhD, MPH, Professor and Director of Clinical Services and Vice Chair, Department of Pathology, Ohio State University Medical Center, Columbus
Ronald Domen, MD, Professor of Pathology, Medicine, and Humanities, Penn State University College of Medicine, Hershey, Pennsylvania

Anemia in persons 65 years and older
Prestorage leukoreduction of RBCs
Effect of direct thrombin inhibitors on prothrombin time and INR values
Association of hemoglobin A1c with cardiovascular disease and mortality
Changes in hepatitis B virus DNA levels in acute HIV infection
Rheumatoid arthritis markers
Middle ear fluid DNA in otitis media
Histone deacetylase inhibition in multiple myeloma

Anemia in persons 65 years and older

Prevalence of anemia rises with advancing age, and evidence suggests that anemia is associated with increased morbidity. While numerous studies have examined anemia in older patients, national data on the prevalence and causes of anemia in the United States is not available. The authors of this study examined data from phases one and two of the third National Health and Nutrition Examination Study (NHANES III; 1988-1994). They performed home interviews, examinations, and blood tests. Blood tests to characterize causes of anemia were available for 2,096 persons 65 years or older. The overall prevalence of anemia in that group was found to be 10.6 percent (11 percent for men and 10.2 percent for women). Non-Hispanic whites had the lowest prevalence (nine percent), followed by Mexican-Americans (10.4 percent), and non-Hispanic blacks (27.8 percent). It was determined that deficiencies of iron, folate, or B12 accounted for one-third (34.3 percent) of all anemia in the elderly (almost 50 percent in this group was due to iron deficiency). Anemia from chronic inflammation accounted for 19.7 percent of cases, and anemia from chronic renal failure accounted for 8.2 percent of cases. Unexplained anemia accounted for 33.6 percent of cases. The authors observed that 17.2 percent of those with unexplained anemia (5.8 percent of the total) had one or more hematologic criteria (excluding bone marrow examination) consistent with myelodysplastic syndrome. Most of the cases of anemia were mild, and only 2.8 percent of women and 1.6 percent of men had hemoglobin values of less than 110 g/L (11 g/dL). The authors concluded that mild anemia is common in the older population, that anemia should not be considered simply a normal part of aging, and that it should be studied further.

Guralnik JM, Eisenstaedt RS, Ferrucci L, et al. Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia. Blood. 2004;104:2263-2268.

Reprints: Jack M. Guralnik, Laboratory of Epidemiology, Demography, and Biometry, National Institute on Aging, 7201 Wisconsin Ave., Room 3C-309, Bethesda, MD 20815;

Prestorage leukoreduction of RBCs

Transfusion support with platelet concentrates and red blood cells is an important adjunct in treating various malignancies. Febrile non-hemolytic transfusion reactions (FNHTR) are adverse events related to the transfusion of allogeneic blood components, characterized by a rise in pretransfusion temperature of at least 1A1C without any other explanation and which may be accompanied by other signs of inflammation, including rigors and chills. White blood cells are considered an important cause of FNHTR, and a reduction in the number of WBCs to fewer than 5 x 106 would be expected to mitigate these effects. The authors undertook a retrospective analysis of FNHTR to platelet concentrates and red blood cells before pre-universal white blood cell reduction (PrUR) (July 1997-January 1998 for platelet concentrates; July 1997-July 1999 for red blood cells) and after its introduction (PoUR) (February 1998-August 2001 for platelet concentrates; August 1999-August 2001 for red blood cells). All transfusion reactions were stratified based on component and date of reaction. Other adverse transfusion reactions were grouped into three periods: July 1997-January 1998, February 1998-July 1999, and August 1999-August 2001. The authors conducted a chi-square test to determine the significance of the differences between the groups. They found that in the PrUR group, there were 231 FNHTRs in 70,396 red blood cell units transfused (0.33 percent) and 29 FNHTRs in 6,502 platelet concentrate units transfused (0.19 percent; P<0.001). In the PoUR group, there were 136 FNHTRs in 72,949 red blood cell units transfused (0.19 percent; P<0.001) and 56 FNHTRs in 50,555 platelet concentrate units transfused (0.11 percent; P<0.001). Of the other adverse events, only TRALI reactions were significantly reduced. The authors concluded that prestorage white blood cell reduction significantly reduces the rate of FNHTRs to platelet concentrates and red blood cells.

Yazer MH, Podlosky L, Clark G, et al. The effect of prestorage WBC reduction on the rates of febrile nonhemolytic transfusion reactions to platelet concentrates and RBC. Transfusion. 2004;44:10-15.

Reprints: Dr. Mark Yazer, 4B1.34 Walter Mackenzie Health Sciences Center, 8440-112 St., Edmonton, Alberta, T6G 2B7, Canada;

Effect of direct thrombin inhibitors on prothrombin time and INR values

Direct thrombin inhibitors are a new class of promising anticoagulation agents most commonly used in the initial management of heparin-induced thrombocytopenia and for anticoagulation in acute coronary syndromes. The agents are frequently used to provide initial anticoagulation, with long-term therapy requiring eventual transition to coumarins. The direct thrombin inhibitors (DTIs) available in this setting are argatroban, bivalirudin, and lepirudin. Unfortunately, however, DTIs not only prolong the activated partial thromboplastin time but can also have some cross-over effect on international normalized ratio values, which can create a challenge when making the transition to warfarin therapy during concurrent DTI administration. Data available on the INR elevation are limited to a few reagents used to measure the prothrombin time (PT) and the concurrently reported INR. In this study, the authors added DTIs to pooled plasmas at various concentrations to estimate the relative anticoagulation effect of these agents on 14 PT reagents available in the United States. They approximated the DTI effect on INRs by each drug to pooled plasma at concentrations between 0.1 and 1.2 B5g/mL and then concurrently tested these samples using 14 PT reagents. By using repeated measures analysis of variance, the authors found significant differences (P<.05) between the median INRs for lepirudin and argatroban for all PT reagents, between lepirudin and bivalirudin for all reagents except PT-Fibrinogen HS Plus (P=.07), and between bivalirudin and argatroban for all reagents except Thromborel S (P=.05). The DTI effect on INRs was dependent on drug, drug concentration, and reagent. Argatroban had the most effect on INRs, while lepirudin had the least effect. Reagents with a lower international sensitivity index were less affected by DTIs. ThromboMax HS was the PT reagent least sensitive to direct thrombin inhibitors.

Gosselin RC, Dager WE, King JH, et al. Effect of direct thrombin inhibitors, bivalirudin, lepirudin, and argatroban, on prothrombin time and INR values. Am J Clin Pathol. 2004;121:593-599.

Reprints: Dr. John T. Owings, University of California, Davis Medical Center, Trauma Division, Room 4209, 2315 Stockton Blvd., Sacramento, CA 95817

Association of hemoglobin A1c with cardiovascular disease and mortality

Diabetes mellitus is associated with increased morbidity and mortality secondary to vascular, renal, retinal, and neuropathic complications. There is also evidence of increased risk of coronary heart disease and stroke in patients with dysglycemia. Hemoglobin A1c concentration is a marker for average blood glucose concentrations over the preceding three months and is useful for characterizing dys glycemia. The authors of this study examined the relationship between hemoglobin A1c levels and coronary heart disease and all-cause mortality in men and women after an average of six years of followup as part of the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk). More than 25,623 adult men and women between 40 and 79 years of age who resided in Norfolk, United Kingdom, were prospectively studied. Hemoglobin A1c was measured by high-performance liquid chromatography. Those patients with known diabetes had mean hemoglobin A1c concentrations of 8.0% B1 1.9%, while the remainder of the study sample had mean concentrations of 5.3% B1 0.7%. Patients with probable but previously undiagnosed diabetes had hemoglobin A1c levels of seven percent or more. Risk for coronary heart disease or cardiovascular disease and total mortality increased throughout the whole range of hemoglobin A1c concentrations, but those with hemoglobin A1c concentrations of less than five percent had the lowest rates. An increase in hemoglobin A1c concentration of one percentage point was associated with a 20 to 30 percent increase in event rates and a relative risk of death from any cause of 1.24 in men and 1.28 in women. Fifteen percent of deaths in the sample group occurred in persons with diabetes, but 72 percent occurred in persons with hemoglobin A1c concentrations of between five percent and 6.9 percent. The authors concluded that their study highlights the independent relationship between blood glucose concentrations and cardiovascular/mortality risk and supports interventions to reduce hemoglobin A1c concentrations in persons without diabetes.

Khaw K-T, Wareham N, Bingham S, et al. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European Prospective Investigation into Cancer in Norfolk. Ann Intern Med. 2004;141:413-420.

Reprints: Kay-Tee Khaw, Clinical Gerontology Unit, Box 251, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge CB2 2QQ, United Kingdom;

Changes in hepatitis B virus DNA levels in acute HIV infection

Hepatitis B virus DNA levels correlate with immune response and clinical outcome of infection. Transitions from immune containment to high-level replication to, in some cases, fulminant hepatitis have occurred during periods of acquired immunodeficiency. Evidence suggests that chronic HIV infection increases the severity of HBV-related liver disease. However, it is not known how HIV infection affects chronic HBV. The authors conducted a study in which they identified nine participants in the Multicenter AIDS Cohort Study (MACS) who had serum specimens available from a minimum of five time points (two before and three after HIV seroconversion). HBV DNA levels were determined at each time point with the COBAS Amplicor HBV DNA assay (Roche Diagnostics), which has a linear range of 2.3 to 5.3 log10 copies/mL of HBV DNA. Other HBV-related serological markers were also measured. Ten patients who did not HIV seroconvert were studied as controls. The study results showed that five of nine patients (56 percent) had marked decreases in HBV DNA levels along with loss of HBeAg (four patients) and, in some cases, development of anti-HBe. One patient demonstrated an increase in HBV DNA, and three patients had stable HBV DNA levels. These results suggest that in the majority of patients with chronic HBV, HBV DNA levels do not necessarily increase after HIV seroconversion. Thus, contrary to what was expected, the authors concluded that acute HIV infection is not consistently associated with an increase in HBV DNA levels.

Thio CL, Netski DM, Myung J, et al. Changes in hepatitis B virus DNA levels with acute HIV infection. Clin Infect Dis. 2004;38:1024-1029.

Reprints: Dr. Chloe L. Thio, 1503 E. Jefferson St., Baltimore, MD 21231;

Rheumatoid arthritis markers

Genetically, rheumatoid arthritis is strongly associated with HLA-DR alleles with a common amino acid sequence from residue 70 to residue 74 of the third hypervariable region of the alpha helix of the DRβ chain, the so-called shared epitope. The shared epitope (SE) is thought to play a role in the binding of a pathogenic autoantigen and subsequent class II major histocompatibility complex (MHC)-restricted presentation to auto-reactive T cells. Human cartilage (HC) gp-39 has been proposed as a candidate autoantigen. The authors investigated presentation by antigen-presenting cells of the immunodominant epitope of HC gp-39 (peptide 263-275) in the context of the SE in the synovial membrane of patients with rheumatoid arthritis. Using the monoclonal antibody 12A (mAb 12A) that is directed against the HLA-DRα β 1*0401/HC gp-39263-275 complex and inhibits specific T cell clone activation in vitro, they demonstrated the presentation of this HC gp-39 peptide by dendritic cells in the synovial membrane of HLA-DR4-positive rheumatoid arthritis patients. Staining with mAb 12A was performed on synovium obtained from clinically swollen joints in 65 patients with rheumatoid arthritis and 67 non-rheumatoid arthritis controls and from joints without clinical effusion in nine additional patients with rheumatoid arthritis. MAb 12A staining was observed in the synovium of 40 of the 65 patients with rheumatoid arthritis. Histologically, the expression of HC gp-39, lymphoid aggregates, CD3, and CD1a, as well as the global inflammation score, were higher in mAb 12A-positive rheumatoid arthritis synovium than in mAb 12A-negative synovium, indicating a follicular synovitis in these samples. Accordingly, mAb 12A stained dendritic cells in the close vicinity of lymphoid aggregates. No mAb 12A staining was detected in synovium obtained from rheumatoid arthritis joints without effusion. No correlations were found between mAb 12A staining and clinical or biologic parameters in rheumatoid arthritis. However, positive staining was observed in 61.5 percent of the inflamed rheumatoid arthritis synovial samples compared with only three percent of the control samples (P<0.001). This mAb 12A staining was not related to intracellular citrullinated peptides, which are another specific histologic marker for rheumatoid arthritis. The authors concluded that presentation by synovial dendritic cells of the immunodominant epitope of HC gp-39 in the context of the shared epitope is associated with characteristic histologic features of follicular synovitis and is highly specific for rheumatoid arthritis. This suggests a contribution to the autoimmune-related tissue inflammation and provides a new and independent tool for the immunopathologic diagnosis of rheumatoid arthritis.

Baeten D, Steenbakkers PGA, Rijnders AMW, et al. Detection of major histocompatibility complex/human cartilage gp-39 complexes in rheumatoid arthritis synovitis as a specific and independent histologic marker. Arthritis Rheum. 2004;50:444-451.

Reprints: Dr. Dominique Baeten, Dept. of Rheumatology, OK121B, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium;

Middle ear fluid DNA in otitis media

Isolating bacteria from middle ear fluid has been considered the standard for the etiologic diagnosis of acute otitis media. Using this criterion, Streptococcus pneumoniae (Pnc), Haemophilus influenzae, and Moraxella catarrhalis are important etiologic agents. Yet only about half of middle ear fluid samples obtained from subjects with acute otitis media (AOM) show growth of any of these major pathogens. Some of the remaining samples show growth of bacteria that are not considered to be pathogenic in AOM (primarily ex-hemolytic streptococci or staphylococci), while others show no growth at all. The etiology of cases of AOM due to bacteria not considered to be pathogenic and cases of AOM with no bacteria detected is not clear. Bacteria not detected by conventional culture methods have been suggested as a possible etiologic agent in these cases, but studies that have specifically looked for such agents—for example, Chlamydia or Mycoplasma organisms—have not suggested that they play a major role. On the other hand, a preceding or concurrent viral infection seems to be a common characteristic of AOM, regardless of bacterial findings. Another approach has been suggested by findings of pneumococcal-specific antigen or nucleic acid in culture-negative middle ear fluid samples. These findings could indicate that the likelihood of Pnc having an etiologic role in AOM is far higher than the approximately 30 percent prevalence determined by bacterial isolation. This would be relevant in choosing therapeutic and preventive measures and, therefore, would be important to verify from a practical viewpoint. The authors undertook a study to assess the extent and significance of pneumococcal nucleic acid detected by polymerase chain reaction (PCR) in a large number of middle ear fluid samples obtained from subjects with AOM. They compared the results of PCR based on the amplification of the pneumolysin gene with the results of pneumococcal culture for 2,595 middle ear fluid samples obtained during AOM events in 831 children who were followed from two to 24 months of age in the Finnish Otitis Media Vaccine Trial. PCR results were positive for 47.1 percent of the samples, and culture results were positive for 27.3 percent. PCR-positive, culture-negative samples were associated with previous Pnc AOM in a time-dependent pattern, as well as with concurrent antibiotic treatment, low volume of middle ear fluid, and concurrent nasopharyngeal carriage. PCR-positive AOM represented a clinically less severe disease than culture-positive Pnc AOM. A positive PCR result seemed to indicate the presence of viable, although often nonculturable, Pnc.

Palmu AAI, Saukkoriipi PA, Lahdenkari MI, et al. Does the presence of pneumococcal DNA in middle-ear fluid indicate pneumococcal etiology in acute otitis media? J Infect Dis. 2004;189:775-784.

Reprints: Dr. Arto A.I. Palmu, Dept. of Vaccines, National Public Health Institute, Mannerheimintie 166, 00300 Helsinki, Finland;

Histone deacetylase inhibition in multiple myeloma

Histone deacetylases affect cell growth at the transcriptional level by regulating the acetylation status of nucleosomal histones. Histone deacetylase (HDAC) inhibition induces differentiation or apoptosis, or both, in transformed cells. HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), potently induce apoptosis of human multiple myeloma cells. The authors conducted a study in which they focused on multiple myeloma as a model to study the transcriptional profile of HDAC inhibitor treatment on tumor cells and to address their pathophysiological implications with confirmatory mechanistic and functional assays. They found that multiple myeloma cells are irreversibly committed to cell death after a few hours of incubation with HDAC inhibitors. Using oligonucleotide microarray analyses to characterize the transcriptional profile of HDAC inhibition in multiple myeloma cells, they found that the commitment of multiple myeloma cells to SAHA-induced apoptosis is associated with early changes in gene expression profile, including suppression of genes mediating cytokine-driven proliferation and survival, drug-resistance, cell cycle control, DNA synthesis/repair, and proteasome function. The authors concluded that these findings shed light on the complex molecular sequelae of HDAC inhibition in tumor cells and provide a preclinical rationale for clinically evaluating SAHA alone and in combination with conventional or investigational anti-tumor therapies to improve patient outcome in multiple myeloma.

Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. PNAS. 2004;101:540-545.

Reprints: Kenneth C. Anderson at




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