Differences in the phenotype, cytokine gene expression profiles, and in vivo alloreactivity of T cells mobilized with plerixafor compared with G-CSF.

Plerixafor (Mozobil) is a CXCR4 antagonist that rapidly mobilizes CD34(+) cells into circulation. Recently, plerixafor has been used as a single agent to mobilize peripheral blood stem cells for allogeneic hematopoietic cell transplantation. Although G-CSF mobilization is known to alter the phenotype and cytokine polarization of transplanted T cells, the effects of plerixafor mobilization on T cells have not been well characterized. In this study, we show that alterations in the T cell phenotype and cytokine gene expression profiles characteristic of G-CSF mobilization do not occur after mobilization with plerixafor. Compared with nonmobilized T cells, plerixafor-mobilized T cells had similar phenotype, mixed lymphocyte reactivity, and Foxp3 gene expression levels in CD4(+) T cells, and did not undergo a change in expression levels of 84 genes associated with Th1/Th2/Th3 pathways. In contrast with plerixafor, G-CSF mobilization decreased CD62L expression on both CD4 and CD8(+) T cells and altered expression levels of 16 cytokine-associated genes in CD3(+) T cells. To assess the clinical relevance of these findings, we explored a murine model of graft-versus-host disease in which transplant recipients received plerixafor or G-CSF mobilized allograft from MHC-matched, minor histocompatibility-mismatched donors; recipients of plerixafor mobilized peripheral blood stem cells had a significantly higher incidence of skin graft-versus-host disease compared with mice receiving G-CSF mobilized transplants (100 versus 50%, respectively, p = 0.02). These preclinical data show plerixafor, in contrast with G-CSF, does not alter the phenotype and cytokine polarization of T cells, which raises the possibility that T cell-mediated immune sequelae of allogeneic transplantation in humans may differ when donor allografts are mobilized with plerixafor compared with G-CSF.

Clinical guide to ABO-incompatible allogeneic stem cell transplantation.

The independent genomic inheritance of the human leukocyte antigen (HLA) and the ABO-blood group system allows for HLA-matched hematopoietic progenitor cell transplantation (HCT) to occur in donors who are not matched for ABO blood groups. In fact, nearly one-half of all HCT will involve recipient-donor ABO incompatibility. This places the recipient at increased risk for acute and delayed hemolytic reactions, delayed RBC engraftment, and pure red blood cell aplasia. Additionally, clinical and laboratory evaluation for potential non-ABO, minor RBC antigen-antibody discrepancies may be beneficial to facilitate safe transfusions before, during, and after transplantation. In addition to posing potential clinical risks, analyses of outcomes in ABO-incompatible HCT have yielded inconsistent results with respect to overall survival, relapse risk, incidence of acute or chronic graft-versus-host disease, and engraftment of platelets and granulocytes. As such, pretransplantation donor-recipient evaluation and management for ABO-incompatible HCT requires adopting unique strategies when major, minor, and bidirectional differences exist. These strategies have the potential to improve patient outcomes and allow for effective management of the blood bank inventory. The purpose of this article is to describe practical approaches to screening for and managing ABO-incompatible HCT, with the goal of reducing preventable morbidity and mortality after transplantation.

Allogeneic hematopoietic stem-cell transplantation for sickle cell disease.

BACKGROUND: Myeloablative allogeneic hematopoietic stem-cell transplantation is curative in children with sickle cell disease, but in adults the procedure is unduly toxic. Graft rejection and graft-versus-host disease (GVHD) are additional barriers to its success. We performed nonmyeloablative stem-cell transplantation in adults with sickle cell disease. METHODS: Ten adults (age range, 16 to 45 years) with severe sickle cell disease underwent nonmyeloablative transplantation with CD34+ peripheral-blood stem cells, mobilized by granulocyte colony-stimulating factor (G-CSF), which were obtained from HLA-matched siblings. The patients received 300 cGy of total-body irradiation plus alemtuzumab before transplantation, and sirolimus was administered afterward. RESULTS: All 10 patients were alive at a median follow-up of 30 months after transplantation (range, 15 to 54). Nine patients had long-term, stable donor lymphohematopoietic engraftment at levels that sufficed to reverse the sickle cell disease phenotype. Mean (+/-SE) donor-recipient chimerism for T cells (CD3+) and myeloid cells (CD14+15+) was 53.3+/-8.6% and 83.3+/-10.3%, respectively, in the nine patients whose grafts were successful. Hemoglobin values before transplantation and at the last follow-up assessment were 9.0+/-0.3 and 12.6+/-0.5 g per deciliter, respectively. Serious adverse events included the narcotic-withdrawal syndrome and sirolimus-associated pneumonitis and arthralgia. Neither acute nor chronic GVHD developed in any patient. CONCLUSIONS: A protocol for nonmyeloablative allogeneic hematopoietic stem-cell transplantation that includes total-body irradiation and treatment with alemtuzumab and sirolimus can achieve stable, mixed donor-recipient chimerism and reverse the sickle cell phenotype. (ClinicalTrials.gov number, NCT00061568.)

Donor demographic and laboratory predictors of allogeneic peripheral blood stem cell mobilization in an ethnically diverse population.

A reliable estimate of peripheral blood stem cell (PBSC) mobilization response to granulocyte colony-stimulating factor (G-CSF) may identify donors at risk for poor mobilization and help optimize transplantation approaches. We studied 639 allogeneic PBSC collections performed in 412 white, 75 black, 116 Hispanic, and 36 Asian/Pacific adult donors who were prescribed G-CSF dosed at either 10 or 16 microg/kg per day for 5 days followed by large-volume leukapheresis (LVL). Additional LVL (mean, 11 L) to collect lymphocytes for donor lymphocyte infusion (DLI) and other therapies was performed before G-CSF administration in 299 of these donors. Day 5 preapheresis blood CD34(+) cell counts after mobilization were significantly lower in whites compared with blacks, Hispanics, and Asian/Pacific donors (79 vs 104, 94, and 101 cells/microL, P < .001). In addition, donors who underwent lymphapheresis before mobilization had higher CD34(+) cell counts than donors who did not (94 vs 79 cells/microL, P < .001). In multivariate analysis, higher post-G-CSF CD34(+) cell counts were most strongly associated with the total amount of G-CSF received, followed by the pre-G-CSF platelet count, pre-G-CSF mononuclear count, and performance of prior LVL for DLI collection. Age, white ethnicity, and female gender were associated with significantly lower post-G-CSF CD34(+) cell counts.

Granulocyte colony-stimulating factor (G-CSF) administration in individuals with sickle cell disease: time for a moratorium?

Granulocyte colony-stimulating factor (G-CSF) is used commonly in an attempt to reduce the duration of neutropenia and hospitalization in patients undergoing chemotherapy and to obtain hematopoietic stem cells (HSC) for transplantation applications. Despite the relative safety of administration of G-CSF in most individuals, including subjects with sickle cell trait, severe and life-threatening complications have been reported when used in individuals with sickle cell disease (SCD), including those who were asymptomatic and undiagnosed prior to administration. The administration of G-CSF has now been reported in a total of 11 individuals with SCD. Seven developed severe adverse events, including vaso-occlusive episodes, acute chest syndrome, multi-organ system failure and death. Precautions, including minimizing the peak white blood cell count, dividing or reducing the G-CSF dose and red blood cell transfusions to reduce sickle hemoglobin (HbS) levels, have been employed with no consistent benefit. These reported data indicate that administration of G-CSF in individuals with SCD should be undertaken only in the absence of alternatives and after full disclosure of the risks involved. Unless further data demonstrate safety, routine usage of G-CSF in individuals with SCD should be avoided.

Does oxidative stress modulate left ventricular diastolic function in asymptomatic subjects with hereditary hemochromatosis?

BACKGROUND: Little is known about the early mechanisms mediating left ventricular (LV) diastolic dysfunction in patients with hereditary hemochromatosis (HH). However, the increased oxidative stress related to iron overload may be involved in this process, and strain rate (SR), a sensitive echocardiography-derived measure of diastolic function, may detect such changes. AIM: we evaluated the relationship between left ventricular diastolic function measured with tissue Doppler SR and oxidative stress in asymptomatic HH subjects and control normal subjects. MATERIALS AND METHODS: Ninety-four consecutive visits of 43 HH subjects, age 30-74 (50 +/- 10, mean +/- SD), and 37 consecutive visits of 21 normal volunteers, age 30-63 (48 +/- 8), were evaluated over a 3-year period. SR was obtained from the basal septum in apical four-chamber views. All patients had confirmed C282Y homozygosity, a documented history of iron overload, and were New York Heart Association functional class I. Normal volunteers lacked HFE gene mutations causing HH. RESULTS: In the HH subjects, the SR demonstrated moderate but significant correlations with biomarkers of oxidative stress; however, no correlations were noted in normal subjects. The biomarkers of iron overload per se did not show significant correlations with the SR. CONCLUSION: Although our study was limited by the relatively small subject number, these results suggest that a possible role of oxidative stress to affect LV diastolic function in asymptomatic HH subjects and SR imaging may be a sensitive measure to detect that effect.

The national marrow donor program 20 years of unrelated donor hematopoietic cell transplantation.

In the 20 years since the National Marrow Donor Program (NMDP) facilitated the first unrelated donor transplant, the organization has grown to include almost 7 million donors, and has facilitated over 30,000 transplants on 6 continents. This remarkable accomplishment has been facilitated by the efforts of over 600 employees, and an extensive international network including 171 transplant centers, 73 donor centers, 24 cord blood banks, 97 bone marrow collection centers, 91 apheresis centers, 26 HLA typing laboratories, and 26 Cooperative Registries. In this article, we review the history of the NMDP, and cite the major trends in patient demographics, graft sources, and conditioning regimens over the last 20 years.

Twenty years of unrelated donor hematopoietic cell transplantation for adult recipients facilitated by the National Marrow Donor Program.

For more than 20 years the National Marrow Donor Program has facilitated unrelated donor hematopoietic cell transplants for adult recipients. In this time period, the volunteer donor pool has expanded to nearly 12 million adult donors worldwide, improvements have occurred in the understanding and technology of HLA matching, there have been many changes in clinical practice and supportive care, and the more common graft source has shifted from bone marrow (BM) to peripheral blood stem cells (PBSCs). The percentage of older patients who are receiving unrelated donor transplants is increasing; currently over 1 in 10 adult transplant recipients is over the age of 60 years. Chronic myelogenous leukemia (CML) was previously the most common diagnosis for unrelated donor transplantation, but it now comprises less than 10% of transplants for adult recipients. Transplants for acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), and myelodysplastic syndromes (MDS) all outnumber CML. Treatment-related mortality (TRM) has declined significantly over the years, particularly in association with myeloablative transplant preparative regimens. Correspondingly, survival within each disease category has improved. Particularly gratifying are the results in severe aplastic anemia (AA) where 2-year survival has doubled in just 10 years.

Donation activities and product integrity in unrelated donor allogeneic hematopoietic transplantation: experience of the National Marrow Donor Program.

Despite many clinical advances in allogeneic hematopoietic cell transplantation (HCT), the one factor that is consistently required to apply HCT to a wide variety of diseases is the successful donation and the safe transport and administration of viable donor cells to the HCT recipient. Since 1987, the National Marrow Donor Program (NMDP) has maintained a registry of volunteer HCT donors for those patients who lack a suitable related donor, facilitated the donor search, and managed the collection and transportation of donor cells to transplant centers for use in increasingly complex therapies. The NMDP has collected data on marrow and peripheral blood stem cell (PBSC) donations as well as additional donations of lymphocytes, whole blood, or platelets. These additional donations are provided for a variety of reasons, including treating post-transplant complications such as graft failure or relapsed disease, supporting immune reconstitution or providing transfusion support. For donor safety, rates of placement of central venous catheters for collecting PBSC are monitored. Data have also been collected on rare events that may affect the integrity of the HCT product (e.g., graft clotting or leaks from the transport bag). Quality assurance and review of these donation processes is an essential component of the transplantation approach. Data from the broad NMDP experience further illuminate factors surrounding the donation process and product integrity.

Recovery and safety profiles of marrow and PBSC donors: experience of the National Marrow Donor Program.

The National Marrow Donor Program (NMDP) has been facilitating hematopoietic cell transplants since 1987. Volunteer donors listed on the NMDP Registry may be asked to donate either bone marrow (BM) or peripheral blood stem cells (PBSC); however, since 2003, the majority of donors (72% in 2007) have been asked to donate PBSC. From the donor's perspective these stem cell sources carry different recovery and safety profiles. The majority of BM and PBSC donors experienced symptoms during the course of their donation experience. Pain is the number 1 symptom for both groups of donors. BM donors most often reported pain at the collection site (82% back or hip pain) and anesthesia-related pain sites (33% throat pain; 17% post-anesthesia headache), whereas PBSC donors most often reported bone pain (97%) at various sites during filgrastim administration. Fatigue was the second most reported symptom by both BM and PBSC donors (59% and 70%, respectively). PBSC donors reported a median time to recovery of 1 week compared to a median time to recovery of 3 weeks for BM donors. Both BM and PBSC donors experienced transient changes in their WBC, platelet, and hemoglobin counts during the donation process, with most counts returning to baseline values by 1 month post-donation and beyond. Serious adverse events are uncommon, but these events occurred more often in BM donors than PBSC donors (1.34% in BM donors, 0.6% in PBSC donors) and a few BM donors may have long-term complications. NMDP donors are currently participating in a randomized clinical trial that will formally compare the clinical and quality-of-life outcomes of BM and PBSC donors and their graft recipients.

Massive transfusion and nonsurgical hemostatic agents.

BACKGROUND: Hemorrhage in trauma is a significant challenge, accounting for 30% to 40% of all fatalities, second only to central nervous system injury as a cause of death. However, hemorrhagic death is the leading preventable cause of mortality in combat casualties and typically occurs within 6 to 24 hrs of injury. In cases of severe hemorrhage, massive transfusion may be required to replace more than the entire blood volume. Early prediction of massive transfusion requirements, using clinical and laboratory parameters, combined with aggressive management of hemorrhage by surgical and nonsurgical means, has significant potential to reduce early mortality. DISCUSSION: Although the classification of massive transfusion varies, the most frequently used definition is ten or more units of blood in 24 hrs. Transfusion of red blood cells is intended to restore blood volume, tissue perfusion, and oxygen-carrying capacity; platelets, plasma, and cryoprecipitate are intended to facilitate hemostasis through prevention or treatment of coagulopathy. Massive transfusion is uncommon in civilian trauma, occurring in only 1% to 3% of trauma admissions. As a result of a higher proportion of penetrating injury in combat casualties, it has occurred in approximately 8% of Operation Iraqi Freedom admissions and in as many as 16% during the Vietnam conflict. Despite its potential to reduce early mortality, massive transfusion is not without risk. It requires extensive blood-banking resources and is associated with high mortality. SUMMARY: This review describes the clinical problems associated with massive transfusion and surveys the nonsurgical management of hemorrhage, including transfusion of blood products, use of hemostatic bandages/agents, and treatment with hemostatic medications.

Exercise capacity of cardiac asymptomatic hereditary hemochromatosis subjects.

PURPOSE: The exercise capacity of cardiac asymptomatic subjects with hereditary hemochromatosis (HH) has not been well described. In this study, we tested whether the iron overload associated with HH affected exercise capacity with a case control study design. METHODS: Forty-three HH and 21 normal control subjects who were New York Heart Association functional class I underwent metabolic stress testing using the Bruce protocol at the clinical center of the National Institutes of Health. Exercise capacity was assessed with minute ventilation (.VE), oxygen uptake (.VO2), and carbon dioxide production (.VCO2) using a breath-by-breath respiratory gas analyzer. RESULTS: The exercise capacity of HH subjects was not statistically different from that of control subjects (exercise time 564 +/- 135 vs 673 +/- 175 s, P = 0.191; peak .VO2 29.6 +/- 6.4 vs 32.5 +/- 6.7 mL.kg(-1).min(-1), P = 0.109; ventilatory threshold 19.0 +/- 3.4 vs 21.0 +/- 5.0 mL.min(-1).kg(-1), P = 0.099; data are for HH vs control subjects). Ventilatory efficiency was comparable between groups (.VE/.VCO2 slope 23.7 +/- 3.2 vs 23.4 +/- 4.2, P = 0.791). No significant correlation between the markers of iron levels and the markers of exercise capacity was noted. Iron depletion by 6-month phlebotomy therapy in 18 subjects who were newly diagnosed did not affect exercise testing variables (exercise time 562 +/- 119 vs 579 +/- 118 s, P = 0.691; peak .VO2 29.5 +/- 3.7 vs 29.1 +/- 4.7 mL.kg(-1).min(-1), P = 0.600; ventilatory threshold 18.5 +/- 2.8 vs 17.9 +/- 3.8 mL.kg(-1).min(-1), P = 0.651; data are from before and after phlebotomy therapy). Abnormal ischemic electrocardiographic responses and complex arrhythmias were more frequently seen in HH subjects. CONCLUSIONS: The aerobic exercise capacity of asymptomatic HH subjects seems not to be statistically different from that of normal subjects. The iron levels do not seem to affect exercise capacity in asymptomatic HH subjects.

Significance of left atrial contractile function in asymptomatic subjects with hereditary hemochromatosis.

Patients with hereditary hemochromatosis (HH) have been reported to develop diastolic functional abnormalities detectable by echocardiography, but it is unknown whether these occur in asymptomatic subjects. Thus, this study tested whether echocardiographic left ventricular (LV) relaxation abnormalities are detectable in subjects with asymptomatic HH. Forty-three asymptomatic subjects with HH (C282Y homozygosity in the HFE gene) and 21 age- and gender-matched control subjects without known HFE mutations underwent echocardiography with comprehensive diastolic functional evaluations. Subjects with HH were in New York Heart Association functional class I and consisted of 22 newly diagnosed patients (group A) and 21 chronically phlebotomized subjects with stable iron levels (group B). Group A subjects showed significant iron overload compared with group B subjects and controls (group C) (ferritin 1,164 +/- 886 [p <0.05 vs groups B and C], 128 +/- 262, and 98 +/- 76 microg/L and transferrin saturation 79 +/- 19% [p <0.05 vs groups B and C], 42 +/- 21%, and 26 +/- 10% for groups A, B, and C, respectively). Echocardiographic evaluation revealed (1) no statistically significant abnormalities of Doppler LV relaxation in HH groups; (2) significant augmentation of atrial contractile function in subjects with HH compared with controls, which was not correlated with iron levels and treatment status; and (3) the preservation of overall LV systolic function in HH groups. In conclusion, the results of this study suggest that the augmentation of atrial contraction appears to be an early detectable echocardiographic cardiac manifestation of abnormal diastolic function in asymptomatic subjects with HH, which may reflect undetectable subclinical LV relaxation abnormalities.

Left ventricular systolic function during stress echocardiography exercise in subjects with asymptomatic hereditary hemochromatosis.

There is no information available on left ventricular (LV) systolic function and the response to stress echocardiography in asymptomatic subjects with hereditary hemochromatosis (HH). To evaluate this topic, 43 asymptomatic subjects with HH homozygous for the C282Y HFE gene mutation (22 untreated subjects [group A] and 21 long-term treated subjects [group B]) were compared with 21 age- and gender-matched normal volunteers negative for HFE mutations. Contractile reserve, as a measure of LV systolic function, was assessed using continuous echocardiographic imaging and electrocardiography during supine bicycle exercise. Nineteen subjects in group A had repeat tests after 6 months of induction phlebotomy therapy to assess the effect of iron removal. Exercise performance and hemodynamic variables of supine bicycle exercise were comparable between subjects with HH and controls. LV contractile reserve of asymptomatic subjects with HH was not impaired at either a 75-W submaximal exercise level (mean +/- SD difference in ejection fraction from baseline 13.8 +/- 6.2%, 11.5 +/- 6.8%, and 13.4 +/- 7.8% in groups A, B, and C, respectively; p = NS for all by analysis of variance) or at peak exercise (difference in ejection fraction from baseline 18.9 +/- 6.9%, 18.4 +/- 7.8%, and 20.3 +/- 8.1% in groups A, B, and C, respectively; p = NS for all by analysis of variance). However, the incidence of abnormal ischemic stress electrocardiographic responses was more frequent in subjects with HH as a whole (33%) compared with normal subjects (10%). Stress imaging revealed no regional wall motion abnormalities, suggesting that these were false-positive results. Iron removal by induction phlebotomy did not affect stress echocardiographic performance. In conclusion, LV systolic function during exercise in asymptomatic subjects with HH is preserved, and 6-month induction phlebotomy does not affect stress echocardiographic performance.

Incidence of cardiac arrhythmias in asymptomatic hereditary hemochromatosis subjects with C282Y homozygosity.

It is not well known whether systemic iron overload per se in hereditary hemochromatosis (HH) is associated with cardiac arrhythmias before other signs and symptoms of cardiovascular disease occur. In the present study, we examined the incidence of cardiac arrhythmia in cardiac asymptomatic subjects with HH (New York Heart Association functional class I) and compared it to that in age- and gender-matched normal volunteers. The 42 subjects with HH and the 19 normal control subjects were recruited through the National Heart, Lung, and Blood Institute-sponsored "Heart Study of Hemochromatosis." They completed 48-hour Holter electrocardiography ambulatory monitoring at the baseline evaluation. The subjects with HH were classified as newly diagnosed (group A) and chronically treated (group B) subjects. All subjects with HH had C282Y homozygosity, and the normal volunteers lacked any HFE gene mutations known to cause HH. Although statistically insignificant, the incidence of ventricular and supraventricular ectopy tended to be greater in the combined HH groups than in the controls. Supraventricular ectopy was more frequently noted in group B compared to in the controls (ectopy rate per hour 11.1 ± 29.9 vs 1.5 ± 3.5, p < 0.05, using the Kruskal-Wallis test). No examples of heart block, other than first-degree atrioventricular node block, were seen in any of the subjects. The incidence of cardiac arrhythmias was not significantly reduced after 6 months of intensive iron removal therapy in the group A subjects. No life-threatening arrhythmias were observed in our subjects with HH. In conclusion, our data suggest that the incidence of cardiac arrhythmias is, at most, marginally increased in asymptomatic subjects with HH. A larger clinical study is warranted to further clarify our observation.

Changes in exercise capacity in subjects with cardiac asymptomatic hereditary hemochromatosis during a follow-up after 5 yrs.

OBJECTIVE: A long-term effect of hereditary hemochromatosis (HH) on aerobic exercise capacity (AEC) has not been well described. DESIGN: Forty-three HH and 21 volunteer control subjects who were asymptomatic underwent cardiopulmonary exercise testing using the Bruce protocol. AEC was assessed with minute ventilation (V(E)), oxygen uptake (V(O)(2)), and carbon dioxide production (V(CO)(2)) at baseline and at a follow-up assessment after 5 yrs. A paired t test was used for analyses of normality data; otherwise, Wilcoxon's signed rank-sum test was used. RESULTS: Thirty-three HH subjects and 18 volunteer control subjects returned for a repeat cardiopulmonary exercise testing at the fifth-year follow-up (80% overall return rate). At the fifth-year follow-up, AEC was not different between the two groups. Compared with baseline measurements, exercise time, peak V(O)(2), and the V(E)/V(CO)(2) slope did not differ statistically at the fifth-year follow-up between both groups. Iron depletion through phlebotomy for 5 yrs did not significantly affect AEC in newly diagnosed HH subjects at baseline (n = 14) and cardiac arrhythmias during exercise tended to decrease after 5 yrs of therapy in this group. CONCLUSIONS: The AEC of asymptomatic HH subjects treated using conventional therapy is not statistically affected by the disease during a 5-yr period.

Changes in left ventricular diastolic function of asymptomatic hereditary hemochromatosis subjects during five years of follow-up.

We have previously reported that left ventricular (LV) diastolic function in those with cardiac asymptomatic hereditary hemochromatosis (HH) is similar to that of volunteer control (VC) subjects, despite a presence of augmented left atrial contractile function. However, concern still exists that those with HH might gradually develop LV diastolic dysfunction despite receiving conventional phlebotomy treatment. To address this concern, we prospectively monitored the LV diastolic function of those with HH and VCs during a 5-year period. A total of 14 subjects with newly diagnosed HH (age 51 ± 12 years, 4 women, group A), 20 with chronic HH (age 51 ± 9 years, 7 women, group B), and 18 VCs (age 50 ± 8 years, 6 women, group C) successfully completed both the baseline evaluation of LV diastolic function, including tissue Doppler imaging, strain rate analysis with color-coded tissue Doppler, and the same studies repeated at 5 years of follow-up. All those with HH were New York Heart Association functional class I, were positive for the C282Y homozygote, and received conventional phlebotomy therapy. No VC had HH genetic mutations. The measures of LV diastolic function were comparable among the groups at 5 years of follow-up by analysis of variance. The echocardiographic measures of active left atrial contraction tended to decrease in the HH groups at 5 years of follow-up from baseline. In conclusion, LV diastolic function does not significantly deteriorate statistically during a 5-year period in subjects with cardiac asymptomatic HH after conventional phlebotomy treatment, regardless of their treatment history.

Heart rate recovery is lower following supine exercise in asymptomatic hereditary hemochromatosis subjects compared with healthy controls.

INTRODUCTION: Heart rate recovery (HRR) has become an important diagnostic and prognostic marker in recent years. Subjects with hereditary hemochromatosis (HH) demonstrate arterial wall changes that reduce compliance. Arterial compliance may influence HRR by altering baroreceptor discharge. The purpose of the present study is to examine differences in HRR between subjects with HH and healthy controls during treadmill (TM) and supine lower extremity ergometry (SLEE) exercise testing. METHODS: Forty subjects with asymptomatic HH (27 men/13 women; mean age: 49.7 +/- 9.9 years) and 21 healthy controls (14 men/7 women; mean age: 47.8 +/- 8.4 years) participated in this study. Each subject underwent a symptom-limited 25-W Supine Lower Extremity Ergometry (SLEE) and Bruce TM exercise test within 1 week of each other. Heart rate recovery was the value obtained at 1 minute postexercise. Peak heart rate, systolic blood pressure, and the double product were also obtained during each exercise test. RESULTS: Peak heart rate was significantly higher, whereas HRR and peak systolic blood pressure were significantly lower during TM compared with SLEE exercise testing in both groups (P < .01). A significantly lower HRR during SLEE in subjects with HH was the only significant difference between groups (35.4 +/- 9.0 vs. 29.2 +/- 8.5, P < .01). DISCUSSION: Heart rate recovery was not significantly different between HH and control subjects during upright exercise. However, HRR was significantly lower during SLEE in HH subjects compared with controls. A higher venous return during SLEE may have allowed for differences in arterial compliance between groups to influence HRR.

Streptococcus agalactiae sepsis after transfusion of a plateletpheresis concentrate: benefit of donor evaluation.

BACKGROUND: Bacterial contamination of platelet (PLT) components is an important cause of transfusion reactions. Recent efforts have focused on heightened surveillance to detect contamination before transfusion to limit recipient morbidity and mortality. Although identifying the cause of contamination is most often viewed in the context of recipient safety, this case illustrates the importance of a thorough evaluation on donor safety. CASE REPORT: A 68-year-old woman experienced a severe febrile reaction after a plateletpheresis transfusion. Blood cultures from the patient and from the plateletpheresis component were both positive for the presence of Streptococcus agalactiae. No abnormalities were identified on review of collection and processing records. The donor was asymptomatic and had a negative review of systems, a normal physical exam, normal laboratory values, and negative blood and urine cultures. One of three stool samples was positive for the presence of occult blood. Colonoscopy revealed a Dukes Stage B colonic adenocarcinoma. Fifteen months after surgical resection and adjuvant chemotherapy, the donor had no evidence of recurrent tumor. CONCLUSION: Identification of bacteria in blood components should trigger a comprehensive donor evaluation, particularly if donor bacteremia is suspected. Organisms that may be associated with an enteric source should prompt a thorough gastrointestinal evaluation. Because the primary reservoir of S. agalactiae in the human body is the gastrointestinal tract, and because no findings suggested an alternate portal of entry in our male donor, a gastrointestinal source was suspected. In this case, an evaluation for organism-specific pathology led to early identification of a potentially curable large bowel lesion.

Placebo-controlled study of intravenous magnesium supplementation during large-volume leukapheresis in healthy allogeneic donors.

BACKGROUND: Marked decreases in ionized magnesium (iMg) levels occur during large-volume leukapheresis (LVL); however, the effect of intravenous (IV) magnesium supplementation in this setting has not been carefully studied. STUDY DESIGN AND METHODS: Thirty healthy allogeneic peripheral blood progenitor cell donors receiving citrate anticoagulant with IV calcium prophylaxis were randomized to receive either IV magnesium (0.2 mg Mg per mL acid citrate dextrose-A) or placebo during LVL, with a double-blind design. RESULTS: Thirty subjects underwent 75 LVL pro- cedures, 37 with magnesium and 38 with placebo. Group characteristics were similar for sex, weight, citrate infusion rate (1.36 mg/kg/min vs. 1.37 mg/kg/min), and volume processed (16 L vs. 17 L). Serum iMg levels remained within the reference range with magnesium supplementation, but decreased 39+/-11 percent below baseline (p<10(-10)) after placebo, with greater decreases after consecutive procedures. Subjects receiving magnesium had more vigorous parathyroid hormone responses and higher glucose levels and also tended to have higher serum potassium and ionized calcium levels. Mild paresthesias, coldness, and nausea occurred in 28, 20, and 7 percent of donors, respectively, with no significant differences between groups. Severe symptoms (chest tightness) occurred in only one subject receiving placebo. CONCLUSION: IV magnesium supplementation exerts a significant impact on serum magnesium levels, but does not reduce the frequency or severity of the relatively mild citrate-related effects observed in LVL performed with continuous IV calcium prophylaxis.