A multicentre study investigating vital sign changes occurring in complicated and uncomplicated transfusions.

BACKGROUND AND OBJECTIVES: Many hospitals require transfusions to be discontinued when vital signs stray from predetermined ranges, regardless of clinical symptoms. Variations in vital signs may be unrelated to transfusion, however, and needlessly stopping a transfusion may delay medical care while increasing donor exposures and healthcare costs. We hypothesized that a detailed study of vital sign changes associated with transfusion of blood product by component, including those associated with potential reactions (complicated) and those deemed to be uncomplicated, would establish a useful framework of reference for treating clinicians and transfusion services alike. MATERIALS AND METHODS: A retrospective electronic record review of transfusion service and transfusion recipient data was completed on 3852 inpatient transfusion episodes over a 6-month period at four academic tertiary care hospitals across the United States. Vital signs pre- and post-transfusion were recorded by trained clinical research nurses. Serious reactions were adjudicated by a panel of transfusion medicine experts. RESULTS: In both uncomplicated transfusions (n = 3765) and those including an adverse reaction (n = 87), vital sign fluctuations were generally modest. Compared to uncomplicated transfusions, transfusions complicated by febrile reactions were associated with higher pretransfusion temperature and higher pretransfusion pulse rates. Episodes of transfusion circulatory overload were associated with higher pretransfusion respiration rates compared to uncomplicated transfusions. CONCLUSION: Most transfusions are associated with only modest changes in vital signs. Pretransfusion vital signs may be an important yet previously understudied predictor of vital sign changes during transfusion. The optimal role of vital sign assessment during blood transfusion deserves further study.

Von Willebrand factor for menorrhagia: a survey and literature review.

BACKGROUND: von Willebrand disease (VWD) is the most common congenital bleeding disorder. In women, menorrhagia is the most common bleeding symptom, and is disabling with iron deficiency anaemia, high health cost and poor quality of life. Current hormonal and non-hormonal therapies are limited by ineffectiveness and intolerance. Few data exist regarding von Willebrand factor (VWF), typically prescribed when other treatments fail. The lack of effective therapy for menorrhagia remains the greatest unmet healthcare need in women with VWD. Better therapies are needed to treat women with menorrhagia. METHODS: We conducted a survey of US haemophilia treatment centres (HTCs) and a literature review using medical subject heading (MeSH) search terms 'von Willebrand factor,' 'menorrhagia' and 'von Willebrand disease' to assess the use of VWF in menorrhagia. Analysis was by descriptive statistics. RESULTS: Of 83 surveys distributed to HTC MDs, 20 (24.1%) provided sufficient data for analysis. Of 1321 women with VWD seen during 2011-2014, 816 (61.8%) had menorrhagia, for which combined oral contraceptives, tranexamic acid and desmopressin were the most common first-line therapies for menorrhagia, whereas VWF was third-line therapy reported in 13 women (1.6%). Together with data from 88 women from six published studies, VWF safely reduced menorrhagia in 101 women at a dose of 33-100 IU kg(-1) on day 1-6 of menstrual cycle. CONCLUSIONS: This represents the largest VWD menorrhagia treatment experience to date. VWF safely and effectively reduces menorrhagia in women with VWD. A prospective clinical trial is planned to confirm these findings.

Risk factors for inhibitor formation in haemophilia: a prevalent case-control study.

Inhibitor formation is a major complication of haemophilia treatment. In a prevalent case-control study, we evaluated blood product exposure, genotype and HLA type on haemophilia A inhibitor formation. Product exposure was extracted from medical records. Genotype was determined on stored DNA samples by detection of virtually all mutations-SSCP (DOVAM-S) and subcycling PCR. HLA typing was performed by PCR amplification and exonuclease-released fluorescence. Cases experienced higher intensity factor, 455 vs. 200 U per exposure, P < 0.005, more frequent central nervous system (CNS) bleeding, seven of 20 (35.0%) vs. one of 57 (1.7%), P = 0.001 and more commonly from inhibitor families, seven of 20 (35.0%) vs. zero of 57 (0%), P < 0.001, and African-American, 12 of 63 (19.0%) vs. six of 117 (5.1%), P = 0.015. Among the latter, CNS bleeding was more commonly the initial bleed, 60% vs. 0%, P < 0.001, and survival was shorter, 14 vs. 38 yr, P = 0.025. Inhibitor formation was uncommon in those with missense mutations, two of 65 (3.1%) vs. 31 of 119 (26.0%), P = 0.008, and unrelated to factor VIII immunogenic epitope, P = 0.388, or HLA type, P > 0.100. Genotype was not associated with race. Time to immune tolerance was shorter for titres <120 vs. > or = 120 BU/mL, six vs. 16 months, P < 0.01, but unaffected by tolerizing dose regimen, P > 0.50. Inhibitor formation is associated with high intensity product exposure, CNS bleeding, African-American race and low frequency of missense mutations. The ideal time to initiate prophylaxis to reduce CNS bleeding and inhibitor formation will require prospective studies.

Tissue plasminogen activator to prevent central venous access device infections: a systematic review of central venous access catheter thrombosis, infection and thromboprophylaxis.

The recent unequivocal demonstration that prophylaxis, three to four weekly factor infusions, is effective in preventing joint disease in children with haemophilia, has provided impetus to initiate prophylaxis early in such children. Yet, nearly a quarter (22%) of the 83% who required central venous access devices for factor infusion developed central venous access catheter (CVAD)-related infection. This limitation of CVAD use prevents many families from initiating prophylaxis. The frequent occurrence of local thrombosis accompanying CVAD-related infection in surgical patients and autopsy cases, the thrombogenic plastic CVAD surfaces, and local clot formation at the insertion site, suggest the potential role of thrombolytic agents in preventing these infections. Yet, correlation between CVAD-related infection and local thrombosis in children with haemophilia are lacking, and thromboprophylaxis to prevent CVAD-related infection is controversial. Tissue plasminogen activator (t-PA), a recombinant serine protease glycoprotein that lyses plasmin-bound fibrin and is safe and effective in the treatment of occluded catheters, has not been evaluated in the prevention of these infections. We performed a literature review of CVAD-related infection, CVAD-related thrombosis, and thromboprophylaxis studies to evaluate the role of t-PA in the prevention of these infections in children with haemophilia. Metanalysis of published thromboprophylaxis trials demonstrate current prophylaxis regimens do not prevent CVAD infection, and further, that thrombosis and infection do not necessarily occur simultaneously. Pilot data demonstrate CVAD infection reduction in haemophilic children by monthly t-PA in 18 haemophilic children, suggesting the potential role of t-PA in CVAD infection prevention. Clinical trials to evaluate t-PA in CVAD infection prevention are justified.

Effect of errors in the sequence of optical densities from the Roche AMPLICOR HIV-1 MONITOR assay on the validity of assay results.

Specifications for the AMPLICOR HIV-1 MONITOR kit indicate that the results are invalid if the optical densities (ODs) from the PCR-amplified sample that are between 0.1 and 2.3 units are out of sequence. However, among 11,904 assays, results were biased only when ODs of 0.2 to 2.0 units were out of sequence, reducing the rate of invalid results from 3.2 to 0.59%.

Multisite comparison of reproducibility and recovery from the standard and ultrasensitive Roche AMPLICOR HIV-1 MONITOR assays.

Reproducibility and recovery from the standard and ultrasensitive Roche AMPLICOR HIV-1 MONITOR kits were compared in 19 laboratories. The results were generally similar, but the consistently low level of recovery from the ultrasensitive assay in one laboratory points to the need to include external controls in order to track assay performance.

Transfusion to blood group A and O patients of group B RBCs that have been enzymatically converted to group O.

BACKGROUND: The transfusion of ABO-incompatible RBCs is the leading cause of fatal transfusion reactions. Group O RBCs, lacking terminal immunodominant A and B sugars to which humans are immunized, are safe for transfusion to persons of any ABO blood group. With the use of a recombinant alpha-galactosidase to remove terminal galactose from group B RBCs, the safety and efficacy of enzyme-converted group-B-to-group-O (ECO) RBC components were studied in transfusion-dependent patients. STUDY DESIGN AND METHODS: Twenty-four patients (blood groups A and O) were randomly assigned to receive transfusion(s) of either ECO or control group O RBCs. If a second transfusion was given, the other blood component was administered. RESULTS: Twenty-one patients were given ECO RBCs; 18 also underwent control transfusions. One patient received only a small aliquot for RBC survival studies, instead of a full-unit transfusion, because his serum was incompatible with ECO RBCs. No adverse events occurred. Both ECO and control transfusions resulted in appropriate Hb increments and comparable (51)Cr-labeled RBC survival studies. One patient developed a transient, weak-positive DAT, without hemolysis. Two weeks after transfusion, 5 of 19 evaluable ECO RBC recipients had increases in anti-B titers. CONCLUSION: ECO RBCs were comparable to group O cells for safety and efficacy in this study. The clinical significance of the increase in anti-B and of occasional serologic incompatibilities with ECO RBCs is unclear. If strategies can be developed to remove A epitopes, enzymatic conversion could be used to create a universal (group O) donor blood supply.

Does collecting repeated blood samples from each subject improve the precision of estimated steroid hormone levels?

Measuring levels of steroid hormones in epidemiologic studies is difficult because pulsatile release can cause the levels of many hormones to vary markedly over short intervals, leading to a loss of precision in between-subject comparisons. Clinicians often control this variation by collecting several samples from each subject at defined intervals and pooling these samples for assay. The number of samples per subject that would adequately control such variation in an epidemiologic study has not been fully investigated. This study examines the effects of collecting 1, 2, or 3 samples per subject on the variances of 11 hormones and sex hormone binding globulin in men and 6 hormones in women. Three samples were collected at 30-minute intervals from each of 20 men and 59 women and were assayed separately. Variances that would be obtained in studies collecting one, two, or three samples per subject were then estimated. Collecting more than one sample substantially reduced the variances of several hormones in men but not in women.

Defining the perimenopause for application in epidemiologic investigations.

The authors present a method for defining the inception of perimenopause that is based on self-reported data. The study sample (n = 1,550) was obtained from a 5-year longitudinal study of 2,569 Massachusetts women aged 45-55 years that began in 1981. The definition was derived from the ability of responses to questions concerning timing of the last menstrual period, menstrual regularity, and presence of menopausal symptoms (hot flashes/sweats) to predict menopause 3 years later. The two items that best defined the inception of perimenopause were 3-11 months of amenorrhea and increased menstrual irregularity for those without amenorrhea. This definition can easily be used in large epidemiologic investigations.

The acute chest syndrome in sickle cell disease: incidence and risk factors. The Cooperative Study of Sickle Cell Disease.

The acute chest syndrome (ACS), a pneumonia-like illness in sickle cell patients, is one of the most frequent causes of their morbidity and hospitalizations. Repeated ACS events may predict the development of chronic lung disease. ACS is reported as a frequent cause of death in these patients. We examine here the incidence and risk factors of ACS in 3,751 patients with sickle cell disease who were observed prospectively for at least 2 years (19,867 patient-years [pt-yrs]) as part of a multicenter national study group. The ACS, defined by a new pulmonary infiltrate on x-ray, occurred at least once in 1,085 patients (2,100 events). ACS incidence was higher in patients with homozygous sickle cell disease (SS; 12.8/100 pt-yrs) and in patients with sickle cell-beta(0) -thalassemic (9.4/100 pt-yrs), and lower in patients with hemoglobin (Hb) SC disease (5.2/100 pt-yrs) and patients with sickle cell-beta(+) thalassemia (3.9/100 pt-yrs). alpha-Thalassemia did not affect the rate of ACS incidence in SS patients. Within each Hb type the incidence was strongly but inversely related to age, being highest in children 2 to 4 years of age (25.3/100 pt-yrs in SS) and decreasing gradually to its lowest value in adults (8.8/100 pt-yrs in SS). In SS children (< 10 years of age), we documented an age-related within-person reduction in ACS attack rates. Adults with a higher ACS rate had a higher rate of mortality (from all causes) than those with low ACS rates. This increased rate of mortality might also have contributed to the decline in ACS rate with age. In multivariate analysis, other factors affecting incidence in SS patients were degree of anemia (lower ACS rates in patients with lower steady-state Hb levels) and fetal Hb (lower rates in patients with high fetal Hb). There was also a positive association between ACS rate and steady-state leukocyte count. The relationship of ACS rate to higher steady-state Hb levels in SS patients is unexplained but might be caused by increased blood viscosity.

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.

Correlates of the prevalence of self-reported hypertension among African-American and white women.

This study examines self-reported hypertension and its correlates in a random sample of 5539 African-American and white middle-aged women residing in Massachusetts. African-American women reported hypertension more frequently than did whites (38.2% vs 19.8%). African-American women were more likely than white women to have seen a doctor in the preceding year and to have had a hysterectomy. The African-American women were less likely to be current smokers and were less educated than white women. Stepwise logistic regression revealed that self-reported hypertension was associated with race, education, health care utilization, and the interaction of education and race. Prevalence differences between African Americans and whites declined with increasing education. However, the model indicates that after controlling for differences in socioeconomic status (based on education) and health care utilization, self-reported hypertension was still more prevalent among African-American women.

The normal menopause transition.

This paper presents analyses from perhaps the largest and most comprehensive prospective cohort study of mid-aged women--the Massachusetts Women's Health Study (MWHS)--with numbers sufficient to provide, for the first time, stable estimates of parameters in the normal menopause transition. The three questions addressed in this analysis are (i) what are the natural menopause transitions and when do they occur, (ii) what factors affect these transitions and (iii) what signs and/or symptoms accompany these transitions? The data were obtained primarily from 5 years of follow-up of 2570 women in Massachusetts who were aged 45-55 years as of January 1, 1982. An initial baseline cross-sectional survey (T0) yielded a total of 8050 completed responses with an overall response rate of 77%. From this cross-sectional sample a cohort of approximately 2570 women was identified, consisting of women who had menstruated in the preceding 3 months and who had not undergone removal of the uterus and/or ovaries. Prospective study of the cohort consisted of six telephone contacts (T1-T6) at 9-month intervals with excellent retention of the respondents. A subset of the full cohort was defined that consisted of women who were premenopausal (rather than perimenopausal) at baseline (T0) (n = 1178). Confirming prior reports, the age at natural menopause occurred at 51.3 years with a highly significant median difference (1.8 years) between current smokers and non-smokers. The new analyses reported here on median age at inception of perimenopause (47.5 years) and factors affecting it are consistent with findings for age at last menstrual period, particularly the overwhelming effect of smoking. Smokers tend to have not only an earlier but also a shorter perimenopause. The length of the perimenopausal transition (estimated at nearly 4 years) has not been previously reported. Moreover, the highest rate of physician consultations is observed among those with longer perimenopause transitions. The relationship between menopause transitions and symptom reporting appears to be transitory, with reported rates showing an increase in the perimenopause and a compensatory decrease in the postmenopause. The implications of combined hormone replacement therapy for future research on menopause in industrial societies is discussed in relation to these findings.

Pain in sickle cell disease. Rates and risk factors.

BACKGROUND AND METHODS: Acute episodes of pain are the principal symptom of sickle cell disease, but little is known about the epidemiologic features of these episodes or risk factors for them, nor is it known whether patients with high rates of such episodes die prematurely. We prospectively studied the natural history of sickle cell disease in 3578 patients ranging from newborns to persons up to 66 years old who were followed at clinical centers across the United States. RESULTS: There were 12,290 episodes of pain in 18,356 patient-years. The average rate was 0.8 episode per patient-year in sickle cell anemia, 1.0 episode per patient-year in sickle beta 0-thalassemia, and 0.4 episode per patient-year in hemoglobin SC disease and sickle beta(+)-thalassemia. The rate varied widely within each of these four groups--e.g., 39 percent of patients with sickle cell anemia had no episodes of pain, and 1 percent had more than six episodes per year. The 5.2 percent of patients with 3 to 10 episodes per year had 32.9 percent of all episodes. Among patients with sickle cell anemia who were more than 20 years old, those with high rates of pain episodes tended to die earlier than those with low rates. High rates were associated with a high hematocrit and low fetal hemoglobin levels. alpha-Thalassemia had no effect on pain apart from its association with an increased hematocrit. CONCLUSIONS: The "pain rate" (episodes per year) is a measure of clinical severity and correlates with early death in patients with sickle cell anemia over the age of 20. Even when the fetal hemoglobin level is low, one can predict that small increments in the level may have an ameliorating effect on the pain rate and may ultimately improve survival. This outcome is particularly encouraging to investigators studying hydroxyurea and other treatments designed to increase the fetal hemoglobin level.

Use of estrogens among middle-aged Massachusetts women.

This study describes estrogen use among 45- to 55-year-old white women in Massachusetts from 1981 to 1987. In a 1981 cross-sectional survey, 7705 white women (77 percent response rate) returned a questionnaire or were interviewed by phone. Premenopausal women were invited into a 4.5-year follow-up study including telephone interviews every nine months, and 2236 (approximately 91 percent of the eligible women) had a complete follow-up. In the cross-sectional survey, 7.9 percent had used oral estrogens in the last two weeks, but most (77 percent) had had a hysterectomy; use varied notably from one area to another. Vaginal estrogens were used by 2.9 percent. Users and nonusers of oral estrogens were quite similar in regard to sociodemographic background. Data from the follow-up surveys showed that estrogen use increased throughout the study period and by the final follow-up women with higher education status reported more estrogen use than those with lower education status. Most women used estrogens only for a short time.

The effect of widowhood on health: a prospective analysis from the Massachusetts Women's Health Study.

Previous research has consistently demonstrated adverse physical and psychological effects following the death of a spouse. Conclusions regarding the effects of widowhood have been hampered, however, by such methodological limitations as lack of adequate comparison groups, non-random samples of the widowed, and lack of data on pre-widowhood status. This paper examined the physical and psychological effects of widowhood in a randomly sampled cohort of women, aged 45-55 years at baseline, who were followed prospectively for five years. Analyses employed a design in which women whose spouses died during the course of the study (N = 76) were compared to age-matched married controls (N = 1625). The following two questions were addressed: (1) What are the physical and psychological effects of widowhood? and (2) What is the effect of widowhood on socioeconomic factors, social support and health behavior? Following the death of a spouse, the percentage of widows reporting psychological symptoms increased. The widows did not report higher rates of physical symptoms or a decrease in health. Widows had higher rates of health care utilization, in particular, taking prescribed medication, which were in part for mental health reasons. There was no evidence of changes in health behaviors among the widows, but social support increased following widowhood and more widows reported a decrease in income. The results highlight the importance of controlling for pre-widowhood status when studying the consequences of widowhood and provide additional evidence that widowhood may not adversely affect physical health for women.

Androgens, estrogens, and sex hormone-binding globulin in middle-aged men.

Although the administration of estrogens and androgens can affect the concentrations of sex hormone-binding globulin (SHBG) in men, the relationships between endogenous estrogens and androgens and SHBG are uncertain. Therefore, in a randomly selected cohort of 1640 middle-aged men we measured androgen, estrogen, and SHBG concentrations and obtained the subjects' weight, ethanol intake, and smoking histories. The data were analyzed by stepwise multiple regression, with SHBG as the dependent variable, to compare the role of hormones with that of other factors in the control of SHBG levels. Neither estrone or estradiol nor the testosterone/estradiol ratio was predictive of SHBG levels. However, SHBG concentrations were positively correlated with total testosterone and negatively correlated with percent free and percent albumin-bound testosterone. SHBG concentrations were negatively correlated with estrone sulfate, but were positively correlated with the testosterone/estrone sulfate ratio and the concentrations of free and albumin-bound testosterone. In addition, in all models tested age and body mass index (wt/ht2), but not smoking or ethanol, were strong predictors of SHBG concentrations. Thus, when present in physiological amounts in the blood as a result of glandular secretion, there is a positive relationship between SHBG concentrations and testosterone and, to a lesser extent, free- and albumin-bound testosterone, but age and body mass index appear to be more important in predicting the SHBG concentration.

A prospective study of factors affecting age at menopause.

This paper describes a multivariate analysis of a 3-year prospective study of the covariates of age at menopause among women who were randomly sampled from a general population. This approach avoids three problems that may account for the inconsistent results of prior studies: recall bias in retrospectively collected data, failure to control confounding in data analyses, and self-selection in the target populations. At baseline, the 2014 subjects in this study were 46.5-56.5 years old and still menstruating. Median age at last menstruation estimated from a model of the marginal distribution of age at menopause, was 50.7 years. When covariates were considered singly, age at menopause varied with smoking, education and income but not with marital status, parity, location, height, weight or use of either oral contraceptives or menopausal estrogens. Multivariate analyses showed that education and income were confounded with smoking status. The results indicate that many previously identified sources of variation in age at menopause reflect confounding with smoking and self-selection in target populations, rather than real effects.

A comparison of responses to mailed questionnaires and telephone interviews in a mixed mode health survey.

This paper compares respondents to mailed questionnaires with those nonrespondents subsequently interviewed by telephone in a survey of Massachusetts women aged 45-55 years conducted in 1981-1982. This mixed mode approach produced 8,050 responses, giving a response rate of 77%. This rate is similar to rates obtained in many surveys that employed in-person interviews, which are still widely used in health surveys but are increasingly expensive. Telephone respondents differed socioeconomically from mail respondents, suggesting that telephone follow-up of nonrespondents may have reduced nonresponse bias in this survey. Thus, a mixed mode approach may be superior to a mail-only approach with respect to this aspect of data quality. Women responding by mail were more likely to hold professional jobs, to have relatively high household incomes, and to have more years of education. Controlling for these socioeconomic differences did not, however, remove differences in reported health outcomes between mail and telephone respondents. These differences may be explained by less complete recall in the telephone interviews or they may arise from actual differences in health profiles between early (i.e., mail) and late (i.e., telephone) respondents. Although a mixed mode approach may reduce nonresponse bias, more research is required concerning the reasons for response differences between modes and to eliminate any differences caused by problems in data quality.