Dose-Response Relationship between Red Blood Cell Distribution Width and In-Hospital Mortality in Oldest Old Patients with Acute Ischemic Stroke.

INTRODUCTION: It is crucial to identify predictors of mortality in the early stage of acute ischemic stroke for the oldest old (aged ≥80 years) because of their poor overall survival outcomes. However, limited data are available as the oldest old have often been excluded from previous clinical studies. Hence, we aimed to assess the predictive effect of red blood cell distribution width on in-hospital mortality and the dose-response relationship between the red blood cell distribution width and in-hospital mortality in oldest old with acute ischemic stroke. METHODS: A retrospective cohort study was performed in two tertiary hospitals. Patients aged ≥80 years admitted due to acute ischemic stroke from January 1, 2014, to January 31, 2020, were included in the study. We divided the eligible patients into 3 groups with tertiles of red blood cell distribution width. Restrictive cubic spline and robust locally weighted regression analysis were performed to test the dose-response relationship between red blood cell distribution width and the in-hospital mortality risk. All-cause in-hospital mortality was the main study outcome. RESULTS: Overall, 606 patients were included in the final analysis. Red blood cell distribution width was categorized into 3 groups (T1: <13.7%, T2: 13.8-15.7%, and T3: >15.7%). The rationality of this categorization was then validated with restricted cubic spline and robust locally regression smoothing scatterplot, respectively. After adjusting for demographic and clinical features, a higher red blood cell distribution width was independently associated with in-hospital mortality and the hazard ratio (HR) was 3.31 (95% CI 2.47-4.45, p < 0.001). There was a positive dose-response relationship between red blood cell distribution width and mortality risk. Sensitivity analysis identified no conspicuous change in the HR. CONCLUSIONS: Red blood cell distribution width may be a valuable and simple measure for predicting in-hospital mortality in oldest old patients with acute ischemic stroke.

Extreme erythrocyte macrocytic and microcytic percentages are highly predictive of morbidity and mortality.

BACKGROUND: The red cell distribution width (RDW) is associated with health outcomes. Whether non-RDW risk information is contained in RBC sizes is unknown. This study evaluated the association of the percentage of extreme macrocytic RBCs (%Macro, RBC volume > 120 fl) and microcytic RBCs (%Micro, RBC volume < 60 fl) and the RDW-size distribution (RDW-sd) with mortality and morbidity. METHODS: Patients (females, n = 165,770; males, n = 100,210) at Intermountain Healthcare were studied if they had a hematology panel between May 2014 and September 2016. Adjusted sex-specific associations of %Macro/%Micro and RDW-sd with mortality and 33 morbidities were evaluated. RESULTS: Among females with fourth-quartile values of %Macro quartile and %Micro (referred to throughout as 4/4), there was an average of 7.2 morbidities versus 2.9 in the lowest risk (LR1) categories, 1/1, 1/2, 2/1, and 2/2 (P < 0.001). Among males, those in the 4/4 category had 8.0 morbidities, while those in the LR1 had 3.4 (P < 0.001). Cox regressions found %Macro/%Micro (4/4 vs. LR1, females: hazard ratio [HR] = 1.97 [95% CI = 1.53, 2.54]; males: HR = 2.17 [CI = 1.72, 2.73]), RDW-sd (quartile 4 vs. 1, females: HR = 1.33 [CI = 1.04, 1.69]; males: HR = 1.41 [CI = 1.10, 1.80]), and RDW (quartile 4 vs. 1, females: HR = 1.59 [CI = 1.26, 2.00]; males: HR = 1.23 [CI = 0.99, 1.52]) independently predicted mortality. Limitations include that the observational design did not reveal causality and unknown confounders may be unmeasured. CONCLUSIONS: Concomitantly elevated %Macro and %Micro predicted the highest mortality risk and the greatest number of morbidities, revealing predictive ability of RBC volume beyond what is measured clinically. Mechanistic investigations are needed to explain the biological basis of these observations. FUNDING: This study was supported by internal Intermountain Heart Institute funds and in-kind support from Sysmex America Inc.

The WHO diagnostic criteria for polycythemia vera-role of red cell mass versus hemoglobin/hematocrit level and morphology.

Regarding diagnosis of polycythemia vera (PV), discussion persists about hemoglobin (Hb) and/or hematocrit (Hct) threshold values as surrogate markers for red cell mass (RCM) and the diagnostic impact of bone marrow (BM) morphology. We performed a retrospective study on 290 patients with PV (151 males, 139 females; median age 65 years) presenting with characteristic BM features (initial biopsies, centralized evaluation) and endogenous erythroid colony (EEC) formations. This cohort included (1) a group of 229 patients when following the 2008 versus 256 patients diagnosed according to the 2016 World Health Organization (WHO) guidelines, all presented with increased RCM; (2) masked PV patients with low Hb (n = 143)/Hct (n = 45) recruited from the 2008 WHO cohort; (3) a cohort of 17 PV patients with elevated diagnostic Hb/Hct levels but low RCM; and (4) nine PV patients with increased RCM, opposing low Hb/Hct values. All patients were treated according to current PV guidelines (phlebotomies 87%, hydroxyurea 79%, and acetylsalicylic acid 87%). Applying the 2016 WHO criteria significantly increased concordance between RCM and Hb values compared with the 2008 WHO criteria (90 vs. 43% in males and 83 vs. 64% in females). Further analysis of the WHO 2016 PV cohort revealed that increased RCM is associated with increased Hb/Hct (93.8/94.6%). Our study supports and extends the diagnostic impact of the 2016 revised WHO classification for PV by highlighting the importance of characteristic BM findings and implies that Hb/Hct threshold values may be used as surrogate markers for RCM measurements.

Disorders of erythrocyte hydration.

The erythrocyte contains a network of pathways that regulate salt and water content in the face of extracellular and intracellular osmotic perturbations. This allows the erythrocyte to maintain a narrow range of cell hemoglobin concentration, a process critical for normal red blood cell function and survival. Primary disorders that perturb volume homeostasis jeopardize the erythrocyte and may lead to its premature destruction. These disorders are marked by clinical, laboratory, and physiologic heterogeneity. Recent studies have revealed that these disorders are also marked by genetic heterogeneity. They have implicated roles for several proteins, PIEZO1, a mammalian mechanosensory protein; GLUT1, the glucose transporter; SLC4A1, the anion transporter; RhAG, the Rh-associated glycoprotein; KCNN4, the Gardos channel; and ABCB6, an adenosine triphosphate-binding cassette family member, in the maintenance of erythrocyte volume homeostasis. Secondary disorders of erythrocyte hydration include sickle cell disease, thalassemia, hemoglobin CC, and hereditary spherocytosis, where cellular dehydration may be a significant contributor to disease pathology and clinical complications. Understanding the pathways regulating erythrocyte water and solute content may reveal innovative strategies to maintain normal volume in disorders associated with primary or secondary cellular dehydration. These mechanisms will serve as a paradigm for other cells and may reveal new therapeutic targets for disease prevention and treatment beyond the erythrocyte.

True Anemia-Red Blood Cell Volume Deficit-in Heart Failure: A Systematic Review.

BACKGROUND: Anemia in heart failure (HF) is commonly diagnosed according to hemoglobin concentration [Hb], hence may be the result of hemodilution or true red blood cell volume (RBCV) deficit. Whether true (nonhemodilutional) anemia in HF can or cannot be generally inferred by [Hb] measurements and clinical correlates remains unclear. The purpose of this study was to systematically review the literature and investigate the status and correlates of RBCV in patients with HF. METHODS AND RESULTS: MEDLINE, Scopus, and Web of Science were searched since their inceptions until April 2016 for articles directly reporting or allowing the calculation of intravascular volumes (RBCV, plasma volume) in patients with HF according to the International Council for Standardization in Hematology. Eighteen studies were included after systematic review, comprising a total of 368 patients with HF (limits for mean age=49-80 years, sex=0%-92% females, left ventricular ejection fraction=26%-61%). Mean RBCV was reduced (limits=67%-88% of normal) in all studies including HF patients with anemia (low [Hb]) (7 studies, n=127), whereas only 2 of 10 studies in nonanemic patients with HF presented lower than normal mean RBCV (90% and 96%). In metaregression analyses, RBCV was positively associated with [Hb] (B=6.10, SE=1.44) and negatively associated with age (B=-1.14, SE=0.23), % females (B=-0.38, SE=0.04), left ventricular ejection fraction (B=-0.81, SE=0.20), and body mass index (B=-3.55, SE=0.46; P<0.001). CONCLUSIONS: Presence or absence of true anemia in patients with HF as determined by RBCV status mainly concurs with diagnosis based on [Hb] and presents negative relationships with age, female sex, left ventricular ejection fraction, and body mass index.

[Red cell distribution width as a risk marker in patients with cardiovascular diseases]. / Ancho de distribución eritrocitaria como potencial biomarcador clínico en enfermedades cardiovasculares.

Red cell distribution width (RDW) is a measurement of the variation in size, as well as an index of heterogeneity of erythrocytes, which is used in combination with other hematologic parameters as an aid to the differential diagnosis of hypochromic anemia. RDW could also serve as a biomarker in the diagnosis and prognosis patients with cardiovascular diseases. However, it is unclear whether the increased heterogeneity is the cause or consequence of other pathophysiological conditions such as renal failure, malnutrition, inflammation and oxidative stress, which among other conditions are actively involved in the genesis and progression of cardiovascular diseases. The aim of this review is to show and discuss recent evidence about the role of RDW measurement as an aid in the diagnosis and prognosis of patients with such diseases. Besides being a simple, inexpensive and routinely measured parameter, it could help in the stratification of patients according to their risk in clinical practice.

Ancho de distribución eritrocitaria como potencial biomarcador clínico en enfermedades cardiovasculares / Red cell distribution width as a risk marker in patients with cardiovascular diseases

Red cell distribution width (RDW) is a measurement of the variation in size, as well as an index of heterogeneity of erythrocytes, which is used in combination with other hematologic parameters as an aid to the differential diagnosis of hypochromic anemia. RDW could also serve as a biomarker in the diagnosis and prognosis patients with cardiovascular diseases. However, it is unclear whether the increased heterogeneity is the cause or consequence of other pathophysiological conditions such as renal failure, malnutrition, inflammation and oxidative stress, which among other conditions are actively involved in the genesis and progression of cardiovascular diseases. The aim of this review is to show and discuss recent evidence about the role of RDW measurement as an aid in the diagnosis and prognosis of patients with such diseases. Besides being a simple, inexpensive and routinely measured parameter, it could help in the stratification of patients according to their risk in clinical practice.

Association of the dispersion in red blood cell volume with mortality.

BACKGROUND: The red cell distribution width (RDW) predicts mortality among many populations. RDW is calculated as the standard deviation (SD) of the red blood cell (RBC) volume divided by mean corpuscular volume (MCV). Because higher MCV also predicts mortality, we hypothesized that the RDW numerator (one SD of RBC volume or 1SD-RDW) predicts mortality more strongly than the RDW. MATERIAL AND METHODS: Adult subjects hospitalized during a contemporary clinical era (10/2005-1/2014, N = 135,963) and a historical era (1/1999-9/2005, N = 119,530) were studied. The RDW was obtained from the complete blood count (CBC), while 1SD-RDW was calculated (RDW multiplied by MCV and divided by 100). RESULTS: In univariable Cox regression (2005-2014 cohort), 1SD-RDW (quintile 5 vs. 1: hazard ratio [HR] = 8.38, 95% confidence interval [CI] = 7.94, 8.85; P < 0.001) was a superior predictor of mortality compared to RDW (quintile 5 vs. 1: HR = 4.78, CI = 4.57, 5.00; P < 0.001). This superiority remained after adjustment for age, sex, basic metabolic profile components and other CBC factors excluding MCV (1SD-RDW: HR = 2.41, CI = 2.28, 2.55; RDW: HR = 2.01, CI = 1.92, 2.11). Further adjustment for MCV strengthened the RDW association (HR = 2.14, CI = 2.04, 2.24; P < 0.001), becoming indistinct from 1SD-RDW (HR = 2.20, CI = 2.08, 2.33; P < 0.001). Findings were similar for the 1999-2005 cohort. CONCLUSIONS: The 1SD-RDW predicted mortality more strongly than RDW, suggesting that 1SD-RDW is superior to RDW as an individual risk predictor. Further, these results indicate that the dispersion of RBC volume and its mean are independent risk markers. Further research is required to understand the clinical value and mechanistic basis of these associations.

Amplitud de distribución eritrocitaria y enfermedad coronaria / Red cell distribution width and coronary artery disease

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Amplitud de distribución eritrocitaria y enfermedad coronaria. Respuesta / Red cell distribution width and coronary artery disease. Response

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In vivo volume and hemoglobin dynamics of human red blood cells.

Human red blood cells (RBCs) lose ∼30% of their volume and ∼20% of their hemoglobin (Hb) content during their ∼100-day lifespan in the bloodstream. These observations are well-documented, but the mechanisms for these volume and hemoglobin loss events are not clear. RBCs shed hemoglobin-containing vesicles during their life in the circulation, and this process is thought to dominate the changes in the RBC physical characteristics occurring during maturation. We combine theory with single-cell measurements to investigate the impact of vesiculation on the reduction in volume, Hb mass, and membrane. We show that vesicle shedding alone is sufficient to explain membrane losses but not volume or Hb losses. We use dry mass measurements of human RBCs to validate the models and to propose that additional unknown mechanisms control volume and Hb reduction and are responsible for ∼90% of the observed reduction. RBC population characteristics are used in the clinic to monitor and diagnose a wide range of conditions including malnutrition, inflammation, and cancer. Quantitative characterization of cellular maturation processes may help in the early detection of clinical conditions where maturation patterns are altered.

Survival and senescence of human young red cells in vitro.

BACKGROUND: A number of experimental investigations in vivo suggest that in humans a decrease of circulating erythrocyte number ensues whenever erythropoietin (EPO) plasma level decreases. Since the process seems to selectively eliminate young red cells (neocytes), it has been named neocytolysis. The experimental models in vivo have revealed and documented multiple forms of neocytolysis but have not fully elucidated the specificity of the target red cells and the relation with EPO level changes. In an attempt to better characterize the neocytolytic process, we have undertaken an in vitro investigation on age-ranked human red cells. METHODS: By centrifugation on Percoll density gradient we separated the red cells population into three subsets, neocytes, middle-aged and old. Then we comparatively investigated the kinetics of survival of the subsets cultured under different conditions: with medium alone, with 10% autologous plasma, with EPO, alone or in combination with autologous monocytes. RESULTS: Neocytes showed a viability and a survival rate lower than the other red cells when cultured in medium or with 10% plasma. EPO at physiological doses increased their survival rate, but not that of the other subsets. This effect was enhanced by co-culture with monocytes. CONCLUSION: Likely neocytes are more sensitive than the other RBCs subsets to presence or absence of survival signals, such as EPO or plasma or monocytes derived factors. These observations could provide an insight into the link between the decrease in EPO plasma level and the reduction of circulating red cells mass and account for the specificity of neocytes clearance.

Red blood cells of sickle cell disease patients exhibit abnormally high abundance of N-methyl D-aspartate receptors mediating excessive calcium uptake.

Recently we showed that N-methyl D-aspartate receptors (NMDARs) are expressed in erythroid precursors (EPCs) and present in the circulating red blood cells (RBCs) of healthy humans, regulating intracellular Ca(2+) in these cells. This study focuses on investigating the possible role of NMDARs in abnormally high Ca(2+) permeability in the RBCs of patients with sickle cell disease (SCD). Protein levels of the NMDAR subunits in the EPCs of SCD patients did not differ from those in EPCs of healthy humans. However, the number and activity of the NMDARs in circulating SCD-RBCs was substantially up-regulated, being particularly high during haemolytic crises. The number of active NMDARs correlated negatively with haematocrit and haemoglobin levels in the blood of SCD patients. Calcium uptake via these non-selective cation channels was induced by RBC treatment with glycine, glutamate and homocysteine and was facilitated by de-oxygenation of SCD-RBCs. Oxidative stress and RBC dehydration followed receptor stimulation and Ca(2+) uptake. Inhibition of the NMDARs with an antagonist memantine caused re-hydration and largely prevented hypoxia-induced sickling. The EPCs of SCD patients showed higher tolerance to memantine than those of healthy subjects. Consequently, NMDARs in the RBCs of SCD patients appear to be an attractive target for pharmacological intervention.

RBC volume deficiency in patients with excessive orthostatic decrease in cerebral blood flow velocity.

BACKGROUND: Orthostatic intolerance (OI) is common but heterogeneous. There is a subgroup of OI patients who have excessive decrease in cerebral blood flow velocity (CBFV) of bilateral middle cerebral arteries (MCAs) during head-up tilt without systemic blood pressure change. This study evaluated the role of blood volume reduction in such patients. METHODS: Patients with idiopathic OI who had excessive orthostatic decrease (>20% of the supine level) in mean CBFV of bilateral MCAs and who also received blood volume determination were collected. The chromium (5¹Cr) dilution method was used for red blood cell (RBC) volume determination in these patients. The blood volume was expressed as a percentage of the expected volume. These patients were further divided into two groups, those with postural tachycardia syndrome (POTS group) and those without (non-POTS group). The data of RBC volume were compared between the two groups. Besides, we used multivariate linear regression to evaluate the factors that predict RBC volume. RESULTS: Twenty-five patients (13 females, median age = 28 years) were enrolled in this study. Nine of these patients had POTS (5 females, median age = 26 years) and 16 did not (8 females, median age = 29.5 years). Compared with the expected volume, the RBC volume was significantly reduced in all patients (median = 82% of the expected volume). Moreover, the RBC volume was significantly lower in the POTS group than that in the non-POTS group (78% vs. 85% of the expected volume, p = 0.013). The orthostatic decrease of MCA flow velocity was 28.3% in the POTS group and 32.5% in the non-POTS group (p = 0.140). The orthostatic pulsatility index increment was 15.4% in the POTS group and 20.5% in the non-POTS group (p = 0.438). Moreover, basic demography and hemoglobin levels were not different between the two groups. After multivariate linear regression (dependent variables including age, sex, body surface, and groups), only the presence of POTS significantly predicted the RBC volume (p = 0.006). CONCLUSION: The results of our study indicated that low RBC volume may play an important role in the pathophysiology of OI in this group of patients. Moreover, its role seems even more relevant in patients with POTS than in those without. Further studies for mechanistic evaluation are needed in the future.

Application of the optimized CO-rebreathing method for determination of hemoglobin mass in patients with polycythemia vera.

Determination of red cell volume (RCV) might contribute to establishing the diagnosis of polycythemia vera (PV). A novel simplified method to detect RCV through CO rebreathing is nowadays applied in healthy young individuals but was not tested in a clinical or PV setting. The aim of the present study is to evaluate whether this spirometric approach is applicable in older subjects and contributes to PV diagnosis in a proof-of-concept approach. At first, RCV was determined by the optimized CO-rebreathing method in healthy subjects >50 years of age (n = 81, age 66 ± 9 years). Failure rate and age distribution of subjects who failed with CO rebreathing were analyzed. Then, RCV was measured in male PV patients (n = 7) and compared to healthy male controls (n = 35). RCV values in relation to several anthropometric references (body weight, body surface area (BSA), lean body mass (LBM)) were calculated to determine the sensitivity and specificity of established RCV thresholds when using optimized CO rebreathing. In healthy subjects, test failure rate was 9.9 %, but failure was not associated with age. Sensitivity and specificity (sens/spec) to detect PV was 100 %/83 % using the criteria of the PV study group. Using criteria based on BSA, sens/spec was 14 %/100 %. An arbitrary threshold of 50 ml/kg LBM yielded sens/spec of 100 %/97 %. In conclusion, this proof-of-concept indicates that optimized CO rebreathing is applicable in older subjects and allows determining RCV for the diagnosis of PV. Normalized values for RCV measures obtained from CO rebreathing are needed to grant sufficient sensitivity and/or specificity.

Hemolysis induced by an extreme mountain ultra-marathon is not associated with a decrease in total red blood cell volume.

Prolonged running is known to induce hemolysis. It has been suggested that hemolysis may lead to a significant loss of red blood cells; however, its actual impact on the erythrocyte pool is unknown. Here, we test the hypothesis that prolonged running with high hemolytic potential decreases total red blood cell volume (RCV). Hemolysis (n = 22) and RCV (n = 19) were quantified in ultra-marathon runners before and after a 166-km long mountain ultra-endurance marathon (RUN) with 9500 m of altitude gain/loss. Assessment of total hemoglobin mass (Hbmass) and RCV was performed using a carbon monoxide rebreathing technique. RUN induced a marked acute-phase response and promoted hemolysis, as shown by a decrease in serum haptoglobin (P < 0.05). Elevated serum erythropoietin concentration and reticulocyte count after RUN were indicative of erythropoietic stimulation. Following RUN, runners experienced hemodilution, mediated by a large plasma volume expansion and associated with a large increase in plasma aldosterone. However, neither Hbmass nor RCV were found to be altered after RUN. Our findings indicate that mechanical/physiological stress associated with RUN promotes hemolysis but this has no impact on total erythrocyte volume. We therefore suggest that exercise 'anemia' is entirely due to plasma volume expansion and not to a concomitant decrease in RCV.

Differences in blood volume components between hyporesponders and responders to erythropoietin alfa: the heart failure with preserved ejection fraction (HFPEF) anemia trial.

BACKGROUND: Hyporesponders to erythropoietin-stimulating agents (ESAs) have been associated with an increased subsequent risk of death or cardiovascular events. We hypothesized that subjects who are hyporesponsive to erythropoietin alfa would have higher plasma volumes and lower red cell deficits than subjects who are responsive to therapy. METHODS: As part of a prospective, single blind, randomized, placebo-controlled study comparing erythropoietin alfa with placebo in older adults (n = 56) with heart failure and a preserved ejection fraction (HFPEF), we performed blood volume analysis with the use of an indicator dilution technique with (131)iodine-labeled albumin. We evaluated differences in plasma volumes and red cell volumes in hyporesponders (eg, <1 g/dL increase in hemoglobin within the first 4 weeks of treatment with erythropoetin alfa) compared with subjects who were responders and controls. RESULTS: Nine of 28 subjects (32%) assigned to ESA were hyporesponders. Hyporesponders did not differ from responders nor control subjects by any baseline demographic, clinical, or laboratory parameter, including hemoglobin. Hyporesponders had a greater total blood volume expansion (1,264.7 ± 387 vs 229 ± 206 mL; P = .02) but less of a red cell deficit (-96.2 ± 126 vs -402.5 ± 80.6 mL; P = .04) and a greater plasma volume expansion (+1,360.8 ± 264.5 vs +601.1 ± 165.5 mL; P = .01). Among responders, the increase in hemoglobin with erythropoietin alfa was associated primarily with increases in red cell volume (r = 0.91; P < .0001) as well as a decline in plasma volume (r = -0.55; P = .06). CONCLUSIONS: Among older adults with HFPEF and anemia, hyporesponders to erythropoietin alfa had a hemodilutional basis of their anemia, suggesting that blood volume analysis can identify a cohort likely to respond to therapy.

Loss of red cell mass in a plasmapheresis machine: effect of rinsing the disposable tubing with normal saline and reinfusion.

The aim of this study was to determine the loss of red cell mass during a plasma donation. If the donor undergoes plasmapheresis 45 times within one year without rinsing the tubing system and reinfusing this normal saline into the donor at the end of the donation, the result is a loss of red cell mass of 11.01 ml per donation. This result translates into an accumulated loss of red cell mass of up to 495.63 ml per year. The loss of blood induced by plasma donations can be reduced to 58.01 ml per year, if the disposable tubing is rinsed with normal saline and reinfused into the donor at the end of each plasma donation.

The relationship between fibrinogen levels after cardiopulmonary bypass and large volume red cell transfusion in cardiac surgery: an observational study.

BACKGROUND: Coagulopathy leading to excessive blood loss and large volume red cell transfusion is a frequent complication of cardiac surgery with cardiopulmonary bypass (CPB) that may be caused by low perioperative fibrinogen levels. We explored the relationship between post-CPB fibrinogen levels and large volume red cell transfusion. METHODS: Patients who underwent cardiac surgery with CPB from 2005 to 2011 at a single institution and had a fibrinogen level measured after CPB were included in this retrospective observational study. The relationship between post-CPB fibrinogen levels and large volume red cell transfusion (defined as ≥5 units transfused on the day of or the day after surgery) was assessed by cubic spline function and receiver operating characteristic analyses. The independent relationship between fibrinogen levels and large volume transfusion was assessed by multivariable logistic regression and propensity score analyses. RESULTS: In the 4606 patients included, the probability of large volume transfusion increased when fibrinogen levels decreased below approximately 2.0 g/L. Using <2.0 g/L as the threshold for low fibrinogen, 1918 (42%) were categorized into the low fibrinogen group, of whom 363 (18.9%) had large volume transfusion compared with 164 (13.5%) of the 2688 patients whose fibrinogen level was ≥2.0 g/L (P < 0.0001). In the low fibrinogen group, the unadjusted odds ratio (95% confidence interval) for large volume transfusion was 1.5 (1.3-1.7). The risk-adjusted odds ratio obtained by logistic regression was 1.8 (1.4-2.2) and by propensity score methods was 1.5 (1.2-2.0). CONCLUSIONS: While this study was not equipped to detect the critical fibrinogen level in bleeding patients, its results suggest that current recommendations that fibrinogen replacement not be initiated in bleeding patients unless fibrinogen levels decrease below 0.8 to 1.0 g/L may be too conservative. Randomized trials are needed to determine whether maintaining higher fibrinogen levels in bleeding patients can reduce blood loss and transfusions and by that means improve clinical outcomes in cardiac surgery.