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When Blood Is Not an Option: Factors Affecting Survival After the Use of a Hemoglobin-Based Oxygen Carrier in 54 Patients with Life-Threatening Anemia

Section Editor(s): Hogue, Charles W. Jr.; London, Martin J.; Levy, Jerrold H.Mackenzie, Colin F. MB ChB, FRCA, FCCM*; Moon-Massat, Paula F. DVM§; Shander, Aryeh MD; Javidroozi, Mazyar MD; Greenburg, A. Gerson MD‡§

doi: 10.1213/ANE.0b013e3181cd473b
Cardiovascular Anesthesiology: Research Reports
Chinese Language Editions

BACKGROUND: In consenting Jehovah's Witness patients and others for whom blood is contraindicated or not available, hemoglobin-based oxygen carrier (HBOC)-201 may enable survival in acutely anemic patients while underlying conditions are treated.

METHODS: Survival factors were identified in a multicenter, unblinded series of severely anemic “compassionate use” patients receiving available standard treatment plus consultant-supported HBOC-201 administration by novice users. Predictors of outcome were sought and compared between survivors and nonsurvivors. A compound variable, hemoglobin-duration deficit product was used to describe the interactive clinical effects of severity and duration of anemia. Mortality, correlations between patient characteristics, and survival to hospital discharge were determined from patient records.

RESULTS: Fifty-four patients (median age 50 years) with life-threatening anemia (median hemoglobin concentration at time of request = 4 g/dL) received 60 to 300 g HBOC-201. Twenty-three patients (41.8%) were discharged. Intraoperative blood loss (45%), malignancy (18%), and acute hemolysis (13%) were the prevailing reasons for anemia. Time from onset of anemia (≤8 g/dL) to HBOC-201 infusion was shorter for survivors than nonsurvivors (3.2 vs 4.4 days, P = 0.027). Mean hemoglobin levels before HBOC-201 infusion in survivors and nonsurvivors were 4.5 and 3.8 g/dL, respectively (P = 0.120). No serious adverse event was attributed to HBOC-201. The hemoglobin-duration deficit product separated survivors from nonsurvivors. Cancer and renal disease were associated with nonsurvival.

CONCLUSION: Earlier, compared with later, administration by inexperienced users of HBOC-201 to patients with anemia was associated with improved chances of survival of acutely bleeding and hemolyzing patients. Survival was more likely if the duration and magnitude of low hemoglobin was minimized before treatment with HBOC-201.

From the *Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, Maryland; †Department of Anesthesiology, Critical Care and Hyperbaric Medicine, Englewood Hospital and Medical Center, Englewood, New Jersey; ‡Department of Surgery, Brown University, Providence, Rhode Island; and §Biopure Corporation, Cambridge, Massachusetts.

Accepted for publication October 2, 2009.

Reprints will not be available from the author.

Address correspondence to Colin F. Mackenzie, MB ChB, FRCA, FCCM, Shock Trauma and Anesthesiology Research (STAR) Organized Research Center, 110 S. Paca St., 4th floor, Box 44, Baltimore, MD 21201. Address e-mail to

The inverse correlation between hemoglobin concentration ([Hb]) and morbidity and mortality is well supported in the literature.1–20 Anemia with [Hb] <8 g/dL increases the likelihood of adverse events (AEs) in patients with underlying cardiac disease,1–8 neurological disorders,9 or renal disease,10–13 those who are critically ill,14–16 elderly,15–19 and patients undergoing orthopedic surgery.20,21 Below a critical [Hb] (reflecting oxygen-carrying capacity), oxygen delivery to tissues is compromised even with maximal cardiovascular compensation, leading to inadequate perfusion, organ ischemia, and the observed increased patient morbidity and mortality. For some anemic patients, human blood products are not acceptable and their [Hb] decreases below critical thresholds, while other less direct modalities are used to maintain tissue perfusion until adequate restoration of red cell mass is achieved.

Hemoglobin-based oxygen carrier (HBOC)-201 (hemoglobin glutamer-250 bovine) (Hemopure®, Biopure Corporation, Cambridge, MA), an HBOC, offers oxygen-carrying capacity to anemic patients for whom blood transfusions are either not readily available or are not an option. HBOC-201 was approved in 2001 for the treatment of surgical anemia in adults in South Africa.22 In the United States, development of HBOC-201 has stagnated; trials are on “clinical hold” for safety issues cited by the Food and Drug Administration (FDA). Critics of HBOCs suggest that the products are toxic with properties that result in myocardial infarction (MI), stroke, acute renal failure (ARF), deleterious increases in arterial blood pressure, methemoglobinemia (metHb), increases in liver enzymes, and death.23,24 These conclusions have been disputed.25–28

Where blood is not an option, for patients with signs and symptoms of ischemia, the risk of mortality is considered unacceptably high if additional oxygen-carrying capacity is not provided; in these situations, the FDA has permitted treatment with HBOC-201 under 21 Code of Federal Regulation (CRF), part 56.104 (c) (emergency or compassionate use [CU]). Individual requests from physicians for CU of HBOC-201 are considered by Biopure Corporation. Information about HBOC-201 is disseminated to the community by individual Jehovah's Witnesses, Bloodless Medicine Programs, and Biopure Corporation.

The purpose of this report, the largest single case series of CU patients administered any type of HBOC, was to identify variables associated with survival after HBOC-201 treatment.

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IRB approval and patient or surrogate consent were obtained for administration of HBOC-201. From November 1998 to October 2000 during active clinical trials and in 2007 when the FDA was considering the trial results, Biopure Corporation provided an identically manufactured and prepared HBOC-201 for CU patients sustaining life-threatening anemia whose attending physicians believed that the patient's underlying condition was reversible. A schematic of the process is provided in Figure 1. Red blood cells were not an option in these patients for religious (i.e., Jehovah's Witnesses) or medical (e.g., incompatible blood and immune reactions) reasons. Each patient's clinical situation was discussed with the attending physician by a Biopure or on-call consultant physician familiar with HBOC-201. Patients were considered for treatment if they had a total [Hb] <6 g/dL, signs of ischemia (electrocardiographic evidence of ischemia and renal function compromise), and when available, increasing lactate levels and base deficit, with total [Hb] <10 g/dL or a potential loss of blood that could result in critically low oxygen-carrying capacity. There was no systematic collection of markers of organ dysfunction (e.g., cardiac enzymes) at preset intervals because of limits placed on blood sampling. Patients were excluded if they were moribund, had severe underlying cardiovascular disease, pronounced comorbid conditions, and/or were older than 80 years. For each patient, the FDA was contacted to request an investigational new drug (IND) number. In parallel, the attending physician was forwarded informational documents about HBOC-201 and a template informed consent form for customization in accordance with institutional policies. Telephone and e-mail guidance regarding dosing and monitoring was provided to the attending physician by the Biopure or consultant physician on a 24-hour, 7-day availability. Recommendations included an initial loading dose of 2 to 4 U (250 mL [30 g Hb]/unit) at a rate compatible with blood volume and hemodynamic status and repeat dosing, 1 to 2 U every 19 to 20 hours or continuous infusion (HBOC-201 half-life of 19 hours).

Figure 1

Figure 1

Attending physicians, most of whom had not previously used HBOC-201, were apprised of the incidence of side effects frequently reported from previous HBOC-201 clinical experience (e.g., increase in arterial blood pressure, plasma volume expansion, increase in metHb concentration ([metHb]), and gastrointestinal discomfort).29–34 Clinicians were advised about management for mitigating side effects (e.g., nitric oxide donor, beta-blocker or calcium channel blocker or changing infusion rate for arterial blood pressure, use of diuretics, methylene blue infusion or use of ascorbic acid to reduce [metHb], and anticholinergics for gastrointestinal discomfort). The same laboratory interference instructions were conveyed to each institution by electronic documents to the laboratory director and phone briefings or e-mails to the attending clinician in charge of the patient's care, indicating that HBOC-201 in the plasma caused interferences with colorimetric laboratory and clinical measurements.35–37

The FDA gave individual patient approval, not as a CU protocol, so physiologic and laboratory data collection was not consistent across patients or the 49 CU sites, although specific common data items necessary to patient care and use of the product were recorded. Pretreatment data were collected 0.5 to 0.25 hours preceding, and closest to, the initial HBOC-201 infusion. Survival outcome was defined as discharged from hospital. AEs of HBOC-201 were not systematically documented; however, they were noted by the attending physician and reported to the medical consultant in daily interactions during the treatment period. No systematic screening for serious AEs (SAEs) was used because a generic data collection protocol was not approved. SAEs were obtained from the patient charts. Based on HBOC-201 safety concerns,23,24,29–34 instances of cardiac, renal, or central nervous system events, clinically relevant increases in liver enzymes, gastrointestinal disturbances, and increases in [metHb] were noted. However, because of the emergency nature of the HBOC-201 administration and unwillingness to draw blood or insert invasive monitoring devices, collection of complete clinical and laboratory data was not always possible. Several sites performed only minimal phlebotomy, indicating these were the wishes of patients and their families.

Baseline characteristics and HBOC-201–related variables were compared using Wilcoxon-Mann-Whitney U test for continuous variables, and χ2 or Fisher exact test where appropriate (based on the expected cell count) for categorical/nominal variables between the survivors and nonsurvivors to identify potential predictors of mortality. Spearman ρ test evaluated correlations. During author discussions about how to account for the interaction between severity and duration of anemia, a compound variable termed “Hb-deficit duration product” was suggested and calculated as the area between a horizontal line representing the Hb of 8 g/dL and patient's Hb curve from the first detection of [Hb] <8 g/dL (available in all patients) to the time of first HBOC-201 infusion (Fig. 2). The Hb cutoff point of 8 g/dL was chosen empirically because it is often used as a transfusion trigger for seriously ill patients. Hb-deficit duration product indicated not just the effects around a single [Hb] value but the total period of anemia, similar to a previous report.38 Analyses were performed using SPSS 13.0 for Windows (SPSS, Chicago, IL). Continuous variables are expressed as median with interquartile range and/or minimal and maximal values.

Figure 2

Figure 2

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FDA Regulatory approval was granted for 79 requests. Each IRB gave approval, and written informed consent was obtained from 54 patients who received 55 courses of HBOC-201 (1 patient received HBOC-201 on 2 separate hospital admissions within a month under the same IND number). One additional request to the FDA was withdrawn because of delays in receiving approval relative to the patient's deteriorating condition (this patient ultimately died). There were 24 patients for whom an IND number was approved but HBOC-201 was not administered, for reasons that included the following: the anticipated further decrease in [Hb] did not occur (n = 7), patient died before HBOC-201 was administered (n = 5), patient improved without HBOC-201 (n = 3), blood transfusion was given (n = 6), consent or IRB approval issues (n = 3, one of whom died), or surgery was not performed (n = 1). For an additional patient, an IND was issued, but the patient did not receive HBOC-201 under that IND, and HBOC-201 was given later under a new IND. This patient is included among the patients who received HBOC-201. Of these 24 patients, 19 survived indicating an overall mortality rate of 20.8%. However, the mortality rate is 50% when we exclude patients who were transfused (n = 6), never reached the expected low Hb levels (n = 7), and 1 patient who did not undergo the planned surgery.

Consideration was given to use of these patients who did not receive HBOC-201 as a control group. With a diversity of disease states, ages, and levels of anemia, comparisons would be nonrevealing because the patients were not given HBOC-201 for many different reasons, including a considerable number of patients receiving transfusions or who never reached very low Hb levels as described above.

The demographic information for patients treated with HBOC-201, cause of anemia, and reason for HBOC-201 administration are summarized in Table 1. The only variables with a normal distribution were age, [Hb] before first HBOC treatment, and lowest [Hb] after HBOC treatment. There were no statistical differences between the patients from the 2 data collection time periods, and the data are pooled for presentation. Overall, 65% of patients were treated for acute blood loss of varying etiologies.

Table 1

Table 1

The duration between hospital admission and start of HBOC-201 treatment was 7.5 vs 3 days for the nonsurvivors and survivors, respectively (P = 0.072; Table 2). All patients were anemic (median [Hb] = 3.9 g/dL) when HBOC-201 administration was initiated, their [Hb] having decreased from the time of hospital admission to eventual treatment with HBOC-201 (Table 2). Most patients (82%) received erythropoietin during hospitalization.

Table 2

Table 2

Of patients treated with HBOC-201, 41.8% were discharged from the hospital. There was no correlation between age, gender, or number of comorbidities and survival. The proportion of patients with malignancy in the nonsurvivor group was significantly (P = 0.001) larger (Table 1). The time from the physician's request for HBOC-201 (IND request) to the first HBOC-201 infusion was equivalent (1 day) in both survivors and nonsurvivors. From admission to the time of HBOC-201 request, there was a decrease of 2.5 g/dL [Hb] in nonsurviving patients compared with a decrease of 0.9 g/dL [Hb] in survivors. However, the most striking factors separating survivors from nonsurvivors were the duration of anemia <8 g/dL before HBOC-201 treatment (Table 2) and the magnitude of the Hb-deficit duration product (Fig. 2). The duration of anemia was shorter in survivors, 3.2 vs 4.4 days (P = 0.027), resulting in smaller Hb-deficit duration product (162 vs 211 g/dL × days, P = 0.039) in survivors.

Clinical diagnoses of MI, stroke, and ARF with or without dialysis were predominantly reported in the nonsurvivor group (10 of 32 patients, 31%) compared with the survivors (2 of 23 patients, 7%); 6 of these 12 patients had preexisting underlying pathologic conditions in these organ systems. Nonsurvivors (n = 10) had 12 SAEs (1 stroke, 3 MI, 4 ARF, and 4 ARF requiring dialysis) compared with 2 SAEs in survivors (n = 2; 1 ARF and 1 ARF requiring dialysis). Table 3 provides details of these 12 patients; none of these SAEs was attributed directly to HBOC-201 by the attending physician.

Table 3

Table 3

Table 3

Table 3

The 3 most frequently reported nonserious AEs were an increase in blood pressure (systolic blood pressure >160 mm Hg), an increase in liver enzymes (outside normal range), and the development of metHb (outside normal range). Systolic blood pressure increased in 10 of 16 survivors (63%) and 9 of 23 nonsurvivors (39%). Of these 19 patients with increased systolic blood pressure, 3 of the 10 survivors and 5 of the 9 nonsurvivors required treatment with antihypertensive drugs. Liver enzymes, measured in only 22 patients, were outside the normal range in 12 of 16 nonsurvivors (75%) and 6 of 6 survivors and were considered transient effects of HBOC-201; none of the patients developed clinical signs of hepatic dysfunction or required medical treatment. Increases in [metHb] were reported in 6 nonsurvivors (12.2% [4.2%–22.3%]) and 7 survivors (6.0% [2.6%–13.6%]). In 7 cases, methylene blue was used to treat the metHb. There was no correlation between units of HBOC-201 given and the maximal [metHb] measured (P = 0.328). No attending physicians reported unexpected difficulty in product use to the Biopure or consultant physicians.

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This case series is unusual, representing a group of acutely anemic patients untreated with blood transfusion. Many clinicians use 8 g/dL as the [Hb] below which blood transfusion is begun in critically ill patients. All current guidelines for red blood cell transfusions recommend that transfusion is indicated when [Hb] is <6 g/dL39,40 because the mortality of groups not treated with blood or an HBOC was significantly increased at <5 g/dL.41,42

There is no published case series of this size involving the use of HBOC-201 in life-threatening situations, but there have been several individual cases reported.43–46 Reports on the association between decreased [Hb] and increased risk of morbidity and mortality are available from large retrospective studies and systematic reviews.41,42 Reports including Jehovah's Witnesses as historical controls collected between 1969 and 2000 generally support the relationship between decreasing [Hb] and increasing morbidity and mortality.47–52 The more recent reanalysis by Carson et al.,42 used as historical control data by Gould48 identified the association of [Hb] <5–6 g/dL with high morbidity and mortality. However, these retrospective data are not an appropriate control group; because they are a more uniform population, these patient data would need to be interpolated and broken into discrete historical intervals (which we are unable to do) to be comparable and used as a control for the patients in this series.

Data are available describing HBOC efficacy in transfusion-sparing and oxygen-carrying capabilities.30,32,33 A recent phase 3 clinical trial of human polymerized Hb (PolyHeme®, Northfield Laboratories, Evanston, IL) showed more AEs and MIs, but no mortality difference when blood was needed but was not available.53 Both trauma and large blood loss surgery trials have described cardiovascular, cerebral, and other complications of HBOCs,24 although the meta-analysis data, methods, and conclusions can be criticized.25–28 Further analysis of these AEs, observed with HBOC-201, the product used in these cases, suggests that they are related to a subpopulation of patients with advanced age and multiple comorbidities.30 Despite the risk of complications and AEs, HBOCs may prove lifesaving under specific circumstances, especially where blood is not an option or available. It becomes important to establish the point at which the benefit overshadows the risk.

In the heterogeneous patient population reported, the common denominator was anemia with historical data suggesting increases in patient mortality when augmentation of oxygen-carrying capacity is not provided.41,42,47 Although 82% of patients in this series received erythropoietin, drugs of this type have no known benefit during acute anemia. Sampling, testing, and abnormal values were insufficient for statistical analysis of hepatic enzymes, renal markers, coagulation, and cardiac enzymes.

An important observation in this case series is that at low [Hb] (<8 g/dL), mortality increased proportional to duration from onset of anemia until administration of HBOC-201. Early treatment often gave good results in terms of subjective statements made about feeling better, relatives commenting about the patients being more alert, and patients stating they had more energy. Delay between identifying need for additional oxygen-carrying capacity and administration of HBOC-201 would prolong the period of impaired perfusion, allowing further accumulation of oxygen debt, and increase the risk of ischemia-related events. Efficient and timely delivery of HBOC-201 to the patient bedside was compromised by various delays including obtaining informed consent, IRB (or administrative surrogate) approval, FDA review and approval to issue a unique IND for each individual patient, shipment of the product, and ultimate arrival and processing of it in the hospital pharmacy (or other dispensing unit).

Patients with rapid blood loss who died waited on average 3.6 days before receiving HBOC-201, a wait not significantly different from the 1.8 days for surviving patients (P = 0.178). The delay before treatment of medical anemia among nonsurvivors was longer than that of survivors (10.6 vs 4.4 days; P = 0.016).

Patients were aware of their high risk of nonsurvival without HBOC-201 infusion and gave informed consent and accepted the potential benefit, knowing there were risks associated with the use of HBOC-201. Risks explicitly noted included arterial blood pressure increase affecting cardiac or brain tissue perfusion. There was no correlation between blood pressure increases or the use of antihypertensives and survival in this series of patients.

Patients with abnormal vascular endothelial function (e.g., history of cardiovascular disease or diabetes) might be at higher risk to develop an adverse blood pressure response to HBOC-201, but none of the 7 diabetic patients and 5 of the 22 patients with cardiovascular disease had blood pressure increases compared with 6 of 33 patients without these comorbidities. Four of 5 patients with cardiovascular comorbidities survived. Although some patients had abnormal liver enzymes, there have been no cases of hepatic failure-related demise reported with HBOC-201 use.

The metHb increase observed with the use of HBOCs is likely due to the lack of sufficient reductase enzyme activity in the plasma. Increases in [metHb] did not affect survival, were independent of HBOC-201 dose, and, when treatment was necessary, generally were responsive to methylene blue infusion. A sufficient quantity of red blood cells containing metHb reductase seems necessary to minimize increases in total [metHb], and a low hematocrit may decrease the effectiveness of methylene blue in these patients. Increases in [metHb], as a percentage of total Hb, decrease the functional oxygen available to tissues, adding to the impact of low [Hb]. Although [metHb] <10% is well tolerated at normal or mild levels of anemia, 10% of an [Hb] <5 g/dL significantly impairs oxygen-carrying capacity and functional oxygen delivery.

Adequate [Hb] is not the only factor necessary to prevent mortality from acute anemia because the survivors had average [Hb] values of 4.5 g/dL compared with 3.8 g/dL in nonsurvivors with considerable overlap in their range of [Hb]. Other factors influencing survival included the duration of the anemia, the rapidity of onset of anemia, cardiopulmonary conditions that affect oxygen delivery, the patient's underlying pathologies and prior physical status, side effects of all medical treatments including HBOC-201, and the intensity of the medical, nursing, and family support to continue treating the patient. Underlying illnesses leading to the low [Hb] may be responsible for mortality, not the failure to reverse dying by increasing [Hb]. Carson et al.48 speculated that transfusion would improve postoperative outcome in patients with [Hb] <5 g/dL, because mortality remains extremely high with [Hb] <5 g/dL. Among the 24 patients with known outcomes for whom an IND was approved but HBOC-201 was not administered, 5 did not survive, leading to an apparent mortality rate of 20.8%. It should be noted, however, that in many of these patients, IND was applied for in anticipation of a severe anemia or blood loss that never happened, or the patient was eventually transfused. Exclusion of these cases (n = 14) would yield a new mortality rate of 50% among the remaining 10 anemic patients for whom an IND was issued, but HBOC-201 was not administered. Although this mortality rate is slightly higher compared with patients who received HBOC, the difference is not statistically significant (P = 0.734).

The limitations of this series of CU patients include the absence of a concurrent comparison control group, detailed systematic collection of markers of organ dysfunction (e.g., cardiac enzymes) at preset intervals, and rigorous assessment of severity of injury or illness. Because limits were placed on blood sampling, only incidences of abnormal laboratory tests were sometimes available, but there were few data on the duration of abnormalities. A control group was not available. Historical data on patients who cannot receive blood are distinctly different from the current population because the literature generally reports on homogeneous patient populations often in a single operative setting.48,49 The in-hospital postoperative ≤30-day mortality rates related to anemia, in Jehovah's Witness patients refusing Hb infusion or transfusion, in a multi-institutional study were [Hb] ≤5 g/dL, 34.4% (n = 32); ≤4 g/dL, 25% (n = 28); ≤3 g/dL, 54.2% (n = 24); and ≤2 g/dL, 100% (n = 7).48

In this report, only patients who were anemic for a variety of medical, surgical, and other reasons (Table 3) received HBOC-201 because blood was not an option. The 25 patients who did not receive HBOC-201, despite issuance of an IND number, are an inadequate control because of the wide variety of reasons for not receiving HBOC-201, as described above. Going forward, an FDA-approved single IND CU protocol, with standardized criteria for HBOC-201 release, data collection, and an independent data safety monitoring board, would minimize delays, potentially improve outcome, and improve the quality of data for analysis. One can speculate that survival in this series of patients, who were perceived to be dying, would potentially have been greater if patients enduring low [Hb] for extended periods resulting in irreversible fatal damage were excluded or, ideally, treated sooner. The Biopure manufacturing facility, name, and operation have been sold to OPK Biotech which will continue to manufacture, pursue United States registration with existing and future collaborations, and evaluate the product HBOC-201 described in this article.

In conclusion, this study adds evidence to the literature that, regardless of the organ system studied or surgical procedure evaluated, “anemia” is an independent risk factor for adverse outcome. This series of patients shows that, when used selectively and earlier in the course of acute anemia in patients when red blood cells are not readily available or for whom red blood cell transfusion is not an option, HBOC-201 administered by first-time users provides physicians with an additional, but unapproved, treatment.

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Drs. Shander, Mackenzie, and Greenburg form the team of consulting physicians who advised the attending physicians on the compassionate use of HBOC-201 described in this case series. Ms. Melissa Zafirelis, Director, Clinical Operations at Biopure Corporation is acknowledged for acquisition of the data presented in this article.Ms. June Clark, Senior Project Administrator at Biopure Corporation, is acknowledged for administrative support.

Supported by Biopure Corporation. Hemopure (HBOC-201) was supplied at no charge to the participant institutions.

Both Drs. Moon-Massat and Greenburg were previously full-time employees of Biopure Corporation. Drs. Shander and Mackenzie were paid consultants to Biopure Corporation. Dr. Shander also has been/is a consultant for Bayer, Hemo Concepts, NovoNordisk, OrthoBiotech, and Zymogenetics, has received grants/research support from Abbott, AstraZeneca, OrthoBiotech, and Zymogenetics and speaking honorariums from Baxter, Bayer, Pfizer, Hemo Concepts, NovoNordisk, OrthoBiotech, and Zymogentics. Dr. Mackenzie was also a paid site principal investigator in a clinical trial with HBOC-201 (Trial HEM-0115). No authors held equity interests in Biopure Corporation.

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