Newborn platelet dysfunction: a storage pool and release defect.

Per cent aggregation, release and content of adenine nucleotides, and specific radioactivity were evaluated in citrated platelet-rich plasma (PRP) prepared from paired samples of maternal and cord blood. Platelets of newborn infants aggregated normally in response to highdose ADP (20 muM), strong collagen suspensions, and thrombin; however, when compared with PRP from the mothers or from normal adults, per cent aggregation in response to lower concentrations of ADP (2 muM), weak collagen, and part particularly epinephrine was markedly reduced. Nucleotide release after stimulation of the newborns' PRP with the latter two inducers was also impaired. ATP and ADP content of the newborns' platelets was also significantly less than that of their mothers or of normal adults, but specific activity was normal. The data suggest that the impairment of ADP release in the platelets of newborn infants is due to decreased sensitivity to external stimuli. Since metabolic ATP is necessary for the platelet release reaction, it is postulated that the platelet dysfunction results from a lack of metabolic ATP.

Legal liability for transfusion injury in the acquired immunodeficiency syndrome era.

The emergence of the acquired immunodeficiency syndrome has wrought changes that have affected not only medicine and science, but many aspects of our social and political structures. In 1983 when it clearly became evident that acquired immunodeficiency syndrome could be transmitted by transfusions of blood components and products, blood banks became the focus of intense scrutiny by the public as well as by the mass media. Suddenly it was known that people could contract acquired immunodeficiency syndrome even though they had not engaged in activities known to place them at increased risk for acquiring infection with the human immunodeficiency virus type 1. In many ways the general fear evoked was, and remains, disproportionate to the risks posed by transfusions. This fear coupled with a general distrust of blood banks may also be reflected in the legal response to people infected with human immunodeficiency syndrome type 1 through transfusions. Further, whether the fault system of our tort law is an appropriate way to determine compensation for people injured by transfusion has been brought into question. For those people injured prior to our recognition of acquired immunodeficiency syndrome, the failings of the current system are most obvious.

Difficulties in demonstrating efficacy of blood substitutes.

Currently, the fear of infectious disease transmission by allogenic blood transfusions has spurred interest in developing a blood substitute FDA approval requires that a sponsor demonstrate that the substitute is effective. The challenge in designing efficacy studies in man is proving that the substitute offers significant advantages over conventional therapies for acute blood loss. This task is complicated by the oxygen reserve and the response to hemodilution following treatment of acute blood loss in man. Paradoxically, the technique that relies on these protective physiologies-isovolemic perioperative hemodilution-many offer the best experimental model to establish efficacy of a blood substitute in man.

The applicability of cGMP to cord blood cell banking.

The Food and Drug Administration will regulate cord blood cells stringently as a distinct category of somatic cells. The FDA has declared that cord blood cell products are subject to licensure and will require a claimed exemption for an investigational new drug (IND) to undertake clinical trials. This regulatory approach will require both establishment and product licenses, requirements that will pose significant difficulties for regulated establishments. The manufacture of cord blood cell products will be divided between delivery rooms or attached laboratories and regional cord cell processing laboratories. It is possible that cooperative manufacturing arrangements, perhaps using a short supply agreement model, will be the most practical way for FDA to regulate cord blood cell product manufacture. Without regard to regulatory or business arrangements for providing cord blood cell products, it is clear that current good manufacturing practices (cGMP) will be required in both the delivery suite and the processing laboratory. The concepts of cGMP will be foreign to many medical practitioners, but embracing them will be crucial to comply with FDA regulatory expectations and will concomitantly ensure uniform product quality.

Transfusion-transmitted AIDS reassessed.

PIP: This editorial traces the recommendations of the Food and Drug Administration with respect to reducing transmission of AIDS by transfusions of blood. Next the findings of a research study which appears in the same issue of this journal are reviewed. In this study, the authors describe 7 persons with negative HIV-antibody tests who donated blood but later had detectable HIV antibodies. The authors estimate the number of blood components that test negative but carry infection that are collected annually in the US. Their estimate of the current risk may be overly pessimistic. Newer, more accurate tests should be implemented as soon as clinical trials have established their efficacy and practicality. While tests are being validated, the education of donors must be intensified and focused. Although continued vigilance over the safety of the blood supply is essential, the risks of HIV transmission by transfusion should be kept in perspective. The risk of acquiring HIV infection through transfusion is low compared with the odds of death from influenza, abortion after the 14th week, and car accidents. The measures instituted to protect patients from acquiring HIV infection through blood transfusions have greatly improved the safety of the nation's blood supply. It is safer than it has ever been, but the slight risks that still remain can be reduced at this time only by intensified and appropriately focused education of blood donors and by more circumspect ordering of blood components by physicians.^ieng

Current status of injectable oxygen carriers.

In this review the current status of what commonly are termed "blood substitutes" is discussed. The term blood substitute is a misnomer because the formulations under development at this time transport respiratory gases but do not perform the metabolic, regulatory, and protective functions of blood. Either hemoglobin or a perfluorochemical form the base to transport oxygen; the advantages and disadvantages of each base are discussed. The availability of a blood substitute in the U.S. will require approval by the Food and Drug Administration (FDA) and, by law, both its efficacy and safety must be demonstrated prior to approval. Showing efficacy of any blood substitute is complicated by the oxygen reserve and the compensatory mechanisms to acute blood loss in man. The challenge is to prove that the administration of these formulations offer clinical advantages compared with replacement of volume alone. Several efficacy models, the most attractive among them being perioperative hemodilution, should provide data that would bring these formulations into clinical practice. When hemoglobin is not within the favorable environment of the red cell, whether the hemoglobin is derived from expression vectors developed through recombinant biotechnology or from lysed human red cells, it acquires a left-shifted oxygen disassociation curve. Further, because the tetramer disassociates when injected intravenously and the resulting dimers are cleared rapidly from the circulation by the kidneys, intravascular dwell time is brief. Hemoglobins have been modified chemically and linked intramolecularly, intermolecularly, and to macromolecules to correct these problems. While these manipulations have normalized the p50 and extended the dwell time significantly, some toxicity problems remain unresolved. The binding of nitric oxide to hemoglobin preparations and the presumably resultant systemic and pulmonary hypertension observed in animals may be the most difficult to overcome, although the implications of these reactions in man is poorly understood. Perfluorochemicals (PFC) provide a fundamentally different and simpler approach to oxygen transport than hemoglobin formulations. Typically, the PFCs used are liquids composed of 8 to 10 carbon atoms that dissolve oxygen and obey Henry's law. Thus, the recipient's inspired oxygen and cardiac output assume importance. Because they are insoluble in water, PFCs are administered as emulsions, that is, as small droplets about 0.1 to 0.2 microns in diameter. In this respect, they are very similar to the lipid emulsions widely used for parenteral nutrition. Egg yolk phospholipid and poloxamers are most commonly used as emulsifiers. PFCs are not metabolized and are excreted unchanged by the lungs, following temporary storage by the monocyte-macrophage system (MMS).(ABSTRACT TRUNCATED AT 400 WORDS)

Blood safety decisions, 1982 to 1986: perceptions and misconceptions.

Although blood bankers and those who treat persons with hemophilia are supportive of most of the recommendations of the Report, the manner in which the analysis was conducted and some of the general conclusions that were reached appear flawed. The flaws may reflect the deficiencies in the process by which the Committee gathered data more than any bias on the part of its members themselves. The Report may accurately reflect the testimony heard, but it is biased by the committee's acceptance as fact the opinions of critics who claim the AIDS epidemic was mismanaged by the blood-collecting agencies, professional organizations, hemophilia organizations, and the federal government. Countervailing views on the various issues are ignored or incompletely discussed. Much testimony was taken from the victims of the transfusion-associated AIDS epidemic. Reliance seems to have been placed upon hindsight testimony (taken 10 years after the events), rather than on documentation of what was known at the time when events unfolded. The Report states that "[t]he Committee's charge did not include the development of assertions about what should have been done at the time,"l(pl:4) yet that is precisely what was done. These comments address just a few of the misconceptions we perceive in the Report. They are based on our understanding of the state of knowledge--or ignorance--at the time that decisions about the safety of the blood supply were made. If we are to avert future threats to the blood supply from emerging infectious diseases, a goal that is universally embraced, we must learn the lessons the past can teach us, as painful as they may be. However, the hazards of judging history in hindsight should be avoided. Neither allegations nor opinions should be accepted as facts without critical examination and without placement in the context of contemporary knowledge; to accept a lesser standard does a great injustice to all who were touched by this tragedy.

Additional studies concerning the metabolism of packed erythrocytes in CPD adenine.

Studies concerning the relationship between glucose level, hematocrit to which cells were packed (within three hours of initial collection) and adenosine triphosphate (ATP) concentration were undertaken in CPD supplemented with adenine (0.25 mM final concentration). It was found that apparently adequate ATP levels could be maintained in 90 per cent hematocrit packed units at 42 days only if glucose was present in amounts 1.5 times or greater than that provided by CPD. Less tight packing of the units to 70 and 80 per cent hematocrit maintained ATP at greater than 50 per cent of the initial level for a full 42 days of storage when 1.25 times the usual glucose concentration was present in the initial anticoagulant. No difference in 2,3-diphosphoglycerate or pH was found in any of the modified media under study.

Computer-assisted audiovisual health history self-interviewing. Results of the pilot study of the Hoxworth Quality Donor System.

BACKGROUND: The safety of blood for transfusion depends, in part, on the reliability of the health history given by volunteer blood donors. To improve reliability, a pilot study evaluated the use of an interactive computer-based audiovisual donor interviewing system at a typical midwestern blood center in the United States. STUDY DESIGN AND METHODS: An interactive video screening system was tested in a community donor center environment on 395 volunteer blood donors. Of the donors using the system, 277 completed surveys regarding their acceptance of and opinions about the system. RESULTS: The study showed that an interactive computer-based audiovisual donor screening system was an effective means of conducting the donor health history. The majority of donors found the system understandable and favored the system over a face-to-face interview. Further, most donors indicated that they would be more likely to return if they were to be screened by such a system. CONCLUSION: Interactive computer-based audiovisual blood donor screening is useful and well accepted by donors; it may prevent a majority of errors and accidents that are reportable to the FDA; and it may contribute to increased safety and availability of the blood supply.

A review of recent events related to surrogate testing of blood to prevent non-A, non-B posttransfusion hepatitis.

A workshop sponsored by the Food and Drug Administration was held recently during which available data were reviewed concerning surrogate testing of blood donated for transfusion in order to reduce the risks of posttransfusion non-A, non-B hepatitis. Clinical studies from which the efficacy of testing for alanine aminotransferase and antibody to hepatitis B core antigen (anti-HBc) could be predicted indicated such testing would be useful, although several studies using tests for anti-HBc developed recently questioned their effectiveness. Different approaches to establishing the cut-off values for the screening tests were presented and difficulties regarding test standardization were discussed. The legal, ethical, and medical implications for donors of surrogate screening programs in the United States also were considered. A meeting sponsored by the private sector that included representatives of the major blood banking organizations and was convened to discuss the workshop proceedings and nationwide screening of the blood supply also is summarized.

Total and partial blood exchange in the rat with hemoglobin prepared by crystallization.

Hemoglobin, prepared by crystallization, has been used as a blood substitute in total (91 to 93%) and partial (70 to 76%) blood replacement studies. Exchange transfusions have been carried out in laboratory animals to a total blood replacement of 91 to 93 per cent with hemoglobin or with albumin solutions. When albumin was used, all animals died at approximately ten minutes after transfusion was completed, whereas all animals transfused with hemoglobin survived for five hours and displayed normal activity during this time. In these studies the plasma half-disappearance time of hemoglobin was 3.5 hours and body distribution of 51Cr-labeled hemoglobin, as a percentage of initial levels, has shown six per cent in the kidney, six per cent in the liver, 10.5 per cent in the marrow and 13 to 14 per cent in the urine at three hours after transfusion. Survival was obtained with all animals transfused with hemoglobin or albumin solutions to a partial blood replacement of 70 to 76 per cent. However, the oxygen capacity of the circulating fluid in the hemoglobin transfused animals was about three times greater than that found in the corresponding albumin-transfused controls. Values of hemoglobin, hematocrit, platelets, and P50 returned to normal pretransfusion levels within five to seven days.

Morphologic effects following massive exchange transfusions with a stroma-free hemoglobin solution. I. Liver.

Hepatic morphology was studied in rats that were exchange transfused with either a stroma-free hemoglobin solution (SFHS) or with various asanguineous resuscitative fluids. The animals under-went 75 per cent blood volume replacement and tissues were collected and fixed at timed intervals after the exchange transfusion. In addition, blood volumes were determined, using chromium labeled red blood cells, in both albumin and SFHS-treated rats at varying time periods after exchange transfusion. One hour following exchange transfusion, livers of animals infused with asanguineous fluids demonstrated marked centrolobular hepatocellular vacuolization and mitochondrial shape alterations consistent with the effects of hypoxia. SFHS appeared to protect the liver from these early abnormalities. However, at later time intervals livers of albumin-treated animals appeared normal, whereas those of SFHS-transfused rats exhibited centrolobular necrosis. Blood volume was reduced approximately 10 per cent during the first 18 hours after exchange transfusion with albumin, while SFHS-treated rats experienced a 42 per cent blood volume decrement in only 6 hours. Blood volumes were near normal in all animals by 48 hours. These findings suggest that SFHS protects the liver from hypoxia immediately after exchange transfusion, presumably by its ability to transport and release oxygen. However, the eventual disappearance of hemoglobin from the intravascular space is associated with a marked reduction in blood volume which is accompanied by hepatic ischemia and centrolobular necrosis.

Evaluation of the safety of Rh immunoglobulin by monitoring viral markers among Rh-negative female blood donors.

BACKGROUND AND OBJECTIVES: Although immunoglobulin (Ig) preparations including RhIg have been noted for their record of safety, recent reports of hepatitis C virus (HCV) transmission by some Ig preparations have raised concern. This analysis examined the safety of RhIg manufactured in the US by comparing the prevalence and incidence of viral markers in Rh-negative and Rh-positive female blood donors. MATERIALS AND METHODS: Demographic and viral marker data were analyzed for allogeneic donations collected from female donors of childbearing age (17-49 years of age) from April 1992 to May 1996. Prevalence and incidence rates were calculated for HCV, human immunodeficiency virus (HIV), and hepatitis B surface antigen (HBsAg). RESULTS: Of the 624,939 female donors included in the study, 96,355 (15.4%) were Rh-negative and 528,584 (84.6%) Rh-positive. There were no significant differences in the prevalence of HCV and HIV between Rh-negative and Rh-positive female donors. HBsAg prevalence was significantly higher among non-white compared to white donors. Following implementation of the more sensitive EIA 2.0 screening test for HCV in April 1992, prevalence and incidence rates declined over time at similar rates for Rh-negative and Rh-positive female donors. CONCLUSIONS: Rh-negative female donors had similar prevalence and incidence rates for most viral markers compared to Rh-positive female donors. This analysis supports the historical safety of RhIg.

Blood preservation. XXVIII. Galactose and maltose maintain red blood cell 2,3-DPG and ATP.

Because there may be inadequate dextrose in the newly licensed CPD-adenine for five or six weeks storage of high hematocrit red blood cells, this laboratory has examined some alternate sugars for their ability to maintain red blood cell metabolism during storage. In the current study, dextrose and fructose were studied as model or prototype nutrients. A third six carbon monosacharide, galactose, three dissacharides, lactose, maltose, and sucrose were studied in the same experiment. Of these, fructose best maintained ATP and 2,3-DPG during the fourth to sixth week of whole blood storage at 4 C. Dextrose was next best during this time and was nearly equivalent to fructose in the first three weeks of storage. Galactose and maltose both maintained ATP and 2,3-DPG, but not nearly so well as did fructose and dextrose. Sucrose and lactose were associated with the most rapid deterioration of ATP and DPG levels and they failed to maintain the progressive fall in pH which is usually associated with continuing, useful metabolism.