The ABO blood group, as the blood types are collectively known, are ancient. Humans and all other apes share this trait, inheriting these blood types from a common ancestor at least 20 million years ago and maybe even earlier, claims a new study published online today in Proceedings of the National Academy of Sciences.
But why humans and apes have these blood types is still a scientific mystery. Through a series of experiments, Landsteiner classified blood into the four well-known types. An antigen is anything that elicits a response from an immune cell called an antibody.
Antibodies latch onto foreign substances that enter the body, such as bacteria and viruses, and clump them together for removal by other parts of the immune system. The human body naturally makes antibodies that will attack certain types of red-blood-cell antigens. For example, people with type A blood have A antigens on their red blood cells and make antibodies that attack B antigens; people with type B blood have B antigens on their red blood cells and make antibodies that attack A antigens.
This is hard to keep track of, so I hope the chart below helps! There is a strong argument to be made that stored RBCs have decreased function after transfusion. Similarly, some patients undergo massive transfusion protocols in which essentially every circulating RBC was recently transfused. The observation that such patients live indicates that stored RBCs do have at least some function posttransfusion.
Finally, chronically anemic patients and those requiring hematological support during reconstitution after BM transplantation do not survive in the absence of transfusion. However, such observations do not indicate that stored blood cells function optimally or even well , especially in the early times after transfusion.
It is also worth noting that even if the transfused blood cells were functioning optimally, this does not necessitate that transfusions would have a positive effect upon medical outcome in a variety of settings in which the indication for transfusion itself is questioned. In aggregate, it seems that current storage technologies allow the transfusion of blood cells that retain some of their native function. That having been noted, it is likewise true that the current metrics by which we measure RBC storage quality do not include the ability to deliver oxygen or regulate vascular tone.
Rather, circulation without any measure of function is the current in vivo criterion that is used. Therefore, as ongoing efforts are made to characterize and improve blood storage conditions, the field must remain mindful of the disconnect between what is measured as metrics of quality and the in vivo function that we are seeking to introduce with transfusion. Several highly provocative retrospective studies have reported that transfusing older RBC units results in significantly worse medical outcomes compared with transfusing fresher RBC units.
However, careful analysis of the literature has also revealed a substantial number of retrospective studies indicating no difference between fresh and old blood, and even some indicating that older blood is safer than younger blood. Ongoing randomized controlled trials testing effects of RBCs stored for longer versus shorter periods of time.
It has been noted that, due to the substantial number of transfusions annually 1 of every 70 Americans , even small effects on medical outcome will have a substantial impact. In this context, it has been argued that the statistical power of the ongoing prospective trials, while sufficient to test larger effects, may miss smaller differences that would be medically meaningful. The field is eagerly awaiting the outcome of the ongoing trials. However, what is clear is that in the standard of practice for transfusing premature infants, no effect of RBC storage age was detected.
Although the potential toxicities and sequelae of transfused RBCs remain controversial, it has been unequivocally demonstrated that a distinct series of biochemical changes occur during storage that gives rise to a litany of chemical and cellular entities known to have biological activities in other contexts. It is thus reasonable to predict that such entities will have effects upon transfusion recipients. Of course, reason does not always predict what is empirically observed, but the extensive experimental evidence on these changes is one driving force behind the strength of opinion that stored RBCs are problematic.
These substances can be divided into several different categories. Free hemoglobin from in-bag hemolysis can scavenge NO, which may increase vascular tone by depriving blood vessels of the NO required to relax appropriately. In addition to NO pathways, it has been documented that stored blood products accumulate leukotrienes, which can likewise affect vascular tone in complicated ways. It has been reported in both mice and dogs that transfusion of stored but not fresh RBCs results in recipients having systemic inflammatory cytokine release.
However, equally consistent with the data are the hypotheses that multiple units must be given and that the effect would be augmented in sick patients with baseline innate immune activation.
Recent studies lend some support to this latter notion in patients experiencing trauma. In addition to inducing cytokines in mice and dogs, transfusion of older units of RBCs resulted in plasma factors that support the growth of ferrophilic bacteria in either mice or human specimens. These findings coincided with findings indicating hemolysis in vivo, such as increased NO consumption and decreased haptoglobin.
The above findings and reports are generating a body of evidence implicating older RBCs in systemic inflammation and the potential promotion of bacterial infection in nonhuman animal models. It has been reported that stored RBCs acquire procoagulant activities. Although provocative, the results of these in vitro studies have yet to be transitioned into in vivo observations.
One of the effects upon exposure of proteins to glucose is a reaction between the aldehyde group of glucose with free amino groups, leading to a Schiff base that rearranges into a series of advanced glycation end AGE products, including carboxy-methyl-lysine. Additional chemistries, including cross-linking of glycans, proceed from this point. Overall, AGEs constitute a complex class of molecular glycation with diverse structures.
There are several receptors that have been described with the capacity to recognize AGEs of different composition. Most notably is the receptor for advanced glycation end products RAGE. RAGE plays an active role in inflammation and innate immune activation. Because RBCs are stored in supraphysiological levels of glucose, it has been hypothesized that AGEs would be increased as a result of storage.
Indeed, it has been reported that stored RBCs have increased AGEs ie, carboxy-methyl-lysine and that they are capable of ligating RAGE, leading to alterations of cultured endothelial cells. It seems clear, or at least very likely, that retrospective approaches have been used to their fullest benefit. The result of combined analyses of retrospective findings leads to a murky view with an equivocal outcome.
Accordingly, ongoing analysis must involve prospective trials. However, for such a prospective trial to be meaningful, it is necessary to ask the correct questions and collect the appropriate data. Above all else, it is essential to frame the hypotheses in a fashion that is amenable to being tested and susceptible to rejection. Of course, the more generalizable knowledge is, the more useful it is. However, the more generalized a hypothesis, the more one risks oversimplifying complex landscapes.
The result can lead to questions that are essentially meaningless in substance and impossible to answer. Blood transfusions are given for a wide number of different indications. The physiological effects of exposure to the biochemical changes that occur in a stored blood product may be vastly different depending upon the pathophysiology of the transfusion recipient. Some retrospective trials have looked at all hospitalized patients who were transfused within a defined period of time and juxtaposed generalized markers of medical outcome between groups of patients receiving RBCs of different storage times.
However, other retrospective trials are certainly more focused and prospective trials are inevitably so due to the need to limit sample size as a practical matter. Nevertheless, even in the narrower context, the problem persists.
Consider a trial that is focused on patients in a particular category of disease eg, trauma patients arriving at the emergency department, patients with sickle cell disease, patients admitted to the intensive care unit, patients undergoing cardiac surgery, etc. Even within these definitions, which are clearly narrower than generalized populations, there is a distinct heterogeneity of recipient pathology that may alter the effects of stored blood transfusion.
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