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Blood groups have been known to exist for centuries ever since man entertained the possibility of replacing blood loss through transfusion. They are responsible for determining compatibility of blood in transfusion medicine and are also responsible for fetal loss in hemolytic disease affecting the fetus or newborn. Blood groups are inherited as Mendelian codominant traits and should be expected to occur in somewhat comparable frequencies in the human race [1]. However, differences do exist in the distribution of blood groups in various human populations. This has been largely attributed to selection pressure as endemic diseases appear to have a predilection for selected blood groups leading to the demise of individuals bearing those susceptible blood group antigens. But certainly, there must be more to blood groups than just causing problems in blood transfusion and predisposing to myriad self-annihilation prospects.

Anemia is an important clinical problem in patients with HIV infection and those with AIDS. In 1998, the Anemia in HIV Working Group issued a consensus statement addressing the impact of anemia on HIV-infected individuals, as well as treatment strategies and future research directions [2]. The Anemia in HIV Working Group reconvened in 2002 to evaluate recently available data and to determine the implications of those data for patient management.

The consensus statement that follows is based on evidence in the published literature, clinical experience, and the expert opinion of the panel. The chairpersons selected panelists from among the participants in the 1998 Anemia in HIV Working Group meeting and other experts who are involved in HIV study and who specialize in the hematological complications of the disease.

Future research should focus on furthering understanding of the causes of anemia, its long-term consequences and prognostic importance, the impact of various HAART regimens on the prevalence of anemia, and optimal dosing strategies for the use of epoetin alfa in special populations. Emerging data suggest that epoetin alfa has effects beyond erythropoiesis [3]. There is evidence, for example, that epoetin alfa has antiapoptotic effects in multiple cell lines, which may have a positive impact on the immunologic response in patients with HIV infection. Moreover, in animal studies, epoetin alfa has been shown to cross the blood-brain barrier and to protect neurons and astrocytes from injury. A recent pilot study of patients demonstrated benefit in acute ischemic stroke, with an improvement in clinical outcome at 1 month. It is thus conceivable that epoetin alfa may one day prove useful in the treatment of neurologic conditions, including stroke and cognitive dysfunction [4].

Cost-benefit analyses are needed to determine the impact of treatment of anemia in HIV-infected patients with epoetin alfa and/ or alternative therapies. Factors involved in cost-benefit studies should include identification of the predictors of a response to therapy, determination of optimal doses and schedule of treatment, calculation of the associated costs of treatment, and consideration of any effects of therapy on the natural history of HIV infection.

Blood Group Disease Associations On the pathological front, however, certain blood groups have been associated with diseases. Individuals of blood group A, for example, are known to be more susceptible to coronary heart disease (CHD) independent of known risk factors than other ABO blood groups. This is further corroborated by the observation that group A individuals also have higher levels of low density lipoprotein (LDL) cholesterol. Although the molecular aspects of this observation still remain to be elucidated, the observation implies that, this antigen has potential to either influence synthesis or inhibit the natural metabolism of these lipids, thus, predisposing individuals to CHD. The same study, on the other hand, reported a lower risk for this condition among group O individuals. Additionally, blood group A and B are known to be highly susceptible to thrombotic disorders in contrast to group O individuals who are more at risk for bleeding than thrombotic events [5]. This observation has been attributed to higher levels of Factor VIII and von Willebrand factor in A and B individuals, while the levels may be as low as 30% in group O individuals. Blood groups A and B antigens have been demonstrated on these coagulation molecules and are thought to prolong their half-life, leading to higher concentration in non-O individuals. Blood group A has also been associated with malignancies such as cancer of the ovary, cervix, rectum, breast, and stomach and leukemia. This is thought to be due to an abundance of high-affinity binding sites for epidermal growth factor (EGF) on blood group A red blood cells compared to blood groups O and B. Since blood groups may be expressed on tissues other than red cells, it is plausible that the binding of EGF to these binding sites may indeed promote cancer development. Conversely, some malignancies have been observed to positively or negatively modulate blood group antigen expression to varying degrees depending on the anatomical site [6].

Blood groups in HIV and other viral infections

HIV infection has been reported to occur in select blood groups in some regions of the world. A study by Sayal et al. in India reported preponderance for infection in group O Rh (D)-positive men and least among groups B positive and D-negative ones. However, a close examination of the results reveals insufficient statistical analysis rendering the differences statistically insignificant. A statistical interrogation of the data in each of the above case does not support the conclusion of statistical significance [7]. It would then appear that current scientific information does not support a potential role for ABO blood groups in HIV infection. In fact, evidence from other studies would suggest the contrary for group O individuals. Since HIV virions have been shown to acquire the blood group antigens of the infected individuals, such virions would be neutralized by naturallyoccurring antibodies in group O individuals, thus offering protection in blood group-discordant couples. It is noted, however, that this protection will not be available if the source of infection was of a similar blood group. Moreover, given the apparently uniform risk of infection among ABO blood groups, it is doubtful if this neutralization is of any clinical consequence, especially with reference to HIV-1 infection. It remains to be demonstrated then whether HIV from blood group A or B is able to infect group O CD4 cells [8].

The lack of direct empirical evidence for ABO blood groups does not; obliterate the possibility of associations in other blood groups. Since secreted blood group substances can be adsorbed onto lymphocyte membranes, the presence of these antigens could potentially alter cell behavior. Blood group antigens, being glycoproteins and glycolipids, are highly charged molecules that are bound to affect their molecular microenvironment, including protein conformation and receptor/CD4 localization and function. Glycosphingolipids and glycoproteins have in fact been demonstrated to facilitate fusion of HIV-1 with CD4 cells by independent investigators, thus, acting as alternative co-receptors for the virus [9]. There exists a theoretical possibility, therefore, that membrane-bound blood group substances on CD4-positive cells may thus affect the affinity of viral-binding proteins and viral infectivity, promoting or diminishing cell susceptibility to infection. Apparently, both the promotive and inhibitory effects of blood groups in HIV infection have been documented. The Duffy antigen receptor for chemokines (DARC) has been reported as a binding site for HIV-1 on red blood cells, which binding increases infectivity for permissive cells. Although some investigators have refuted the role of this antigen in HIV-1 infection, the preponderance of evidence is heavily in favor of this role, including recent findings of sequence similarities between HIV-1 V3 loop and the Plasmodium vivax Duffy binding protein, both of which bind to DARC [10].

Anemia Anaemia is the most important prognostic indicator in AIDS patients. A large-scale study involving over 4000 patients established an increasing hazard ratio of 1.42, 2.56, and 5.26 for mild, moderate, and severe anaemia, respectively. Various mechanisms have been suggested, including bone marrow suppression by various cytokines, toxic depletion by the virus, and immune destruction following sensitization with viral proteins. However, the degree of anaemia has not been correlated with the amount of erythrocyte-bound HIV, a phenomenon that might account for the autoimmune haemolytic anaemia that commonly occurs in HIV-infected individuals. Of interest is the observation by Martins-Silva et al. that HIV infection alters red cell and lymphocyte membrane fluidity and membrane protein activity and brings about changes in transmembrane calcium transportation. These changes may disrupt erythrocyte membrane stability, thus, promoting haemolysis and ultimately anaemia [11]. Blood group antigens have also been reported to occur on trans-membrane transport channels. These transport channels have an influence on membrane structure and integrity and HIV binding to these transport channels may explain some of the mechanisms that contribute to membrane instability with consequent haemolysis and cytopaenias in HIV patients. Binding of R5 viruses to CCR5, for example, has been shown to elicit phospholipase C production. Furthermore, others have reported that phospholipase C is translocated to the periphery of activated natural killer (NK) cells with possible role in cell-mediated cytotoxicity. However, the role of this enzyme in haemolytic processes in HIV patients remains a matter for further enquiry [12].

Conclusions

Beyond their well-known role in oxygen transportation, red blood cells have demonstrated their significance in enhancing or preventing various diseases, including HIV infection. While RBCs can facilitate HIV infection through receptor binding and immune cell interactions, they can also serve as mechanical barriers and competitively bind to the virus, preventing its spread. Additionally, RBCs play crucial roles in defending against malaria and ensuring adequate oxygen delivery in cardiovascular diseases. Further research in this field is essential for a comprehensive understanding of RBCs' multifaceted roles and their potential implications for disease prevention and treatment.

Despite use of lower dosages of zidovudine and the introduction of HAART, mild-to-moderate anemia still occurs in a substantial portion of HIV-infected persons and is associated with increased mortality, increased disease progression, and reduced quality of life. Female sex, African American race, medications used for treatment of HIV infection, high HIV-RNA levels, and low CD4 cell count are risk factors for the development of anemia in HIV-infected persons. The Anemia in HIV Working Group agreed that guidelines for the treatment of anemia should be updated.

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