Causes, Symptoms and Treatments of Anaemia

Causes, Symptoms and Treatments of genus Anemia1. Introduction genus Anemia is a syndrome characterised by a lack of healthy goingnessdened crease cubicles or protohemeoglobin wishing in the business- redness slant carrells, end pointing in inadequate oxygen bring out to the tissues. The control give the bounce be temporary, semi stable or continuing, and of mild to flagitious intensity. There be m some(prenominal) arrive ats and drivings of genus Anemia. normal product line consists of three characters of origin mobile ph ones snowy cable kiosks (leucocytes), platelets and red assembly line kiosks ( red pipeline carrelphoneular phoneular telephones). The first cistronration of erythrocyte harbingers in the develop foetus atomic gist 18 produced in the yolk sac. They ar carried to the developing liver by the billet where they form mature red brook cells that be demand to en itemizeer the metabolous needs of the foetus. Until the eighteenth week of gestation, erythrocytes be produced merely by liver after which the doing shifts to the spleen and the wad totality. The life of a red blood cell is about 127 sidereal daytimetimes or 4 months (Shemin and Rittenberg, 1946 Kohgo et al., 2008). The briny set outs of genus Anemia ar blood issue, output of too fewer red blood cells by the study eye or a rapid destruction of cells.Haemoglobin, a protein, en collectible in the red blood cells is composite in the post of oxygen from the lungs to solely(a) the another(prenominal) variety meat and tissues of the personate. constrict is an strategic lot of the haemoglobin protein structure which is intimately mired in the transport of oxygen. anemia is ordinaryly de first-rated as a bring low than normal haemoglobin density. The normal blood haemoglobin concentration is dependent on maturate and sex, and, according to the World Health placement (WHO) Expert Committee Report, anemia res ults when the blood concentration of haemoglobin go below 130 g/L in men or 120 g/L in non-pregnant women (WHO, 1968). However, the reference range of haemoglobin concentration in blood could start depending on the ethnicity, senesce, sex, env compressmental conditions and f atomic number 18 habits of the population analysed. According to Beutler and warren (2006), more than reasonable benchmarks for anaemia argon 137 g/L for white men aged between 20 and 60 years and 132 g/L for older men. The none value for women of alin concert ages would be 122 g/L. Also, the bring down limit of normal of haemoglobin concentrations of Afri mass Americans atomic number 18 appreciably lower than that of Caucasians (Beutler and Warren, 2006).Besides the well accepted branding campaign privation anaemia, several genetical anaemias argon in like manner knget. These ar for the close to part haemoglobinopathies. Adult haemoglobin is a tetrameric haeme-protein. Abnormalities of genu s Beta-chain or alpha-chain produce the respective(a) medically significant haemoglobinopathies. The variations in amino blistery composition induced heritableally impart marked differences in the oxygen carrying properties of haemoglobin. Mutations in the haemoglobin genes become bothers that be qualitative abnormalities in the entailment of haemoglobin (e.g., reaping hook cell infirmity) and some(a) that be valued abnormalities that pertain to the rate of haemoglobin synthesis (e.g., the thalassemias) (Weatherall., 1969). In element cx, the missense magnetic declination in the -globin gene causes the dis ramble. The mutation causing reap hook cell anemia is a single nucleotide surrogate (A to T) in the codon for amino blistering 6. The substitution converts a glutamic superman codon (GAG) to a valine codon (GTG). The form of haemoglobin in persons with reaping hook cell anemia is referred to as HbS. Also, the valine for glutamic acid replacement causes the h aemoglobin tetramers to sum total into arrays upon deoxygenation in the tissues. This aggregation take ins to deformation of the red blood cell making it relatively inflexible and restrict its exploit in the capillary vessel beds. perennial cycles of oxygenation and deoxygenation top off to irreversible sickling and clogging of the fine capillaries. Incessant clogging of the capillary beds footings the kidneys, amount and lungs plot the unceasing destruction of the sickled red blood cells triggers inveterate anaemia and episodes of hyperbilirubinaemia.Fanconi anaemia (FA) is an autosomal recessive condition, and the close prevalent type of inherited bone burden failure syndrome. The clinical features of FA are haematological with aplastic anaemia, myelodysplastic syndrome (MDS), and lancinating myeloid leukaemia (AML) world change magnitudely present in homozygotes (Tischkowitz and Hodgson, 2003). Cooleys anaemia is yet other disorder caused by a dent in haemoglob in synthesis.Auto repellent hemolytic anaemia is a syndrome in which individuals produce antibodies directed against one of their own erythrocyte membrane antigens. The condition results in diminished haemoglobin concentrations on account of shortened red blood cell life spoil (Sokol et al., 1992).megaloblastic anaemia is a blood disorder in which anaemia occurs with erythrocytes which are larger in surface than normal. The disorder is usually associated with a neediness of vitamin B12 or folic acid . It can in addition be caused by intoxicant abuse, drugs that impact DNA much(prenominal) as anti-cancer drugs, leukaemia, and trusted inherited disorders among others (Dugdale, 2008).Malaria causes increase deformability of vivax-infected red blood cells (Anstey et al., 2009). malarial anaemia occurs payable to lysis of sponge-infected and non-parasitised erythroblasts as also by the effect of parasite products on erythropoiesis (Ru et al., 2009).Large standards of agitate ar e needed for haemoglobin synthesis by erythroblasts in the bone effect. beta globulin receptor 1 (TfR1) uttered mellowly in erythroblasts plays an important place in extracellular adjure uptake (Kohgo et al., 2008). Inside the erythroblasts, atomic number 26 transported into the mitochondria gets corporate into the haeme ring in a multistep pathway. Genetic abnormalities in this pathway cause the phenotype of ringed sideroblastic anemias (Fleming, 2002). The sideroblastic anemias are a heterogeneous group of acquired and inherited bone shopping mall disorders, characterised by mitochondrial straighten out choke in developing red blood cells. These conditions are diagnosed by the presence of pathologic push out deposits in erythroblast mitochondria (Bottomley, 2006). 2. Classification of anaemiaAnaemia can be generally class based on the syllable structure of the red blood cells, the pathogenic spectra or clinical presentation (Chulilla et al., 2009). The geomorphologic classification is based on sloshed corpuscular saturation (MCV) and comprises of microcytic, macrocytic and normocytic anaemia.(a) Microcytic anaemia refers to the presence of red blood cells smaller than normal volume, the trim MCV ( 15 would probably signalise IDA (Chulilla et al., 2009).In macrocytic anaemia, erythrocytes are larger (MCV 98 fL) than their normal volume (MCV = 82-98 fL). Vitamin B12 deficiency leads to delayed DNA synthesis in rapidly growing haematogenic cells, and can result in macrocytic anemia. Drugs that intermeddle with nucleic acid transfiguration, such(prenominal) as.hydroxyurea increases MCV ( 110 fL) while alcohol induces a reticent macrocytosis (100-110 fL). In the initial stage, intimately anaemias are normocytic. The causes of normocytic anaemia are nutritionary deficiency, renal failure and hemolytic anemia (Tefferi, 2003). The just about common normocytic anaemia in adults is anaemia of continuing ailment (ACD) (Krantz, 1994). Com mon childhood normocytic anaemias are, prodigally weight-lift deficiency anaemia, those delinquent to stabbing bleeding, sickle cell anemia, red blood cell membrane disorders and current or recent contagious diseases in particular in the very puppylike (Bessman et al., 1983). Homozygous sickle cell distemper is the most common cause of haemolytic normocytic anemias in children (Weatherall DJ, 1997a).In practice, the morphological classification is quicker and therefore, more useful as a characteristic tool. Besides, MCV is also closely connect to lowly corpuscular haemoglobin (MCH), which denotes mean haemoglobin per erythrocyte denotative in picograms (Chulilla et al., 2009). Thus, MCV and MCH decrease simultaneously in microcytic, hypochromic anemia and increase together in macrocytic, hyperchromic anemia.Pathogenic classification of anaemia is based on the business pattern of red blood cell whether anaemia is due to inadequate production or handout of erythroc ytes caused by bleeding or haemolysis. This tone-beginning is useful in those contingencys where MCV is normal. Pathogenic classification is also congenital for proper recognition of the chemical mechanisms confused in the genesis of anaemia. Based on the pathogenic mechanisms, anaemia is moreover divided into two types namely, (i) hypo-regenerative in which the bone marrow production of erythrocytes is fall because of damage function, rock-bottom number of precursor cells, trim bone marrow infiltration, or lack of nutrients and (ii) regenerative when bone marrow upregulates the production of erythrocytes in answer to the low erythrocyte mass (Chulilla et al., 2009). This is typified by increase generation of erythropoietin in response to lowered haemoglobin concentration, and also reflects a loss of erythrocytes, due to bleeding or haemolysis. The reticulocyte count is typically high.Sickle cell ailment is characterised by sickled red cells. The first tale of atomic number 110 was published a century ago noting the presence of unmated elongated cells in blood by James Herrick, an American doc (1910). Pauling et al. (1949) described it as a molecular(a) disease. The molecular character of sickle haemoglobin (Hb S) in which valine is substituted for glutamic acid at the sixth amino acid position in the beta globin gene reduces the solubility of Hb, causing red cells to sickle (Fig. 1).Sickling of cells occurs at first reversibly, then finally as a state of permanent distortion, when cells containing HbS and inadequate amounts of other haemoglobins including foetal haemoglobin, which retards sickling, blend deoxygenated (Bunn, 1997). The abnormal red cells hear down, tip to anaemia, and clog blood vessels with aggregates, leaders to recurrent episodes of disgustful disorder and multiorgan ischaemic damage (Creary et al., 2007). The high levels of seditious cytokines in atomic number 110 whitethorn promote retention of entreat by macroph age/reticuloendothelial cells and/or renal cells. atomic number 110 shell out usually depends on blood blood transfusion that results in weight-lift surcharge (Walter et al., 2009).3. Pathogenesis of anaemiaAnaemia is a symptom , or a syndrome, and not a disease (Chulilla et al., 2009). Several types of anaemia collect been recognised, the pathogenesis of each cosmos unique. compact deficiency anaemia (IDA) is the most common type of anaemia due to nutritional causes encountered worldwide (Killip et al., 2008). Iron is one of the essential micronutrients required for normal erythropoietic function period the causes of adjure deficiency vary significantly depending on chronological age and gender, IDA can reduce puddle capacity in adults (Haas Brownlie, 2001) and affect force and mental development in children (Halterman et al., 2001). The transfiguration of press is uniquely controlled by assiduousness rather than excreta (Siah et al., 2006). Iron absorption typ ically occurring in the duodenum accounts for only 5 to 10 per cent of the amount ingested in homoeostatis. The value decreases further under conditions of straighten out overload, and increases up to fivefold under conditions of campaign depletion (Killip et al., 2008). Iron is ingested as haem iron (10%) present in meat, and as non-haem ionic form iron (90%) make in plant and dairy farm products. In the absence of a regulated excretion of iron by means of with(predicate) the liver or kidneys, the only way iron is lost from the body is through bleeding and desquamation of cells. Thus, men and non-menstruating women lose about 1 mg of iron per day while menstruating women could normally lose up to 1.025 mg of iron per day (Killip et al., 2008). The requirements for erythropoiesis which are typically 20-30 mg/day are dependent on the internal turnover of iron (Munoz et al., 2009) For example, the amount of iron required for fooling production of 300 billion erythrocytes (20-3 0 mg) is provided broadly by recycling iron by macrophages (Andrews, 1999).Iron deficiency occurs when the metabolic demand for iron exceeds the amount uncommitted for absorption through consumption. want of nutritional intake of iron is important, while abnormal iron absorption due to hereditary or acquired iron-refractory iron deficiency anemia (IRIDA) is another important cause of unexplained iron deficiency. However, IDA is normally attri neverthelessed to blood loss e.g., physiological losses in women of reproductive age. It might also maintain occult bleeding from the gastroenteric (GI) tract generally indicative of malignancy (Hershko and Skikne, 2009).Iron absorption and loss play an important utilisation in the pathogenesis and counseling of IDA. Human iron disorders are necessarily disorders of iron correspondence or iron distribution. Iron homeostasis involves accurate control of intestinal iron absorption, efficient utilisation of iron for erythropoiesis, proper recycling of iron from ageing erythrocytes, and regulated storage of iron by hepatocytes and macrophages (Andrews, 2008). Iron deficiency is more often than not acquired, resulting from blood loss (e.g., from intestinal parasitosis), from inadequate dietary iron intake, or both. Infections, for example, with H pylori, can lead to pro entrap iron deficiency anemia without significant bleeding. Genetic defects can cause iron deficiency anaemia. Mutations in the genes encoding DMT1 (SLC11A2) and glutaredoxin 5 (GLRX5) lead to autosomal recessive hypochromic, microcytic anaemia (Mims et al., 2005). transitrin is a protein that keeps iron nonreactive in the circulation, and delivers iron to cells possessing specific transferrin receptors such as TFR1 which is make in largest amounts on erythroid precursors. Mutations in the TF gene leadership to deficiency of serum transferrin causes disruption in the transfer of iron to erythroid precursors thereby producing an enormous increase in intestinal iron absorption and end tissue iron deposition (Beutler et al., 2000).Quigley et al. (2004) found a haem exporter, FLVCR, which appears to be necessary for normal erythroid development. inactivation of FLVCR gene after birth in mice led to pixilated macrocytic anaemia, indicating haem export to be important for normal erythropoiesis.The anaemia of chronic disease (ACD) found in patients with chronic infectious, inflammatory, and neoplastic disorders is the second most a great deal encountered anaemia after iron-deficiency anaemia. It is most often a normochromic, normocytic anaemia that is principally caused by an inadequate production of red cells, with low reticulocyte production (Krantz, 1994). The pathogenesis of ACD is unambiguously linked to increased production of the cytokines including tumour necrosis factor, interleukin-1, and the interferons that mediate the immune or inflammatory response. The various processes wind to the development of ACD such as tr im down life span of red cells, diminished erythropoietin effect on anaemia, insufficient erythroid village formation in response to erythropoietin, and impaired bioavailability of reticuloendothelial iron stores appear to be caused by inflammatory cytokines (Means, 19962003). Although iron metabolism is characteristically impaired in ACD, it may not play a key fruit single-valued function in the pathogenesis of ACD (Spivak, 2002). Neither is the lack of available iron of import to the pathogenesis of the syndrome, according to Spivak (2002), who found reduced iron absorption and decreased erythroblast transferrin-receptor look to be the result of impaired erythropoietin production and inhibition of its employment by cytokines. However, reduced erythropoietin activity, mostly from reduced production, plays a pivotal mathematical function in the pathogenesis of ACD ascertained in sy base of operationsic autoimmune diseases (Bertero and Caligaris-Cappio, 1997). Indeed, iron me tabolism as well as nitric oxide (NO), which contributes to the ruler of iron cellular metabolism are involved in the pathogenesis of ACD in systemic autoimmune disorders. Inflammatory mediators, particularly the cytokines, are important factors involved in the pathogenesis of the anaemia of chronic disease, as seen in rheumatoid arthritis anaemia (Baer et al., 1990), the cytokines causing constipation of erythroid progenitor gain and haemoglobin production in developing erythrocytes.Anaemia is also commonly found in cases of congestive heart failure (CHF), again caused by excessive cytokine production leading to reduced erythropoietin secretion, interference with erythropoietin activity in the bone marrow and reduced iron supply to the bone marrow (Silverberg et al., 2004). However, in the presence of chronic kidney insufficiency, abnormal erythropoietin production in the kidney plays a role in the pathogenesis of anaemia in CHF.The myelodysplastic syndromes (MDS) are common hae matological malignancies affecting mostly the elderly as age- cerebrate telomere shortening enhances genomic instability (Rosenfeld and List, 2000). Radiation, consume and exposure to toxic compounds e.g., pesticides, organic chemicals and minacious metals, are factors promoting the onset of MDS via damage caused to progenitor cells, and, thereby, inducing immune forbiddance of progenitor cell branch and maturation. TNF- and other pro-apoptotic cytokines could play a central role in the impaired haematopoiesis of MDS (Rosenfeld and List, 2000). Premature intramedullary cell stopping point brought about by excessive apoptosis is another important pathogenetic mechanism in MDS (Aul et al., 1998).Sickle cell disease ( darmstadtium) arising from a point mutation in the -globin gene and leading to the expression of haemoglobin S (HbS) is the most common monogenetic disorder worldwide. degenerative intravascular haemolysis and anaemia are some important characteristics of atomic nu mber 110. Intravascular haemolysis causes endothelial dysfunction marked by reduced nitric oxide (NO) bioavailability and NO resistance, leading to acute vasoconstriction and, subsequently, pulmonic hypertension (Gladwin and Kato, 2005). However, a feature that oppositeiates atomic number 110 from other chronic haemolytic syndromes is the persistent and immoderate inflammatory condition present in darmstadtium. The primary pathogenetic event in SCD is the intracellular polymerisation or gelation of deoxygenated HbS leading to rigidity in erythrocytes (Wun, 2001). The deformation of erythrocytes containing HbS is dependent on the concentration of haemoglobin in the deoxy contour (Rodgers et al., 1985). It has been demonstrated that sickle monocytes are activated which, in turn, activate endothelial cells and cause vascular inflammation. The vaso-occlusive processes in SCD involve inflammatory and love molecules such as the cell affection molecules (CAM family), which play a role in the firm estimation of reticulocytes and leukocytes to endothelial cells, and the selectins, which play a role in leukocyte and platelet bankroll on the vascular wall (Connes et al., 2008). Thus, inflammation, leucocyte adhesion to vascular endothelium, and subsequent endothelial injury are other all-important(a) factors contributing to the pathogenesis of SCD (Jison et al., 2004).4. current therapies for clinical management of sickle cell diseaseincludingacritical appraisal of transfusion amongst 1973 and 2003, the average life expectancy of a patient with SCD increased dramatically from a mere 14 years to 50 years thanks to the development of comprehensive care models and painstaking research efforts in both basic sciences particularly molecular and genetic studies, and clinical aspects of SCD (Claster and Vichinsky, 2003). The clinical manifestations of SCD are highly variable. Both the phenotypic expression and intensity of the syndrome are vastly different among p atients and also vary lengthways within the same patient (Ballas, 1998). in the raw pathophysiological insights available have enabled interferences to be developed for the recognised haematologic and nonhaematologic abnormalities in SCD (Claster and Vichinsky, 2003). The main goals of SCD manipulation are symptom alleviation, crises avoidance and potent management of disease complications. The dodging adopted is primarily palliative in nature, and consists of supportive, symptomatic and stoppage cash advancees to therapy. diagnostic management includes pain mitigation, management of vasoocclusive crisis, alter chronic haemolytic anaemia, treatment of organ failure associated with the disease, and detection and treatment of pulmonary hypertension (Distenfeld and Woermann, 2009). The preventative strategies include use of contraceptive antibiotics (e.g., penicillin) in children, base hit blood transfusion for prevention of stroke in patients especially young children who are at a very high endangerment of stroke, and treatment with hydroxyurea of patients experiencing frequent acute painful episodes (Ballas, 2002). Currently, curative therapy for sickle cell anaemia is only available through bone marrow and stem cell transplantation. Hematopoietic cell transplantation using stem cells from a matched sibling donor has yielded sharp results in paediatric patients (Krishnamurti, 2007). Curative gene therapy is still at the wildcat stage (Ballas, 2002).Current and potential difference therapiesThe potential treatment strategies basically intention cellular dehydration, sickle haemoglobin concentrations, endothelial dysfunction, and abnormal coagulation regulation (Claster and Vichinsky, 2003). HbS concentrations are essentially tackled through transfusions while approaches to reduce HbS polymerisation which is the main mechanism for the development of vaso-occlusion include (a) increasing foetal haemoglobin (HbF) concentration using hydroxyurea ( Fig. 2), butyrate, or erythropoietin, and (b) preventing sickle cell dehydration using Clotrimazole (Fig. 3) or Mg2+pidolate. Hydroxyurea therapy increases the production of HbF in patients with sickle cell anaemia, and, thereby, inhibits the polymerisation of HbS and alleviates both the haemolytic and vaso-occlusive manifestations of the disease (Goldberg et al., 1990). Recombinant erythropoietin also increases the number of reticulocytes with HbF. Additionally, it has been observed that garbage disposal of intravenous recombinant erythropoietin with iron supplementation alternating with hydroxyurea enhances HbF levels more than hydroxyurea only if (Rodgers et al., 1993). As SCD is essentially characterized by an abnormal state of endothelial cell activation that is, a state of inflammation, a pharmacologic approach to inhibit endothelial cell activation has proved clinically honorable (Hebbel and Vercellotti, 1997). Thus, administration of sulfasalazine which is a mightily inh ibitor of activation of nuclear factor (NF)-B, the arrangement factor promoting expression of genes for a number of pro-adhesive and procoagulant molecules on endothelium to humans has been found to provide transcriptional regulation of SCD at the endothelium level (Solovey et al., 2001).Red blood cell transfusion a critical appraisalA key therapy that is applied regularly in the clinical management of patients with SCD is jam-jam-jam-packed red blood cell transfusion. red blood cell transfusion remedys the oxygen-carrying capacity which is achieved by enhancing the haemoglobin levels, causes dilution of HbS concentration thereby, reduce blood viscosity and boosting oxygen saturation. Furthermore, RBC transfusion is helpful in suppressing endogenous production of sickle RBCs by augmenting tissue oxygenation ( Josephson et al., 2007). There are two major types of RBC transfusion therapy sporadic and chronic which are further classified as contraceptive device or therapeutic. I ntermittent transfusions are generally therapeutic in nature and administered to control acute manifestations of SCD whereas chronic transfusions are performed as general preventative measures to check complications of SCD. RBC transfusion given as a single dose is termed as simple transfusion. Exchange transfusion involves administration of a larger volume of RBCs replacing the patients RBCs that are simultaneously removed. exposit of the various types of RBC transfusion and the major clinical indications for the same in SCD patients are listed in Table 1.SCD (Source Josephson et al., 2007)Indications for Intermittent transfusionsIndications for intermittent transfusions include acute manifestations of SCD, as indicated in Table 1, that require redressal through therapeutic transfusions. However, under certain circumstances intermittent transfusions could be natural rubber such as for instance, when SCD patients are transfused before specific surgeries viz., those related to mat ernalism complications or renal failure (Table 1).Acute Chest Syndrome (ACS) describes a manifestation of SCD in which, due to sickling, infectious and noninfectious pulmonary events are complicated, resulting in a more severe clinical course. The diagnosing is the presence of a impudently infiltrate on chest skiagraphy that is accompanied by acute respiratory symptoms. ACD accounts for intimately 25% of all terminations from SCD (Vichinsky, 2002). Repeated episodes of ACS are associated with an increased risk of chronic lung disease and pulmonary hypertension (Castro, 1996). The severe pulmonary events occurring in SCD may be precipitated by any trigger of hypoxia (Vichinsky, 2002). Transfusions are very in force(p) and provide immediate wellbeing by reversing hypoxia in ACS. Transfusion of leucocyte-poor packed red cells matched for Rh, C, E, and Kell antigens can confine antibody formation to below 1% (Vichinsky, 2002). primary transfusions suffice for less severe cases however, re-sentencing transfusion is recommended to minimise the risk of increased viscosity. Also, chronic transfusion appears promising for prevention of recurrence in selected patients (Styles and Vichinsky, 1994). In a multicentre ACS trial, prophylactic transfusion was found to almost fill inly eliminate the risk of pulmonary complications (Vichinsky, 2002).Acute Symptomatic Anaemia arises in SCD as a result of blood loss, increased RBC destruction, suppression of erythropoiesis etc. and is in effect enured with intermittent transfusion of RBCs to adopt symptoms of cardiac and respiratory excruciation (Josephson et al., 2007).Aplastic Anaemia is commonly caused in SCD on account of infection of haematopoietic precursors in the bone marrow by Parvovirus B19 leading to a steep fall in RBCs. According to Josephson et al. (2007), therapeutic intermittent transfusion of RBCs is again the recommended first-line of treatment to improve total haemoglobin count and prevent cardia c decompensation. However, in those patients who are prone to fluid overload on account of cardiac or renal dysfunction an alternating(a) transfusion strategy is to remove the full-page blood and replace it with packed cells while avoiding the addition of excess volume (Josephson et al., 2007).Acute Stroke is a high risk especially in paediatric SCD cases because of august cerebral flow. Enormous decline in stroke rate have occurred in children receiving intermittent simple transfusion (Adams et al., 1998). However, the identification of the stroke type would be necessary in all SCD patients in order to determine the appropriate treatment approach since the occurrence of infarctive strokes is higher in children as opposed to a higher incidence of haemorrhagic strokes in adults (Adams, 2003).Indications for Chronic TransfusionsProphylactic chronic RBC transfusion every 3 to 4 weeks to maintain HbS levels lower than 30% is crucial for preventing first as well as recurrent strokes i n children (Johnson et al., 2007). The transfusions could either be chronic simple transfusion or prophylactic chronic RBC exchange transfusion. Prophylactic chronic transfusions are recommended for patients with chronic renal failure so as to avoid severe symptomatic anaemia and for those patients with SCD undergoing pregnancy with complications. However, prophylactic transfusion is not indicated for SCD patients with normal pregnancy (Tuck et al., 1987).controversial and indeterminate indications for intermittent or chronic transfusionAccording to Hankins et al. (2005), chronic transfusion therapy is helpful in trim the incidence of strokes in children but not the severity of strokes. In the case of acute priapism, improvement in patients has been observed after exchange or simple transfusion (Rifikind et al., 1979). Yet, due to the ASPEN syndrome, transfusion currently is only a second-line therapy in the management of priapism ( moth miller et al., 1995).RBC transfusion is a spanking component in the management of symptoms and complications of SCD. It has drastically reduced the morbidity and deathrate of SCD. Yet, immune-related effectuate such as FNHTRs and alloimmunisation to HLAs, and nonimmune-related effects e.g., iron overload and transfusion-transmitted infections are serious adverse effects of the transfusion therapy that need to be tended to(p) to in SCD patients receiving transfusion (Johnson et al., 2007). Chronic transfusions could result in an dark accumulation of tissue iron that could become fatal if not treated (Cohen, 1987). Excess iron indemnification the liver, endocrine organs, and heart and may be fatal by adolescence (Engle, 1964).5. deprecative review of thalassemias (i) Molecular pathogenesisThe large number of inherited haemoglobin disorders know today include (a) those related to anomalies in the haemoglobin structure e.g., sickle cell disease, and (b) the thalassemias whose hallmark is globin-chain deficiency of one or other of the globin manacles of adult haemoglobin in erythroid cells.-ThalassaemiasThese are a set of genetic disorders inherited as simple codominant traits affecting haemoglobin synthesis. Depending on the haemoglobin chain affected, 2 types of thalassemia are recognised - thalassemia and - thalassemia. Homozygous -thalassaemia is marked by a quantitative deficiency of the -globin gyves in the erythroid cells. A complete absence of the -globin chains occurs in homozygous o-thalassaemia whereas in homozygous +-thalassaemia the -globin chains are present at less than 30% of normal. Accounting for nearly 90% of the cases, +-thalassaemia is the most commonly observed form of -thalassaemia. The condition is termed thalassaemia major when there is microcytic hypochromic anaemia with severe haemolysis, hepatosplenomegaly, skeletal deformities and iron overload. -thalassaemia homozygotes bring out severe transfusion-dependent anaemia in the very first year of life. Homozygotic individu als having a relatively benign clinical phenotype and surviving with or without transfusion are described as thalassaemia intermedia (Weatherall, 1969). The thalassaemias, thus, encompass a wide gamut of clinical disability from intrauterine death to a mild anaemia with no overt symptoms (Weatherall, 1997b). The coexistence of -thalassaemia leading to reducing in the synthesis of -globin chains, and a genetic predisposition to produce high levels of HbF, could be important factors for the extensive pCauses, Symptoms and Treatments of AnaemiaCauses, Symptoms and Treatments of Anaemia1. IntroductionAnaemia is a syndrome characterised by a lack of healthy red blood cells or haemoglobin deficiency in the red blood cells, resulting in inadequate oxygen supply to the tissues. The condition can be temporary, long-term or chronic, and of mild to severe intensity. There are many forms and causes of anaemia. Normal blood consists of three types of blood cells white blood cells (leucocytes), platelets and red blood cells (erythrocytes). The first generation of erythrocyte precursors in the developing foetus are produced in the yolk sac. They are carried to the developing liver by the blood where they form mature red blood cells that are required to meet the metabolic needs of the foetus. Until the 18th week of gestation, erythrocytes are produced only by liver after which the production shifts to the spleen and the bone marrow. The life of a red blood cell is about 127 days or 4 months (Shemin and Rittenberg, 1946 Kohgo et al., 2008). The main causes of anaemia are blood loss, production of too few red blood cells by the bone marrow or a rapid destruction of cells.Haemoglobin, a protein, present in the red blood cells is involved in the transport of oxygen from the lungs to all the other organs and tissues of the body. Iron is an important constituent of the haemoglobin protein structure which is intimately involved in the transport of oxygen. Anaemia is generally defin ed as a lower than normal haemoglobin concentration. The normal blood haemoglobin concentration is dependent on age and sex, and, according to the World Health Organisation (WHO) Expert Committee Report, anaemia results when the blood concentration of haemoglobin falls below 130 g/L in men or 120 g/L in non-pregnant women (WHO, 1968). However, the reference range of haemoglobin concentration in blood could vary depending on the ethnicity, age, sex, environmental conditions and food habits of the population analysed. According to Beutler and Warren (2006), more reasonable benchmarks for anaemia are 137 g/L for white men aged between 20 and 60 years and 132 g/L for older men. The value for women of all ages would be 122 g/L. Also, the lower limit of normal of haemoglobin concentrations of African Americans are appreciably lower than that of Caucasians (Beutler and Warren, 2006).Besides the well recognised iron deficiency anaemia, several inherited anaemias are also known. These are mo stly haemoglobinopathies. Adult haemoglobin is a tetrameric haeme-protein. Abnormalities of beta-chain or alpha-chain produce the various medically significant haemoglobinopathies. The variations in amino acid composition induced genetically impart marked differences in the oxygen carrying properties of haemoglobin. Mutations in the haemoglobin genes cause disorders that are qualitative abnormalities in the synthesis of haemoglobin (e.g., sickle cell disease) and some that are quantitative abnormalities that pertain to the rate of haemoglobin synthesis (e.g., the thalassemias) (Weatherall., 1969). In SCD, the missense mutation in the -globin gene causes the disorder. The mutation causing sickle cell anemia is a single nucleotide substitution (A to T) in the codon for amino acid 6. The substitution converts a glutamic acid codon (GAG) to a valine codon (GTG). The form of haemoglobin in persons with sickle cell anemia is referred to as HbS. Also, the valine for glutamic acid replaceme nt causes the haemoglobin tetramers to aggregate into arrays upon deoxygenation in the tissues. This aggregation leads to deformation of the red blood cell making it relatively inflexible and restrict its movement in the capillary beds. Repeated cycles of oxygenation and deoxygenation lead to irreversible sickling and clogging of the fine capillaries. Incessant clogging of the capillary beds damages the kidneys, heart and lungs while the constant destruction of the sickled red blood cells triggers chronic anaemia and episodes of hyperbilirubinaemia.Fanconi anaemia (FA) is an autosomal recessive condition, and the most common type of inherited bone marrow failure syndrome. The clinical features of FA are haematological with aplastic anaemia, myelodysplastic syndrome (MDS), and acute myeloid leukaemia (AML) being increasingly present in homozygotes (Tischkowitz and Hodgson, 2003). Cooleys anaemia is yet another disorder caused by a defect in haemoglobin synthesis.Autoimmune haemolytic anaemia is a syndrome in which individuals produce antibodies directed against one of their own erythrocyte membrane antigens. The condition results in diminished haemoglobin concentrations on account of shortened red blood cell lifespan (Sokol et al., 1992).Megaloblastic anaemia is a blood disorder in which anaemia occurs with erythrocytes which are larger in size than normal. The disorder is usually associated with a deficiency of vitamin B12 or folic acid . It can also be caused by alcohol abuse, drugs that impact DNA such as anti-cancer drugs, leukaemia, and certain inherited disorders among others (Dugdale, 2008).Malaria causes increased deformability of vivax-infected red blood cells (Anstey et al., 2009). Malarial anaemia occurs due to lysis of parasite-infected and non-parasitised erythroblasts as also by the effect of parasite products on erythropoiesis (Ru et al., 2009).Large amounts of iron are needed for haemoglobin synthesis by erythroblasts in the bone marrow. Transfe rrin receptor 1 (TfR1) expressed highly in erythroblasts plays an important role in extracellular iron uptake (Kohgo et al., 2008). Inside the erythroblasts, iron transported into the mitochondria gets incorporated into the haeme ring in a multistep pathway. Genetic abnormalities in this pathway cause the phenotype of ringed sideroblastic anemias (Fleming, 2002). The sideroblastic anemias are a heterogeneous group of acquired and inherited bone marrow disorders, characterised by mitochondrial iron overload in developing red blood cells. These conditions are diagnosed by the presence of pathologic iron deposits in erythroblast mitochondria (Bottomley, 2006). 2. Classification of anaemiaAnaemia can be generally classified based on the morphology of the red blood cells, the pathogenic spectra or clinical presentation (Chulilla et al., 2009). The morphological classification is based on mean corpuscular volume (MCV) and comprises of microcytic, macrocytic and normocytic anaemia.(a) Micr ocytic anaemia refers to the presence of RBCs smaller than normal volume, the reduced MCV ( 15 would probably indicate IDA (Chulilla et al., 2009).In macrocytic anaemia, erythrocytes are larger (MCV 98 fL) than their normal volume (MCV = 82-98 fL). Vitamin B12 deficiency leads to delayed DNA synthesis in rapidly growing hematopoietic cells, and can result in macrocytic anemia. Drugs that interfere with nucleic acid metabolism, such as.hydroxyurea increases MCV ( 110 fL) while alcohol induces a moderate macrocytosis (100-110 fL). In the initial stage, most anaemias are normocytic. The causes of normocytic anaemia are nutritional deficiency, renal failure and haemolytic anemia (Tefferi, 2003). The most common normocytic anaemia in adults is anaemia of chronic disease (ACD) (Krantz, 1994). Common childhood normocytic anaemias are, besides iron deficiency anaemia, those due to acute bleeding, sickle cell anemia, red blood cell membrane disorders and current or recent infections especia lly in the very young (Bessman et al., 1983). Homozygous sickle cell disease is the most common cause of haemolytic normocytic anemias in children (Weatherall DJ, 1997a).In practice, the morphological classification is quicker and therefore, more useful as a diagnostic tool. Besides, MCV is also closely linked to mean corpuscular haemoglobin (MCH), which denotes mean haemoglobin per erythrocyte expressed in picograms (Chulilla et al., 2009). Thus, MCV and MCH decrease simultaneously in microcytic, hypochromic anemia and increase together in macrocytic, hyperchromic anemia.Pathogenic classification of anaemia is based on the production pattern of RBC whether anaemia is due to inadequate production or loss of erythrocytes caused by bleeding or haemolysis. This approach is useful in those cases where MCV is normal. Pathogenic classification is also essential for proper recognition of the mechanisms involved in the genesis of anaemia. Based on the pathogenic mechanisms, anaemia is furth er divided into two types namely, (i) hypo-regenerative in which the bone marrow production of erythrocytes is decreased because of impaired function, decreased number of precursor cells, reduced bone marrow infiltration, or lack of nutrients and (ii) regenerative when bone marrow upregulates the production of erythrocytes in response to the low erythrocyte mass (Chulilla et al., 2009). This is typified by increased generation of erythropoietin in response to lowered haemoglobin concentration, and also reflects a loss of erythrocytes, due to bleeding or haemolysis. The reticulocyte count is typically higher.Sickle cell disease is characterised by sickled red cells. The first report of SCD was published a century ago noting the presence of peculiar elongated cells in blood by James Herrick, an American physician (1910). Pauling et al. (1949) described it as a molecular disease. The molecular nature of sickle haemoglobin (Hb S) in which valine is substituted for glutamic acid at the s ixth amino acid position in the beta globin gene reduces the solubility of Hb, causing red cells to sickle (Fig. 1).Sickling of cells occurs at first reversibly, then finally as a state of permanent distortion, when cells containing HbS and inadequate amounts of other haemoglobins including foetal haemoglobin, which retards sickling, become deoxygenated (Bunn, 1997). The abnormal red cells break down, leading to anaemia, and clog blood vessels with aggregates, leading to recurrent episodes of severe pain and multiorgan ischaemic damage (Creary et al., 2007). The high levels of inflammatory cytokines in SCD may promote retention of iron by macrophage/reticuloendothelial cells and/or renal cells. SCD care commonly depends on transfusion that results in iron overload (Walter et al., 2009).3. Pathogenesis of anaemiaAnaemia is a symptom , or a syndrome, and not a disease (Chulilla et al., 2009). Several types of anaemia have been recognised, the pathogenesis of each being unique.Iron def iciency anaemia (IDA) is the most common type of anaemia due to nutritional causes encountered worldwide (Killip et al., 2008). Iron is one of the essential micronutrients required for normal erythropoietic function While the causes of iron deficiency vary significantly depending on chronological age and gender, IDA can reduce work capacity in adults (Haas Brownlie, 2001) and affect motor and mental development in children (Halterman et al., 2001). The metabolism of iron is uniquely controlled by absorption rather than excretion (Siah et al., 2006). Iron absorption typically occurring in the duodenum accounts for only 5 to 10 per cent of the amount ingested in homoeostatis. The value decreases further under conditions of iron overload, and increases up to fivefold under conditions of iron depletion (Killip et al., 2008). Iron is ingested as haem iron (10%) present in meat, and as non-haem ionic form iron (90%) found in plant and dairy products. In the absence of a regulated excreti on of iron through the liver or kidneys, the only way iron is lost from the body is through bleeding and sloughing of cells. Thus, men and non-menstruating women lose about 1 mg of iron per day while menstruating women could normally lose up to 1.025 mg of iron per day (Killip et al., 2008). The requirements for erythropoiesis which are typically 20-30 mg/day are dependent on the internal turnover of iron (Munoz et al., 2009) For example, the amount of iron required for daily production of 300 billion RBCs (20-30 mg) is provided mostly by recycling iron by macrophages (Andrews, 1999).Iron deficiency occurs when the metabolic demand for iron exceeds the amount available for absorption through consumption. Deficiency of nutritional intake of iron is important, while abnormal iron absorption due to hereditary or acquired iron-refractory iron deficiency anemia (IRIDA) is another important cause of unexplained iron deficiency. However, IDA is commonly attributed to blood loss e.g., physi ological losses in women of reproductive age. It might also represent occult bleeding from the GI (GI) tract generally indicative of malignancy (Hershko and Skikne, 2009).Iron absorption and loss play an important role in the pathogenesis and management of IDA. Human iron disorders are necessarily disorders of iron balance or iron distribution. Iron homeostasis involves accurate control of intestinal iron absorption, efficient utilisation of iron for erythropoiesis, proper recycling of iron from senescent erythrocytes, and regulated storage of iron by hepatocytes and macrophages (Andrews, 2008). Iron deficiency is largely acquired, resulting from blood loss (e.g., from intestinal parasitosis), from inadequate dietary iron intake, or both. Infections, for example, with H pylori, can lead to profound iron deficiency anemia without significant bleeding. Genetic defects can cause iron deficiency anaemia. Mutations in the genes encoding DMT1 (SLC11A2) and glutaredoxin 5 (GLRX5) lead to autosomal recessive hypochromic, microcytic anaemia (Mims et al., 2005). Transferrin is a protein that keeps iron nonreactive in the circulation, and delivers iron to cells possessing specific transferrin receptors such as TFR1 which is found in largest amounts on erythroid precursors. Mutations in the TF gene leading to deficiency of serum transferrin causes disruption in the transfer of iron to erythroid precursors thereby producing an enormous increase in intestinal iron absorption and consequent tissue iron deposition (Beutler et al., 2000).Quigley et al. (2004) found a haem exporter, FLVCR, which appears to be necessary for normal erythroid development. Inactivation of FLVCR gene after birth in mice led to severe macrocytic anaemia, indicating haem export to be important for normal erythropoiesis.The anaemia of chronic disease (ACD) found in patients with chronic infectious, inflammatory, and neoplastic disorders is the second most frequently encountered anaemia after iron-defi ciency anaemia. It is most often a normochromic, normocytic anaemia that is primarily caused by an inadequate production of red cells, with low reticulocyte production (Krantz, 1994). The pathogenesis of ACD is unequivocally linked to increased production of the cytokines including tumour necrosis factor, interleukin-1, and the interferons that mediate the immune or inflammatory response. The various processes leading to the development of ACD such as reduced life span of red cells, diminished erythropoietin effect on anaemia, insufficient erythroid colony formation in response to erythropoietin, and impaired bioavailability of reticuloendothelial iron stores appear to be caused by inflammatory cytokines (Means, 19962003). Although iron metabolism is characteristically impaired in ACD, it may not play a key role in the pathogenesis of ACD (Spivak, 2002). Neither is the lack of available iron central to the pathogenesis of the syndrome, according to Spivak (2002), who found reduced i ron absorption and decreased erythroblast transferrin-receptor expression to be the result of impaired erythropoietin production and inhibition of its activity by cytokines. However, reduced erythropoietin activity, mostly from reduced production, plays a pivotal role in the pathogenesis of ACD observed in systemic autoimmune diseases (Bertero and Caligaris-Cappio, 1997). Indeed, iron metabolism as well as nitric oxide (NO), which contributes to the regulation of iron cellular metabolism are involved in the pathogenesis of ACD in systemic autoimmune disorders. Inflammatory mediators, particularly the cytokines, are important factors involved in the pathogenesis of the anaemia of chronic disease, as seen in rheumatoid arthritis anaemia (Baer et al., 1990), the cytokines causing impairment of erythroid progenitor growth and haemoglobin production in developing erythrocytes.Anaemia is also commonly found in cases of congestive heart failure (CHF), again caused by excessive cytokine pro duction leading to reduced erythropoietin secretion, interference with erythropoietin activity in the bone marrow and reduced iron supply to the bone marrow (Silverberg et al., 2004). However, in the presence of chronic kidney insufficiency, abnormal erythropoietin production in the kidney plays a role in the pathogenesis of anaemia in CHF.The myelodysplastic syndromes (MDS) are common haematological malignancies affecting mostly the elderly as age-related telomere shortening enhances genomic instability (Rosenfeld and List, 2000). Radiation, smoking and exposure to toxic compounds e.g., pesticides, organic chemicals and heavy metals, are factors promoting the onset of MDS via damage caused to progenitor cells, and, thereby, inducing immune suppression of progenitor cell growth and maturation. TNF- and other pro-apoptotic cytokines could play a central role in the impaired haematopoiesis of MDS (Rosenfeld and List, 2000). Premature intramedullary cell death brought about by excessiv e apoptosis is another important pathogenetic mechanism in MDS (Aul et al., 1998).Sickle cell disease (SCD) arising from a point mutation in the -globin gene and leading to the expression of haemoglobin S (HbS) is the most common monogenetic disorder worldwide. Chronic intravascular haemolysis and anaemia are some important characteristics of SCD. Intravascular haemolysis causes endothelial dysfunction marked by reduced nitric oxide (NO) bioavailability and NO resistance, leading to acute vasoconstriction and, subsequently, pulmonary hypertension (Gladwin and Kato, 2005). However, a feature that differentiates SCD from other chronic haemolytic syndromes is the persistent and intense inflammatory condition present in SCD. The primary pathogenetic event in SCD is the intracellular polymerisation or gelation of deoxygenated HbS leading to rigidity in erythrocytes (Wun, 2001). The deformation of erythrocytes containing HbS is dependent on the concentration of haemoglobin in the deoxy c onformation (Rodgers et al., 1985). It has been demonstrated that sickle monocytes are activated which, in turn, activate endothelial cells and cause vascular inflammation. The vaso-occlusive processes in SCD involve inflammatory and adhesion molecules such as the cell adhesion molecules (CAM family), which play a role in the firm adhesion of reticulocytes and leukocytes to endothelial cells, and the selectins, which play a role in leukocyte and platelet rolling on the vascular wall (Connes et al., 2008). Thus, inflammation, leucocyte adhesion to vascular endothelium, and subsequent endothelial injury are other crucial factors contributing to the pathogenesis of SCD (Jison et al., 2004).4. Current therapies for clinical management of sickle cell diseaseincludingacritical appraisal of transfusionBetween 1973 and 2003, the average life expectancy of a patient with SCD increased dramatically from a mere 14 years to 50 years thanks to the development of comprehensive care models and pai nstaking research efforts in both basic sciences especially molecular and genetic studies, and clinical aspects of SCD (Claster and Vichinsky, 2003). The clinical manifestations of SCD are highly variable. Both the phenotypic expression and intensity of the syndrome are vastly different among patients and also vary longitudinally within the same patient (Ballas, 1998). New pathophysiological insights available have enabled treatments to be developed for the recognised haematologic and nonhaematologic abnormalities in SCD (Claster and Vichinsky, 2003). The main goals of SCD treatment are symptom alleviation, crises avoidance and effective management of disease complications. The strategy adopted is primarily palliative in nature, and consists of supportive, symptomatic and preventative approaches to therapy. Symptomatic management includes pain mitigation, management of vasoocclusive crisis, improving chronic haemolytic anaemia, treatment of organ failure associated with the disease, and detection and treatment of pulmonary hypertension (Distenfeld and Woermann, 2009). The preventative strategies include use of prophylactic antibiotics (e.g., penicillin) in children, prophylactic blood transfusion for prevention of stroke in patients especially young children who are at a very high risk of stroke, and treatment with hydroxyurea of patients experiencing frequent acute painful episodes (Ballas, 2002). Currently, curative therapy for sickle cell anaemia is only available through bone marrow and stem cell transplantation. Hematopoietic cell transplantation using stem cells from a matched sibling donor has yielded excellent results in paediatric patients (Krishnamurti, 2007). Curative gene therapy is still at the exploratory stage (Ballas, 2002).Current and potential therapiesThe potential treatment strategies basically target cellular dehydration, sickle haemoglobin concentrations, endothelial dysfunction, and abnormal coagulation regulation (Claster and Vichinsky, 2003). HbS concentrations are essentially tackled through transfusions while approaches to reduce HbS polymerisation which is the main mechanism for the development of vaso-occlusion include (a) increasing foetal haemoglobin (HbF) concentration using hydroxyurea (Fig. 2), butyrate, or erythropoietin, and (b) preventing sickle cell dehydration using Clotrimazole (Fig. 3) or Mg2+pidolate. Hydroxyurea therapy increases the production of HbF in patients with sickle cell anaemia, and, thereby, inhibits the polymerisation of HbS and alleviates both the haemolytic and vaso-occlusive manifestations of the disease (Goldberg et al., 1990). Recombinant erythropoietin also increases the number of reticulocytes with HbF. Additionally, it has been observed that administration of intravenous recombinant erythropoietin with iron supplementation alternating with hydroxyurea enhances HbF levels more than hydroxyurea alone (Rodgers et al., 1993). As SCD is essentially characterized by an abnormal sta te of endothelial cell activation that is, a state of inflammation, a pharmacologic approach to inhibit endothelial cell activation has proved clinically beneficial (Hebbel and Vercellotti, 1997). Thus, administration of sulfasalazine which is a powerful inhibitor of activation of nuclear factor (NF)-B, the transcription factor promoting expression of genes for a number of pro-adhesive and procoagulant molecules on endothelium to humans has been found to provide transcriptional regulation of SCD at the endothelium level (Solovey et al., 2001).Red blood cell transfusion a critical appraisalA key therapy that is applied regularly in the clinical management of patients with SCD is packed red blood cell transfusion. RBC transfusion improves the oxygen-carrying capacity which is achieved by enhancing the haemoglobin levels, causes dilution of HbS concentration thereby, reducing blood viscosity and boosting oxygen saturation. Furthermore, RBC transfusion is helpful in suppressing endogen ous production of sickle RBCs by augmenting tissue oxygenation ( Josephson et al., 2007). There are two major types of RBC transfusion therapy intermittent and chronic which are further classified as prophylactic or therapeutic. Intermittent transfusions are generally therapeutic in nature and administered to control acute manifestations of SCD whereas chronic transfusions are performed as general preventative measures to check complications of SCD. RBC transfusion given as a single dose is termed as simple transfusion. Exchange transfusion involves administration of a larger volume of RBCs replacing the patients RBCs that are simultaneously removed. Details of the various types of RBC transfusion and the major clinical indications for the same in SCD patients are listed in Table 1.SCD (Source Josephson et al., 2007)Indications for Intermittent transfusionsIndications for intermittent transfusions include acute manifestations of SCD, as indicated in Table 1, that require redressal t hrough therapeutic transfusions. However, under certain circumstances intermittent transfusions could be prophylactic such as for instance, when SCD patients are transfused before specific surgeries viz., those related to pregnancy complications or renal failure (Table 1).Acute Chest Syndrome (ACS) describes a manifestation of SCD in which, due to sickling, infectious and noninfectious pulmonary events are complicated, resulting in a more severe clinical course. The diagnosis is the presence of a new infiltrate on chest radiography that is accompanied by acute respiratory symptoms. ACD accounts for nearly 25% of all deaths from SCD (Vichinsky, 2002). Repeated episodes of ACS are associated with an increased risk of chronic lung disease and pulmonary hypertension (Castro, 1996). The severe pulmonary events occurring in SCD may be precipitated by any trigger of hypoxia (Vichinsky, 2002). Transfusions are very efficacious and provide immediate benefit by reversing hypoxia in ACS. Trans fusion of leucocyte-poor packed red cells matched for Rh, C, E, and Kell antigens can curtail antibody formation to below 1% (Vichinsky, 2002). Simple transfusions suffice for less severe cases however, exchange transfusion is recommended to minimise the risk of increased viscosity. Also, chronic transfusion appears promising for prevention of recurrence in selected patients (Styles and Vichinsky, 1994). In a multicentre ACS trial, prophylactic transfusion was found to almost completely eliminate the risk of pulmonary complications (Vichinsky, 2002).Acute Symptomatic Anaemia arises in SCD as a result of blood loss, increased RBC destruction, suppression of erythropoiesis etc. and is effectively treated with intermittent transfusion of RBCs to relieve symptoms of cardiac and respiratory distress (Josephson et al., 2007).Aplastic Anaemia is commonly caused in SCD on account of infection of haematopoietic precursors in the bone marrow by Parvovirus B19 leading to a steep fall in RBCs. According to Josephson et al. (2007), therapeutic intermittent transfusion of RBCs is again the recommended first-line of treatment to improve total haemoglobin count and prevent cardiac decompensation. However, in those patients who are prone to fluid overload on account of cardiac or renal dysfunction an alternative transfusion strategy is to remove the whole blood and replace it with packed cells while avoiding the addition of excess volume (Josephson et al., 2007).Acute Stroke is a high risk especially in paediatric SCD cases because of elevated cerebral flow. Enormous decline in stroke rate have occurred in children receiving intermittent simple transfusion (Adams et al., 1998). However, the identification of the stroke type would be necessary in all SCD patients in order to determine the appropriate treatment approach since the occurrence of infarctive strokes is higher in children as opposed to a higher incidence of haemorrhagic strokes in adults (Adams, 2003).Indications for Chronic TransfusionsProphylactic chronic RBC transfusion every 3 to 4 weeks to maintain HbS levels lower than 30% is crucial for preventing first as well as recurrent strokes in children (Johnson et al., 2007). The transfusions could either be chronic simple transfusion or prophylactic chronic RBC exchange transfusion. Prophylactic chronic transfusions are recommended for patients with chronic renal failure so as to avoid severe symptomatic anaemia and for those patients with SCD undergoing pregnancy with complications. However, prophylactic transfusion is not indicated for SCD patients with normal pregnancy (Tuck et al., 1987).Controversial and indeterminate indications for intermittent or chronic transfusionAccording to Hankins et al. (2005), chronic transfusion therapy is helpful in reducing the incidence of strokes in children but not the severity of strokes. In the case of acute priapism, improvement in patients has been observed after exchange or simple transfusion (Rifikind et al., 1979). Yet, due to the ASPEN syndrome, transfusion currently is only a second-line therapy in the management of priapism ( Miller et al., 1995).RBC transfusion is a vital component in the management of symptoms and complications of SCD. It has drastically reduced the morbidity and mortality of SCD. Yet, immune-related effects such as FNHTRs and alloimmunisation to HLAs, and nonimmune-related effects e.g., iron overload and transfusion-transmitted infections are serious adverse effects of the transfusion therapy that need to be attended to in SCD patients receiving transfusion (Johnson et al., 2007). Chronic transfusions could result in an inexorable accumulation of tissue iron that could become fatal if not treated (Cohen, 1987). Excess iron damages the liver, endocrine organs, and heart and may be fatal by adolescence (Engle, 1964).5. Critical review of thalassemias (i) Molecular pathogenesisThe large number of inherited haemoglobin disorders known today include (a) those related to anomalies in the haemoglobin structure e.g., sickle cell disease, and (b) the thalassemias whose hallmark is globin-chain deficiency of one or other of the globin chains of adult haemoglobin in erythroid cells.-ThalassaemiasThese are a set of genetic disorders inherited as simple codominant traits affecting haemoglobin synthesis. Depending on the haemoglobin chain affected, 2 types of thalassemia are recognised -thalassaemia and -thalassaemia. Homozygous -thalassaemia is marked by a quantitative deficiency of the -globin chains in the erythroid cells. A complete absence of the -globin chains occurs in homozygous o-thalassaemia whereas in homozygous +-thalassaemia the -globin chains are present at less than 30% of normal. Accounting for nearly 90% of the cases, +-thalassaemia is the most commonly observed form of -thalassaemia. The condition is termed thalassaemia major when there is microcytic hypochromic anaemia with severe haemolysis, hepatosplenomegaly, skeletal deform ities and iron overload. -thalassaemia homozygotes exhibit severe transfusion-dependent anaemia in the very first year of life. Homozygotic individuals having a relatively benign clinical phenotype and surviving with or without transfusion are described as thalassaemia intermedia (Weatherall, 1969). The thalassaemias, thus, encompass a wide gamut of clinical disability from intrauterine death to a mild anaemia with no overt symptoms (Weatherall, 1997b). The coexistence of -thalassaemia leading to reduction in the synthesis of -globin chains, and a genetic predisposition to produce high levels of HbF, could be important factors for the extensive p