A Brief Review on Anemia & Its Clinical Management

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Information about A Brief Review on Anemia & Its Clinical Management

Published on February 17, 2014




A reduction of hemoglobin concentration in blood
is termed as anemia. Especially women’s are
suffering from anemia due to loss of blood in
menstrual cycle, poor nutrition foods and in
postpartum females and different types of diseases
in humans which causes anemia. To treat this
there is no specific medicine is available except
iron tablets though they are not safe and may
cause serious health problems. That’s why in this
particular review article I will emphasis on the
naturally occurring products which may be
beneficial in anemia.

ISSN: 2348 –0882 ========================================================================== Int. J. Pharm. Res. Sci., 2014, 02(1), 37-41. A Brief Review on Anemia & Its Clinical Management Babita Gautam*, Arunbala, Anshubala, Ajay kumar, Chetan kr Dubey , Shalini Tripathi. *Department of Pharmacy, Rameshwaram Institute of Technology and Management Lucknow, UPTU Email- ---------------------------------------------------------------------------------------------------------------------------------have enough RBC or when yours RBC do not Abstract: A reduction of hemoglobin concentration in blood work properly [2] is termed as anemia. Especially women’s are Symptoms: In case of anemia following suffering from anemia due to loss of blood in symptoms are appearmenstrual cycle, poor nutrition foods and in Fatigue, Weakness, Shortness of breath, Light postpartum females and different types of diseases headedness, Palpitations, Decrease energy, in humans which causes anemia. To treat this Looking pale, Dizziness, Heart attack, Rapid heart there is no specific medicine is available except rate, Low blood pressure, Rapid breathing iron tablets though they are not safe and may Causes: Following are the causes which may cause serious health problems. That’s why in this cause anemiaparticular review article I will emphasis on the External bleeding, Chronic disease, Pregnancy, naturally occurring products which may be Bleeding disorders, Infections, Hereditary beneficial in anemia. conditions, Jaundice, Imbalance nutrition. Types of anemia: Anemia has various types, Keywords: Hemoglobin, anemia and its types, some of which are named belowcauses, diagnosis and treatments. Sickle cell anemia, A plastic anemia, Thalassemia, Bone marrow related anemia, Hemolytic anemia, Pernicious anemia, Anemia from active bleeding, Introduction Anemia is a medical condition in which the red Iron deficiency anemia, Anemia of chronic blood cells or hemoglobin is less than normal. The disease, Anemia related to kidney disease, normal level of hemoglobin is generally different Anemia related to pregnancy. in males and females. For men, anemia is Anemia Treatment Reference typically defined as hemoglobin level is less than approaches 13.5gm/100 ml and in women less than 12 Hemolytic In case of this [3] [1] gm/100 ml. Anemia causes serious problems anemia anemia, Special blood due to loss of blood in the body by various transfusions reasons. In the tropics, due to endemicity of Pernicious This [4] malaria, between 10-20 % of the population anemia Treatment involves a presents less than 10gm/dl of hemoglobin. shot of vitamin B12 Hemoglobin is a main part of RBC which binds once a month oxygen and oxyhemoglobin. If there is less or Sickle cell Drugs, like [5] abnormal RBCs in your blood, it is the reason that anemia Analgesic , opiods your body will not get enough oxygen. Women Thalassemia Deferoxamine, [6] and people with chronic disease are at increased deferasirox, risk of anemia. Anemia occurs when you don’t deferiprone 37

ISSN: 2348 –0882 ========================================================================== Int. J. Pharm. Res. Sci., 2014, 02(1), 37-41. Alcoholism Diazepam, disulfuram, [7] Iron deficiency anemia Iron sulfate [8] hematopoietic stem [9] cell transplantation Combination Table.1 (various types of anemia and its treatment approaches) Figure.1.normal RBCs [13] Aplastic anemia Sickle cell anemia: Sickle cell anemia is caused by an autosomal recessive inherited disorder which results as hemolysis. The genetic abnormality is due to substitution of the amino acid valine for glutamic acid at the sixth position on the beta globulin chain and was first described over one hundred yrs ago [10]. Hemoglobin S, the hemoglobin that is produced as a result of this defeat, is a hemoglobin tetramer (alpha 2/ beta S2) that is poorly soluble and polymerizes when [11] deoxygenated. Over all the incidence of sickle cell disease exceeds that of most other serious genetic disorder including cystic fibrosis and hemophilia [12]. Sign and symptoms: Sickle cell anemia has symptoms likeShortness of breath, Dizziness, Headaches, Coldness of hand and feet, Paler than normal skin or mucous membranes (the tissue that lines your nose, mouth, and other organs and body cavities), Jaundice (a yellowish color of the skin or whites of the eyes). Figure.2 sickle shapedRBCs Treatment: Folic acid and penicillin: Children born with sickle-cell disease will undergo close observation by the pediatrician and will require management by a hematologist to assure they remain healthy. These patients will take a 1 mg dose of folic acid daily for life. From birth to five years of age, they will also have to take penicillin daily due to the immature immune system that makes them more prone to early childhood illnesses [14]. Analgesics: Painful crises are treated symptomatically with analgesics; pain management requires opioid administration at regular intervals until the crisis has settled. For milder crises, subgroups of patients manage on NSAIDs (such as diclofenac or naproxen). For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia (PCA) devices are commonly used in this setting. Diphenhydramine is also an effective agent that is frequently prescribed by doctors in order to help control any itching associated with the use of opioids [15]. Blood transfusions: Blood transfusions are often used in the management of sickle cell disease in acute cases and to prevent complications by 38

ISSN: 2348 –0882 ========================================================================== Int. J. Pharm. Res. Sci., 2014, 02(1), 37-41. decreasing the number of red blood cells (RBC) that can sickle by adding normal red blood cells [16] Hemolytic anemia: Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is an X-linked disorder, in this type of anemia there is rupture blood cells in blood stream which leads to acute hemolytic anemia. Although many G-6-PD variants have been described, susceptibility to some drugs has been mainly confined to the G-6-PD Mediterranean variant largely found in Sardinia. Its incidence in the North is different from that of the South [17] Many patients who are already anemic, they also have jaundice. Splenomegaly, reticulocytosis and increased osmotic fragility of RBCs. [18] Symptoms: following symptoms are observedFeeling grumpy, Weakness, Headaches, Brittle nails, Blue color to the whitish of eye, Pale skin color, Shortness of breath Important test for hemolytic anemia: [19] Absolute reticulocyte count- The reticulocyte count is used to estimate the degree of effective erythropoiesis, which can be reported as absolute reticulocyte count or as a reticulocyte percentage. Coombs testUsed for the autoimmune hemolytic anemia, and a condition of a low count RBC immune system lysis or breaking of RBC membranes causing RBC destruction. Coombs test, indirect - it's mostly for prenatal pregnant women, It detects antibodies against RBCs that are present unbound in the patient's serum. Donath-landsteiner test-The DonathLandsteiner test is used for detecting harmful antibodies related to a rare disorder called paroxysmal cold hemoglobinuria. The antibodies form and destroy red blood cells when the body is exposed to cold temperatures [20]. Platelet count- This test measures the number of platelets in blood. It is used to evaluate bleeding disorders [21] this test may be used when disorders caused by low blood platelets such as thrombocytopenia are suspected Serum LDH- The LDH level is measured in order to check for tissue damage, especially to the heart, liver, kidney, skeletal muscle, brain, and lungs — all of which elevates the normally low LDH level in the blood. Hemosiderin in the urine- This test detects hemosiderin in urine. Hemosiderin is a pigment formed when hemoglobin breaks down. This test is used to evaluate and manage disorders involving the destruction of red blood cells [21] Febrile of cold agglutinins- Agglutinins are antibodies that cause the red blood cells to clump together Cold agglutinins are active at cold temperatures. Febrile (warm) agglutinins are active at normal body temperatures. This article discusses the blood test used to measure the level of these antibodies in the blood. Treatment: [22] Blood transfusion may be needed. Hemolytic anemia caused by an overactive immune system drugs that suppress the immune system may be used. When blood is destroyed at a fast pace the body may need extra folic acid and iron supplements to replace what is being lost. Pernicious anemia: Pernicious anemia is a type of vitamin B12 deficiency anemia. The body needs vitamin B12 to make red blood cells. You get this vitamin from eating foods such as meat, poultry, shellfish, eggs, and dairy products. A special protein, called intrinsic factor, helps your intestines absorb vitamin B12. This protein is released by cells in the stomach. When the stomach does not make enough intrinsic factor, the intestine cannot properly absorb vitamin B12 [23] 39

ISSN: 2348 –0882 ========================================================================== Int. J. Pharm. Res. Sci., 2014, 02(1), 37-41. Symptoms: There are following symptoms of pernicious anemiaDiarrhea or constipation. Fatigue, lack of energy, or light-headedness when standing up or with exertion , Loss of appetite , Pale skin , Problems concentrating , Shortness of breath, mostly during exercise , Confusion , Depression, Loss of balance . which is or was prevalent in the regions where the trait is common. This selective survival advantage on carriers (known as heterozygous advantage) may be responsible for perpetuating the mutation in populations. In that respect, the various thalassemias resemble another genetic disorder affecting hemoglobin, sickle-cell disease. [28] Anemia in pregnancy: According to WHO, anemia in pregnancy is defined as hemoglobin level is less than 11 g/dl and hematocrit level is less than 33% at any stage of pregnancy [26]. Anemia of pregnancy affects women of low socioeconomic status. According to WHO 52% of pregnant women from undeveloped or developed countries area anemic as compared with 20% from industrialized nation [24].The risk of anemia in pregnancy increases with progression of pregnancy by CDC criteria among low income pregnant women in the US 8% are anemic in the first trimester ,12% in the second & 34% in the third [25] . Hydremia of pregnancy was first proposed by German & French physician in the 1830s formally demonstrated in 1934 by Dieckmann & Degner [26].Folate deficiency is historical regarded as the second most common cause of anemia of pregnancy after iron deficiency & B12 dificiency is more prevalent. In studies, from India, Turkey, Africa, Newfoundland, & Venezuela 10% to 100% of pregnant women have a folate deficiency where as 30% to 100% have vit. B12 deficiency. The prevalence of folate or vit b12 deficiency increased with gestation [27]. Alpha (α) thalassemias Thalassemia: Thalassemia can cause significant complications, including pneumonia, iron overload, bone deformities and cardiovascular illness. However this same inherited disease of red blood cells may confer a degree of protection against malaria, The α thalassemias involve the genes HBA1 [29]. And HBA2 [30]. inherited in a Mendelian recessive fashion. There are two gene locii and so four alleles. Beta (β) thalassemias Beta thalassemias are due to mutations in the HBB gene on chromosome 11[31] also inherited in an autosomal-recessive fashion. Aplastic anemia: Aplastic anemia is a term which defined as destruction of bone marrow to produce RBC. Aplastic anemia is rare disease but approx. 2000 patient diagnosed in America in every year [32]. Two mechanisms have been suggested for bone marrow failure. The first mechanism is direct hematopoietic injury by chemicals (e.g. benzene). The second mechanism, supported by clinical observations and laboratory studies, is immunemediated suppression of marrow cells [33]. Figure. 3 Abnormal celFigure. 4 Normal cells [34] (Fig no 3 Showing Abnormal shape of RBCs due to bone marrow Suppression) 40

ISSN: 2348 –0882 ========================================================================== Int. J. Pharm. Res. Sci., 2014, 02(1), 37-41. Pathophysiology of aplastic anemia: Figure 4. Immune destruction of hematopoiesis [35]. Antigen representing cells (APCs) trigger T-cell to activate and proliferate. A transcription factor which binds to the interferon-y promoters’ site and induce gene expression and reduce gene transcription [36]. Patient with aplastic anemia shows constitutive T-bet expression and low SAP levels, TNF-a and IFN-y up regulate other T-cell cellular receptor and also the FAS receptor Increased production of interleukin-2 leads to polyclonal expansion of T- cell. Activation of fas ligand leads to apoptosis of target cell which inhibit the transcription of cellular genes and entry into the cell cycle [37]. INF-y is a potent inducer of many cellular genes and NOS (nitric oxide synthase) and production of toxic gas and NO [38]. The processes ultimately lead to reduced cell cycling and cell death by apoptosis. Iron deficiency anemia: Urinary tract. Iron deficiency causes approximately half of all anemia cases worldwide, and affects women more often than men. World estimates of iron deficiency occurrence are somewhat vague, but the true number probably exceeds one billion people [39]. The most significant cause of iron-deficiency anemia is parasitic worms: hookworms, whipworms, and roundworms. Worms cause intestinal bleeding, which is not always noticeable in faeces, and is especially damaging to growing children. [40] Malaria, hookworms and vitamin A deficiency contribute to anemia during pregnancy in most underdeveloped countries [40]. Diagnosis, cause and treatment of anemia [41] : In the below table different types of anemia, description, causes, and their diagnosis and treatments are described. Iron-deficiency anemia (or iron-deficiency anaemia) is a common anemia (low red blood cell or hemoglobin levels) caused by insufficient dietary intake and absorption of iron, or iron loss from bleeding which can be from a variety of sources such as intestinal, uterine or from the 41

ISSN: 2348 –0882 ========================================================================== Int. J. Pharm. Res. Sci., 2014, 02(1), 37-41. Type of anemia Aplastic anemia Thalassemia Hemolytic anemia Sickle cell anemia Description Bone marrow fails to produce different type of blood cells Diagnosis Bleeding in mucous membranes, gingivitis, and shortness of breath. Irregular production Affect equally of hemoglobin there males and are two types of females, both thallesemia i.e major types of and minor thalassemia are found in an area of northern Africa and southern Europe. Premature Considered destruction of RBC’s when there is marked increase in red blood cells production by bone marrow. Inherited type of anemia, sickleshaped RBC has impaired ability tosqueezethrough vessels. Short lifespan of RBC (1020 days) Causes Treatments Known causes are hereditary conditions (fanconi’s anemia), HIV virus, hepatitis, rheumatoid arthritis. Transfusion, bone marrow or stem cell transplantation, immunosuppressant drugs Thalassemia major is more common in families who intermarry Transfusions to supply enough red blood cells to achieve moderate anemia and avoid iron overload are standard approaches for thalassemia major. Causes associated with disorders such as systemic lupus erythematosus, lymphoma, and paroxysmal nocturnal hemoglobinuria. Other causes are high exposure to certain metals or chemicals. Joint and bone Disease and genetic pain, infections, trait occurs primarily and heart in people of African failure can descent and people occur. from India and Mediterranean regions. Corticosteroids for autoimmune anemia, immunosuppressive drugs may be used. Transfusion is used in many cases. Measures to avoid cycling and control pain. Including hydration, hydroxyurea, NSAIDs and narcotic analgesics. Bone marrow transplantation 37

ISSN: 2348 –0882 ========================================================================== Int. J. Pharm. Res. Sci., 2014, 02(1), 37-41. Sideroblastic anemia Group of anemia caused by impaired ability of bone marrow to produce RBC’S Symptoms of anemia are jaundice, enlarged liver and spleen, fever, headache, loss of appetite, vomiting, and leg sores. Table. 2 Herbal treatment for anemia [42]: Herbal medicines are the oldest remedies known to mankind. The demand for herbal products is growing exponentially throughout the world because herbal drugs having no side effects as compare to other drugs and major pharmaceutical companies are currently conducting extensive research on plant materials for their potential medicinal value some herbal drugs are given below. Table. 3 Herbal drugs Work Ash gourd Ash gourd can prevent the risk of anemia by checking the amount of blood lost from the lungs, nose and if there are piles Celery Celery has a high quantity of iron and magnesium content. Iron is a component of Heme, which necessary for the production of hemoglobin in the blood Chicory Chicory is an effective tonic for the blood Fenugreek Its leaves are helpful in building the volume of blood in the body Onion Onion has rich iron content. Hence onion is the most effective remedy for anemia Caused by excessive Deferoxamine, and alcohol use, certain Folate , pyridoxine are medications, including used, chloramphenicol, or other disorders, including some cancers and rheumatoid arthritis. More common in the elderly Homeopathic treatment for anemia [43]: Homeopathic treatments are used since ancient time in India and other countries. It is popular because of its availability, cheap in cost and mostly due to fewer side effects. Few drugs and their contribution is mentioned in the below table .4 Oral iron supplements: There are two forms of supplemental iron: ferrous and ferric. Ferrous iron is better absorbed and is the preferred form of iron tablets. Ferrous iron is available in three forms: ferrous fumarate, ferrous sulfate, and ferrous gluconate. A 325 mg iron supplement contains the following amounts of elemental iron depending on the type of ironFerrous fumarate. 108 mg of elemental iron, Ferrous sulfate 65 mg of elemental iron, Ferrous gluconate ,35 mg of elemental iron. Dosage: Depending on the severity of your anemia, as well as your age and weight, your doctor will recommend a dosage of 60 - 200 mg of elemental iron per day. This means taking one iron pill 2 - 3 time during the day. Side Effects and Safety: Common side effects of iron supplements include- Constipation and 38

ISSN: 2348 –0882 ========================================================================== Int. J. Pharm. Res. Sci., 2014, 02(1), 37-41. diarrhea are very common, Nausea and vomiting, Black stools are normal when taking iron tablets. Supplements: A healthy diet, rich in iron, must be consumed. Whole grain cereals, legumes and pulses are good sources of iron. Anemia that is caused due to deficiency of vitamins can be avoided by a proper intake of vitamins in the diet. Consult a diet chart for better guidance. Pregnant women can take multivitamin pills and other nutritional supplements at the advice of the doctor. Beetroot is also very good source of iron intake. Conclusion: This review contains different type of anemiasickle cell anemia, hemolytic anemia, pernicious anemia, iron deficiency anemia, aplastic anemia and Thalassemia and the ways by which they cause, diagnose, and treated. Acknowledgment: We would like to thank the University for providing the resources to carry on our research and our teachers and friends for their support. Drugs Works Ferrumetallicum It’s a great homeopathic remedy but it will not cure every case of anemia Pulsatilla it’s the great antidote to iron and hence is indicated in the anemic condition produced by large or continued doses of it Calcareacarbonica Use in anemic and debilited condition Arsenicum Being a direct poison to the RBC takes first rank in case of pernicious anemia or anemia due to a material of toxic influence Helonias An excellent remedy in anemia and chlorosis it suits especially anemia from prolonged hemorrhage in women Secale This remedy produces a progressive general anemia it shown by the peculiar cachexia of anemia, pale, bloodless jaundiced color Natrummuriaticum This is one of the best remedies in anemic conditions there is paleness and inspite of the fact that the patient eats well, there is emaciation Table. 4: Few drugs and their contribution 38

ISSN: 2348 –0882 ========================================================================== Int. J. Pharm. Res. Sci., 2014, 02(1), 37-41. References 1. Yap GS, Steverson MM, inhibition of in vitro erythropoesis by solube mediators in plasmodium chanbaundi as malaria: lack of a major role of interleukin, tumor necrosis factor alpha and gamma INF infect immune 1994:62:357-62. 2. Eschbach JW,anemia management in chronic kidney disease: role of factor affecting epoetin responsiveness, J am soc Nephrol 2002: 13:1412-4. 3. Power A, Silberstein LE, autoimmune hemolytic anemia, in: Hoffman R, Benj EJ, shuttle, et al hematology, 5ed 2008 chap 47. 4. Antony AC, Megaloblastic anemias. In: Hoffman R, Benj EJ, still SS, et al., Eds. Hematology: basic principles and practice. 5 Ed Philadelphia, Pa: Elsevier Churchil Livingstone: 2008: chap 39 5. power a, Silberstein LE, autoimmune hemolytic anemia, in: Hoffman R, benj EJ, shattil, et al hematology, 5ed 2008 chap 47 6. Oniyangi,O.andOmari,A.A.(2006)Malaria, chemoprophylaxis in sickle cell disease. Cochrane Database Syst. Rev. 2006, CD003489 7. Tesoriere L, D'Arpa D, Butera D, Allegra M, Renda D, et al. (2001) Oral supplements of vitamin E improve measures of oxidative stress in plasma and reduce oxidative damage to LDL and erythrocytes in beta-thalassemia intermedia patients. Free Radic Res 34: 529–540. 8. Mason, B.J.,Heyser, C.J (2010) Acamprosate: a prototypic neuromodulator in the treatment of alcohol dependence. CNS & neurological disorder drug targets, 9(1): 23-32 9. Thomason, Ronald W.; Almiski, Muhamad S. (April 2009). "Evidence That Stainable Bone Marrow Iron Following Parenteral Iron Therapy Does Not Correlate With Serum Iron Studies and May Not Represent Readily Available Storage Iron". American Journal of Clinical Pathology 131 (4): 580–585. doi:10.1309/AJCPBAY9KRZF8NUC. PMID 19289594. Retrieved 2009-05-04. 10. Kasper, Dennis L; Braunwald, Eugene; Fauci, Anthony; et al. (2005). Harrison's Principles of Internal Medicine, 16th ed. New York: McGraw-Hill. ISBN 978-0-07140235-4 11. L,Itano HA,et al. Sickle cell anemia, a molecular disease. Science 1949:109:443. 12. Bunn HF,Pathogenesis and treatment of sickle cell anemia. New Eng J Med 1997 13. National heart, lung, and blood institute . the management of sickle cell disease. 4th edition: 2002. 14. 15. Williams TN, Uyoga S, Macharia A, et al. Bacteraemia in Kenyan children with sickle-cell anaemia: a retrospective cohort and case-control study. Lancet 2009; 374:1364-70. 16. Dunlop RJ, Bennett KC. Pain management for sickle cell disease. Cochrane Database Syst Rev 2006:CD003350. 17. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children With sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998; 339:5-11. 18. Salvidio, E.; Pannacciulli, I; Tizianello. A.; Gaetani, G.F.;Paravidino,G.:Glucose39

ISSN: 2348 –0882 ========================================================================== Int. J. Pharm. Res. Sci., 2014, 02(1), 37-41. 6-phosphatedehydrogenase deficiency in Italy. Acta haemat. 41: 331-340(1969). 19. Packman CH. Hemolytic Anemia Resulting from Immune Injury. In:Williams Hematology Lichtman MA, Beutler E, Kipps TJ, Seligsohn U, Kaushansky K, Prchal JT, eds. Mc Graw Hill Professional, Philadelphia, 2005:729– 51. 20. power a, Silberstein LE, autoimmune hemolytic anemia, in: Hoffman R, benj EJ, shattil, et al hematology, 5ed 2008 chap 47) 21. Schwartz RS. Autoimmune and intravascular hemolytic anemias. In: Goldman L, Ausiello D, eds. Cecil Medicine. 24th ed. Philadelphia, Pa: Saunders Elsevier; 2011:chap 163. 22. Henry JB: Clinical Diagnosis and Management by Laboratory Methods, 20th ed. Saunders, 2001) 23. Schrier SL, price EA, extrinsic no immune hemolytic anemias, in: Hoffman r, et al hematology basic principle and practices 5 Ed, 2008. chp 48) 24. UN children’s fund U, WHO. Iron deficiency anemia assessment prevention & control: WHO 2001. 25. Healthy people 2010, US government 2000. 26. Dieckmann WJ, Wegner CR, the blood in normal pregnancy, blood & plasma volume arch intern med 1934. 27. Rasmussen there a causal relationship between iron deficiency or iron deficiency anemia and weight at birth, length of gestation abd perinial mortality? J Nutr 2001:131(2S-2): 590S-601S. 28. Ac¸kurt F, Wetherilt H, Lo¨ker M, et al. Biochemical assessment of nutritional status in pre- and post-natal Turkish women and outcome of pregnancy. Eur J Clin Nutr 1995; 49(8):613–22. 29. Online 'Mendelian Inheritance in Man' (OMIM) 30. Online 'Mendelian Inheritance in Man' (OMIM) 141850 31. Gajewski JL, Champlin RE: How to manage severe aplastic anemia May1994:69–82. 32. Young NS, aplastic anemia in young NS ed – the bone marrow failure syndrome Philadelphia PA-W B saunders 1997. 33. 34. Chen J, Young NS. An immune model of bone marrow failure mediated by disparity in Minor histocompatibility Blood. 2004 35. Selleri C, Maciejewski JP, Sato T, Young NS. Interferon-_ constitutively expressed in the stromal microenviroment of human marrow cultures mediates potent hematopoietic inhibition. Blood. 1996; 87:4149-4157 36. Maciejewski JP, Selleri C, Anderson S, Young NS. Fas antigen expression on CD34_ human marrow cells is induced by interferon-gamma andtumor necrosis factor-alpha and potentiates cytokinemediated hematopoietic suppression in vitro.Blood. 1995; 85:3183-3190. 37. Chen J, Young NS. A murine model of bone marrow failure mediated by disparity in minor histocompatibility antigens Blood. 2004; 106:12a. Abstract 132. 38. Review of numbers of infections 39. Calis JC, Phiri KS, Faragher EB et al. (2008). "Severe anemia in Malawian children". N. Engl. J. Med. 358 (9): 888– 99. 40. Dreyfuss ML, Stoltzfus RJ, Shrestha JB et al. (2000). "Hookworms, malaria and vitamin A deficiency contribute to anemia and iron deficiency among pregnant 40

ISSN: 2348 –0882 ========================================================================== Int. J. Pharm. Res. Sci., 2014, 02(1), 37-41. women in the plains of Nepal". J. Nutr. 130 (10): 2527–36.). 41. Zuckerman KS. Approach to the anemias. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed. Philadelphia, Pa: Saunders Elsevier; 2007:chap 162. 42. anemia 43. 41

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