Folate deficiency during pregnancy, pernicious anemia, stem cell factor, neutrophils, hematology, hemostasis, platelets

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Biomedical Science
BMS 460
D.Rao Veeramachaneni

27 September Folate deficiency during first two months of pregnancy may result in neural tube defects Women with reduced activity of 5,10-methylene-tetrahydrofolate reductase exhibit elevated levels of homocysteine and are at risk for bearing children with neural tube and other birth defects, e.g., spina bifida Pharmacologic doses of folic acid have been shown to reduce the incidence of neural tube defects by lowering plasma levels of homocysteine Methylenetetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10- methyleneTHF to 5-methylTHF, a cosubstrate for homocysteine remethylation to methionine Folate → dihydrofolate → tetrahydrofolate ↔ methylene-THF → methyl-THF Homocysteine is a teratogen for the CNS and heart Failure to recycle homocysteine into methionine or to convert it into cysteine results in elevated levels of homocysteine Mutations in MTHFR gene causes deficiency of this enzyme, the most prevalent inborn error of folate metabolism, and has variable clinical manifestations from asymptomatic to severe psychomotor retardation, microcephalus and seizure. The enzymatic block can be bypassed by a secondary pathway using betaine (trimethylglycine) as a substrate Pernicious Anemia B 12d/or folate deficiency Vitamin B 12d folate (B ) 9re essential for DNA synthesis A deficiency of these nutrients impairs maturation of hematopoietic cell precursors resulting in anemia, leukopenia, and thrombocytopenia B 12nds to intrinsic factor (IF) secreted by gastric mucosa, absorbed in ileum, and transported to bone marrow No IF secretion due to autoimmune gastric mucosal atrophy No absorption of vitamin B 12 Megaloblastic anemia associated with B defi12ency is almost always associated with absorption problems whereas in folate deficiency it is nutritional Body reserves of B 12 last for years whereas folate reserves are modest and a deficiency may arise within months Causes of B d12iciency Nutritional deficiency (rare) Gastrectomy Atrophic gastritis Intestinal blind loop Fish tape worm Ileal resection Crohn’s disease Causes of folate deficiency Nutritional deficiency Malabsorption syndromes Celiac disease Tropical sprue Jejunal resection Drugs, alcohol Pregnancy, lactation B12 meat, soy, eggs, dairy Folate – vegetables, fruits; absorbed in duodenum, jejunum Stem Cell Factor (SCF; c-kit ligand) and its Receptor (c-kit receptor) Hematopoietic growth factors Each cell lineage is under the control of its own set of glycoprotein growth factors (cytokines) Stem cell factor (SCF; also known as c-kit ligand) A protein ligand produced by fetal tissues and stromal cells of the bone marrow Binds to the stem cell factor receptor (c-kit receptor), a tyrosine kinase, and activates it to phosphorylate different substrates; i.e., by itself is a weak stimulator of hematopoiesis but makes hematopoietic stem cells responsive to other cytokines Blocking the ATP-binding site prevents the phosphorylation of substrates involved in down-stream signaling Target to treat leukemias A mutation in genes expressing the components of SCF receptor-ligand complex Causes anemia Affects melanocyte development and survival of primordial germ cells in fetal testis and ovary Typical life span of neutrophils, platelets, and red blood cells and their bone marrow precursors In peripheral blood Granulocytes – 50% stored, 50% functional; 6 – 12 days Platelets – 30% stored, 70% functional; 8 – 10 days Erythrocytes – all functional, 120 days In peripheral tissues Granulocytes – 2-3 days Blood contains young (band cells) and old neutrophils (cells with five segmented nuclei), but most have nuclei with three segments Approximately 6% of all circulating WBCs are non-segmented (band cells), whereas all others undergo nuclear segmentation As they age their nuclei become more segmented, and the oldest ones have five segments Arneth Index Segmentation of nuclei of neutrophils can be used to examine the average age of neutrophils Left shift indicates that fewer nuclei are segmented; i.e., there is a prevalence of young PMNs – an infection is in progress Right shift indicates that there are more aging PMNs – relative lack of blood- forming activity (in liver disease and advanced pernicious anemia) Hematology Plasma is the clear yellowish fluid remaining after the cells have been removed, and serum refers to the fluid and solutes remaining after the cells and fibrinogen have been removed Serum is best defined as defibrinated plasma, which means it does not clot and cannot be used for study of coagulation factors and substances entrapped in the fibrin meshwork of the clot Total body weight 8% blood 92% other fluids and tissues Whole blood – percentage by volume 55% plasma 45% formed elements Plasma – percentage by weight 7% proteins 91% water 2% other solutes Formed elements – number per cubic mm 140,000-340,000 platelets 5,000-9,000 leukocytes 4.2-6.2 million erythrocytes Proteins in plasma 54% albumins 38% globulins 4% fibrinogens 1% prothrombin Other solutes in plasma Ions Nutrients Waste products Gases Regulatory substances Leukocytes 60-70% neutrophils 20-25% lymphocytes 3-8% monocytes
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