Blood cells – oxygenation of tissues, coagulation, protection against infection tissue repair

Hematopoietic Factors-Erythrocyte

-vitaminB12, folate-iron-erythropoietin

-platelet -oprelvekin (IL-11)

-granulocyte -filgrastin (G-CSF)-sargramostin (GM-CSF)

Cobalamin VitaminB12 dTMP SYNTHESIS – biochemical reactions that produce deoxythymidylate (Dtmp)

Dtmp – essential constituent of DNA synthesis

Cycle of Cobalamin Synthesis –Dihydrofolate to tetrahydrofolate by dihydrofolate reductase

G-CSF(granulocyte colony-stimulating factor) – a hematopoetic growth factor that regulates production and fx of neutrophils

GM-CSF(granulocyte-macrophage colony-stimulating factor) – hematopoetic growth factor that regulates production of granulocytes and other myeloid cells

Granulocytes-Basophils-Eosinophils-Neutrophils

Hemochromatosis – condition of chronic excess total body iron caused either by an inherited abnormality of iron absorption or by frequent transfusions to treat certain types of hemolytic disorders (ex. Thalassemia major)

Megaloblastic Anemia - deficiency in serum hemoglobin and erythrocytes in which the erythrocytes are abnormally large.

-results from either folate or VitB12 deficiency anemia

**Pernicious Anemia – FORM of megaloblastic anemia resulting from deficiency of intrinsic factor, a protein produced by gastric mucosal cells and required for intestinal absorption of VitB12

Microcytic Anemia – deficiency in serum hemoglobin and erythrocytes in which the erythrocytes are abnormally smalle

-caused by iron deficiency

Neutropenia – abnormally low number of neutrophils in the blood; patiens are susceptible to serious infection

Thrombocytopenia – abnormally low number of platelets in the blood; patients with thrombocytopenia are susceptible to hemorrhage

BLOOD CELL DEFICIENCIES

Iron Deficiency Anemia

Microcytic HypoChromic anemia – caused by iron deficiency (the most common type of anemia)

Megaloblastic Anemias – caused by deficiency of vitamin b12 or folic acid, cofactors required for the normal maturation of red blood cells.

Pernicious Anemia – the most common type of vitamin b12 deficiency anemia, caused by a defect in the synthesis of intrinsic factor, a protein required for efficient absorption of dietary VitB12, or by surgical removal of that part of that stomach that secretes intrinsic factor

Other Blood Cell Deficiencies*deficiency in the concentration of lineages of blood cells can be a manifestation of disease or side-effects of radiation or cancer chemo*recombinant DNA-directed synthesis of hematopoetic growth factors now makes possible the treatment of patients with deficiencies in NEUTROPHILS, ERYTHROCYTES and PLATELETS, which some of these growth factors play an important role in hematopoetic stem cell transplantation

IRON-essential metallic component of heme (molecule responsible for the bulk of oxygen transported in the blood)-most iron contained in hemoglobin-some are bound to transferrin (transport protein) and ferritin (storage protein)-deficiency of iron occurs most often in women because of menstruation, vegetarians and malnourished persons coz of inadequate iron intake-children and preggy have increased requirements for iron-excessive amounts are highly toxic-no mechanism for efficient absorption of iron, regulation of body iron content occurs through modulation of intestinal absorption

ABSORPTION, TRANSPORT AND STORAGE OF IRON-intestinal epithelial cells actively absorb inorganic iron via DMT1 (divalent metal transporter) and heme iron via the HCP1 (heme carrier protein 1)-iron that is absorbed and released from absorbed heme iron is actively transported into the blood by ferroprotein

(FP) or complexed with apoferritin (AF) and stored as ferritin- iron is transported by transferrin (Tf) to erythoid precursors in the bone marrow for synthesis of hemoglobin (Hb) or to hepatocytes for storage as ferritin-transferrin iron complex binds to transferrin receptors (TfR) in erythroid precursors and hepatocytes and internalized-after release of iron, TfR-tF complex is recycled to the plasma membrane and Tf is released-Macrophages that phagocytize senescent erythrocytes (RBC) reclaim the iron from RBC hemoglobin and either export ir or store it as ferritin

Hepatocytes use several mechanisms to take up iron and store the iron as ferritin, ferroxidase (FO), ferroportin (FP), ferrireductase (FR)

IRON ABSORPTION-Dietary iron in the form of heme and ferrous ion (Fe2+) are taken up by a divalent metal transporter 1 (DMT1) in intestinal epithelial cells-intestinal cell iron is stored as ferrtin or ferrous iron is transported across basolateral membrane by ferroportin and oxidized to ferric iron (Fe+3) by ferroxidase

TRANSPORT AND STORAGE-ferric iron is transported in a complex with transferritin- excess iron is stored in the protein-bound form in gastrointestinal epithelial cells, macrophages and hepatocytes, parenchymal cells of the skin, heart and other organs

ELIMINATION-minimal amounts of iron are lost from the body with sweat and saliva and in exfoliated skin and intestinal mucosal cells

CLINICAL USE-PREVENTION OR TREATMENT of iron deficiency anemia -iron deficiency can be diagnosed from red blood cell changes (microcytic cell size due to diminished hemoglobin content) and from measurements of serum and bone marrow iron stores-dietary ferrous iron supplementation w/ ferrous sulfate, ferrous gluconate and ferrous fumarate- parenteral administration of colloid containing a core of iron oxyhydroxide surrounded by a core of carbohydrate, include iron dextran, sodium ferric gluconate complex¸iron sucrose-should not be given in hemolytic anemia because iron stores are elevated, not depressed

SIGNS AND SYMPTOMS-necrotizing gastroenteritis shock, metabolic acidosis, coma and death (acute) – most common in children as a result of accidental ingestions of iron supplmentation

-hemochromatosis --- due to frequent transfusions (chronic iron overload) – damages heart, liver, pancreas – often occurs in persons with inherited abnormality or iron absorption and those who receive frequent transfusions for treatment of hemolytic disorders (thalassemia major)

TREATMENT-(acute) removal of unabsorbed tablets from the gut, correction of acid-base and electrolye abnormalities, parenteral administration of deferoxamine-(chronic) phlebotomy, iron chelator such as deferozamine or deferasirox

VITAMIN B12-COBALAMIN-cobalt-containing molecules-cofactor in the transfer of 1-carbon units, a step necessary for the synthesis of DNA-deficiency of Vitaminb12 manifests first as anemia-deficiency can cause neurologic defects

VITAMINB12 PHARMACOKINETICS-PRODUced only in bacteria-cannot be synthesized by multicellular organism-absorbed from the gastrointestinal tract in the presence of intrinsic factor (a product of parietal cells of the stomach)-plasma transport is accomplished by transcobalamin II-stored in the liver in large amounts (5years)-cyanocobalamin and hydroxocobalamin-hydroxocobalamin has longer half-life

VITAMIN B12 PHARMACODYNAMICS-CONVERSION of methylmalonyl-coenzyme A(CoA) to succinyl-CoA -conversion of homocystein to methionine, which is linked to folic acid metabolism and synthesis of deoxythymidylate (dTMP), a precursor required for DNA synthesis-in vb12 deficiency, folates accumulate as N5-methyltetrahydrofolate, the supply of tetrahydrofolate is depleted and production of erythrocytes slow.-administration of folic acid to patients with vb12 helps refilltetrahydrofolate pool and corrects anemia-exogenous folic acid does not correct neurologic defects of vb12 def

CLINICAL USE AND TOXICITY-2 Types of vitaminb12 : hydroxocobalamin and cyanocobalamin-treatment of pernicious anemia and anemia caused by gastric resection-vitaminb12 deficiency anemia is caused by inadequate absorption, therapy should be by replacement of vitaminb12 by parenteral therapy

FOLIC ACID-REQUIRED for normal DNBA synthesis, and deficiency usually represents as megaloblastic anemia-deficiency in folic acid during pregnancy increases the risk of neural tube defects in the fetus

PHARMACOKINETICS FOLIC ACID-ABSORBED From the gastrointestinal tract-modest amounts are stored in the body, so a decrease in dietary intake is followed by nemia within a few months

PHARMACODUNAMICS FOLIC ACID-FOLIC acid converted to tetrahydrfolate by dihydrofolate reductase-dTMP cycle which supplies the dTMP required for DNA synthesis-rapidly dividing cells are highly sensitive to folic acid deficiency-antifolate drugs – used for treatment of various infections and cancers

CLINICAL USE AND TOXICITY-DEFIciency caused by dietary insufficiency and malabsorption-oral folic acid supplementation-maternal folic acid deficiency associated with increased risk of neural tube defects in fetus, folic acid supp is recommended before and during pregnancy-folic acid corrects the anemia but not the neurologic deficits of vitb12 deficiency-vitb12 must be ruled out before folic aic is selectd as the sole therapeutic agent in the treatment of a patient with megaloblastic anemia-no recognized toxicity

HEMATOPOIETIC GROWTH FACTORS-SEVErAL growth factors, produced by recombinant DNA technology, have FDA approval for treatment of patients with blood cell deficiencies

ERYTHROPOIETIN-PROduced by the kidney-reduction in its synthesis is responsible for the anemia of renal failure-through activation of receptors on erythroid progenitors in the bone marrow, it stimulates the production of red cells and increases their release from the bone marrow-acute toxicity is minimal- hemoglobin level is 12g/dL-increased hematocrit = increased risk of thrombosis and cardiovascular events

DARBAPOETIN ALFA-GLYCOSYLATED FORM OF ERythropoeitin-longer half-life

METHOXYPOLYETHYLENE GLYCOL-EPOETIN

-long-lasting form of erythropoietin that can be administered once or twice a month

RECOMBINANT HUMAN ERYTHROPOIETIN (epoetin alfa)-for the anemia associated with renal failure and effective for patients with other forms of anemia (primary bone marrow disorders or anemias secondary to cancer chemotherapy or HIV treatment, bone marrow transplantation, AIDS, cancer)-complications are hypertension and thrombosis-serum hemoglobin concentration of patients treated with erythropoietin should not exceed 12g/dL coz hemoglobin concentrations above this target have been linked to an increased rate of mortality and cardiovascular events

MYELOID GROWTH FACTORS-Filgrastin (granulocyte colony-stimulating factor/G-CSF) and sargramostim (granulocyte-macrophage colony-stimulating factor/GM-CSF) stimulate production and fx of neutrophiols-GM-CSF stimulates production of myeloid and megakaryocyte progenitors-G-CSF sometimes GM-CSF mobilize hematopoietic stem cells (increase their concentration In peripheral blood)-both growth factors are used to accelerate the recovery of neutrophils after cancer chemo and treat forms of secondary and primary neutropenia (aplastic anemia, congenital neutropenia)-if given to patients after autologous stem celltransplantation, G-CSF reduce time to engraftment and the duration of neutropenia, and also used to mobilize the peripheral blood stem cells in prep for autologus and allogeneic stem cell transplantation-toxicity of G-CSF is minimal-can cause bone pain-GM-CSF can cause fever, arthralfias, capillary damage with edema-Pegfilgrastim, a covalent conjugation product of filgrastim and PEG, has much longer serum half-life than recombinant G-CSF

MEGAKARYOCYTE GF-Oprelvekin (interleukin 11[IL-11]) stimulates growth of primitive megakaryocytic progenitors and increases number of peripheral platelets-IL-11 is used for treatment of patients who have had episode of thrombocytopenia after cancer chemo.-it reduces the need for platelet transfusions.-adverse effects of IL-11 are fatigue, headache, dizziness and fluid retention

-Romiplostin is a novel megakaryocyte gf that depends on peptide selected from a peptide library on bases of thrombopoietin receptor activation.-approved for treatment of patients with chronic idiopathic thrombocytopenia who have failed to respond to conventional treatment-halflife : 3-4days