Coagulants, Hemostatics, Hematinics

Lecturer: Dr. Guevarra
Hematinics • agents that tends to stimulate blood cell formation or to increase the hemoglobin in the blood Hemostasis and Hemostatics • finely regulated dynamic process of maintaining fluidity of the blood, repairing vascular injury, and limiting blood loss while avoiding vessel occlusion (thrombosis) and inadequate perfusion of vital organs • dysregulated hemostasis include hereditary or acquired defects in the clotting mechanism and secondary effects of infection or cancer • agents that maintains hemostasis are called hemostatics Coagulants • exogenous substances used to promote blood coagulation. The endogenous blood coagulation factors are considered to be coagulants only when administered as drugs Blood • blood volume: 4-4.5L in females ; 4.5-5L in males • functions includes: – transport of various molecules (O2, CO2, nutrients, metabolites, vitamins, electrolytes, etc.), – heat (regulation of body temperature) – transmission of signals (hormones) – buffering – immune defense • Red blood cells (RBCs) - transport O2 and pH regulation • White blood cells (WBCs) - divided into neutrophilic, eosinophilic and basophilic, granulocytes, monocytes, and lymphocytes. (Neutrophils play a role in nonspecific immune defense; monocytes and lymphocytes participate in specific immune responses) • Platelets (thrombocytes) – hemostasis Hematopoiesis • production from undifferentiated stem cells of circulating erythrocytes, and platelets • produces over 200 billion new blood cells/d in the normal person and more in conditions that cause loss or destruction of blood cells • requires iron, folic acid, cobalamin and growth factors for proliferation and differentiation of blood cells

Date: December 16 , 2009

Erythropoiesis • The young red cell is called a retlculocyte and normally takes about 4 days to mature into an erythrocyte. • In health, erythropoiesis is regulated and maintained within a narrow range. • <l% of the body's total red blood cells are produced/day • It is stimulated by hypoxia. However, oxygen lack does not act directly on the haemopoietic tissues but instead stimulates the production of a hormone, erythropoietin and other hematopoietic factors. Hematopoietic Growth Factors • glycoprotein hormones that regulate the proliferation and differentiation of hematopoietic progenitor cells in the bone marrow • includes erythropoietin (epoetin alfa), granulocyte colonystimulating factor (G-CSF), granulocyte-macrophage colonystimulating factor (GM-CSF), and interleukin-11 (IL-11) G-CSF and GM-CSF • is produced by endothelium, macrophages, and a number of other immune cells • The natural human glycoprotein exists in two forms • is present on precursor cells in the bone marrow, and, in response to stimulation by this factor, initiates proliferation and differentiation into mature granulocytes

Myeloid Growth Factors

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for example. which is corrected when IF is Page 2 of 8 NICOLE LALUCES®KARLA LIGERALDE®ABBY MARALIT®MON PALMA®VIRRA ROSALES®VIN SANCHEZ VINCENT REOLALAS®AURORA AUREA REYES . • The Schilling test. growth factors and transfusion • megaloblastic anemia • typical finding is macrocytic anemia. Ferrous iron that is absorbed or released from absorbed heme iron in the intestine is actively transported into the blood or complexed with apoferritin and stored as ferritin • In the blood. plasma erythropoietin levels are increased. which measures absorption and urinary excretion radioactively labeled VitB12. often with associated mild or moderate leucopenia or thrombocytopenia (or both). megaloblastic anemia. anemia can also be caused by defective production of erythropoietin as. ataxia. in renal disease • a deficiency in oxygen-carrying erythrocytes. ans other CNS dysfunctions • Once a diagnosis of megaloblastic anemia has been made. • It occurs when the erythropoietic tissues cannot supply enough normal erythrocytes to the circulation. folic acid. Transport and Storage of Iron: • Intestinal epithelial cells actively absorb inorganic iron and heme iron. the TfR-Tf complex is recycled to the plasma membrane and Transferrin is released • Macrophages that phagocytise senescent erythrocytes (RBC) reclaim the iron from the RBC haemoglobin and either export it or store it as ferritin Iron storage and cycling Iron absorption Absorption. increased destruction and when demand exceeds capacity. ie. but it is significantly less efficacious than G-CSF in this regard Iron • The transferrin – iron complexes (TfR-Tf) bind to transferring receptors in erythroid precursors and hepatocytes and are internalized • After release of the iron. iron is transported by transferrin to erythroid precursors in the bone marrow for synthesis of haemoglobin or to hepatocytes fro storage as ferritin Anemia • There is a reduction in blood hemoglobin concentration due to a decrease in the number of circulating erythrocytes and/or in the amount of hemoglobin they contain. hemolytic anemia. it must be determined whether Vit B12 or Folic Acid deficiency is the cause can be accomplished by measuring serum levels of the vitamins. hemoglobinopathies etc • treatment: supplementation of iron. cobalamin. • However. to increase their concentration in peripheral blood • GM-CSF’s biologic actions: – Multipotential hematopoietic groth factor that stimulates proliferation and differentiation of early and late granulocytic progenitor cells as well as erythroid and megakaryocyte progenitors – stimulates the function of mature neutrophils – together with interleukin-2 stimulates T-cell proliferation and appears to be a locally active factor at the site of inflammation – it also mobilizes peripheral blood stem cells. • In anemias due to abnormal red cell production. can be used to further define the mechanism of VitB12 malabsorption when this is found to be the cause of the megaloblastic anemia • Pernicious Anemia – results from defective secretion of IF by the gastric mucosal cells • The Schilling test shows diminished absorption of radioactively labeled Vit B12. a characteristic hypercellular bone marrow with an accumulation of megaloblastic erythoid and other precursor cells • group of disorders characterized by the presence of distinctive morphologic appearances of the developing red cells in the bone marrow • cause is deficiency of either cobalamin (vitamin B12) or folate or genetic or acquired abnormalities affecting the metabolism of these vitamins or defects in DNA synthesis not related to cobalamin or folate • • Neurologic syndrome associated with Vit B12 deficiency usually begins with paresthesias and weakness in peripheral nerves and progress to spasticity. is the most common and can easily be treated • includes iron deficiency anemia.• G-CSF stimulates proliferation and differentiation of progenitors already committed to the neutrophil lineage and and prolongs their survival in the circulation • also has a remarkable ability to mobilize hematopoietic stem cells.

transcobalamin II • excess vitamin B12 is transported to the liver for storage Indication/Dosage • Oral preparations: 5001000 µg • parenteral injection is available as cyanocobalamin or hydroxocobalamin • 100-1000 µg of vitamin B12 IM daily or every other day for 1-2 weeks then maintenance therapy consists of 100-1000 µg IM once a month for life • if neurologic abnormalities are present. dyspepsia due to gastric mucosa atrophy • Neurological abnormalities • Optic atrophy • Mental disturbances Additional Notes • serves as a cofactor for several essential biochemical reactions in humans • consists of a porphyrinlike ring with a central cobalt atom attached to a nucleotide • deoxyadenosylcobalamin and methylcobalamin are the active forms • Cyanocobalamin and hydroxocobalamin and other cobalamins found in food sources are converted to the active forms • ultimate source of vitamin B12 is from microbial synthesis • Sources: certain microorganisms that grow in soil.administered with radioactive B12. legumes which are contaminated by bacteria producing Vitamin B12 • Metabolic functions: o Essential for normal maturation of erythroblasts and epithelial cells o Propionate catabolism Page 3 of 8 NICOLE LALUCES®KARLA LIGERALDE®ABBY MARALIT®MON PALMA®VIRRA ROSALES®VIN SANCHEZ VINCENT REOLALAS®AURORA AUREA REYES . since the vitamin can then be normally absorbed COBALAMIN Mechanism of action: • (cobalamin) serves as a cofactor for the enzyme methylmalonyl CoA mutase • (mecobalamin or methylcobalamin) serves as a cofactor for the enzyme methionine synthase • Necessary for the transfer of methyl groups Name of Drug Cyanocobalamin Injection Hydroxycobalamin Mecobalamin Pharmacokinetics • average diet contains 5-30 µg of vit B12 daily • 1-5 µg of which is usually absorbed • Storage: liver 3000-5000 µg • Complexes with intrinsic factor (produced by parietal cells). maintenance should be given every 1-2 weeks for 6 months before switching to monthly injections • oral cobalamins are not used to treat Vit B12 deficiency with neurologic manifestations but can be used for pernicious anemia (500µg BID) • Megaloblastic anemia GITglosstits. water. or in the intestinal lumen of animals. complex is absorb in the distal ileum by a receptor-mediated transport system • daily requirement: 2 µg • Vit B12 deficiency results from malabsorption due to either lack of IF or to loss or malfunction of the specific absorptive mechanism in the distal ileum • bound to a plasma glycoprotein.

• Excretion: urine and stool • folic acid deficiency and megaloblastic anemia can develop within 1-6 months after the intake of folic acid stops Indication • megaloblastic anemia • oral preparations: • 400 µg folic acid daily for adults are satisfactory • 600 µg for pregnant women • 500 µg for nursing mothers Additional notes • Metabolic function: thymydilate synthesis Iron deficiency anemia • most common cause of chronic anemia and one of the most prevalent forms of malnutrition • Stages: • negative iron balance • iron-deficient erythropoiesis • iron deficiency anemia clinical manifestation: pallor. and green vegetables. dizziness. • Long term therapy with phenytoin can also cause folate deficiency. increased cardiac output. but only rarely causes megaloblastic anemia FOLIC ACID Mechanism of action: • provide precursors for the synthesis of amino acids. and to a lesser extent. other generalized symptoms of tissue hypoxia. vasodilation Page 4 of 8 NICOLE LALUCES®KARLA LIGERALDE®ABBY MARALIT®MON PALMA®VIRRA ROSALES®VIN SANCHEZ VINCENT REOLALAS®AURORA AUREA REYES . tachycardia. kidney. trimethoprim and pyrimethamine.Clinical Pharmacology: • Folate deficiency results in megaloblastic anemia that is microscopically indistinguishable from the anemia caused by Vit B12 deficiency • Folic acid deficiency is often caused by by inadequate dietary of intake of folates. purines. exertional dyspnea. liver. • Folic acid deficiency can be caused by drugs. fatigue. and DNA Name of drug Folic acid Pharmacokinetics • average diet contains 500-700 µg of folates daily. • 50-200 µg of which is usually absorbed in proximal jejunum (5-20 mg of folates are stored in the liver and other tissues) • pregnant women may absorb as much as 300-400 µg of folic acid daily • sources: yeast. inhibit dihydrofolate reductase and may result in a deficiency of folate cofactors and ultimately in megaloblastic anemia. Methotrexate.

second is to • headache. anaphylaxis and death (48-72H) • formula: kg x 2. 2 mg in mechanism for oxygen menstruation. given 60periodically monitor iron storage levels to 90mins avoid the serious toxicity associated with • IV administration eliminates the iron overload. birth and delivery from the lungs pregnancy (3-15% in a normal to other tissues. fever. NEC< nausea. period rarely. it is important to • dilute in D5 0. iron deficiency at one time can deliver more iron than can be safely Page 5 of 8 NICOLE LALUCES®KARLA LIGERALDE®ABBY MARALIT®MON PALMA®VIRRA ROSALES®VIN SANCHEZ VINCENT REOLALAS®AURORA AUREA REYES . about 25% of oral iron Ferrous sulfate given as ferrous salt can be Hydrated 20% absorbed Dessicated 30% Ferrous gluconate 12% Ferrous fumarate 33% Ferrous lactate 19% • 200-400 mg of elemental iron should be given daily to correct iron deficiency most rapidly • Patients unable to tolerate such large doses of iron can be given lower daily doses of iron. constipation. nausea. back pain. or iron necessary to correct the which bypasses this regulatory system. give repeated small doses of arthralgias.9 NaCl. and diarrhea. about 50-100mg of iron can be Ferrous Salt Elemental Iron incorporated into hemoglobin Preparation Content daily. and. epigastric discomfort. Acute toxicity. parenteral iron over a protracted flushing. which results in slower but still complete correction of iron deficiency • Treatment should be continued for 3-6 months after correction of the cause of the iron loss PARENTERAL IRON Mechanism of action: • forms the nucleus of the iron-porphyrin heme ring. local pain and tissue staining that which is subject to the regulatory often occur with the IM route and mechanism provided by the intestinal allows delivery of the entire dose uptake system. person and ~25% in iron • In the absence of deficient states) adequate iron. Unlike oral iron therapy. abdominal cramps. which together with globin chains forms hemoglobin Name of drug Pharmacokinetics Indication Additional notes Iron dextran • iron deficiency anemia • reserved for patients with documented iron • IV infusion or IM injection deficiency who are unable to tolerate or • give total dose of iron required to absorb oral iron and for patients with correct the hemoglobin deficit extensive chronic blood loss who cannot be and provide the patient with 500 maintained with oral iron alone mg of iron stores.DRUGS FOR ANEMIA IRON PREPARATIONS Mechanism of action: • forms the nucleus of the iron-porphyrin heme ring. bloody diarrhea. bronchospasm. black stools Name of drug Pharmacokinetics Indication Additional notes IRON • Absorption takes place in the • Hemoglobin reversibly • iron deficiency anemia duodenum and the proximal binds oxygen and • Available preparations jejunum provides the critical • absorption: 1mg/day. which together with globin chains forms hemoglobin Adverse effects: Hypersensitivity reactions. small • iron needed in body: 10-20 mg erythrocytes with /day (women>children>men) insufficient hemoglobin are formed • In a iron-deficient individual.3x 15 – hgb in g/dl • For patients who are treated chronically + 500mg with parenteral iron. parenteral administration. vomiting. nausea and vomiting. urticaria. light-headedness.

coma. and bloody diarrhea followed by shock. a hypoproliferative marrow. longer for pegfilgrastim • uses: • myelosuppressive chemotherapy producing neutropenia • in autologous stem cell transplantation MEGAKARYOCYTE GROWTH FACTORS (INTERLEUKIN 11) • A 65-85kDa protein produced by fibroblasts and stromal cells in the bone marrow • Oprelvekin. with vomiting. arthralgias. tissue injury. abdominal pain. and CV effects (including anemia due to hemodilution. and a normal or increased serum ferritin • • Decrease EPO response – interleukin. and dyspnea. the recombinant form of IL-11 is produced by expression in E. increased red cell protoporphyrin. and conditions (such as cancer) associated with the release of proinflammatory cytokines—is one of the most common forms of anemia seen clinically and probably the most important in the differential diagnosis of iron deficiency HEMATOPOIETIC GROWTH FACTOR ERYTHROPOIETIN • originally purified from the urine of patients with severe anemia • recombinant human erythropoietin (rHuEPO. liver. Darbepoetin alfa with a longer half life MYELOID GROWTH FACTORS (G-CSF & GM-CSF) Filgrastim • originally purified from cultured Sargramostim human cell lines • recombinant human G-CSF (rHuGCSF. malaise. headache. dyspnea due to fluid accumulation in the lungs. and other organs • leads to organ failure and death • can be treated by intermittent phlebotomy and Deferasirox by reducing liver iron concentrations Anemia of Chronic Disease • encompasses inflammation. epoetin alfa) is produced in a mammalian cell expression system • Less likely to cause anaphylactic reactions • low serum iron. filgrastim) is produced through bacterial expression and recombinant human GM-CSF (rHuGM-CSF.stored in intestinal cells and macrophages in the liver and tissues Iron sucrose complex Iron sodium gluconate complex acute iron toxicity • seen in children • include necrotizing gastroenteritis. dizziness. transferrin saturation in the range of 15–20%. complications include severe metabolic acidosis. and transient atrial arrhythmias) • Hypokalemia has also been seen in some Page 6 of 8 NICOLE LALUCES®KARLA LIGERALDE®ABBY MARALIT®MON PALMA®VIRRA ROSALES®VIN SANCHEZ VINCENT REOLALAS®AURORA AUREA REYES . TNF Hepcidin – found in liver in chronic inflammation decreases iron uptake and metabolism • Toxicity – rapid increase in hematocrit and hemoglobin and include hypertension and thrombotic complications • (Chronic Renal Failure) CRF: usual dose is 50–150 U/kg 3x/week IV – hemoglobin levels of 10–12 g/dL are usually reached within 4–6 weeks if iron levels are adequate. allergic reactions • AE: • Fatigue. pancreas. a potent iron-chelating compound. sargramostim) is produced in a yeast expression • serum half-lives of 2-7 hours after IV or SQ. infection. myalgias. and death • treated with Deferoxamine. lethargy. can be given systemically to bind iron that has already been absorbed and to promote its excretion in urine and feces chronic iron toxicity • secondary to iron overload (hemochromatosis) • results when excess iron is deposited in the heart.coli • Half-life: 7-8 hours when the drug is injected subcutaneously • Thrombopoietin – a 65-85kDa glycosylated protein is expressed by a variety of organs and cell • It is approved for the secondary prevention of thrombocytopenia in patients receiving cytotoxic chemotherapy for treatment of nonmyeloid cancers • Give by subcutaneous injection at a dose of 50mcg/kg/d • It is started 6-24 hours after completion of chemotherapy and continued fro 14-21 days or until the platelet count passes the • AE: • G-CSF causes bone pain • GM-CSF can cause fever. and a capillary leak syndrome characterized by peripheral edema and pleural or pericardial effusions. 90% of these patients respond – 4-13H half life.

Thrombin 4. Adverse effects: hypersensitivity d. K2 – menaquinone produced by intestinal flora 3. Absorbable Gelatin Sponge (Gelfoam) 2.) salts for absorption from the • vitamin K repletion is best intestinal tract achieved with intravenous or oral administration. Source: Phytonadine is a fat-soluble vitamin found in green. Plasma Fractions 1. Others 1.and drug-induced cystitis. Paraaminomethylcarboxylic acid (Hemostan) 3. myopathy. Serine Protease Inhibitor 1.P.S. and patients with cirrhosis and thrombocytopenia have low serum thrombopoietin levels nadir and rises to > 50. kidney and ureters because of the potential for excessive clotting • AE: intravascular thrombosis from inhibition of plasminogen activator. Pharmacokinetics: 1. FIBRINOLYTIC INHIBITORS: AMINOCAPROIC ACID AND TRANEXAMIC ACID • adjunctive therapy in hemophilia • therapy for bleeding from fibrinolytic therapy • prophylaxis for rebleeding from intracranial aneurysms • postsurgical bleeding and bladder hemorrhage secondary to radiation. Preparation: Phytonadine 10mg/ml amp Name of Drug Pharmacokinetics Indication/Dosage Additional Notes VITAMIN K • found primarily in leafy green • vitamin K1 is available in oral vegetables and parenteral forms • dietary requirement is low. Lyophilized Factor VIII 2. Oxidized Cellulose (Oxygel.types • Hepatocytes – major source of human thrombopoietin. Classification: 1. • effect delayed for 6 hours but synthesized by bacteria that the effect is complete by 24 colonize the human intestine hours when treating • 2 natural forms exist: vitamins K1 depression of prothrombin and K2. surgical) 3. Factor IX 3. or Vitamin K3 b. K3 – synthetic water-soluble form b.000 cells/microliter patients COAGULANTS/HEMOSTATICS A. and olive oil 1. diarrhea. Fat-soluble Vitamin K and its Analogues 1. • Aminocaproic acid • oral dosage is 6 g QID. Effect delayed up to 6 hours after ingestion but is complete after 24 hours c. Prototype: Vitamin K Analogue a. canola. Cryoprecipitate b. Factor VIII – available in the following preparations: a. K1 – phytonadione derived from plants 2. chest and • vitamins K1 and K2 require bile back pain. Menadione U. Aprotinin (Trasolyl) d. • administered to all newborns to prevent the hemorrhagic disease of vitamin K deficiency. abdominal discomfort. which is especially common in premature infants. such as soybean. Page 7 of 8 NICOLE LALUCES®KARLA LIGERALDE®ABBY MARALIT®MON PALMA®VIRRA ROSALES®VIN SANCHEZ VINCENT REOLALAS®AURORA AUREA REYES . Traneximic acid + (Cyclokapron) 2. leafy vegetables and oils. Fibrinogen e. Fibrin form 2. Requires bile salts for intestinal absorption 2. Aminocaproic acid (Amicar) c. IV at a 5 g loading dose should be infused over 30 minutes to avoid hypotension • CI: in patients with DIC or GU bleeding of the upper tract. hypotension. Anti-fibrinolytic Agents 1. Phytonadine or Vitamin K1 (Aqua-Mephyton) 2. Vitamin K1 activity by excess warfarin or (phytonadione) is found in food vitamin K deficiency and Vitamin K2 (menaquinone) is • IV administration should be found in human tissues and is slow( rapid infusion can synthesized by intestinal bacteria produce dyspnea. and nasal stuffiness. Thromboplastin 5. eg. Systemic Coagulants: a. and even death.

stroke.SERINE PROTEASE INHIBITORS: APROTININ • Tranexamic acid • similar to lysine.5% of cases Page 8 of 8 NICOLE LALUCES®KARLA LIGERALDE®ABBY MARALIT®MON PALMA®VIRRA ROSALES®VIN SANCHEZ VINCENT REOLALAS®AURORA AUREA REYES . synthetic inhibitor of fibrinolysis • competitively inhibits plasminogen activation • analog of aminocaproic acid • Aprotinin • serine protease inhibitor • inhibits fibrinolysis by free plasmin • inhibits the plasminstreptokinase complex in patients who have received that thrombolytic agent • reduce bleeding by as much as 50% from many types of surgery • rapidly absorbed orally and cleared by the kidney • orally with a 15 mg/kg loading dose followed by 30 mg/kg/day QID • • increased risk of myocardial infarction. and renal damage in aprotinintreated patients • association with anaphylaxis has been reported in <0.

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