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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NICOLE LALUCESKARLA LIGERALDEABBY MARALITMON PALMAVIRRA ROSALESVIN SANCHEZ VINCENT REOLALASAURORA AUREA REYES

 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, ie, to increase their concentration in peripheral blood GM-CSFs 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, 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, 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, Transport and Storage of Iron: Intestinal epithelial cells actively absorb inorganic iron and heme iron. 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, 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. It occurs when the erythropoietic tissues cannot supply enough normal erythrocytes to the circulation. In anemias due to abnormal red cell production, increased destruction and when demand exceeds capacity, plasma erythropoietin levels are increased. However, anemia can also be caused by defective production of erythropoietin as, for example, in renal disease a deficiency in oxygen-carrying erythrocytes, is the most common and can easily be treated includes iron deficiency anemia, megaloblastic anemia, hemolytic anemia, hemoglobinopathies etc treatment: supplementation of iron, folic acid, cobalamin, growth factors and transfusion megaloblastic anemia typical finding is macrocytic anemia, often with associated mild or moderate leucopenia or thrombocytopenia (or both), 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, ataxia, ans other CNS dysfunctions Once a diagnosis of megaloblastic anemia has been made, it must be determined whether Vit B12 or Folic Acid deficiency is the cause can be accomplished by measuring serum levels of the vitamins. The Schilling test, which measures absorption and urinary excretion radioactively labeled VitB12, 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, which is corrected when IF is

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NICOLE LALUCESKARLA LIGERALDEABBY MARALITMON PALMAVIRRA ROSALESVIN SANCHEZ VINCENT REOLALASAURORA AUREA REYES

administered with radioactive B12, 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 g of vit B12 daily 1-5 g of which is usually absorbed Storage: liver 3000-5000 g Complexes with intrinsic factor (produced by parietal cells); complex is absorb in the distal ileum by a receptor-mediated transport system daily requirement: 2 g 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, transcobalamin II excess vitamin B12 is transported to the liver for storage

Indication/Dosage Oral preparations: 5001000 g parenteral injection is available as cyanocobalamin or hydroxocobalamin 100-1000 g of vitamin B12 IM daily or every other day for 1-2 weeks then maintenance therapy consists of 100-1000 g IM once a month for life if neurologic abnormalities are present, 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 (500g BID) Megaloblastic anemia GITglosstits, 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, water, or in the intestinal lumen of animals, legumes which are contaminated by bacteria producing Vitamin B12 Metabolic functions: o Essential for normal maturation of erythroblasts and epithelial cells o Propionate catabolism

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NICOLE LALUCESKARLA LIGERALDEABBY MARALITMON PALMAVIRRA ROSALESVIN SANCHEZ VINCENT REOLALASAURORA AUREA REYES

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.

Folic acid deficiency can be caused by drugs. Methotrexate, and to a lesser extent, trimethoprim and pyrimethamine, inhibit dihydrofolate reductase and may result in a deficiency of folate cofactors and ultimately in megaloblastic anemia. Long term therapy with phenytoin can also cause folate deficiency, but only rarely causes megaloblastic anemia

FOLIC ACID Mechanism of action: provide precursors for the synthesis of amino acids, purines, and DNA

Name of drug Folic acid

Pharmacokinetics average diet contains 500-700 g of folates daily, 50-200 g 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 g of folic acid daily sources: yeast, liver, kidney, and green vegetables. 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 g folic acid daily for adults are satisfactory 600 g for pregnant women 500 g 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, fatigue, dizziness, exertional dyspnea, other generalized symptoms of tissue hypoxia, tachycardia, increased cardiac output, vasodilation

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NICOLE LALUCESKARLA LIGERALDEABBY MARALITMON PALMAVIRRA ROSALESVIN SANCHEZ VINCENT REOLALASAURORA AUREA REYES

DRUGS FOR ANEMIA IRON PREPARATIONS Mechanism of action: forms the nucleus of the iron-porphyrin heme ring, which together with globin chains forms hemoglobin Adverse effects: Hypersensitivity reactions. Acute toxicity, NEC< nausea, vomiting, bloody diarrhea, nausea, epigastric discomfort, abdominal cramps, constipation, and diarrhea, 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; 2 mg in mechanism for oxygen menstruation, birth and delivery from the lungs pregnancy (3-15% in a normal to other tissues. person and ~25% in iron In the absence of deficient states) adequate iron, small iron needed in body: 10-20 mg erythrocytes with /day (women>children>men) insufficient hemoglobin are formed In a iron-deficient individual, about 50-100mg of iron can be Ferrous Salt Elemental Iron incorporated into hemoglobin Preparation Content daily, 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, 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, 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; second is to headache, light-headedness, fever, give repeated small doses of arthralgias, nausea and vomiting, back pain, parenteral iron over a protracted flushing, urticaria, bronchospasm, and, period rarely, anaphylaxis and death (48-72H) formula: kg x 2.3x 15 hgb in g/dl For patients who are treated chronically + 500mg with parenteral iron, it is important to dilute in D5 0.9 NaCl; given 60periodically monitor iron storage levels to 90mins avoid the serious toxicity associated with IV administration eliminates the iron overload. Unlike oral iron therapy, 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, parenteral administration, or iron necessary to correct the which bypasses this regulatory system, iron deficiency at one time can deliver more iron than can be safely

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NICOLE LALUCESKARLA LIGERALDEABBY MARALITMON PALMAVIRRA ROSALESVIN SANCHEZ VINCENT REOLALASAURORA AUREA REYES

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, with vomiting, abdominal pain, and bloody diarrhea followed by shock, lethargy, and dyspnea; complications include severe metabolic acidosis, coma, and death treated with Deferoxamine, a potent iron-chelating compound, 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, liver, pancreas, 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, infection, tissue injury, and conditions (such as cancer) associated with the release of proinflammatory cytokinesis 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, epoetin alfa) is produced in a mammalian cell expression system Less likely to cause anaphylactic reactions

low serum iron, increased red cell protoporphyrin, a hypoproliferative marrow, transferrin saturation in the range of 1520%, and a normal or increased serum ferritin

Decrease EPO response interleukin, 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 50150 U/kg 3x/week IV hemoglobin levels of 1012 g/dL are usually reached within 46 weeks if iron levels are adequate; 90% of these patients respond 4-13H half life; 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; filgrastim) is produced through bacterial expression and recombinant human GM-CSF (rHuGM-CSF; sargramostim) is produced in a yeast expression

serum half-lives of 2-7 hours after IV or SQ; 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, the recombinant form of IL-11 is produced by expression in E.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, malaise, arthralgias, myalgias, and a capillary leak syndrome characterized by peripheral edema and pleural or pericardial effusions; allergic reactions AE: Fatigue, headache, dizziness, and CV effects (including anemia due to hemodilution, dyspnea due to fluid accumulation in the lungs, and transient atrial arrhythmias) Hypokalemia has also been seen in some

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NICOLE LALUCESKARLA LIGERALDEABBY MARALITMON PALMAVIRRA ROSALESVIN SANCHEZ VINCENT REOLALASAURORA AUREA REYES

types Hepatocytes major source of human thrombopoietin, and patients with cirrhosis and thrombocytopenia have low serum thrombopoietin levels

nadir and rises to > 50,000 cells/microliter

patients

COAGULANTS/HEMOSTATICS A. Classification: 1. Systemic Coagulants: a. Fat-soluble Vitamin K and its Analogues 1. Phytonadine or Vitamin K1 (Aqua-Mephyton) 2. Menadione U.S.P. or Vitamin K3 b. Anti-fibrinolytic Agents 1. Traneximic acid + (Cyclokapron) 2. Paraaminomethylcarboxylic acid (Hemostan) 3. Aminocaproic acid (Amicar) c. Serine Protease Inhibitor 1. Aprotinin (Trasolyl) d. Plasma Fractions 1. Factor VIII available in the following preparations: a. Cryoprecipitate b. Lyophilized Factor VIII 2. Factor IX 3. Fibrinogen e. Others 1. Absorbable Gelatin Sponge (Gelfoam) 2. Oxidized Cellulose (Oxygel, surgical) 3. Thrombin 4. Thromboplastin 5. Fibrin form 2. Prototype: Vitamin K Analogue a. Source: Phytonadine is a fat-soluble vitamin found in green, leafy vegetables and oils, such as soybean, canola, and olive oil 1. K1 phytonadione derived from plants 2. K2 menaquinone produced by intestinal flora 3. K3 synthetic water-soluble form b. Pharmacokinetics: 1. Requires bile salts for intestinal absorption 2. Effect delayed up to 6 hours after ingestion but is complete after 24 hours c. Adverse effects: hypersensitivity d. 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, 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. 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, chest and vitamins K1 and K2 require bile back pain, and even death.) salts for absorption from the vitamin K repletion is best intestinal tract achieved with intravenous or oral administration, administered to all newborns to prevent the hemorrhagic disease of vitamin K deficiency, which is especially common in premature infants. 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- and drug-induced cystitis. Aminocaproic acid oral dosage is 6 g QID; 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, eg, kidney and ureters because of the potential for excessive clotting AE: intravascular thrombosis from inhibition of plasminogen activator, hypotension, myopathy, abdominal discomfort, diarrhea, and nasal stuffiness.

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NICOLE LALUCESKARLA LIGERALDEABBY MARALITMON PALMAVIRRA ROSALESVIN SANCHEZ VINCENT REOLALASAURORA AUREA REYES

SERINE PROTEASE INHIBITORS: APROTININ

Tranexamic acid similar to lysine; 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, stroke, and renal damage in aprotinintreated patients association with anaphylaxis has been reported in <0.5% of cases

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NICOLE LALUCESKARLA LIGERALDEABBY MARALITMON PALMAVIRRA ROSALESVIN SANCHEZ VINCENT REOLALASAURORA AUREA REYES