anticoagulant, thrombolytic, and antiplatelet drugs cooper woods, ph.d. twoods@lsuhsc.edu

Anticoagulant, Thrombolytic, and Antiplatelet Drugs

Cooper Woods, Ph.D.

twoods@lsuhsc.edu

Homeostasis: Cessation of bleeding from an injured blood vessel

Primary Hemostasis

• This stage occurs within seconds

• 1. Vasospasm: Vasoconstriction of the blood vessel by Prostacyclin (PI2), Thromboxane A2 (TXA2) and serotonin (5-HT). Slows down the bleeding.

• 2. Platelet Plug: Adherence of platelets to collagen of damaged endothelial cells. Platelet aggregation: Role of thrombin, adenosine diphosphate (ADP), PI2, TXA2, 5-HT and prostaglandins.

Secondary Hemostasis

• This stage takes several minutes. Stabilizes the soft clot and maintains vasoconstriction.

• 3. Fibrin Clot: Conversion of prothrombin to thrombin. Thrombin stimulates the conversion of fibrinogen (Blood protein) to polymerized fibrin (mesh).

• 4. Dissolution of the clot by fibrinolysis: Plasminogen is converted to plasmin, the enzyme that dissolves the fibrin.

The hemostatic process is a protective mechanism to prevent blood loss from the circulatory system.

Platelet Adhesion and Aggregation

• Injury exposes collagen and von Willebrand Factor

• GPIa/IIa (low shear) and Ib (high shear) on the platelet surface bind collagen and vWF

• Platelets become activated– Thrombin (IIa) activates

PAR1/PAR4– Activate gp IIb/IIIa receptors

and Cox-1– Release thromboxane A2,

PAF, ADP– P2Y1/ P2Y12 activated by ADP

Blood Coagulation:

• Initiated by the Extrinsic Pathway– VII binds TF exposed by vascular injury– VIIa can also activate IX in the

presence of TF– Activation of XII not required for

hemostasis• Each step of the cascades involves:

– Protease (from previous step)– Zymogen– Non-enzymatic cofactors

• V (Xa)• VIII (IXa)• TF (VIIa)

– Ca2+

– Organizing surface (platelets)

• Thrombin cleaves peptides from fibrinogen to produce fibrin monomers (gel)

• XIIIa crosslinks fibrin monomers with transglutamination

Clotting Time • Prothrombin Time; Prothrombin Ratio(PR) and Internationalized

Ratio(INR)– Measures of the extrinsic/common pathway

• PT reference range: 12-15 sec; measures factors II,V,VII,X and fibrinogen.; Used in conjunction with aPTT

– PT: blood is combined with liquid citrate (chelates calcium; anticoagulant) in a testtube. There is a specific ratio of blood to citrate. The mixture is centrifuged and the plasma is collected. Thromboplastin (Tissue factor) is added to plasma and analyzed for clotting time.

• INR normal range: 0.8-1.2

• Activated Partial Thromboplastin Time (aPTT)– Measure of the intrinsic pathway

• aPPT normal range: 25-37 seconds• aPPT:blood is combined with liquid citrate (chelates calcium; anticoagulant)

in a testtube. There is a specific ratio of blood to citrate. The mixture is centrifuged and the plasma is collected. A phospholipid (silica, kaolin, etc) and calcium are added to the plasma sample and analyzed for clotting time.

• Partial Thromboplastin: thromboplastin is not added to the plasma sample.

Bleeding Disorders

• Primary Hemostasis– Platelet Defects, von Willenbrand Disease– Mucosal bleeding

• Gingiva• Skin• Heavy Menses

• Secondary Hemostasis– Defects in clotting mechanism – Hemophilia– Deep hemorrhage

• Joints• Muscle• Retroperitoneum

THR

Thrombosis and Embolism

• White Thrombi– Platelet rich– Formed in high shear/flow

– artery– Can cause ischemia/organ

failure• Red Thrombi

– Fibrin rich / RBCs trapped– Often Deep Venous Origin– Swelling and Pain– Pulmonary Embolism

• Acute right heart failure sudden death

• Lung ischemia

Fibrinolysis• Removal of unwanted clots• Balanced against removal of

clots necessary for hemostasis• Activated by the conversion of

plasminogen to plasmin• Plasmin

– non-specific protease that cleaves fibrin as well as other plasma proteins

– Binds fibrin• t-PA

– released from ECs– Binds fibrin (bound is blocked

from inhibition)– Rapidly cleared– Inhibited by PAI 1/2

Natural Anti-coagulant Mechanisms

• Prostacyclin (PGI2)– Produced by ECs– Vasodilator/Inhibitor of Platelet Activation

• Antithrombin– Plasma protein– Inhibits Intrinsic and Common Pathway

• Heparan Sulfate– Produced by ECs– Stimulates anti-thrombin

• Protein C + Protein S– Degrades Va and VIIIa– Activated by thrombin in the presence of anti-thrombin

• Tissue Factor Inhibitor Protein– inhibits factor Xa and the factor VIIa–tissue factor complex

Anticoagulants (Parenteral)

• Heparin Sodium, Heparin Calcium– Glycosaminoglycan

secreted by mast cells– Catalyzes the inhibition

of multiple coagulation factors by antithrombin

– Thrombin (IIa), IXa, and Xa

• Antithrombin– “suicide substrate”– Proteases become

trapped (1:1)

Anticoagulants (Parenteral)• Heparin Sodium, Heparin Calcium: Unfractionated: 5000-30,000 g/mol.

Naturally occurring mixture of sulfated muccopolysaccharides produced by mast cells and basophils.

– Clinical Use: Prevention and treatment of embolism (i.e., post-op or following myocardial infarction), deep vein thrombosis, pulmonary embolism. Initial management of unstable angina or acute myocardial infarction.

– MOA: Increases the activity of antithrombin III and inactivates thrombin. High doses will inhibit platelet aggregation.

– Pharmacokinetics: Administration: Not absorbed from the gut; i.v. and s.c.. Immediate onset (30-60 mins); Hepatic elimination and excretion, some excreted unchanged in urine. Dosage is determined by the activated partial thromboplastin time (aPPT; 1.5-2 times is normal).

– Side effects: Thrombocytopenia (early or delayed), hemorrhage.

– Contraindications: existing bleeding condition or bleeding tendency.

– Drug Interactions: Risk of bleeding is increased by salicylates

– In case of overdose: protamine sulfate (positive charge binds heparin).

Anticoagulants (Parenteral) cont.• Enoxaparin,

Dalteparin, Tinzaparin: Heparin Analog; Fractionated, Low molecular weight heparin (LMWH; 2000-9000 g/mol)– Increased

bioavailability (s.c.)

– Less frequent dosing

– Equal efficacy

Factor IIa is thrombin

Anticoagulants (Parenteral)

• Enoxaparin, Dalteparin, Tinzaparin: Heparin Analog; Fractionated, Low molecular weight heparin (LMWH; 2000-9000 g/mol) Fondaparinux (Pentasaccharide of active heparin residues)

– Clinical Use: Prevention and treatment of embolism (i.e., post-op or following myocardial infarction), deep vein thrombosis.

– MOA: Inhibits factor Xa, very little effect on factor IIa; aPPT is not used to measure its anticoagulant activity. Binds less to plasma proteins.

– Pharmacokinetics: Administration: i.v. and s.c. outpatient basis for DVT patients. Immediate onset (30-60 mins); Hepatic elimination and excretion, some excreted unchanged in urine.

– Side effects: Thrombocytopenia (early or delayed), hemorrhage.

– Contraindications: existing bleeding condition or bleeding tendency.

– In case of overdose: • Enoxaparin, Dalteparin, Tinzaparin protamine sulfate (positive charge binds

heparin). – Limited Effectiveness• Fondaparinux – none.

Anticoagulants (Parenteral)

• Lepirudin: Hirudin analog

– Clinical Use: Approved for use in patients with heparin-induced thrombocytopenia. Approved for use in PCI.

– MOA: Binds and inhibits thrombin.

– Pharmacokinetics: Administration: i.v. adjusted according to aPTT. Kidney excretion.

– Side effects: Hemorrhage.

– Contraindications: existing bleeding condition or bleeding tendency. Caution with patients with renal disfunction.

– In case of overdose: No antidote.

– Long-term treatment can lead to development of antibodies to the lepirudin-thrombin complex

Anticoagulants (Parenteral)

• Bivalirudin: Hirudin analog

– Clinical Use: Approved for use in patients with as an alternative to Heparin in PCI patients.

– MOA: Binds and inhibits thrombin. Also blocks platelet activation. Thrombin cleaves bivalirudin to eventually regain activity.

– Pharmacokinetics: Administration: i.v. adjusted according to aPTT. Kidney excretion.

– Side effects: Hemorrhage.

– Contraindications: existing bleeding condition or bleeding tendency. Caution with patients with renal disfunction.

Anticoagulants (Parenertal)

• Argatroban: L-arginine analog– Clinical Use: Approved for use in patients with

heparin-induced thrombocytopenia and PCI.

– MOA: Binds reversibly to and inhibits thrombin.

– Pharmacokinetics: Administration: i.v. adjusted according to aPTT. Hepatic metabolism and bile excretion.

– Side effects: Hemorrhage.

– Contraindications: existing bleeding condition or bleeding tendency. Caution with patients with hepatic dysfunction.

– Argatroban vs. Lepirudin – Renal Insufficiency = Argatroban, Hepatic Insufficiency = Lepirudin

Anticoagulants (Parenteral)

• Drotrecogin Alfa: recombinant activated Protein C

– Clinical Use: reduction of mortality in adult patients with severe sepsis.

– MOA: Proteolytic inactivation of factors Va and VIIIa .

– Pharmacokinetics: Administration: i.v.

– Side effects: Hemorrhage.

– Contraindications: existing bleeding condition or bleeding tendency.

– In case of overdose: No antidote.

Anticoagulants (Oral)• Coumarins: dicumarol and warfarin; warfarin is

structurally related to vitamin K.

– Clinical Use: Treatment of embolism, deep vein thrombosis or atrial fibrillation, patients with prosthetic valves (at risk for thrombosis).

– MOA: Inhibits the synthesis of factors II, VII, IX and X by inhibiting the production of active vitamin K.

Active form

Anticoagulants (Oral)

• Coumarins: dicumarol and warfarin; warfarin is structurally related to vitamin K.

Pharmacokinetics: Route of administration: p.o.; 100% absorbed; 99% bound to plasma proteins; 8-12 hour delay of onset of activity; Hepatic elimination and excreted in the urine. Dicumarol is incompletely absorbed from the gut.

– Side effects: Hemorrhage.

– Contraindications: Patients with Hemophilia. Pregnancy.

– Drug Interactions: Drugs that inhibit CytoP450– Enzymes will increase levels, ie cimetidine, – Macrolide antibiotics, antifungal agents. Drugs that induce– CytoP450 enzymes will decrease levels, ie rifampin and – Barbituates.

– In case of overdose: Vitamin K (phytonadione)

Fibrinolytic Drugs: (Thrombolytics)

• Tissue Plasminogen Activator (t-PA); alteplase, reteplase, Tenecteplase– MOA: It is a serine protease

which activates plasminogen (bound to fibrin) and increases plasmin levels. Clot specific and must bind to fibrin.

– Reteplase • less fibrin specific

– Tenecteplase • longer half-life • more fibrin specific

Fibrinolytic Drugs: (Thrombolytics)

• Urokinase; enzyme obtained from urine– MOA: Directly activates

plasminogen– isolated from human kidney,

therefore less chance of evoking an allergic reaction.

• Streptokinase: – protein obtained from

streptocci – anistreplase (a preformed

complex of streptokinase and plasminogen)

– MOA: Combines with plasminogen to form an active complex that converts plasminogen to plasmin to dissolve the fibrin.

Thrombolytics

– Clinical Use: pulmonary embolism with hemodynamic instability, severe deep venous thrombosis, acute myocardial infarction. t-PA – acute ischemia stroke

– Pharmacokinetics: Parental administration, i.v.

– Side effects: hemorrhage, hypersensitivity reactions and reperfusion arrythmias.

– Contraindications: Bleeding disorders; recent surgery; severe hypertension.

– Drug Interactions: Increases risk of bleeding with dicumarol, warfarn, heparin, aspirin, ticlopidine, abciximab.

– In case of overdose: Aminocaproic acid inhibits fibrinolysis by competitively blocking plasminogen activation.

Inhibitors of Fibrinolysis• Aminocaproic acid, Tranexamic

acid – MOA: lysine analog that competes

for lysine binding sites on plasminogen and plasmin blocking binding to fibrin

– Clinical Use: adjunctive therapy in hemophilia, as therapy for bleeding from fibrinolytic therapy, and as prophylaxis for rebleeding from intracranial aneurysms

– Side Effects:intravascular thrombosis from inhibition of plasminogen activator

– Contraindications: disseminated intravascular coagulation or genitourinary bleeding of the upper tract

Inhibitors of Fibrinolysis• Aprotinin

– MOA: serine protease inhibitor that inhibits fibrinolysis by free plasmin

– Clinical Use: reduce bleeding associated with surgery

– Side Effects: Minimal

– Contraindications: disseminated intravascular coagulation or genitourinary bleeding of the upper tract

Antiplatelet Agents

Antiplatelet Agents - Aspirin

• Clinical Use: Prevention of atherosclerosis, thrombosis, transient ischemic attacks; unstable angina.

• MOA: Irreversible cyclooxygenase inhibitor and inhibits the formation of thromboxane A2.

• Pharmacokinetics: Oral administration

• Side effects: Bleeding; gastrointestinal irritation, hypersensitivity reactions and thrombocytopenia.

• Contraindications: Bleeding disorders, hypersensitivity and Reye’s syndrome.

• Drug Interactions: Increased hypoglycemic effects of sulfonylureas, inhibits uricosuric effect of probenecid.

• In case of overdose: Forced Alkaline Diuresis

Antiplatelet Agents - Dipyridamole

• Clinical Use: Prosthetic valves; may be used as an adjunct with aspirin or warfarin therapy. Benefit of Dipyridamole + aspirin is debatable

• MOA: Lowers platelet calcium and increases the formation of cAMP (weak antiplatelet drug) , coronary vasodilator.

• Pharmacokinetics: Oral administration

• Side effects: GI distress, headache, dizziness and rash.

• Contraindications: Hypersensitivity to this drug

• Drug Interactions: Increases risk of bradycardia with Beta adrenergic receptor antagonists.

Platelet

cAMPATP

Adenosine

Adenosine A2 Receptor

Adenylate cyclase

Antiplatelet Agents -Ticlopidine (Ticlid ®)

• Clinical Use: Patients intolerant to aspirin; prevents thrombotic stroke.

• MOA: Inhibits ADP-induced expression of platelet glycoprotein receptors and reduces fibrinogen binding and platelet aggregation. Effects on platelet function are irreversible.

• Pharmacokinetics: Oral administration; eliminated in the urine and feces

• Side effects: Nausea, diarrhea, bleeding; mild to moderate neutropenia, leukopenia, thrombocytopenia.

• Contraindications: Bleeding disorders, severe liver disease

• Drug Interactions: Inhibits cytoP450 drug metabolizing enzymes.

Antiplatelet Agents - Clopidogrel (Plavix®)

• Clinical Use: Prevention of atherosclerosis, thrombosis, transient ischemic attacks; unstable angina. Prevention of stent thrombosis.

• MOA: Inhibits the binding of ADP to its receptor which is involved in the activation of platelet glycoprotein receptors binding to fibrinogen.

• Pharmacokinetics: Oral administration; eliminated in urine and feces.

• Side effects: Nausea, diarrhea, bleeding; mild to moderate neutropenia, leukopenia, thrombocytopenia. – Less severe than Ticlopidine

Antiplatelet Agents – Prasugrel (Effient)

• Clinical Use: Prevention of atherosclerosis, thrombosis, transient ischemic attacks; unstable angina. Prevention of stent thrombosis.

• MOA: Inhibits the binding of ADP to its receptor which is involved in the activation of platelet glycoprotein receptors binding to fibrinogen.

• Pharmacokinetics: Oral administration; eliminated in urine and feces.

• Side effects: Nausea, diarrhea, bleeding; mild to moderate neutropenia, Leukopenia, thrombocytopenia.

Wiviott S et al. N Engl J Med 2007;357:2001-2015

Cumulative Kaplan-Meier Estimates of the Rates of Key Study End Points during the Follow-up Period

Antiplatelet Agents• Abciximab

– Clinical Use: Percutaneous transluminal coronary angioplasty as adjunct with aspirin and heparin.

– MOA: Binds to platelet glycoprotein IIb/IIIa receptors and prevents binding to fibrinogen. Also binds the vitronectin receptor.

– Pharmacokinetics: Parental administration, i.v.

– Side effects: Bleeding, thrombocytopenia, hypotension and bradycardia.

– Contraindications: Aneurysm, bleeding, recent surgery, stroke

– Drug Interactions: Unknown

Antiplatelet Agents – Eptifibatide, Tirofiban

• Clinical Use: Percutaneous transluminal coronary angioplasty as adjunct with aspirin and heparin.

• MOA: Binds to platelet glycoprotein IIb/IIIa receptors and prevents binding to fibrinogen.

– Does not bind vitronectin.

• Pharmacokinetics: Parental administration, i.v.

• Side effects: Bleeding, thrombocytopenia, hypotension and bradycardia.

• Contraindications: Aneurysm, bleeding, recent surgery, stroke

• Drug Interactions: Unknown

Hemostatic Agents for Bleeding Disorders

• Vitamin K– confers biologic activity upon

prothrombin and factors VII, IX, and X

• Plasma Fractions– Factor VIII – Hemophilia A– Factor IX – Hemophilia B– Freeze-dried concentrates

• Factor IX • Factor X• Factor VII

• Desmopressin Acetate– increases the factor VIII

activity

Anti-anemics

Hematopoiesis

• Countinous replacement of blood cells– Mature erythrocytes

• Lack nucleus – cannot synthesize proteins/lipids • Finite lifespan = ~120 days

– Anemia– Hypoxemia

• Requires– Minerals – iron, cobalt, and copper– Vitamins – folic acid, B12, pyridoxine, ascorbic acid,

and riboflavin– Deficiencies in these factors Anemia

Hematopoiesis – Erythropoietin• Stimulates proliferation

and maturation of committed erthroid progenitors

• Kidney senses changes in oxygen and modifies erythropoietin secretion

• Anemia or hypoxemia – serum levels increase

• Suppressed by infection or inflammation

Antianemia Agents – Erythropoietins

• Recombinant human erythopoietin (epoetin alfa), Epogen, Procrit, and exprex, darbapoetin alfa (Aranesp)

– Clinical Use: anemia of renal insufficiency, inflammation, and associated with cancer or the therapy of cancer

– MOA: Stimulates proliferation and maturation of red blood cells.

– Pharmacokinetics: Route of administration: i.v., s.c. Hematocrit should be monitored to determined appropriate dose.

– Side effects: Aggravation of hypertension. Thrombosis.

– Contraindications: Pre-existing uncontrolled hypertension.

– Iron deficiency: Virtually all patients will develop iron deficiency as a result of an inability to mobilize iron stores in support of increased erythropoiesis.

Essential Iron Male(mg/kg) Female(mg/kg)

Hemoglobin 31 28

Myoglobin & Enzymes

6 5

Storage 13 4

Total 50 37

Iron Metabolism

Iron Deficiency

• Most common nutritional disorder

• Insufficient dietary intake– Usually mild

• Blood loss– Usual cause of severe

cases• Poor absorbance

– Gastrectomy– Malabsorption in the small

intestine• Pregnancy• Infancy

Iron Deficiency - Diagnosis

• Microcytic anemia – indicator of iron deficiency– other tests must be used to confirm the

diagnosis

• Iron deficiency vs. iron deficient erythropoiesis due to inflammation– Iron stores are increased, but release

from RE is blocked• Elevated plasma ferritin

– Plasma Iron is decreased– Erythroid marrow supply is inadequate

Antianemia AgentsOral Iron Therapy

• Ferrous sulfate, ferrous gluconate, ferrous fumarate, polysaccharide-iron complex.

– Clinical Use: Iron Deficiency.

– MOA: Replaces the iron necessary for RBC’s to transport oxygen. Treatment requires several months.

– Pharmacokinetics: Route of administration: p.o.; Eliminated in the feces, urine and sweat.

– Side effects: Nausea, gastrointestinal discomfort, heartburn, diarrhea or constipation.

– Contraindications: Patients with Peptic Ulcer disease, Ulcerative Colitis and Hemolytic Anemia.

– Drug Interactions: Antacids may inhibit absorption.

– Iron Poisoning: High concentrations of ferric salts are toxic. Fatalities are rare and may occur in children 1-2 yrs. Poisoning: Abdominal pain, diarrhea, vomiting drowsiness, cyanosis.

• Treatment: Administer a laxative (clean out intestine) or IV deferoxamine mesylate (chelates iron) or GI lavage (pump stomach) with sodium bicarbonate or phosphate solution.

Antianemia AgentsParenteral Therapy

• Sodium ferric gluconate, Iron Dextran, Iron sucrose,– Clinical Use: Iron Deficiency. Alternative to oral therapy.

– MOA: Replaces the iron necessary for RBC’s to transport oxygen.

– Pharmacokinetics: Route of administration: i.m. or i.v.; Eliminated in the feces, urine and bile. Sodium ferric gluconate and iron sucrose are i.v. only.

– Side effects: Anaphylaxis.• Sodium ferric gluconate – far fewer hypersensitivity reactions• Iron Dextran – second line to sodium ferric gluconate• Iron sucrose – similar to sodium ferric gluconate – limited data

– Contraindications: Patients with liver disease and asthma.• Iron Dextran – patients with rheumatoid arthritis or allergies

Copper Deficiency

• Extremely Rare– Intestinal bypass– Parenteral nutrition– Malnourished infants– Excessive amounts of Zinc

• Low plasma copper + Leukopenia or anemia– Cupric sulfate, p.o.

Pyridoxine (Vitamin B6)

• Sideroblastic anemia– Impaired hemoglobin synthesis– Accumulate iron in the perinuclear mitochondria of the erythroud

precursor

• Proven benefit in correcting sideroblastic anemia associated with isoniazid and pyrazinamide (anti-tuberculous drugs, vitamin B6 antagonists)

• Drug interaction: Levodopa (Parkinson’s)

• Poor responsiveness in sideroblastic abnormalities associated with lead, chlorampenicol and idiopathic acquired sideroblastic anemia

Megaloblastic Anemias

Vitamin B12 and Folic Acid

Vitamin B12 and Folic Acid Function

• Key roles in purine and pyrimidine synthesis – DNA

• Deficiency of either– Decreased protein

synthesis– Disrupted Methylation

Reactions– Decreased polyamine

synthesis– Shunting of folate into

methyltetrahydrofolate• Ultimately leads to

megaloblastic anemia

Antianemia Agents

•Cyanocobalamin, Crystalline– Clinical Use: Vitamin B 12 Deficiency or intrinsic factor

deficiency.

– MOA: Converted to methylcobalamin or deoxyadenosyl-cobalamin, cofactors for biochemical reactions which is essential for growth, cell replication, hematopoiesis.

– Pharmacokinetics: Route of administration: p.o., or i.m. ; Eliminated in the feces, urine and breast milk

– Adverse effects: Rare hypersensitivity.

Antianemia Agents

• Hydroxycobalamin, crystalline– Clinical Use: Vitamin B 12 Deficiency or intrinsic factor

deficiency.

– MOA: Converted to methylcobalamin or deoxyadenosyl-cobalamin, cofactors for biochemical reactions which is essential for growth, cell replication, hematopoiesis.

– Pharmacokinetics: Route of administration: p.o., or i.m. ; Eliminated in the feces, urine and breast milk

– Adverse effects: Rare hypersensitivity.– More sustained effect compared to cyanocobalamin

Anemia due to Folic Acid Deficiency

• Iron deficiency as a result of intestinal disease or pregnancy (increased demand on the system).

• Megaloblastic anemia

– Folic Acid– Leucovorin Calcium (Folinic Acid)

Antianemia Agents

•Folic Acid: – Clinical Use: Folic acid Deficiency in alcoholism and

malabsorptive syndromes.

– MOA: Replaces the folic acid necessary for DNA synthesis, cell proliferation and development.

– Pharmacokinetics: Route of administration: p.o., or i.m. ; Eliminated in the feces, urine and breast milk

– Side effects: Flushing and allergy.

– Contraindications: Patients with other anemias, i.e., pernicous, aplastic or normocytic due to incomplete treatment.

Antianemia Agents

• Leucovorin Calcium (Folinic Acid), folic acid metabolite (Derivative of tetrahydrofolic acid)– Clinical Use: Folic acid Deficiency.

– MOA: Replaces the folic acid necessary for DNA synthesis.

– Pharmacokinetics: Route of administration: p.o., or i.m. ; Eliminated in the feces, urine and breast milk

– Side effects: Flushing and allergy.

– Contraindications: Patients with other anemias, i.e., pernicous, aplastic or normocytic.

Myeloid and Megakaryocyte Growth Factors

Myeloid Growth Factors• G-CSF

– Stimulates proliferation of progenitor cells committed to the neutrophil lineage

– Activates neutrophil phagocytic activity– Prolongs their lifetime

• GM-CSF– Broader stimulatory activity– Similar Neutrophil stimulatory activity

• Clinical Use: Neutropenia (esp. Chemotherapy related), Autologous stem cell transplant

• Toxicity:– G-CSF- Bone pain– GM-CSF - fever, malaise, arthralgias,

myalgias, and a capillary leak syndrome

Megakaryocyte Growth Factors• IL-11

– MOA: Stimulates the growth of primitive megakaryocytic progenitors, Increases peripheral platelets and neutrophils

– Clinical Use: Thrombocytopenia

– Side Effects: fatigue, headache, dizziness, and cardiovascular effects

• Thrombopoietin– MOA: stimulates the growth of

primitive megakaryocytic progenitors

– Clinical Use: INVESTIGATIONAL - thrombocytopenia