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Anticoagulant, Thrombolytic, and Antiplatelet Drugs Cooper Woods, Ph.D. [email protected] 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 • Each step of the cascades involves: – VII binds TF exposed by vascular injury – VIIa can also activate IX in the presence of TF – Activation of XII not required for hemostasis – 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 T H R 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; 20009000 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 ATP Adenosine cAMP Adenylate cyclase Adenosine A2 Receptor 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. Cumulative Kaplan-Meier Estimates of the Rates of Key Study End Points during the Follow-up Period Wiviott S et al. N Engl J Med 2007;357:2001-2015 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. Iron Metabolism Essential Iron Male(mg/kg) Female(mg/kg) Hemoglobin 31 28 Myoglobin & Enzymes 6 5 Storage 13 4 Total 50 37 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 Agents Oral 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 Agents Parenteral 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 deficiency. 12 Deficiency or intrinsic factor – MOA: Converted to methylcobalamin or deoxyadenosylcobalamin, 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 deficiency. 12 Deficiency or intrinsic factor – MOA: Converted to methylcobalamin or deoxyadenosylcobalamin, 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