1. Anticoagulant, Thrombolytic, and Antiplatelet Drugs
Cooper Woods, Ph.D.

2. 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.

3. 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

4. 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

5. Clotting Time
Prothrombin Time; Prothrombin Ratio(PR) and Internationalized Ratio(INR)
Measures of the extrinsic/common pathway
PT reference range: 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:
Activated Partial Thromboplastin Time (aPTT)
Measure of the intrinsic pathway
aPPT normal range: 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.

6. Bleeding Disorders Primary Hemostasis Secondary Hemostasis
Platelet Defects, von Willenbrand Disease
Mucosal bleeding
Gingiva
Skin
Heavy Menses
Secondary Hemostasis
Defects in clotting mechanism – Hemophilia
Deep hemorrhage
Joints
Muscle
Retroperitoneum

7. 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

8. 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

9. Natural Anti-coagulant Mechanisms
Prostacyclin (PGI2)
Produced by ECs
Vasodilator/Inhibitor of Platelet Activation
Antithrombin
Plasma protein
Inhibits Intrinsic and Common Pathway
Heparan Sulfate
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

10. 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)

11. Anticoagulants (Parenteral)
Heparin Sodium, Heparin Calcium: Unfractionated: ,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; 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).

12. Anticoagulants (Parenteral) cont.
Enoxaparin, Dalteparin, Tinzaparin: Heparin Analog; Fractionated, Low molecular weight heparin (LMWH; g/mol)
Increased bioavailability (s.c.)
Less frequent dosing
Equal efficacy
Factor IIa is thrombin

13. Anticoagulants (Parenteral)
Enoxaparin, Dalteparin, Tinzaparin: Heparin Analog; Fractionated, Low molecular weight heparin (LMWH; 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.

14. 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

15. 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.

16. 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

17. 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.

18. 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

19. 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)

20. 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

21. 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.

22. 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.

23. 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

24. 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

25. Antiplatelet Agents

26. 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

27. 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
cAMP
Adenosine
Adenylate cyclase
Adenosine A2 Receptor

28. 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.

29. 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

30. 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.

31. Cumulative Kaplan-Meier Estimates of the Rates of Key Study End Points during the Follow-up Period
Figure 1. Cumulative Kaplan-Meier Estimates of the Rates of Key Study End Points during the Follow-up Period. Panel A shows data for the primary efficacy end point (death from cardiovascular causes, nonfatal myocardial infarction [MI], or nonfatal stroke) (top) and for the key safety end point (Thrombolysis in Myocardial Infarction [TIMI] major bleeding not related to coronary-artery bypass grafting) (bottom) during the full follow-up period. The hazard ratio for prasugrel, as compared with clopidogrel, for the primary efficacy end point at 30 days was 0.77 (95% confidence interval [CI], 0.67 to 0.88; P<0.001) and at 90 days was 0.80 (95% CI, 0.71 to 0.90; P<0.001). Data for the primary efficacy end point are also shown from the time of randomization to day 3 (Panel B) and from 3 days to 15 months, with all end points occurring before day 3 censored (Panel C). In Panel C, the number at risk includes all patients who were alive (regardless of whether a nonfatal event had occurred during the first 3 days after randomization) and had not withdrawn consent for follow-up. The P values in Panel A for the primary efficacy end point were calculated with the use of the Gehan-Wilcoxon test; all other P values were calculated with the use of the log-rank test.
Wiviott S et al. N Engl J Med 2007;357:

32. 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

33. 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

34. 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

35. Anti-anemics

36. Hematopoiesis Countinous replacement of blood cells Requires
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

37. 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

38. 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.

39. Iron Metabolism Essential Iron Male(mg/kg) Female(mg/kg) Hemoglobin 3128
Myoglobin & Enzymes 6 5
Storage 13 4
Total 50 37

40. 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

41. 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

42. 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.

43. 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

44. Copper Deficiency Extremely Rare
Intestinal bypass
Parenteral nutrition
Malnourished infants
Excessive amounts of Zinc
Low plasma copper + Leukopenia or anemia
Cupric sulfate, p.o.

45. 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

46. Megaloblastic Anemias
Vitamin B12 and Folic Acid

47. 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

48. 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.

49. 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

50. 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)

51. 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.

52. 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.

53. Myeloid and Megakaryocyte Growth Factors

54. 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

55. 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