Drug induced ghematopoiesis

Aznan Lelo Tri WidyawatiAznan Lelo, Tri WidyawatiDep Farmakologi & TerapeutikDep. Farmakologi & Terapeutik,

Fakultas Kedokteran

25 April 2009, PP for GP, Medan

H t i iHematopoiesisBlood Cell Formation

M tl i b f t llMostly in bone marrow from stem cellsRate regulated by cytokines & growth factors

Stem CellsAll the blood cell lineages are derived from aderived from a single multi-potential HSC (hematopoietic t ll) Th

HSC

stem cell). The stem cell can self-renew and can also givecan also give rise to more committed progeny whoseprogeny whose developmental fate is more restricted along one or more differentiation pathways.

Terms to knowTerms to know• extramedullary • ineffective y

hematopoiesisformation of blood cells in sites other than the bone

hematopoiesisinability of the bone marrow to generate asites other than the bone

marrow i.e. liver, spleen,why? demand for cells

th i i

marrow to generate a reasonable number of blood cells

• multi or pluri• erythropoiesis -rbc production

• granulopoiesis - wbc

• multi or pluri potential stem cellalso called a colony g p

(granulocyte production)• thrombopoiesis -

platelet production

forming cell - the cell that gives rise to all blood cells - the most immature

llplatelet production cell

Erythropoiesisrbc production

Red Blood Cell DisordersRed Blood Cell DisordersAnemias • Hemolytic AnemiasAnemias• Anemia of Blood Loss:

Acute vs. Chronic

y• Hereditary Spherocytosis• Sickle Cell Disease

• Anemia of ↓ Erythropoiesis

• Iron deficiency anemia

• Immunohemolytic Anemia• Thalassemia

• Iron deficiency anemia• Megaloblastic anemia• Anemia of chronic

• Paroxysmal Nocturnal Hemoglobinuria

• HA from mechanicalAnemia of chronic disease

• Aplastic anemia

HA from mechanical trauma to RBCs

Polycythemiay y

Nutritional Requirements for Erythropoiesis

1. protein and amino acids2 vitamin B12 and folic acid2. vitamin B12 and folic acid

- both are involved in DNA synthesis3 it i B ( id i )3. vitamin B6 (pyridoxine)4. vitamin C5. iron6 copper6. copper7. cobalt

Iron deficiency AnemiaIron deficiency Anemia• Most common form of nutritional anemia

– Iron balance is maintained by regulation of absorption of dietary iron

– ↑ Fe needs/erythropoiesis: absorbed iron transferred↑ Fe needs/erythropoiesis: absorbed iron transferred to plasma transferrin with ↓ iron loss through mucosal ferritin

• Negative iron balance/anemiaNegative iron balance/anemia– ↓ stored Fe (serum ferritin) and BM stainable Fe → ↓serum iron and ↑ in serum transferrin iron-binding capacity (TIBC)capacity (TIBC)

• Etiology: – low dietary intake, malabsorption (gastrectomy),

blood loss ↑ demand (pregnancy)blood loss, ↑ demand (pregnancy)

B12 DeficiencyB12 Deficiency

• Gastric resectionGastric resection• Ileal absorption defect (Crohn’s, resection)

B t i l th (bli d l )• Bacterial overgrowth (blind loop)• Drug induced (phenytoin, alcohol)• Fish Tapeworm

Folic Acid DeficiencyFolic Acid Deficiency

CausesCauses• Dietary

Al h l• Alcohol• Malabsorption (Crohn’s, sprue)• Pregnancy• Drug induced (methotrexate phenytoin)Drug induced (methotrexate, phenytoin)

Macrocytic AnemiasMacrocytic Anemias

• MCV >95MCV >95• B12 and Folate deficiency• Drug induced disorders of DNADrug induced disorders of DNA

synthesis– methotrexate, AZT, pentamidine, trimethoprimmethotrexate, AZT, pentamidine, trimethoprim– Alcohol

• Liver disease• Hypothyroidism• Congenital disorders of DNA synthesisg y

Normocytic AnemiasNormocytic Anemias

• Acute blood lossAcute blood loss• Chronic disease

R l F il– Renal Failure– Rheumatoid Arthritis

• Hemolytic anemia• Marrow failure

– Drug induced– Cancer

Aplastic AnemiaAplastic Anemia

• Suppression of multipotent myeloid stemSuppression of multipotent myeloid stem cells:

Anemia neutropenia thrombocytopenia– Anemia, neutropenia, thrombocytopenia• Etiology:

idi thi i di ti l t i d– idiopathic, irradiation, myelotoxic drugs, chemicals, viruses

Idi ti ti• Idiosyncratic reaction: – chloramphenicol, sulfonamides

Sideroblastic AnemiaSideroblastic AnemiaCharacteristic iron deposit in marrow RBCp• defective iron utilization in heme synthesisCongenitalg• sex-linked and autosomal recessive: rare• some respond to pyridoxineAcquired• Drug induced:

– INH, Chloramphenicol, ETOH, lead• Malignancy

Mechanisms of Drug-induced I di t d Bl d D iImmune-mediated Blood Dyscrasias

Drug

Bind and activatecomplement

Cell lysis

HAPTEN MECHANISM

Anti-DrugAb Bind to Fc receptor

of macrophages

Immune

IMMUNE COMPLEX MECHANISM

ImmuneComplex

Lysis by complementand/or macrophages

AUTOANTIBODY MECHANISM

AutoAbAutoAbLysis by complementand/or macrophages

Drug-induced Immune-mediated H l i A iHemolytic Anemia

Hapten Immune Complex AutoantibodyHapten Mechanism

Immune Complex Mechanism

Autoantibody Mechanism

Ampicillin Diclofenac Cephalosporinsp p pCarbenicillin Isoniazid Diclofenac

Penicillin Tetracycline LevodopaMethicillin Quinidine Methyldopa

Cephalosporin Thiopental ProcainamideTetracycline Chlorpromazine NomifensineTolbutamide Nomifensine Tolmentin

T. Deloughery, Lists drugs causing aplastic anemia, agranulocytosis, and thrombocytopenia. Immunol. Allergy Clin. of North Am. 18, 829 (1998)

Drug-Induced Hemolytic AnemiaDrug Induced Hemolytic Anemia

• Pathogenic mechanisms not fully understood, but schemes based on:– Drug-red cell interaction

I t ti f d i d d tib d ith RBC– Interaction of drug-induced antibody with RBC– Mechanism of hemolysis

Drug-Induced Hemolytic AnemiaDrug Induced Hemolytic Anemia

• High-Affinity Drug Drug-DependentHigh Affinity Drug, Drug Dependent Antibody (hapten)– Penicillin (high dose) is prototypePenicillin (high dose) is prototype– Methyldopa– Drug binds to RBC membraneDrug binds to RBC membrane– Detection of Ab requires drug presence– Hemolysis only with bound drugHemolysis only with bound drug– Ab is IgG, hemolysis moderate, extravascular,

complement not activatedp

Drug-Induced Hemolytic AnemiaDrug Induced Hemolytic Anemia

• Low-Affinity Drug Drug-DependentLow Affinity Drug, Drug Dependent Antibody (immune complex)

Drugs provoke formation of IgM or IgG– Drugs provoke formation of IgM or IgG– Complement activated on RBC surface

Hemolysis and detection require drug– Hemolysis and detection require drug presenceAbrupt severe intravascular hemolysis– Abrupt, severe intravascular hemolysis

– Renal failure commonDAT (+) for C3d negative for IgG– DAT (+) for C3d, negative for IgG

Drug-Induced Hemolytic AnemiaDrug Induced Hemolytic Anemia

• Drug-Independent (autoantibody)• Drug-Independent (autoantibody)– Drug interaction with RBC membrane,

i i t i i lt ticausing intrinsic alteration– IgG autoantibody capable of reacting

with all RBCs in absence of drug– Mild to moderate extravascular

hemolysis

Antidepressant andianemia

Venlafaxine• Venlafaxine• Fluoxetine Vaginal

bleeding• Bupropion• Venlafaxine is an antidepressant that is thought to treat

bleedingp g

depression through potent inhibition of dopamine reuptake.

• Fluoxetine is a specific inhibitor of serotonin reuptakep p• Buproprion is thought to be a week inhibitor of dopamine

and norepinephrine reuptake • Exact mechanism of vaginal bleeding associated with g g

antidepressant is unknown, but theories suggest that modulation of hormone may play a role.

Antidepressantdep essa

Cytocrome P 450Cytocrome P 450

Metabolisme of estrogen & steroid

Changes in ovulation & cycle behavior

Granulopoiesiswbc (granulocyte) production

Leukocyte Number AbnormalitiesLeukocyte Number Abnormalities

L k i d d bLeukopenia = decreased numbers– malnutrition, chronic disease states– drug induced - glucocorticoids, anti-cancer drugs, etc.g g , g ,

Leukocytosis = increased numbers– Normal component of inflammatory response to

inj ries and infectionsinjuries and infectionsLeukemia, Lymphomas = grossly increased numbers, abnormal forms; many subcategoriesnumbers, abnormal forms; many subcategories– bone marrow and blood stream (leukemia) or tissue

spaces (lymphoma) fill with cancerous (nonfunctional) leukocytesleukocytes

Drug induced leukopeniaDrug induced leukopenia• Clozapine-associated “moderate p

leukopenia”/“agranulocytosis” surface in the first 6 months

If “ d t l k i ”/“ l t i ” did t– If “moderate leukopenia”/“agranulocytosis” did not develop during the first 6 months, the chance of a drug-induced agranulocytosis was negligible but not zero

• Chloramphenicol Toxicity :Agranulocytosis aplastic anaemia in neonates– Agranulocytosis, aplastic anaemia, in neonates, failure of liver conjugation leads to grey baby syndrome.

Take home massagesTake home massages

1 Most antibiotics induced neutropenia1. Most antibiotics induced neutropenia2. Careful use and WBC monitor3 D ithd l i fi t h i3. Drug withdrawal is first choice4. Don’t forget find other reason of

neutropenia

Thrombopoiesisplatelet production

Bleeding Disorders: Hemorrhagic Diatheses

• Bleeding disorders from BV wall abnormalities• Bleeding disorders from BV wall abnormalities• Disseminated Intravascular Coagulation• Bleeding from thrombocytopenia

ITP• ITP• Drug-induced thrombocytopenia• HIV associated thrombocytopeniay p• Thrombotic microangiopathies: TTP / HUS• Bleeding related to CF abnormalities• Deficiency of Factor VIII-vWF Complex• Deficiency of Factor VIII-vWF Complex• Von Willebrand Disease• Hemophilia A (FVIII deficiency)

H hili B (FIX d fi i )• Hemophilia B (FIX deficiency)

Bleeding Disorders: Hemorrhagic Diatheses

D i d d th b t iDrug-induced thrombocytopenia• Quinine, Rifampin, Bactrim, Interferon,• Danazol Carbamazepine Vancomycin• Danazol, Carbamazepine, Vancomycin• Acetaminophen• GP IIb-IIIa blocking drugs (Abciximab)g g ( )• Herbal remedies (Jui™ )• Dietary supplements, tahini (pulped sesame

d )seeds)Heparin Induced Thrombocytopenia with

Thromboses (HITT)Thromboses (HITT)

Drug Induced ThrombocytopeniaDrug Induced Thrombocytopenia

• Quinine Rifampin Bactrim InterferonQuinine, Rifampin, Bactrim, Interferon,• Danazol, Carbamazepine,Vancomycin

A t i h• Acetaminophen• GP IIb-IIIa blocking drugs (Abciximab)• Herbal remedies (Jui™ )• Dietary supplements tahini (pulpedDietary supplements, tahini (pulped

sesame seeds)

Acquired thrombocytopenia with h t d l t l t i lshortened platelet survival

• Associated with • Associated withAssociated with bleeding– Immune-mediated

Associated with thrombosis– Thrombotic– Immune-mediated

thrombocytopenia (ITP)

– Thrombotic thrombocytopenic purpura( )

– Most drug-induced thrombocytopenias

p p– DIC– Trousseau’s

– Most others syndrome– Heparin-associated

thrombocytopenia

Heparin Induced Thrombocytopenia ith Th b (HITT)with Thromboses (HITT)

• Drug induced thrombocytopeniaDrug induced thrombocytopenia– 5% of patients treated with unfractionated

heparin by any routeheparin by any route• Etiology: acquired antibodies against

PF4/heparin complexes on PLT surfacePF4/heparin complexes on PLT surface

IMMUNE HEMOLYSISDrug-Related

• Immune Complex MechanismQ i idi Q i i I i id– Quinidine, Quinine, Isoniazid

• “Haptenic” Immune Mechanism– Penicillins, Cephalosporins

• True Autoimmune Mechanism– Methyldopa, L-DOPA, Procaineamide,

Ibuprofen

DRUG-INDUCED HEMOLYSISImmune Complex Mechanism

• Drug & antibody bind in the plasma• Immune complexes eitherp

– Activate complement in the plasma, or– Sit on red blood cell

A ti tib d l i d b RE• Antigen-antibody complex recognized by RE system

• Red cells lysed as “innocent bystander” of• Red cells lysed as innocent bystander of destruction of immune complex

• REQUIRES DRUG IN SYSTEM Q

DRUG-INDUCED HEMOLYSISHaptenic Mechanism

• Drug binds to & reacts with red cell f t isurface proteins

• Antibodies recognize altered protein, ±drug, as foreign

• Antibodies bind to altered protein & initiate pprocess leading to hemolysis

DRUG-INDUCED HEMOLYSISTrue Autoantibody Formation

• Certain drugs appear to cause antibodies• Certain drugs appear to cause antibodies that react with antigens normally found on RBC surface and do so even in theRBC surface, and do so even in the absence of the drug

Platelet dysfunctionPlatelet dysfunction

• Drug induced• Drug induced– aspirin– indomethacin– non-steroid antiinflammatory drugsy g

Increased Red Cell LossIncreased Red Cell Loss

• AcquiredAcquired• Intravascular

PNH– PNH– Sepsis

• Extravascular– Drug induced– Hypersplenism

Case reportCase report

Plavix® and Ginkgo induced ecchymosisecchymosis

P P f l / h f lPatient Profile/Chief Complaint• 69 yo, male• C.C: few ecchymosis over bil forearm • Mx:

Gi ’ ® (Gi k Bil b ) 40 bid– Gina’ex ® (Ginkgo Biloba) 40mg bid – Plavix ® (Clopidogrel) 75mg qd

Past History• Stroke、HTN• Mx：

– Ascotyl/A.S.A. 100mg– Aprovel/Irbesartan 150mg – Corosan/Dipyridamole 75mgCorosan/Dipyridamole 75mg

• Concurrent drugs– Acetaminophen/Tinten 500mg/ tab PO 1# tid prn – Chlorzoxazone/Mesin 200mg/tab PO 1# tid prn – Sennosides/Through 20mg/tab PO 1# hs prnSennosides/Through 20mg/tab PO 1# hs prn – Isosorbide/Imdur 60mg/tab PO 1# qd – Bisoprolol/Concor 5mg/tab PO 0.5# bid – Amlodipine/Norvasc 5mg/tab PO

Clopidogrel(Pl ®)(Plavix®)

• a thienopyridine derivative, irreversibly inhibits ADP-induced platelet aggrevation by inhibiting binding of ADP to its receptor and inhibiting binding of ADP to its receptor and subsequent ADP-mediated activation of glycoprotein IIb/IIIa complex.g y p p

Clopidogrel (Plavix®)• Warning

Clopidogrel (Plavix®)g

Thrombotic thrombocytopenic purpura (TTP):TTP has been reported rarely following use of Plavix, sometimes after a short exposure (<2 weeks).after a short exposure ( 2 weeks).TTP is a serious condition and requires urgent referral to a hematologist for prompt treatment. It is characterized by thrombocytopenia, microangiopathic hemolytic anemiathrombocytopenia, microangiopathic hemolytic anemia(schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever. TTP was not seen during clopidogrel’s clinical trials, which included over g p g17,500 clopidogrel-treated patients. In world-wide postmarketing experience, however, TTP has been reported at a rate of about four cases per million patients exposed, or about 11 illi i Th b k d i 11 cases per million patient-years. The background rate is thought to be about four cases per million person-years.

GINKGO -- ANTIPLATELET AGENTS

• Interaction Effect: increased risk of bleeding• Clinical Management: Concomitant use of Ginkgo and • Clinical Management: Concomitant use of Ginkgo and

antiplatelet agents is not recommended. If both agents are taken simultaneously, monitor bleeding

d d f bl d time and signs and symptoms of excessive bleeding to determine if platelet function has been adversely affected by Ginkgo. ff y g

• Onset: delayed • Severity: major • Documentation: fair • Documentation: fair • Probable Mechanism: ginkgolide B may inhibit platelet

activating factor (PAF) induced platelet aggregation

Micromedex