Drugs Affecting Hematopoiesis

Classification of Hematopoietic Disorders

• $\uparrow$ cell count ⇒ polycythemia
• $\downarrow$ cell count ⇒ leukopenia, thrombocytopenia, anemias (iron-deficiency, megaloblastic)

Iron-Deficiency Anemia (IDA)

• Type: hypochromic, microcytic
• Main causes: GI bleeding, reduced intake/malabsorption, increased needs (newborns, children, pregnancy), menstrual/occult loss

Iron Metabolism Essentials

• Dietary intake: $14 \pm 4\ \text{mg/day}$
• Absorption (duodenum, active, Fe$^{2+}$>Fe$^{3+}$): $\approx 1\ \text{mg/day}$; increases in IDA
• Plasma pool: $\approx 3\ \text{mg}$, turns over $\sim 10$×/day
• Recycling: RES → bone marrow $25\ \text{mg/day}$
• Physiologic loss: stool, urine, skin, cells

Oral Iron Therapy

• Max absorbable: $50{-}100\ \text{mg/day}$ ⇒ prescribe $200{-}400\ \text{mg/day}$ elemental Fe
• Duration: $3{-}6$ months (saturate stores before Hb rises)
• Preparations:
  • Ferrous sulfate (± folic acid)
  • Ferrous gluconate
  • Ferric oxide / sorbitol complexes
• SE: GI discomfort, constipation/diarrhea, dark stools

Parenteral Iron

• Given only as complexes: iron-dextran, sodium ferric gluconate, ferumoxytol, ferric carboxymaltose, iron sucrose
• Dosing: total $1{-}2\ \text{g}$ IM/IV over $10{-}20$ days (or single slow infusion)
• SE: frequent allergic reactions (test dose mandatory)

Iron Poisoning

• Acute (children, >$10$ tablets): necrotizing GI, shock, metabolic acidosis → treat with lavage + deferoxamine
• Chronic (hemochromatosis): Fe deposition in heart, liver, pancreas; usually genetic

Megaloblastic Anemias

• Features: hyperchromic, macrocytic; gastric atrophy common
• Key vitamins: B$_{12}$ (cyanocobalamin), folic acid – neither synthesized endogenously

Vitamin B$_{12}$

• Dietary sources: liver, meat, eggs, cereals; requires intrinsic factor for absorption
• Liver store: $3000{-}5000\ \mu\text{g}$; daily need $\approx 2\ \mu\text{g}$ (deficit develops over years)
• Deficiency → pernicious anemia ± neurologic damage
• Therapy (IM only when deficient):
  • Loading: $100{-}1000\ \mu\text{g}$ daily/every 2 days for $1{-}2$ weeks
  • Maintenance: same dose monthly, lifelong
  • Neurologic signs: weekly for $6$ months then monthly

Folic Acid

• Sources: vegetables, yeast, liver, kidney
• Daily need: $50{-}200\ \mu\text{g}$ (pregnancy $300{-}400\ \mu\text{g}$); liver store $5{-}20\ \text{mg}$
• Deficiency develops within $1{-}6$ months after intake stops
• Drug-induced deficit: methotrexate, trimethoprim, azathioprine, zidovudine, phenytoin, phenobarbital

Hematopoietic Growth Factors

Erythropoietin (EPO)

• Recombinant $\alpha$-EPO (SC/IV); darbepoetin $\approx 3$× longer $t_{1/2}$
• Stimulates erythroid progenitors; uses: CKD anemia, marrow disorders, prematurity, HIV, malignancy
• SE: hypertension; overdose ⇒ severe HTN, thrombotic CV death

Myeloid Growth Factors (Neutropenia)

• G-CSF: filgrastim, tbo-filgrastim (daily), pegfilgrastim (single dose)
• GM-CSF: sargramostim
• Indications: prevent/treat chemo- or transplant-related neutropenia
• SE: bone pain

Thrombopoietic Agents (Thrombocytopenia)

• Interleukin-11 analogue: oprelvekin (SC, $t_{1/2}$ $7{-}8$ h)
• Thrombopoietin analogues
• Stimulate megakaryocyte & multilineage progenitors → ↑ platelets, neutrophils

Plasma Substitutes – Dextrans

• Dextran $70\,(6\%)$: plasma expander; anti-thrombotic (↓ platelet adhesion, fibrin polymerisation); used peri-surgically, vascular stenoses, artificial tears
• Dextran $40\,(10\%)$: improves microcirculation (↓ viscosity, ↑ RBC flexibility)