Pharmacology 2: Hematopoiesis

What regulate blood cell production, maturation, and function?

Hematopoietic growth factors and cytokines

What interact synergistically and have overlapping effects?

Numerous hematopoietic growth factors

What can growth factors be?

Multilineage or lineage-specific

What does pharmacological strategies for anemia treatment involve?

Stimulation of appropriate growth factors

What is over expressed in most AML patients?

The Flt3 receptor is over expressed which is why it’s targeted by the RTK inhibitor midostaurin to silence intracellular signaling

What is the primary target?

Erythropoietin because it is lineage-specific

What is EPO transcription regulated by?

HIF-1a which are controlled by local oxygen.

What happens to HIF-1a in normal/high oxygen conditions?

It is hydroxylated, facilitating binding to the E3 ubiquitin ligase complex (pVHL)

What is done to ubiquitinated HIF-1a?

Trafficked to the proteasome and degraded

What happens under low oxygen conditions?

HIF-1a is not hydroxyagted or ubiquitinated allowing HIF-1a to translocate into the nucleus and up regulate EPO expression

Increase EPO levels increase?

O2 conditions, providing negative feedback regulation of physiological EPO production

What can arise genetically?

Deficiencies of RBCs from chronic kidney disease (due to elimination of cells that trigger EPO production) or anemia from anticancer therapies (many destroy hematopoietic stem cells)

What are needed in these cases?

Erythropoietin-stimulaitng agents (ESA)

What are therapeutic options for EPO derivatives, which stimulate the EPO receptor?

1) Recombinant human erythropoietin (rhEPO)

2) Methoxy polyethylene glycol (PEG)-epoetin beta: Longest ½ life due to PEG

3) Darbepoetin alfa: additional sialic acid groups increases ½ life to 3X relative to EPO

What are ESAs known to be?

Abused by athletes and use is regulated in sport

What is the type of anemia for iron deficiency?

Microcytic, hypochromic with MCV <80 fL and MCHC <30%

What are laboratory abnormalities with iron deficiency?

Low SI <30 mcg/dL with increased TIBC, resulting in a % transferrin saturation (SI/TIBC) of <10%; low serum ferritin level (<20 mcg/L)

What type of anemia with folic acid deficiency?

Macrocytic, normochromic with MCV >100 fL and normal or elevated MCHC

What are laboratory abnormalities with folic acid?

Low serum folic acid (<4 ng/mL)

What type of anemia is with Vitamin B12?

Same as folic acid deficiency

What are laboratory abnormalities associated with Vitamin B12 deficiency?

Low serum cobalamin (<100 pmol/L) accompanied by increased serum homocysteine (>13 μmol/L), and increased serum (>0.4 μmol/L) and urine (>3.6 μmol/mol creatinine) methylmalonic acid

What to do with iron deficiency?

Supplemental iron preparations (oral or parenteral)

What is vitamin B12 (cobalamin)?

Cofactor for essential biochemical reactions (production of methionine, tetrahydrofolate)

What does deficiency of iron cause?

Megaloblastic anemia, neuropathy; deficiency in geriatric due to decreased GI absorption 

What should be replacement therapy with?

Cyanocobalmin (parenteral)

What is folic acid required for?

Amino acid, purine, DNA base pair synthesis; relatively common deficiency (megaloblastic anemia); prenatal supplementation advised

What is acute iron toxicity?

accidental pediatric overdose; can be lethal; necrotizing gastroenteritis followed by metabolic acidosis; treated with whole bowel irrigation or deferoxamine to chelate with iron & promote fecal excretion (activated charcoal is ineffective)

What is chronic iron toxicity?

(hemochromatosis); excess iron deposited in organs (heart, lungs, liver) leading to organ failure; seen in B-thalassemia patients; treated by blood removal, deferoxamine chelation

What are erythropoietin-stimulating agents (ESAs)?

1) Recombinant human erythropoietin (rhEPO); Epoetin alfa

2) Methoxy polyethylene glycol (PEG)-epoetin beta (FYI): longer ½ life due to PEG

3) Darbepoetin alfa (FYI): additional sialic acid groups increases ½ life 3x vs. EPO

What do all ESA stimulate?

Production & differentiation by triggering EPO-receptor JAK/STAT-mediated differentiation of precursors into erythrocytes/RBCs. Increased RBC levels increases oxygen-carrying capacity

What are ADR of ESA?

Polycythemia, hyperviscoisty, inc. risk stroke or MI, HTN

Who are at higher risk for death, serious CVS effects?

Anemia or CKD

What is SCD?

Genetic mutation leading to RBC with curved shape (HbS) 

What are the symptoms of SCD?

Include hemolytic anemia, increased infection risk, acute pain crises

What predominates treatment methods in SCD?

Restoration of normal RBC shape/function predominates treatment methods

What can increase HbF (fetal hemoglobin) levels?

 5-azacytidine

Hydroxyurea

 : inhibit ribonucleotide reductase to induce HbF

5-azacytidine

DNA demethylation to increase HbF

Hydroxyurea

inhibit ribonucleotide reductase to induce HbF

What are other options for SCD?

• Gene editing(Casgevy, Lyfgenia)

• Stem cell transplant (curative)

• Biologic to decrease clotting (Crizanlizumab (Adakveo)

What does deficiencies of thrombocytes impact?

Blood clotting (thrombocytopenia)

What does lineage-specific growth factor thrombopoietin mediate?

JAK/STAT-dependent differentiation of precursor cells into platelets

How is TPO expressed?

Constitutively expressed (unlike EPO); effects are controlled by expression of the TPO receptor on target cells (platelet progenitors, megakaryocytes, and platelets themselves/

What is the only FDA approved therapeutic?

Recombinant human interleukin 11 (oprelvekin) is only currently available

Why are the ADRs significant?

Due to expression of the receptor outside of hematopoietic lineages (edema, arrhythmia, hypokalemia, anaphylaxis)

What do platelets have a half-life of?

Circulating half-life of 10 days

How is oprelvekin administered?

Administered prophylactically (1-2 weeks prior to need for increased platelet counts)

What does myelosuppression due to cancer or cancer chemotherapy often result in?

Low neutrophil count and reduces a patient’s ability to combat infections

What are clinically approved agents for neutropenia?

1) Recombinant human G-CSF (filgrastim)

2) Pegylated filgrastim (PEG-G-CSF)

3) Recombinant human GM-CSF (sargramostim; FYI): immunostimulatory;

increases neutrophil numbers.

Recombinant human G-CSF (filgrastim)

Mimics endogenous G-CSF growth factor effects; dose-dependent increase in neutrophil

Pegylated filgrastim (PEG-G-CSF)

metabolized more slowly than filgrastim, allowing for single daily injections

Recombinant human GM-CSF

immunostimulatory; increases neutrophil numbers.

What is a common ADR?

Bone pain which resolves upon discontinuation of the therapy

What can production of hematopoietic cells be disrupted by?

Cancer chemotherapy, cancer, and other clinical disorders resulting in anemia, neutropenia, and thrombocytopenia

What are pharmacological agents to restore normal cell counts based on?

Growth factor analogs