Erythropoiesis

Aplastic Anemia Differentials

*Megaloblastic Anemia* -reduced ability to make DNA (e.g. B12 deficiency) *Myelophthisic (bone wasting) anemia* -accelerated hematopoietic destruction -usually from invasive carcinoma (esp. prostate cancer) -hypo-cellular bone marrow *Myelodysplastic Syndrome (MDS)* -ineffective (dysplastic) hematological cells -diversion of stem cells to the dysplastic line, usually cancerous -hyper-cellular bone marrow *Hematopoietic cancers* -leukemia, lymphoma, multiple myeloma -diversion of precursor cells to the cancerous lines Other anemias

Erythrocyte properties

*no nuclei* -can't synthesize mRNA or proteins -cytoskeleton weakens as cells age -recognition proteins are lost as cells age *no mitochondria* -nearly all energy is from glycolysis -absolute requirement for glucose for energy -can't use fatty acids, amino acids or keto acids lifespan 100-120 days -90% are destroyed by *macrophages of spleen, liver*, etc. -10% hemolyze in kidney, elsewhere

Myelophthisic (bone wasting) anemia

A type of anemia resulting from aplastic anemia -accelerated hematopoietic destruction -usually from invasive carcinoma (esp. prostate cancer) -hypo-cellular bone marrow

Megaloblastic Anemia

A type of anemia resulting from aplastic anemia -reduced ability to make DNA (e.g. B12 deficiency)

Myelodysplastic Syndrome (MDS)

Anemia differential resulting from aplastic anemia -ineffective (dysplastic) hematological cells -diversion of stem cells to the dysplastic line, usually cancerous -hyper-cellular bone marrow

Hematopoietic cancers

Anemia differential resulting from aplastic anemia -leukemia, lymphoma, multiple myeloma -diversion of precursor cells to the cancerous lines

Polycythemia symptoms and complications

Blood viscosity -HPTN, headache, tinnitus (ringing in ears), vertigo, angina pectoris, intermittent claudication (pain/cramp in leg); visual disturbances Thrombosis: -stroke, MI, venous thrombosis Hepatomegaly/splenomegaly erythema (ruddy complexion) increased histamine (if basophils increased) -pruritus (itching), gastric ulcer bleeding (1%)

Aplastic anemia

Bone marrow failure -reduced cell numbers (of bone marrow?) in biopsy all hematopoietic line usually affected -erythrocytes, leukocytes, thrombocytes, B cells, etc. anemia is normocytic (normal size), normochromic (normal color: 1/3 central pallor) -occasionally microcytic -hypersegmented neutrophils 20% genetic; 80% acquired incidence: -range 2/million in Europe to 14/million in Japan -bimodal incidence (20-25yr old peak and >60 yr old peak)

Limiting steps in Erythropoiesis

Erythropoiesis is dependent on *ERYTHROPOIETIN* (renal hormone) and *Folate and B12* --in BFU-E and CFU-E stages Final maturation stages are *IRON-dependant* ---erythroblast --> reticulocytes -- > erythrocytes/RBCs

Erythropoiesis

Formation of erythrocytes (RBCs) from common myeloid progenitor RBCs are myeloid Sequence: -Common myeloid progenitor -blast (burst) forming unit-erythroid (*BFU-E*) -colony forming unity-erythroid (*CFU-E*) -*Proerythroblast* -*Erythroblast* (several stages: basophilic --> polychromatic --> orthochromatic (normoblast)) -*reticulocyte* (polychromatic erythrocyte) (1st enucleate stage) -*erythrocyte* (RBCs) Stimulated by *ERYTHROPOIETIN* -BFUs make CFUs -CFUs form colonies in bone marrow

Renal hormone *erythropoietin* (EPO)

Hormone that stimulates erythropoiesis

Other required factors in regulation of erythropoiesis

Hormones: -thyroid hormone (+) -cortisol (+ in stressed state) -estrogen/testosterone (+) Cytokines: -IL3 -GM-CSF -others

Erythropoietic stimulating agents

Indications for use on patients: -Anemia of chronic kidney disease -Preparation for surgery with high risk of blood loss -Anemia related to: Zidovudine (antiviral drug in AIDS tx) , chemotherapy -Prematurity related anemia

Normocytic and normochromic (occasionally microcytic)

Low EPO (renal) anemia is...

Kidney

Makes 90% of EPO

Treatment of Polycythemia

Phlebotomy -may cause iron deficiency Myelo-suppresants -hydroxyurea-alkylating agent 3-4% risk of leukemic conversion x/long term use -radioactive phosphorus (32P) -Drugs

Hepcidin (cont.)

Protects against excessive circulating iron glycoprotein from liver 6-8 hour half-life inhibits *ferroportin* (FPN), a membrane iron transporter, to reduce: -GI iron absorption -macrophage RBC breakdown -Hepatic iron release

reticulocytes

RBC precursors elevation defines anemia as "chronic" In severe anemia from bone marrow disorders: -elevated reticulocytes = increased RBC production as in chronic anemia -Normal reticulocytes may not differentiate between acute and chronic -Low reticulocytes = decreased production of RBCs as in anemia from disorders of erythropoiesis or iron deficiency

Anemia

Reduced renal function (40-50%) results in ....

Hepcidin

Regulatory hormone of erythropoiesis -the liver secretes this hormone when plasma iron is high -it inhibits iron absorption and RBC breakdown -delay time up to 3 days (same as iron)

Regulation by erythropoietin (EPO)

Renal interstitial cells make this hormone -glycoprotein, 6-8 hour half-life low blood O2 stimulates this hormone action: Stimulate erythropoiesis and inhibit hepcidin secretion Corrects low O2 -feedback inhibition

replacement of EPO

Treatment of renal anemia

Symptoms of Aplastic Anemia

With a genetic cause, constellation of other signs and symptoms (hydrocephalus) *Anemia (low RBC) -pallor, headache, palpitations, fatigue, pale gums *leukopenia (low WBC) -recurrent infections of the mouth and pharynx -systemic infections -oral/pharyngeal ulcerations *thrombocytopenia (low platelets) -bleeding tendency (including mucosal and gingival) -petechia, purport and ecchymosis Dental complications: -Gingival hemorrhage -Mucosal petechia, purpura & ecchymosis (different sizes of sub-epithelial hemorrhage) -Oral/pharyngeal ulcers -Fungal infections (Fungal infections present the greatest risk to these leukopenic patient)

treatment of aplastic anemia

immunosuppression is autoimmune -5yr survival 75% (vs. 30% untreated) Bone marrow transplant if congenital -tx of choice under age 40 -not used over age 65 transfusion -used sparingly until diagnosis and tx are determined infectious cases -broad spectrum antibiotics -hematopoietic cytokines (C-CSF, GM-CSF, etc.)

Polycythemia

increased RBC (Hct > 55%)

Liver

makes 10% of EPO

Hematopoiesis

multipotent (pluripotent) stem cell gives rise to all blood cells Two main branches: 1. *Lymphoid* (lymph organs) -Natural killer cells (NK) -B cells --> plasma cells -T cells -dendritic cells 2. *Myeloid* (bone marrow) -erythrocytes -megakaryocytes --> thrombocytes -mast cells -Myeloblasts --> -monocytes--> macrophages -basophils -neutrophils -eosinophils -dendritic cells *Cytokines* cause differentiation -interleukins -colony stimulating factors (CSF) -others

secondary polycythemia

physiologic -normal response to high altitude, smoking, etc. -compensation for lung or cardiovascular disease Other: -induced by liver or endocrine tumors From internet: is usually due to *increased erythropoietin (EPO) production* either in response to chronic hypoxia (low blood oxygen level) or from an erythropoietin secreting tumor.

erythropoietin (EPO)

regulatory hormone of erythropoiesis -the kidney excretes this hormone when O2 delivery is low -This hormone stimulates erythropoiesis and inhibits hepcidin secretion -delay time up to 3 weeks

primary polycythemia

-myeloproliferative condition, *very often cancerous* -platelets and leukocytes may also increase -if only erythrocytes: _____________ rubra vera or erythremia

Recombinant human erythropoietin (rHuEPO, epoetin)

1st generation Erythropoietic stimulating agents 8.5 hour half life

Darbepoietin alpha

2nd generation Erythropoietic stimulating agents Two N-linked carbohydrate chains to increase half-life; 25.3 hour half-life

Continuous Erythropoietin Receptor Activator (CERA)

3rd generation Erythropoietic stimulating agents Linked to 30 kD polyethylene glycol to increase half-life; 1 30 hour half-life FDA approved, but legal issues are preventing sale in the US

Causes of aplastic anemia

Congenital, syndromes: -fanconi anemia: rare, inherited blood disorder that leads to bone marrow failure -amegakaryocytic thrombocytopenia -familial aplastic anemia Acquired: -infectious: viruses and atypical mycobacteria -autoimmune -radiation or toxic chemicals (ex: benzene) -liver disease -pregnancy -transfusion -idiopathic