1. Self renewal
2. Ability to differentiate
3. Homing
4. Mobilization

Myeloid cells = granulocytes, monocytes, megakaryocytes, red blood cells

Lymphoid cells = plasma cells, natural killer cells, T lymphocytes

• decline in RNA and protein production
• decline in size
•  loss of nucleus

• Recent blood loss
• Iron deficiency anemia

• PHD enzyme is activated
• PHD hydroxylates HIF-1 alpha
• Hydroxylated HIF-1 alpha is a substrate for ubiquitination by the VHL complex
• When HIF-1 alpha is ubiquitinated, this marks HIF-1 alpha for degradation by the cell proteosome
• The EPO gene is not transcribed

• During low oxygen tension, less PHD is active and HIF-1 alpha is NOT hydroxylated
• HIF-1 alpha accumulates and enters the nucleus of peritubular cells and dimerizes with HIF-1 beta
• The dimerization between HIF-1 alpha and HIF-1 beta forms an active transcription complex and the EPO gene is transcribed

• EPO binds to the EPO-receptor
• The EPO receptor is a tyrosine kinase receptor that dimerizes upon EPO binding
• After dimerization, Jak2 kinases bind to the cytoplasmic portion of the receptor and become phosphorylated
• Jak2 then activates the STAT pathway through phosphorylation
• STAT dimerizes and enters the nucleus where it activates the transcription of genes needed for erythropoiesis

• Bleeding
• Hemolysis
• High altitude
• Pulmonary disease
• JAK2 activating mutations in myeloproliferative disorders

• Chronic kidney disease
• Iron, folate, or vitamin B12 deficiency
• Chronic inflammatory conditions
• Sideroblastic anemia
• Thalassemia
• Malignant infiltration of bone marrow
• Aplastic anemia
• Drug induced bone marrow toxicity

Fetus: 2 alpha and 2 gamma chains

Adult: 2 alpha and 2 beta chains

Lower affinity

This explains why fetal red blood cells have a higher affinity for oxygen

• There are two types of iron transporters: Heme transporter (for heme iron) and Divalent Metal Transporter-1 (for free iron)
• For DMT1, iron in the ferric state (Fe3+) must be reduced to the ferrous state (Fe 2+) by membrane bound cytochrome B  before transport
• Inside the epithelial cell, Fe can be stored by binding to mucosal ferritin
• Iron is transported across the basolateral membrane by specific transporters (ferrous iron by ferroportin-1) and then oxidized by hephaestin (Fe2+ --> Fe3+)
• Iron (bound to transferrin) can be transported to the liver for storage or incorporated into hemoglobin in the bone marrow

• Removal of endothelial cells is the initiating factor not only for activation of the extrinsic pathway, but also activation of circulating platelets
• Damage and removal of endothelial cells exposes vWF bound to the subendothelial matrix
• vWF binds the glycoprotein Ib (GpIb) receptor on platelets mediating platelet adhesion and activation
• Activated platelets bind fibrinogen through glycoprotein IIb/IIIa causing platelet aggregation
• vWF also stabilizes factor VIII and extends its t1/2

Mean Corpuscular Volume

The average volume of red blood cells

Used in diagnosing anemia and treatment monitoring

Microcytic = below normal range = due to iron deficiency anemia

Mean Corpuscular Hemoglobin Concentration

The average hemoglobin concentration in a volume of red blood cells

Red Cell Distribution Width

The measure of size variability of red blood cells

Some types of anemia have increased RDW (iron deficiency anemia, megaloblastic anemia, microangiopathic anemia)

Prothrombin Time

• A sample of patient plasma is mixed with tissue factor (thromboplastin, factor III) and excess calcium to overcome anti-coagulation in the test tube
• The time required to form a clot is measured and that is PT
• Measures extrinsic and common pathways of the coagulation cascade

• Heparin treatment
• Coumarin treatment
• Liver disease
• Vit K deficiency

Activated Partial Thromboplastin Time

• Lipids and tissue factors are added to a patients plasma
• Measures intrinsic and common pathway of coagulation cascade

• Heparin therapy
• Liver disease
• Vit K deficiency
• Hemophilia A and B
• von Willebrand disease

APTT: all coagulation factors except VII and XIII

PT: VII and factors in the common pathway

• Dietary deficiency
• Impaired absorption (intestinal disease and inflammation)
• Increased requirement in young children and pregnant women
• Increased loss from chronic bleeding

1. Storage iron
2. Transport iron
3. Erythron iron (RBcs and precursors)

Ferritin

Transferrin

1. Hemoglobin S concentration
2. pH
3. Deoxygenation (transit) time

• Low pH decreases the affinity of oxygen for hemoglobin
• This results in more deoxyhemoglobin which is the form of Hbg S that polymerizes

• In the microvascular system, hemoglobin is in the deoxygenated state --> thus more Hbg S is polymerized
• When Hbg S polymerizes, the RBC takes on the characteristic sickle shape
• These sickled cells are more likely to damage organs such as the spleen and bone marrow because RBCs require more time to travel through the microvascular beds
• Since the RBCs have a longer transit time in these organs, they are more likely to get trapped and occlude microvessels in these organs
• In inflammed tissue, RBCs adhere to endothelial cells of the microvascular system, thus Hgb remains in deoxygenated state for longer periods

• Normal platelet count
• Prolonged APTT
• Prolonged bleeding time
• Low plasma VIII

• Symptoms are similar to thrombocytopenia
• Spontaneous mucosal bleeding
• Excessive and prolonged bleeding from wounds
• Bruising

Linked to the X chromosome

Recessive

• Normal bleeding time, platelet count, and PT
• Prolonged APTT

• Excessive bleeding after trauma or surgery
• Spontaneous hemarthroses

• Easy bruising
• Spontaneous mucosal bleeding

• Metabolism of hydroxyurea produces NO
• NO activates sGC or hydroxyurea directly activates sGC
• Activated sGC converts GTP to cGMP
• cGMP activates transcription of the gamma chain gene
• This mechanism requires a functional nucleus, thus it can only work on a red cell precursor
• NO production is beneficial since it causes vasodilation and decreased adhesion of RBCs to endothelial cells

Keratinocyte Growth Factor

Recombinant growth factor that stimulates division and survival of epithelial cells

Uses:

• Treatment of oral mucositis in patients receiving chemotherapy
• Leukemia and lymphoma patients undergoing chemotherapy

• Solid tumors, such as carcinomas
• Many solid tumors are derived from epithelial cells and since this recombinant protein promotes growth of epithelial cells, it should not be given to these patients

• Epoetin Alpha
• Darbepoetin Alpha
• Methoxy-PEG-epoetin

• Epoetin Alpha has the same amino acid sequence as endogenous EPO
• Darbepoetin Alpha has four amino acids that have been changed to Asparagine, which are sites for glycosylation --> glycosylation of Asparagine increases plasma t1/2
• Methoxy-PEG-Epoetin has increased solubility, prolonged t1/2, and is antigenic

• Antibody production to the recombinant EPO
• A sudden burst in erythropoiesis after administration can cause relative or absolute iron deficiency
• Thrombotic events
• HTN

• Pegylated recombinant human megakaryocyte growth and differentiation factor (PEG-rhMGDF)
• Romiplostim

• Recombinant human IL-11
• Enhances production of megakaryocytes and platelets
• Increases platelet production during chemotherapy

• Fluid retention (edema, plasma expansion, exacerbation of effusions)
• Hypersensitivity
• Cardiac arrhythmias
• Dilution anemia

• Granulocyte-macrophage colony stimulation factor

• Neutropenia recovery after chemotherapy
• After stem cell transplantation, used for homing
• Mobilize precursor cells from bone marrow

• Bone pain
• High doses cause neutrophilia
• Lung infiltration
• Edema

• Bleeding episodes (hemophilia A and B, VII deficiency)
• Reserved for patients that are actively bleeding

• Hemophilia A
• vWD

• water retention through activation of type 2 vasopressin receptors in renal tubule cells
• hyponatremia
• unstable blood pressure

• Deamination increases anti-diuretic activity
• Replacement with D-arginine decreases vasopressor activity --> less type 1 vasopressin receptor  activity and more type 2 activity --> high anti-diuretic:vasopressor ratio compared to vasopressin (ADH)

2 epsilon, 2 zeta

2 gamma, 2 alpha

reticuloendothelial system

spleen

macrophages

transferrin