Erythrocytosis

Question 1

Erythrocytosis definition

Answer 1

Increase in the total number of RBCs

Question 2

Main issue that arises from too many RBCs in blood

Answer 2

Increase viscosity —> too thick for exchange of O2 and can clot

Question 3

Hemoglobin (hgb)

Answer 3

Amount normal

Men = 14-16 g/dL
Women = 12-14 g/dL

Higher in men due to their androgens like testosterone which drive hgb production

Question 4

Hematocrit (hct)

Answer 4

Percent of total blood volume made up of RBCs

Normal men = 42-48%
Women = 36-42%

Roughly 3x hgb value

Question 5

Basic things to consider if patient has an increase in hemoglobin

Answer 5

1. Are they taking testosterone?
2. Cancer?
3. Any condition that causes chronic hypoxia (like pulmonary and heart disease)

Question 6

RBC production regulation

Answer 6

Done by the protein, erythropoietin (EPO)

When tissue sense hypoxia…kidneys make EPO…which stimulates bone marrow to make RBCs

Source of EPO (80% kidney, 20% liver)

Question 7

Synthesis of EPO

Answer 7

When hypoxic…

—> HIF-1alpha and HIF-1beta dimerizes …
act as transcription factors for EPO production
“HIF = hypoxia inducing factor”

Question 8

Conditions and mechanism of decreasing EPO production

Answer 8

When not hypoxic

Hydrolase and acetyl-transferase modify the HIF-1alpha so that it binds to VHL (von Hippel-Lindau)

VHL will tag HIF-1alpha for ubiquitylation and degradation in a proteosome

Question 9

Synthesis of RBC

Answer 9

When EPO is made…it will activate the JAK/STAT pathway (specificaly JAK2)

1. EPO = ligand that binds to kinase receptors
2. Kinase receptors will dimerize
3. Phosphorylation of JAK2 on the receptors occurs
4. Signaling by 2nd messengers tell the stem cells to make RBCs

Question 10

If you have a patient with high RBC count (high erthrocytosis)…what should you do next?

Answer 10

Check to see if EPO is high or low?

You would expect low EPO

Question 11

If patient just had a blood transfusion…what should EPO levels be like

Answer 11

Low

Question 12

If a patient had hemorrhaging, what should the EPO levels be like

Answer 12

High

Question 13

Disease that is associated with a high eryhrocytosis but low EPO

Answer 13

Polycythemia vera (PVC)

Usually have conserved point mutation in JAK2 (part 2 of pathway)…V617F

Allows the JAK2 to always be turned on…so making RBCs without the need for EPO

Low grade malignancy

Can detect this mutation via PCR or single nucleotide polymorphism (SNP)

Question 14

If have high RBCs but low EPO…

But JAK2 V617F mutation PCR came back negative…

Answer 14

Think different diagnosis

1. Essential thrombocytosis (50% with the mutation)
2. Agnogenic myeloud metaplasia (increase in fibroblasts, 50% with mut)
3. Chronic myelogenous leukemia (CML)…increase in WBC

Question 15

Genetic mutation for chronic myelogenous leukemia (CML)

Answer 15

BCR-ABL

Question 16

If JAK mutation came back negative … and EPO is normal (which is high for someone with increased hgb…)

What else could cause this high EPO

Answer 16

Hypoxia

Smokers

Heart and lung disease

Supplemental EPO (doping)

High O2 affinity hgb, mutation in hgb molecule that will bind to O2 with more affinity…kidney will sense low O@ in the tissue and make EPO

EPO SECRETING TUMORS

Question 17

EPO secreting tumors (‘PHUCK’)

Answer 17

P-phenochromocytoma (rare adrenal tumor)

H - hepatoma (liver cancer)

U - uterine leimyoma

C - cerebellar hemangioblastom

K - kidney = most common, (hypernephroma)

Question 18

If EPO secreting tumor is suspected … what is next step

Answer 18

CT scan to check for tumor…look for big and amorphous kidney

Question 19

Mechanism for kidney cancer that would cause high RBCs AND higher than expected corresponding levels of EPO

Answer 19

In kidney cancer

VHL is mutated…there is no degradation of HIF-1alpha…so you will get a constitutively active gene for EPO production and thus high hgb

Also get an active gene (VEGF - vascular endothelial growth factor)

Causes angiogenesis which promtoes tumor oxygenation and growth

Question 20

High RBC and ‘high’ EPO =

Answer 20

Kidney cancer

Question 21

Treatment for kidney cancer with EPO secreting tumor

Answer 21

Drug to inhibit pathway when VEGF binds to receptros because when VEGF off..

No blood supply to support tumor growth

Drugs:

Monoclonal antibodies for VEGF

Small molecule kinase inhibitors (inhibit VEGF)

mTOR inhibitors