Erythrocytosis Flashcards
(21 cards)
Erythrocytosis definition
Increase in the total number of RBCs
Main issue that arises from too many RBCs in blood
Increase viscosity —> too thick for exchange of O2 and can clot
Hemoglobin (hgb)
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
Hematocrit (hct)
Percent of total blood volume made up of RBCs
Normal men = 42-48%
Women = 36-42%
Roughly 3x hgb value
Basic things to consider if patient has an increase in hemoglobin
- Are they taking testosterone?
- Cancer?
- Any condition that causes chronic hypoxia (like pulmonary and heart disease)
RBC production regulation
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)
Synthesis of EPO
When hypoxic…
—> HIF-1alpha and HIF-1beta dimerizes …
act as transcription factors for EPO production
“HIF = hypoxia inducing factor”
Conditions and mechanism of decreasing EPO production
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
Synthesis of RBC
When EPO is made…it will activate the JAK/STAT pathway (specificaly JAK2)
- EPO = ligand that binds to kinase receptors
- Kinase receptors will dimerize
- Phosphorylation of JAK2 on the receptors occurs
- Signaling by 2nd messengers tell the stem cells to make RBCs
If you have a patient with high RBC count (high erthrocytosis)…what should you do next?
Check to see if EPO is high or low?
You would expect low EPO
If patient just had a blood transfusion…what should EPO levels be like
Low
If a patient had hemorrhaging, what should the EPO levels be like
High
Disease that is associated with a high eryhrocytosis but low EPO
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)
If have high RBCs but low EPO…
But JAK2 V617F mutation PCR came back negative…
Think different diagnosis
- Essential thrombocytosis (50% with the mutation)
- Agnogenic myeloud metaplasia (increase in fibroblasts, 50% with mut)
- Chronic myelogenous leukemia (CML)…increase in WBC
Genetic mutation for chronic myelogenous leukemia (CML)
BCR-ABL
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
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
EPO secreting tumors (‘PHUCK’)
P-phenochromocytoma (rare adrenal tumor)
H - hepatoma (liver cancer)
U - uterine leimyoma
C - cerebellar hemangioblastom
K - kidney = most common, (hypernephroma)
If EPO secreting tumor is suspected … what is next step
CT scan to check for tumor…look for big and amorphous kidney
Mechanism for kidney cancer that would cause high RBCs AND higher than expected corresponding levels of EPO
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
High RBC and ‘high’ EPO =
Kidney cancer
Treatment for kidney cancer with EPO secreting tumor
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
