The Iron Disorder Study Group presents "Too many RBCs: polycythemia (or erythrocytosis) in a nutshell."
Nutshell guides necessarily oversimplify some information. These guides are intended to get members of Iron Disorder Study Group up to speed.
Terms to know before we get started
Red blood cells (RBCs) are made in bone marrow and are the part of blood that carries oxygen to every part of the body via a protein called hemoglobin. Hemoglobin binds gases: RBCs bind to oxygen when you breathe in, drop off the oxygen to tissues, and pick up carbon dioxide to take back to be exhaled. RBCs live about 120 days, and your body is constantly making new ones to replace the old ones. These new red cells are called erythroblasts. Read more about RBCs here.
White blood cells (WBCs) are responsible for a key part of the body's immune system. Like red blood cells, the white blood cells are formed from the stem cells of the bone marrow. Read more about WBCs here.
Platelets, also known as thrombocytes, are small cell fragments in the blood that form clots and stop or prevent bleeding. Also made in bone marrow. Read more about platelets here.
Erythroblasts: newly produced Red Blood Cells
Hepcidin: the body's master iron regulatory hormone. Long story short, it can help trap iron in cells, so in this way, it serves as a ferritin building hormone under certain circumstances. If hepcidin drops, cells release iron for use in RBCs.
Erythroferrone: a hormone that can suppress hepcidin. As RBCs are made, the amount of this hormone increases.
Hemoglobin is the iron-containing protein inside red blood cells that gives them their red color and lets them carry oxygen. Each hemoglobin molecule can carry four oxygen molecules at a time. As red blood cells move through the lungs, hemoglobin grabs oxygen and then drops it off in tissues throughout the body. Hemoglobin also picks up carbon dioxide on the return trip to the lungs, where it can be exhaled. Without enough hemoglobin, the body can’t deliver enough oxygen to cells. If it drops below 13g/dL (12g/dL if female) you are anemic. Read more about hemoglobin here.
Hematocrit is a measure of how much of your blood is made up of red blood cells (RBCs). It's expressed as a percentage. For example, if your hematocrit is 45%, that means 45% of your blood's volume comes from red blood cells, and the rest is plasma (the liquid part), white blood cells, and platelets.
EPO or
erythropoietin: a hormone that stimulates red blood cell production
Erythrocytosis: the body makes too many Red Blood Cells. These extra cells thicken your blood, making it harder for it to flow. This can cause problems like headaches, dizziness, feeling tired, or even blood clots.
Polycythemia: an older term for
Erythrocytosis.
Phlebotomy: a doctor orders blood to be taken, usually a "unit" of 500ml, which is then generally disposed of as medical waste. FDA rules disallow blood donation for Polycythemia Vera but usually allow it for erythrocytosis.
The problem, stated simply
Higher RBC Count = Higher Hematocrit.
When you have more red blood cells, the percentage of your blood taken up by these cells increases, which raises your hematocrit level.
If you have a normal number of red blood cells, your hematocrit might be around 40-50%. If you have too many red blood cells (like in erythrocytosis), your hematocrit could rise above 50%, making your blood thicker.
This blood thickness or viscosity is the problem. Thick blood can mean health issues, discussed below.
Normal Labs
The normal lab ranges in human beings are based on population averages that were set decades ago. The common normal ranges that we are concerned with are:
Hematocrit (HCT) as a percent
Men: 42 - 52 (some labs use 50, some 54, we've seen 60)
Women: 37 - 47
Hemoglobin (HGB) in g/dL
Men: 13.5 - 18.0
Women: 12.5 - 16.0
Red Blood Cells (RBCs) x10E6/uL
Men: 4.7 - 6.0
Women: 4.2 - 5.4
In PV and erythrocytosis: anything over 6 for men and 5.4 for women. Can go to 7 or higher.
White Blood Cells (RBCs) x10E3/uL
Men: 3.5 - 10.5
Women: 3.5 - 10.5
In PV but NOT erythrocytosis: an average of 11 to 20. A lot of things can cause an elevated WBC count however.
Platelets x10E3/uL
Men: 150 - 450
Women: 150 - 450
Incidentally, the average hematocrit of healthy males living at 4,000 meters (13,100 feet) in Bolivia is 52.
The common target hematocrit in PV is to stay at or below 45%. The common target when on Testosterone is to stay at or below 54%. Discussion of high hematocrit when on Testosterone is available here at the Vorck Ferritin Protocol page.
The types of "too many RBCs"
Primary Erythrocytosis (Not-PV!) is also rare. It can be caused by genetic mutations leading to increased erythropoietin (EPO) sensitivity or dysregulated oxygen sensing. Examples include mutations in the EPOR (erythropoietin receptor) gene or genes affecting the hypoxia pathway, such as VHL, HIF2A (EPAS1), or PHD2.
Secondary Erythrocytosis (SE) is actually quite common. Generally, EPO levels are low in primary causes, and elevated in secondary causes. Increases in EPO can come from:
The common causes of SE
Smoking (a hypoxic process)
Sleep apnea (a hypoxic process)
Testosterone use
Uterine fibroids, PCOS, hyperandrogenism
The less common causes
Chronic obstructive pulmonary disease (COPD) (a hypoxic process)
High altitude living or exposure (a hypoxic process)
Carbon monoxide exposure (leaky furnaces count) (a hypoxic process)
Elevated levels of Growth Hormone or IGF-1
The rare causes
Right-to-left cardiac shunts (heart disease)
Renal tumors that produce EPO
Dehydration (yes, this is really a rare cause)
Reduced plasma volume due to severe burns or diuretic overdose
To distinguish between causes, physicians evaluate:
JAK2 and EPO tests, as mentioned
Oxygen saturation during sleep to rule out hypoxia-related causes
Arterial blood gases to assess hypoxia or respiratory causes
Imaging to identify tumors or renal abnormalities
Genetic testing for mutations in the following genes for primary erythrocytosis if everything else ruled out:
- EPO gene (not EPO level), VHL, HIF2A (EPAS1), EPOR, PHD1 and PHD2, BPGM (2,3-Bisphosphoglycerate Mutase), GATA1
The symptoms
Polycythemia Vera (PV) and erythrocytosis share similar symptoms due to the increased thickness (viscosity) of the blood and its effects on circulation. The increased blood volume and resistance to flow can strain the cardiovascular system, leading to symptoms such as hypertension (high blood pressure) and others.
Common Symptoms of PV or Erythrocytosis:
Red or pink flushed skin
Hypertension (High Blood Pressure)
Fatigue
Breathlessness and/or feeling like you can't get enough air in
Pruritus (itching) of your hands and/or legs (sometimes after a hot shower, which triggers a histamine release)
Blurry vision or visual disturbances
Left lower side pain from an enlarged spleen (splenomegaly)
Thrombosis (blood clots) (the risk of this on Testosterone is highly debated)
General body-wide malaise and discomfort, common in PV, but not SE.
These issues can happen even if your platelet level is normal. Thicker blood (increased viscosity) moves more slowly through blood vessels, which makes it easier for clots to form, even if your platelets (the cells that help blood clot) are normal. This includes the pulmonary arteries in the lungs, and this increased resistance in these vessels can cause temporary rises in blood pressure in the lungs, leading to pulmonary hypertension. This also forces your heart to work harder to push blood through your body, raising your blood pressure. Even though more red blood cells carry more oxygen, blood that's too thick doesn’t flow well to deliver oxygen where it's needed.
The treatments
Phlebotomy aka "therapeutic phlebotomy"
Simple blood donation for secondary erythrocytosis (people with PV are not allowed to donate, per FDA rules)
Traditional root cause treatments: CPAP for sleep apnea, smoking cessation, etc
Drug: Rusfertide, in development at Protagonist Therapeutics, study. Rusfertide is a mimetic or "clone" of hepcidin. It can override erythroferrone, which throttles back the out-of-control RBC making process.
Drug: Divesiran,
in development at Silence Pharma, study. Divesiran creates more hepcidin by upregulating the TMPRSS6 gene to create more of the hormone. This drug can also override erythroferrone, which throttles back the out-of-control RBC making process.
Drug: Hydroxyurea. ONLY used to treat PV (and some other diseases like Sickle Cell) and works by "inhibit[ing] the formation of DNA by blocking an enzyme known as ribonucleotide reductase. This results in the decreased ability of the bone marrow to produce red blood cells." It also can reduce WBCs and platelets.
Why high RBCs can make ferritin hard to build
When the body produces erythroblasts, these are stimulated by EPO and they produce erythroferrone. Erythroferrone is a hormone that is intended to prevent the body from storing iron in ferritin and using that iron for RBCs instead. When your RBC rate is normal, things are in balance.
When a large amount of RBCs are being made, a lot of erythroferrone is being produced, and erythroferrone suppresses hepcidin. Hepcidin normally blocks "too much" iron from being absorbed in the gut to prevent toxicity, and hepcidin also helps to "trap" iron that is already in your body in cells, and this trapped iron is ferritin. If hepcidin is suppressed, however, iron will flow out of cells, dropping ferritin, and letting that iron enter the bloodstream, where the body will use it for hemoglobin. Iron is also more easily absorbed in the digestive system when hepcidin is low. This action diverts iron away from storage and into use in making hemoglobin, the molecule that gives RBCs their oxygen-carrying capacity.
An easy way to think of this process is to think of erythroferrone as the "emergency bleeding to death hormone." That's not quite 100% accurate, but it helps us understand. If you're bleeding, you're losing blood and the body's oxygen level is dropping, the body is making more RBCs, and needs iron to give those RBCs oxygen carrying capacity. Storing iron as ferritin would be the worst thing the body can do at a time when there is blood loss. The only problem is that in Polycythemia Vera and erythrocytosis, there is no actual blood loss, the body is just acting as if there were.
Here is the feedback loop explained:
1. Something causes the kidneys to release more EPO. This can be from blood loss (a drop in oxygen levels) or from a hypoxic process (sleep apnea, smoking, which are also drops in oxygen levels). It can also be from Testosterone injections -- nothing to do with an oxygen level drop, Testosterone directly stimulates EPO.
2. EPO travels to the bone marrow, stimulating erythroid progenitor cells to produce more erythroblasts.
3. Erythroblasts in the bone marrow produce erythroferrone in response to EPO signaling.
4. Erythroferrone suppresses the liver hormone hepcidin, which regulates iron availability. By reducing hepcidin levels, the body increases iron absorption from the gut and releases iron from ferritin -- all of this iron is now prioritized for hemoglobin synthesis.
5. As oxygen delivery improves and blood volume stabilizes, EPO production decreases, and the body's response returns to baseline.
If the feedback loop is disordered:
• If step 5 above does not occur, and EPO stays high like when doing Testosterone, the process continues producing too many RBCs and ferritin cannot build.
• If we were to keep hepcidin high somehow, keeping iron trapped and out of the blood so RBCs are "iron starved," the body still recycles iron from dying RBCs, which will pile up in cells and be stored as ferritin. So your RBCs would drop and ferritin would go up if we were able to keep hepcidin high.
Sources
Cellular iron: ferroportin is the only way out
https://pubmed.ncbi.nlm.nih.gov/16054057/
Iron homeostasis: fitting the puzzle pieces together
https://pubmed.ncbi.nlm.nih.gov/18396134/
Erythroferrone structure, function, and physiology: Iron homeostasis and beyond
https://pubmed.ncbi.nlm.nih.gov/33372284/
Iron sequestration and anemia of inflammation
https://pubmed.ncbi.nlm.nih.gov/19786207/
Secondary erythrocytosis
https://pubmed.ncbi.nlm.nih.gov/36927204/
Erythrocytosis: Diagnosis and investigation
https://pubmed.ncbi.nlm.nih.gov/38695361/
Testosterone therapy and secondary erythrocytosis
https://pubmed.ncbi.nlm.nih.gov/34987178/
Acquired polycythemia vera
https://rarediseases.info.nih.gov/diseases/7422/polycythemia-vera
Version history
Ver 1, 12/24/2024