Familial polycythemia caused by mutation in the VHL gene is a rare genetic blood disease where a person is born with too many red blood cells because their body “thinks” it is low in oxygen even when oxygen is normal. [1] In most families this condition is the same as Chuvash polycythemia or familial erythrocytosis type 2, where a special change (mutation) in both copies of the VHL gene makes a protein that does not work properly. [1][2] Because this VHL protein is damaged, a body switch called HIF (hypoxia-inducible factor) stays turned on, and the kidneys keep making too much erythropoietin (EPO), the hormone that tells the bone marrow to make red blood cells. [2][3] The result is very high hemoglobin and hematocrit, thick blood, and a higher risk of blood clots, bleeding, and early health problems if it is not carefully followed. [3][4]
This disease is usually autosomal recessive, which means a child must receive one changed VHL gene from each parent. [1] Parents often have only one changed gene and are healthy, but their children who inherit two changed copies get lifelong high red blood cells, usually starting in childhood or young adult life. [1][5]
Familial polycythemia caused by mutation in the VHL gene is a rare inherited blood disease. In this condition, the body makes too many red blood cells from birth or early life. This makes the blood thicker than normal and raises the risk of blood clots, stroke, and heart attack. Doctors also call it VHL-associated familial erythrocytosis or Chuvash polycythemia when it is due to a specific VHL mutation. [1]
The VHL gene normally helps cells sense how much oxygen is in the body. When the VHL gene is mutated, this oxygen-sensing system becomes over-active. The body wrongly “thinks” there is not enough oxygen, even when oxygen is normal. As a response, the kidneys and liver release too much erythropoietin (EPO), a hormone that tells the bone marrow to make more red blood cells. [2]
Too many red blood cells increase hemoglobin and hematocrit levels. The blood becomes thick and sticky. This can cause headaches, redness of the face, dizziness, vision problems, tingling in hands and feet, shortness of breath, and a feeling of fullness in the head. Over time, there is a higher risk of vein and artery clots, such as deep vein thrombosis, pulmonary embolism, and stroke. [3]
Other names
Doctors and scientists use several other names for familial polycythemia caused by VHL mutation: [1]
Chuvash polycythemia
Chuvash erythrocytosis
Familial erythrocytosis type 2 (ECYT2)
Von Hippel–Lindau–associated congenital erythrocytosis
VHL-related congenital polycythemia
All of these names describe the same basic problem: a VHL gene mutation that causes the body to “sense” false low oxygen and to make too many red blood cells. [1][2]
Types
Experts sometimes divide familial polycythemia from VHL mutation into simple types based on the exact gene change and how severe the disease looks: [2][3]
Classic Chuvash type (VHL c.598C>T, p.R200W)
This is the best known type and is common in people from the Chuvash Republic of Russia and some other regions. [2] Hemoglobin and hematocrit are high, EPO is high or normal, and there is increased risk of blood clots and early death if not monitored. [3][4]
Ischia / Croatian type (VHL H191D and similar variants)
Found in some families from the Italian island of Ischia and Croatia. [5] The basic mechanism is the same (faulty oxygen sensing), but the pattern of symptoms and complications can be a bit different from classic Chuvash type. [5]
Other VHL exon-2 or exon-3 mutations without cancer
Some rare families have other VHL changes that cause congenital polycythemia but not the usual VHL cancer syndrome. [6] These people have life-long high red blood cells but may not have brain, eye, or kidney tumors.
VHL mutations with both erythrocytosis and tumor risk
In a few rare cases, the same VHL mutation can cause both high red blood cells and the typical von Hippel–Lindau disease with kidney cancers or other tumors. [7]
Heterozygous carriers (one changed VHL gene)
People with only one changed VHL gene (carriers) often have normal blood counts, but some may have slightly higher hemoglobin or certain vascular changes compared to the general population. [8]
All of these types share the same core problem: VHL cannot control HIF properly, so hypoxia signals and EPO are too high, and red blood cells rise. [2][3]
Causes
The main true cause is always a change in the VHL gene. Many other factors only help to bring out or worsen the disease, but they do not cause it alone.
Homozygous VHL mutation (two changed genes)
The key cause is having a damaging VHL mutation in both copies of the gene, usually inherited one from each parent. [1][2] Without normal VHL protein, HIF is not broken down, EPO goes up, and the marrow makes too many red blood cells. [2][3]
Specific founder mutation (R200W) in some populations
The R200W VHL mutation is very common in the Chuvash Republic and some other areas, where many families share a common ancestor. [2][4] This explains why the disease clusters in these regions.
Other hypoxia-sensing VHL mutations (like H191D)
Some other VHL changes (for example H191D) also damage oxygen sensing and lead to congenital erythrocytosis in families. [5] They work through the same pathway: increased HIF activity and EPO.
Autosomal recessive inheritance in consanguineous families
When parents are related (for example, cousins), both may carry the same VHL mutation. [1] This makes it more likely that a child will inherit two changed copies and develop familial polycythemia.
Impaired breakdown of HIF-1α and HIF-2α
VHL normally marks HIF proteins for destruction when oxygen is normal. [2][3] When VHL is mutated, HIF stays high, turning on genes that increase red blood cell production and blood vessel growth.
High erythropoietin (EPO) production by the kidney
Extra HIF signaling tells the kidney to produce more EPO even if oxygen levels are normal. [3][9] High EPO is a direct driver of extra red blood cell production in this disease.
Increased sensitivity of bone marrow stem cells to EPO
Stem cells in the bone marrow may respond more strongly to EPO because of the abnormal hypoxia pathway, so even moderate EPO levels can cause large rises in red blood cell mass. [3]
Geographic founder effect (clustered families)
In areas like Chuvashia or Ischia, one original ancestor carried the VHL mutation. [2][5] Over many generations, the mutation spread through the local population, making familial cases more common.
Modifier genes in the hypoxia pathway (PHD2, HIF2A, etc.)
Other genes in the same oxygen-sensing system (PHD2/EGLN1, HIF2A/EPAS1) can also affect erythrocytosis. [10] In some families, these may act together with VHL variants to influence how severe the disease is.
Iron balance changes (iron deficiency or overload)
Iron is needed for red blood cell production. If iron is low, the body cannot make as many cells even when EPO is high; if iron is replaced, hemoglobin can rise sharply. [11] So iron levels modify how strongly the VHL mutation shows itself.
Living at high altitude
High altitude adds real low oxygen on top of the false low oxygen signal from VHL mutation. [12] This can push EPO even higher and worsen the red blood cell increase in affected people.
Chronic lung disease or low oxygen from other illnesses
Lung problems (like chronic obstructive lung disease or sleep apnea) lower blood oxygen. [13] In someone with a VHL mutation, this extra hypoxia can further raise EPO and red blood cells.
Smoking-related hypoxia
Smoking increases carbon monoxide and reduces effective oxygen delivery. [14] In VHL-related polycythemia, this can further stimulate EPO and make the blood even thicker.
Obstructive sleep apnea
Repeated night-time drops in oxygen with loud snoring can add another hypoxic signal. [13] When combined with VHL mutation, red blood cells can rise further.
Kidney changes or cysts
The kidneys make EPO. If a person with VHL mutation also has kidney cysts or lesions, these can sometimes produce extra EPO and aggravate erythrocytosis. [7][15]
Dehydration (relative rise in hematocrit)
When the body loses water (due to sweating, diarrhea, or poor intake), plasma volume falls and hematocrit looks even higher, making the polycythemia appear worse, even though red cell mass did not change much. [16]
Male sex
Men naturally have higher hemoglobin than women. [17] In males with VHL mutation, this baseline difference can make their polycythemia appear more marked and may increase their risk of clots.
Older age in affected carriers
As affected people age, vascular damage and other risk factors accumulate. [3][8] This can increase the chance of thrombosis and strokes in older adults with long-standing VHL-related polycythemia.
Hormonal factors (for example pregnancy or testosterone use)
Pregnancy and some hormones (like testosterone) can alter blood volume and red cell production. [18] In someone with VHL mutation, these changes may temporarily raise or unmask polycythemia.
Lack of medical follow-up and treatment
Not truly a cause, but a strong worsening factor. Without monitoring, control of iron, and clot prevention, long-term complications such as stroke, pulmonary hypertension, and early death become more likely. [3][4]
Symptoms
Many people have signs from thick blood and poor blood flow, plus problems from blood clots and high pressure in the lungs or brain. [1][3]
Headache
Headaches are very common because thick blood flows more slowly through brain vessels and can raise pressure inside the head. [1][3] People often describe a heavy, tight, or pounding pain, especially when they bend over or strain.
Dizziness and light-headedness
When blood is thick, it may not flow easily to the brain during sudden standing or effort, causing spinning feelings or near-fainting. [1] This can be scary and may lead to falls.
Shortness of breath (dyspnea)
Even though there are many red blood cells, the heart and lungs must work harder to push thick blood through the vessels. [3][4] That can make walking, climbing stairs, or light exercise feel tiring and “out of breath.”
Ruddy or flushed skin (plethora)
The face, hands, and lips often look very red or dark because there is so much blood in the small skin vessels. [1][3] This “ruddy” look is a classic sign of polycythemia.
Tiredness and weakness (fatigue)
Many people feel very tired all day, even after sleep. [1] The heart and muscles use extra energy fighting against thick blood, and small clots or poor circulation can make muscles and brain feel weak.
Blurred vision or visual changes
Tiny vessels in the eyes can be over-filled or blocked by small clots, causing blurry sight, dark spots, or brief loss of vision. [3][4] Sudden severe visual changes are an emergency because they may signal stroke.
Ringing in the ears (tinnitus)
Some people hear buzzing or ringing sounds because of changed blood flow in the small vessels around the ears and brain. [3]
Nosebleeds and other bleeding
Even though the blood is thick, vessel walls may be fragile and platelets may not work normally, so nosebleeds, gum bleeding, or easy bruising can occur. [3][4]
Blood clots in the legs (deep vein thrombosis)
Thick blood and abnormal vessel walls raise the risk of clots in the deep veins of the legs. [3][11] This can cause leg pain, swelling, redness, and warmth, and clots can travel to the lungs.
Stroke or mini-stroke (transient ischemic attack)
Clots can block brain arteries, causing weakness on one side, trouble speaking, or facial droop. [3][11] Chuvash polycythemia is known to have a higher rate of stroke and early death if not managed. [3][4]
Chest pain or signs of heart strain
The heart must pump harder against thick blood and sometimes high pulmonary artery pressure. [4][23] This can lead to chest pain, palpitations, or heart failure signs in severe cases.
Shortness of breath due to pulmonary hypertension
In many patients, the pressure in the lung arteries is high, even at rest, which causes breathlessness, fatigue, and sometimes swelling of legs and belly. [4][23]
Varicose veins and visible superficial veins
Abnormal blood vessel tone and high blood volume can cause bulging, twisted veins in the legs and sometimes in other places. [3][7] These veins may ache or itch.
Benign vertebral hemangiomas and vascular lesions
Some patients develop small, benign blood vessel growths in the spine or other bones, which may cause back pain or be found on imaging. [7]
Low blood pressure (hypotension) and fainting
Interestingly, people with Chuvash polycythemia often have lower systemic blood pressure than normal, possibly from abnormal vessel relaxation. [7] This can cause fainting, especially when standing up quickly.
Diagnostic tests
Doctors use many tests together to confirm familial VHL-related polycythemia and to exclude other causes like polycythemia vera or secondary erythrocytosis from lung disease. [2][4][19]
Physical examination tests
General physical exam and vital signs
The doctor checks weight, height, temperature, heart rate, breathing rate, and blood pressure, and looks for ruddy skin, shortness of breath, or signs of clot or stroke. [1][3] This gives the first idea that polycythemia and related problems may be present.
Skin and mucous membrane inspection
The doctor carefully looks at the color of the face, lips, tongue, hands, and nail beds. [1] Dark red or purple color suggests high red blood cell levels, and bruises may signal bleeding problems.
Heart and lung examination
Using a stethoscope, the doctor listens for extra heart sounds, murmurs, or fast rate, and for crackles or other abnormal lung sounds. [3] These findings can suggest heart strain or pulmonary hypertension from long-term thick blood.
Abdomen and spleen examination
The doctor feels the abdomen for a large spleen or liver and for tenderness. [19] A big spleen can occur in polycythemia and may help distinguish different causes.
Manual tests
Capillary refill and peripheral circulation test
The doctor presses on a fingernail or skin and sees how fast color returns. Slow refill can show poor small-vessel blood flow in very thick blood. [3]
Peripheral pulse examination
Pulses in the wrists, ankles, and neck are felt by hand to check strength, regularity, and symmetry. [3] Weak or asymmetric pulses might suggest large clots or vascular disease.
Simple walking or exercise tolerance test
A short walk test (for example, 6-minute walk) can show how quickly shortness of breath, chest discomfort, or fatigue appear and whether oxygen saturation drops with effort. [23]
Basic neurological bedside exam
The doctor tests strength, sensation, vision, speech, balance, and reflexes at the bedside. [3] Any weakness, slurred speech, or visual field loss may signal past or current stroke from blood clots.
Lab and pathological tests
Complete blood count (CBC) with red cell indices
This key blood test measures hemoglobin, hematocrit, and red blood cell count, and also white cells and platelets. [2][22] In familial VHL polycythemia, hemoglobin and hematocrit are high, often with fairly normal white cells and platelets, which helps distinguish it from polycythemia vera.
Peripheral blood smear
A drop of blood is examined under the microscope. [2] The shape and size of red cells, and the presence or absence of immature cells, help rule out other bone marrow diseases or myeloproliferative neoplasms.
Serum erythropoietin (EPO) level
Blood is tested for the amount of EPO. In VHL-related polycythemia, EPO is usually normal or high, not low. [2][14] High or in-range EPO suggests secondary or congenital erythrocytosis rather than polycythemia vera, where EPO is often low.
Arterial blood gas and oxygen saturation / P50 test
These tests check how much oxygen is in the blood and how strongly hemoglobin holds oxygen. [30] Normal oxygen and normal P50 make high-affinity hemoglobin mutations less likely and support VHL-related hypoxia sensing problems.
Iron studies (ferritin, transferrin, iron)
Iron tests show whether iron is low, normal, or high. [11] People with long-standing erythrocytosis may become iron-deficient, which can hide the true size of the red cell mass; replacing iron may reveal the full degree of polycythemia.
VHL gene sequencing and hereditary erythrocytosis panel
DNA testing looks specifically for mutations in the VHL gene and sometimes other genes (PHD2, HIF2A, EPOR, and so on). [10][16][24] Finding a disease-causing VHL mutation in both copies of the gene confirms familial VHL-related polycythemia (familial erythrocytosis type 2).
Electrodiagnostic tests
Resting electrocardiogram (ECG)
ECG records the heart’s electrical activity. It can show right-heart strain, previous heart attacks, rhythm problems, or signs of pulmonary hypertension, which may occur in long-standing Chuvash polycythemia. [23]
24-hour ambulatory blood pressure and heart rate monitor
A small device records blood pressure and pulse many times during the day and night. [7] It can confirm the lower-than-usual systemic blood pressure often seen in this disease and detect heart rate changes or arrhythmias.
Overnight oximetry or polysomnography (sleep study)
A sleep study uses sensors and sometimes brain and muscle electrical recordings to see if oxygen levels drop during sleep and to diagnose sleep apnea. [13] This helps find extra hypoxia causes that worsen erythrocytosis in VHL-mutant patients.
Imaging tests
Echocardiogram (heart ultrasound)
Ultrasound pictures of the heart show chamber size, pumping strength, and estimate the pressure in the lung arteries. [23] Many patients with Chuvash polycythemia have raised pulmonary artery pressure, and this test helps measure severity.
Doppler ultrasound of leg and abdominal veins
This imaging uses sound waves to show blood flow in the veins and can detect clots (deep vein thrombosis) or abnormal flow in varicose veins and abdominal veins. [3][7] It is important because thrombosis is a major complication in this disease.
Brain MRI or CT scan
Cross-section images of the brain help to identify past or current strokes, bleeding, or other vascular lesions in people with neurological symptoms. [3][11][19] Finding brain injury from clots shapes treatment, including stronger clot-prevention measures.
Non-pharmacological treatments (therapies and others)
1. Therapeutic phlebotomy (venesection)
Phlebotomy means regularly removing a controlled amount of blood through a vein, similar to blood donation. In familial VHL-related polycythemia, this is the main non-drug treatment to bring hematocrit down to a safer level and to reduce blood thickness. Doctors choose how much blood to remove and how often, based on age, symptoms, and heart and lung status, because removing too much blood can reduce oxygen delivery. [1]
2. Careful hydration
Drinking enough water each day helps keep the blood less concentrated. Good hydration can reduce headache, dizziness, and fatigue and may lower the risk of clotting linked to thick blood. Patients are usually advised to sip water regularly, especially in hot weather, during exercise, or when they have fever or diarrhea. People with heart or kidney disease must ask doctors how much fluid is safe for them personally. [2]
3. Avoiding smoking and vaping
Smoking lowers oxygen levels and damages blood vessels. In someone who already has excess red blood cells from a VHL mutation, smoking further stresses the circulation and increases clot risk. Stopping all forms of tobacco and nicotine, including vaping, is one of the most powerful lifestyle treatments. Doctors can offer counseling, nicotine replacement, or medicines to help quitting. [3]
4. Limiting high altitude exposure
High altitude has less oxygen. Even in healthy people, the body makes more red blood cells at altitude. For a person with VHL-related familial polycythemia, high altitude can sharply worsen blood counts. Whenever possible, long stays at high mountains or work at altitude should be avoided. If travel is necessary, a hematologist should give an individual plan and monitoring advice. [4]
5. Treating sleep apnea and other breathing disorders
Conditions such as obstructive sleep apnea cause repeated drops in oxygen at night. This can stimulate even more EPO and red blood cell production. Sleep study, weight control, and devices such as CPAP can improve oxygen levels and may help stabilize hematocrit. Treating chronic lung or heart disease is equally important. [5]
6. Regular exercise with moderation
Gentle to moderate aerobic exercise (like walking, cycling, or swimming) helps blood flow, supports heart health, and reduces blood pressure and weight. It may lower clot risk. Very intense or dehydrating exercise without drinking fluids can be harmful, so activity plans should be discussed with a doctor, especially if there is a history of clots, chest pain, or severe shortness of breath. [6] [1]
7. Weight management and metabolic health
Extra body weight, high blood pressure, diabetes, and high cholesterol all increase clot risk. Healthy eating, physical activity, and sometimes structured weight-loss programs are important parts of treatment. Even modest weight loss can improve blood pressure, sleep apnea, and vascular health, helping to counter the dangers of thick blood. [7]
8. Avoiding dehydration from diuretics, heat, and illness
Some medicines, such as strong diuretics (“water tablets”), plus hot weather, saunas, vomiting, or diarrhea can cause dehydration and make the blood thicker. Patients and doctors should review the need for strong diuretics and adjust doses carefully. During sickness, extra oral fluids and earlier medical review are often recommended. [8] [2]
9. Compression stockings for venous support
Graduated compression stockings can support leg veins in people with past clots, varicose veins, or long periods of sitting. They help venous blood flow back to the heart and may lower deep vein thrombosis risk, especially during long travel or hospital stays. Correct size and pressure class should be chosen by a health professional. [9] [3]
10. Careful planning for pregnancy
Pregnancy itself increases clot risk. Women with familial polycythemia due to VHL mutation need pre-pregnancy counseling with a hematologist and obstetrician who understand high-risk pregnancies. Phlebotomy, aspirin, or anticoagulants may be adjusted, and close monitoring is needed. Contraception choices should also avoid estrogen-containing pills if clot risk is high. [10]
11. Education about warning signs of clotting and bleeding
Patient and family education is a powerful therapy. Learning to recognize chest pain, sudden shortness of breath, severe headache, limb swelling, or new weakness helps people seek rapid care. Education also includes understanding bleeding symptoms if on aspirin or blood thinners, and knowing when to go to the emergency department. [11] [4]
12. Limiting alcohol intake
Heavy alcohol use can damage the liver, change clotting factors, and worsen blood pressure. It may interact with medicines like aspirin, increasing bleeding risk. A low to moderate intake or complete avoidance is often suggested, depending on liver status and overall risk. [12] [5]
13. Avoiding unnecessary iron supplements
Iron is needed to make hemoglobin. In a person with excess red blood cells, routine iron supplements can worsen polycythemia. Iron is only given when a hematologist confirms iron deficiency and decides that benefits outweigh the risk of raising hematocrit. Patients should not start iron pills on their own. [13]
14. Safer travel habits
During long trips by car, bus, or airplane, sitting still for many hours increases clot risk. Standing up regularly, walking in the aisle, doing ankle exercises, staying hydrated, and wearing compression stockings when advised can lower this risk. Some high-risk patients may also need temporary blood thinners during long trips, but this is decided by doctors. [14] [1]
15. Regular follow-up visits and blood tests
Continuous monitoring is itself a treatment strategy. Regular checks of hemoglobin, hematocrit, oxygen saturation, blood pressure, and organ function help doctors adjust phlebotomy, medicines, and lifestyle advice. Early detection of changes lowers the chance of serious complications. [15]
16. Psychological and social support
Living with a rare genetic blood disorder can cause anxiety, fear of clots, or stress about family planning. Counseling, patient groups, or online communities for VHL or familial erythrocytosis can help people feel supported and improve adherence to treatment. Good mental health also supports healthy habits. [16] [2]
17. Genetic counseling for family members
Because VHL-related familial polycythemia is inherited, genetic counseling helps family members understand their risk, testing options, and reproductive choices. Early diagnosis in relatives allows surveillance and lifestyle adjustments before complications happen. [17]
18. Avoiding anabolic steroids and performance-enhancing drugs
Some bodybuilding or performance drugs, including anabolic steroids or injected EPO, can raise red blood cell mass even more. For someone with VHL-related polycythemia this is dangerous and should be strictly avoided. Honest discussion with doctors about any substance use is important. [18] [3]
19. Careful planning for surgery or immobilization
Periods of bed rest, casts, or major surgery increase clot risk. Non-drug strategies such as early mobilization, leg exercises, compression devices, and tailored phlebotomy before planned surgery may be used alongside medication. Patients should always inform surgeons and anesthetists about their condition. [19] [4]
20. Vaccinations and infection control
Serious infections can trigger clotting events and destabilize chronic conditions. Routine vaccines (such as influenza and pneumonia vaccines when indicated) and good hygiene reduce infection risk. This is especially important in patients who later need immune-modulating drugs like interferon or JAK inhibitors. [20] [5]
Drug treatments
Important: The medicines below are not all specifically approved for “familial polycythemia caused by mutation in VHL”. They are approved for other conditions, and specialists may use them off-label to control hematocrit, prevent clots, or treat related VHL disease. Never start, stop, or change any medicine without a hematologist. [1]
1. Low-dose aspirin
Aspirin is an antiplatelet drug that makes platelets less sticky and reduces clot formation. Low doses (often 75–100 mg once daily in adults) are widely used to prevent heart attack and stroke in high-risk patients. In polycythemia vera, low-dose aspirin reduces thrombotic events, and many experts extrapolate its use to familial erythrocytosis when there is no contraindication, but bleeding risk must always be checked. [2]
2. Clopidogrel (PLAVIX)
Clopidogrel is another antiplatelet that blocks the P2Y12 ADP receptor on platelets. It is FDA-approved to reduce risk of heart attack and stroke in people with cardiovascular disease. Typical adult dose is 75 mg once daily. Doctors may choose it instead of or in addition to aspirin when aspirin is not tolerated or when clot risk is very high. Main side effect is increased bleeding, including stomach or brain bleeding. [3]
3. Hydroxyurea (HYDREA, DROXIA, SIKLOS)
Hydroxyurea is a cytoreductive drug that slows down bone marrow cell production. It is approved for myeloproliferative diseases and sickle cell disease and is often used off-label in high-risk polycythemia vera to control blood counts. Adult dosing is individualized and usually given once daily by mouth, with dose adjustments based on blood tests. Side effects include low blood counts, infection risk, mouth ulcers, and possible long-term cancer risk, so it is used carefully in hereditary erythrocytosis. [4]
4. Ruxolitinib (JAKAFI)
Ruxolitinib is an oral JAK1/JAK2 inhibitor approved for myelofibrosis and for polycythemia vera after inadequate response to hydroxyurea. By blocking JAK2 signaling, it reduces over-active blood cell production and can improve symptoms like itch and spleen enlargement. Adult dosing is usually twice daily and adjusted according to platelets and other counts. Side effects include low blood counts, infections, weight gain, and increased risk of shingles. In VHL-related familial polycythemia there is only very limited evidence, so use is highly specialized. [5]
5. Interferon alfa-2b (INTRON A)
Interferon alfa-2b is an immune-modulating protein given by injection. It is used for several cancers and viral infections and has been used off-label to control blood counts in young patients with polycythemia vera because it can reduce abnormal marrow clones without causing much DNA damage. Dosing is usually subcutaneous several times per week, with careful titration. Side effects include flu-like symptoms, mood changes, thyroid problems, and low blood counts. [6]
6. Peginterferon alfa-2b (SYLATRON, PEG-Intron)
Peginterferon alfa-2b is a long-acting form of interferon given once weekly or less often. It is approved for melanoma and chronic hepatitis C but can be used off-label in myeloproliferative neoplasms to control erythrocytosis. The pegylated form often gives steadier blood levels and fewer flu-like effects. Side effects are similar to standard interferon and include fatigue, depression, and thyroid dysfunction, so mental health monitoring is important. [7]
7. Belzutifan (WELIREG)
Belzutifan is a first-in-class oral HIF-2α inhibitor approved for adults with VHL disease who need treatment for VHL-associated renal cell carcinoma, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors. By blocking HIF-2α, it reduces expression of target genes, including EPO, and can lower EPO levels and hemoglobin. Typical dose in VHL disease is once daily (for example 120 mg), adjusted for side effects such as anemia, fatigue, and low oxygen. In theory, it directly targets the VHL-HIF pathway that drives familial polycythemia, but its use for isolated erythrocytosis is still experimental. [8]
8. Anticoagulants: warfarin
Warfarin is an oral vitamin K antagonist that thins the blood by reducing clotting factors. It is used when a patient with familial polycythemia has had a serious clot like deep vein thrombosis, pulmonary embolism, or stroke. Dosing is once daily and guided by INR blood tests to keep clotting at a safe level. Side effects include bleeding and interactions with many foods and drugs, so close monitoring is essential. [9] [4]
9. Direct oral anticoagulants (DOACs)
Drugs like apixaban, rivaroxaban, edoxaban, and dabigatran directly block key clotting factors. They are approved for treatment and prevention of venous thromboembolism and for stroke prevention in atrial fibrillation. They offer fixed dosing without routine INR tests, but kidney function and interactions must be checked. In familial polycythemia they are used according to general clotting guidelines, not specifically for the disease itself. [10] [5]
10. Statins (e.g., atorvastatin)
Statins lower LDL cholesterol and stabilize blood vessel walls. They are approved for prevention of heart attack and stroke in high-risk people. In patients with familial polycythemia, statins do not change red blood cells, but they reduce overall cardiovascular risk when cholesterol is high. Usual dosing is once daily at night or morning. Side effects may include muscle pain and rare liver enzyme changes. [11] [1]
11. Antihypertensive drugs (ACE inhibitors, ARBs, beta-blockers)
High blood pressure increases the danger of clots and stroke in anyone, especially in someone with thick blood. Standard blood pressure medicines (such as ACE inhibitors, ARBs, and beta-blockers) are used according to usual hypertension guidelines. They are taken once or twice daily and chosen based on kidney function, heart status, and side-effect profile. Controlling blood pressure is a key part of overall treatment. [12] [2]
12. Proton pump inhibitors (PPIs)
PPIs such as omeprazole and pantoprazole reduce stomach acid. They are sometimes prescribed to protect the stomach when long-term aspirin or other antiplatelet drugs are needed. They do not affect red blood cells directly but can lower the risk of stomach ulcers and bleeding. Doses are usually once daily before meals. Long-term use must be reviewed because of possible nutrient absorption issues. [13] [3]
13. Allopurinol
Allopurinol lowers uric acid levels and is approved for gout management. Rapid changes in blood cell turnover, such as after phlebotomy or cytoreductive therapy, can raise uric acid and cause gout or kidney stones. Allopurinol, taken once or twice daily, can help prevent these problems. Common side effects include rash and stomach upset, and rare severe skin reactions require urgent care. [14] [4]
14. Pain-relief strategies avoiding NSAID overuse
Paracetamol (acetaminophen) is often preferred for mild pain in people on aspirin or anticoagulants because many NSAIDs can further increase bleeding and affect kidneys. Doses must follow package and doctor advice to avoid liver damage. The goal is balanced pain control without extra clotting or bleeding risk. [15] [5]
15. Short-term oxygen therapy (medical gas)
Oxygen given by mask or nasal cannula in hospital or at home is a drug in gas form. It is used when oxygen levels are low due to lung or heart problems or during acute events. For VHL-related familial polycythemia, oxygen does not cure the genetic defect but supports organs during crises such as pulmonary embolism or heart failure. [16] [1]
16. Low-molecular-weight heparin (LMWH)
LMWH injections (such as enoxaparin) are used for prevention and treatment of clots, especially around surgery, pregnancy, and hospital stays. Dosing is by weight and kidney function. In familial polycythemia, LMWH is often used short-term when clot risk is temporarily high. Side effects are mainly bleeding and, rarely, low platelets. [17] [2]
17. Iron chelators (rare situations)
If a patient has received many blood transfusions or has iron overload from other reasons, iron chelators like deferasirox may be used to lower iron stores. In simple familial polycythemia this is uncommon, but in complex VHL disease or after certain treatments it may be considered. These drugs are taken orally or intravenously and require close monitoring of kidneys and liver. [18] [3]
18. Antidepressants and sleep medications (supportive)
Chronic disease and interferon-based therapies can cause depression, anxiety, and insomnia. When counseling alone is not enough, doctors may prescribe antidepressants or sleep aids. These medicines do not treat polycythemia directly but improve quality of life and adherence to other treatments. Choices must consider interactions with anticoagulants and other drugs. [19] [4]
19. Vaccines as medical products
Vaccines are regulated biological products. Flu and pneumonia vaccines are especially important in people with chronic heart or lung disease or those on immune-modifying drugs. Vaccination lowers infection-triggered complications, which can be dangerous in someone with thick blood and limited reserve. [20] [5]
20. Experimental targeted agents
Emerging research is testing more HIF-pathway inhibitors and other targeted agents in VHL-related disease and congenital erythrocytosis. These medicines are only used in clinical trials or highly specialized centers. Their goal is to correct the abnormal oxygen-sensing pathway more directly than current symptomatic treatments. [21]
Dietary molecular supplements
Note: Evidence for supplements in VHL-related familial polycythemia is limited. They should never replace phlebotomy or prescription drugs. Always discuss supplements with a doctor. [1]
1. Omega-3 fatty acids (fish oil)
Omega-3 fats from fish oil may improve blood vessel health and slightly reduce platelet stickiness. Usual supplemental doses range from 500–2000 mg of combined EPA/DHA daily. They may support heart and brain circulation when used with medical therapy. High doses can increase bleeding tendency, especially with aspirin or anticoagulants, so doctors must supervise use. [2]
2. Folic acid
Folic acid is needed for DNA and blood cell production. A typical supplement dose is 400–800 micrograms daily. In people with high homocysteine levels, folate can help lower this clot-related risk marker. However, in polycythemia, folate does not correct the genetic cause, so it is mainly used when a deficiency is proven. [3]
3. Vitamin B12
Vitamin B12 supports nerve function and red blood cell production. If tests show B12 deficiency, replacement injections or tablets can correct anemia and improve nerve symptoms. Common oral doses are 500–1000 micrograms daily. In familial polycythemia, B12 is only given when levels are low; it does not otherwise treat the disease. [4]
4. Vitamin D
Vitamin D influences bone, immune, and muscle health. Low levels are common worldwide. Typical supplemental doses range from 800–2000 IU daily, adjusted by blood tests. Adequate vitamin D supports general health, fall prevention, and immune balance, which is useful if patients receive immune-modulating drugs like interferon. [5]
5. Magnesium
Magnesium is vital for muscle and nerve function and may help with blood pressure control and heart rhythm stability. Typical oral doses are 200–400 mg daily, depending on kidney function. Too much magnesium can cause diarrhea or, with kidney disease, high blood levels, so dosing should be guided by a clinician. [6]
6. Coenzyme Q10 (CoQ10)
CoQ10 supports mitochondrial energy production and has been studied in heart failure and statin-related muscle symptoms. Doses often range from 100–200 mg daily with food. It does not treat polycythemia directly, but may support heart energy in those with cardiac strain from long-standing thick blood. [7]
7. Curcumin (turmeric extract)
Curcumin has anti-inflammatory and antioxidant effects in laboratory studies. Typical supplement doses are 500–1000 mg daily of standardized extract with piperine or other absorption enhancers. Because curcumin may mildly affect platelets and clotting, people on aspirin or anticoagulants must check with their doctor before taking it. [8]
8. Green tea extract (EGCG-rich)
Green tea polyphenols have antioxidant and possible vascular benefits. Standardized extracts provide around 150–400 mg of EGCG daily. Overuse can stress the liver, so doses should stay within supplement guidelines. Green tea does not change red blood cell counts but may help vessel health in a healthy lifestyle plan. [9]
9. Probiotics
Probiotic supplements supply beneficial gut bacteria that may reduce inflammation and improve digestion, especially when patients take multiple medicines. Doses are usually described as billions of CFU once daily. While they do not alter hematocrit, better gut health can support overall wellbeing and nutrient absorption. [10]
10. Multivitamin tailored by doctor
A low-dose multivitamin without extra iron is sometimes used to ensure balanced micronutrient intake, particularly in people with dietary restrictions. The key is to choose a product that does not contain high doses of iron or vitamin K (if on warfarin) unless specifically recommended. The goal is gentle nutritional support, not disease cure. [11]
Immunity-supporting and regenerative / stem-cell-related drugs
These options are specialized and not routine for most people with VHL-related familial polycythemia. They are included for completeness and must only be used under expert supervision. [1]
1. Interferon alfa-based therapies
Interferon alfa-2b and peginterferon alfa-2b modulate the immune system and can reduce abnormal blood cell production. They may “reset” marrow behavior without strongly damaging DNA, which is why they are considered more “regenerative” than classic chemotherapy in some myeloproliferative diseases. However, they can cause flu-like symptoms, mood changes, and thyroid problems, so careful mental and physical health monitoring is required. [2]
2. Belzutifan as HIF-pathway targeted therapy
Belzutifan directly targets the HIF-2α pathway that is over-active when VHL is mutated. By reducing HIF-2α activity, it lowers EPO and some tumor-related signals. This can be seen as pathway-level “correction” rather than simple symptom control. At present, belzutifan is approved for VHL-associated tumors, not isolated polycythemia, but it is an example of disease-mechanism-directed therapy. [3]
3. Hematopoietic stem cell transplant (HSCT)
HSCT replaces the bone marrow with donor stem cells. It is a powerful but high-risk procedure used for severe blood cancers and some inherited marrow failure syndromes. For VHL-related polycythemia alone, HSCT is usually not recommended because the gene defect is present in all body cells, not only in the marrow, and transplant risks are high. It is mentioned here as a theoretical regenerative option. [4]
4. Growth factor support after other treatments
In certain situations, doctors may use growth factors like G-CSF to stimulate white cells after cytoreductive therapy or infection. In familial polycythemia, this is rare and must be balanced against any risk of stimulating unwanted cell growth. It is more about immune recovery than polycythemia treatment and is supervised very closely. [5]
5. Vaccines as immune trainers
Vaccines (for example, against influenza or pneumonia) do not regenerate tissues, but they “train” the immune system to prevent severe infections. In people receiving interferon, ruxolitinib, or after major surgery, preventing infection is a key part of protecting overall health and preserving organ function. [6]
6. Experimental gene-targeted approaches
In the future, gene-editing or RNA-based therapies might directly correct or silence disease-causing VHL variants or downstream signals. These are currently at a research stage and not available as standard treatment. They are mentioned as potential regenerative strategies because they aim to modify the root cause rather than just the blood counts. [7]
Surgeries and procedures
1. Repeated therapeutic phlebotomy (procedure)
Although not a “surgery” with an operation room, phlebotomy is an invasive procedure where a needle is placed in a vein and a set volume of blood is removed under controlled conditions. It is the frontline intervention for many patients, sometimes done every few weeks or months, to keep hematocrit in a safer range. [1]
2. Resection of VHL-related tumors
In some patients, VHL mutations cause tumors in kidneys, brain, or pancreas. Surgical removal of these tumors can prevent bleeding, neurological damage, or cancer spread. While these operations do not directly treat polycythemia, they are central to overall management of VHL disease. [2]
3. Splenectomy (rare)
If the spleen becomes very large, painful, or over-active in destroying blood cells, surgeons may consider splenectomy (removal of the spleen). This is rarely done in simple familial polycythemia, but it may be needed if there are additional blood disorders. After splenectomy, vaccines and infection precautions become very important. [3]
4. Vascular procedures for clot complications
When clots occur, procedures such as catheter-directed thrombolysis, clot removal, or placement of stents may be needed in veins or arteries. These surgeries are done in emergency or urgent settings to restore blood flow to organs like lungs, brain, or limbs. They treat complications of polycythemia rather than the underlying cause. [4]
5. Neurosurgical or ophthalmologic operations
In VHL disease, hemangioblastomas in the brain, spine, or retina sometimes need surgical removal or special eye procedures to prevent vision loss or neurological damage. Again, these do not fix erythrocytosis, but they are essential parts of comprehensive care in people who have both VHL-related tumors and familial polycythemia. [5]
Preventions
Do not smoke or vape; avoid second-hand smoke. [1]
Maintain healthy body weight and control blood pressure, cholesterol, and blood sugar. [2]
Stay well hydrated every day, especially in heat, during illness, and with exercise. [3]
Avoid long periods of stillness; move regularly on long trips or at work. [4]
Keep up with scheduled phlebotomy and clinic visits even when you feel well. [5]
Treat sleep apnea, lung disease, and heart problems promptly. [6]
Avoid unnecessary hormonal therapy (like estrogen pills) if clot risk is high; use safer contraception. [7]
Discuss any new medicine or supplement, especially those affecting clotting, with your doctor. [8]
Plan pregnancy, surgery, and long travel in advance with your hematologist to adjust clot protection. [9]
Encourage at-risk family members to get genetic counseling and early evaluation. [10]
When to see doctors
People with familial polycythemia caused by VHL mutation should see a hematologist regularly, even when they feel fine. Routine visits help adjust phlebotomy, check blood counts, and screen for VHL-related tumors. [1]
Emergency care is needed if there is sudden chest pain, shortness of breath, coughing blood, severe or new headache, weakness on one side of the body, vision loss, confusion, or trouble speaking, because these can mean heart attack, pulmonary embolism, or stroke. Painful swollen leg, sudden severe abdominal pain, or loss of consciousness also require urgent help. [2]
You should also contact your doctor soon if you notice rapidly increasing headaches, frequent nosebleeds, new dizziness, severe itching, night sweats, major weight loss, or any sign of depression or suicidal thoughts, especially after starting interferon or other strong medicines. Do not stop prescribed medicines suddenly without medical advice. [3]
What to eat and what to avoid
Eat: Plenty of vegetables and fruits of many colors to support vessel and heart health. [1]
Eat: Whole grains, beans, and nuts instead of refined white flour and sugary snacks. [2]
Eat: Moderate amounts of lean protein (fish, skinless poultry, legumes); oily fish 1–2 times weekly for omega-3 fats, if not on strong anticoagulants that make bleeding risk very high. [3]
Eat: Healthy fats from olive oil, avocado, and nuts rather than trans fats and deep-fried foods. [4]
Eat: Enough fluids, mainly water; herbal teas and clear soups can help hydration. [5]
Avoid: Excess salt, which raises blood pressure and strains the heart. [6]
Avoid: Large amounts of red meat and processed meats that raise cardiovascular risk. [7]
Avoid: Excess alcohol, energy drinks, and sugary soft drinks that harm liver, heart, and weight. [8]
Avoid: Body-building supplements, anabolic steroids, or illicit drugs that can affect blood, liver, and heart. [9]
Avoid: Iron supplements and iron-fortified products unless your hematologist clearly tells you that you are iron deficient and you need them. [10]
Frequently asked questions (FAQs)
1. Is familial polycythemia caused by VHL mutation the same as polycythemia vera?
No. Polycythemia vera is a myeloproliferative neoplasm usually linked to JAK2 mutations in bone marrow cells. Familial VHL-related polycythemia is a congenital disorder of oxygen sensing, with a germline mutation in the VHL gene. Both raise red blood cells, but the mechanisms, risks, and cancer associations are different, so follow-up and treatment plans are not identical. [1]
2. Can this condition be cured?
Right now, there is no simple cure that removes the VHL mutation from all body cells. Most people live with the condition using life-long monitoring, phlebotomy, and risk-reducing treatments. Future gene-targeted therapies may offer deeper correction, but they are still in the research phase. [2]
3. Will every family member get the disease?
VHL-related familial polycythemia is inherited, but the exact pattern can vary, and not every relative is automatically affected. Genetic counseling and testing can show who carries the mutation. Some carriers may have milder disease, and early detection helps prevent complications. [3]
4. Does keeping hematocrit “too low” cause problems?
Yes, if hematocrit is pushed too low, oxygen delivery to tissues can fall, leading to fatigue, shortness of breath, and other symptoms. In congenital erythrocytosis, doctors try to find a safe middle range rather than making hematocrit completely “normal” for the lab reference. This is why phlebotomy targets are tailored to each person. [4]
5. Is low-dose aspirin safe for everyone with this condition?
No. Aspirin increases bleeding risk and is not safe for people with active ulcers, prior brain bleeding, severe bleeding disorders, or aspirin allergy. Guidelines for aspirin use in prevention have changed, especially for older adults. The decision to use aspirin must always be individualized by a doctor who knows your full history. [5]
6. Do I always need drug treatment, or can I use lifestyle only?
Some patients with mild polycythemia and few risk factors may be managed mainly with phlebotomy and lifestyle changes. Others, especially with a history of clots or very high counts, need antiplatelet or anticoagulant drugs and sometimes cytoreductive therapy. The treatment plan depends on your age, symptoms, clot history, organ status, and family situation. [6]
7. Can belzutifan replace phlebotomy?
At present, belzutifan is approved for VHL-associated tumors, not specifically for familial erythrocytosis. It can lower EPO and hemoglobin, but long-term data on using it mainly for polycythemia are limited. In most cases phlebotomy remains the basic treatment, and any targeted drug is considered only in specialized centers or trials. [7]
8. What is the main danger if my condition is not treated?
The main dangers are blood clots in veins or arteries, such as deep vein thrombosis, pulmonary embolism, heart attack, or stroke. Over years, untreated thick blood also strains the heart and lungs and can cause high blood pressure in lung vessels. Prompt diagnosis and ongoing care greatly lower these risks. [8]
9. How often will I need phlebotomy?
The frequency of phlebotomy is different for every person. Some may need it every few weeks at first and then every few months; others need it only occasionally. It depends on how fast your hematocrit climbs, your symptoms, and how you tolerate lower levels. Regular blood tests guide this schedule. [9]
10. Can children with this condition be treated the same as adults?
Children require special care. Their bodies are still growing, and long-term drug side effects are more important. Pediatric hematologists usually focus first on careful monitoring, lifestyle adjustments, and mild interventions and are cautious with cytoreductive drugs. Decisions are made together with families after discussing benefits and risks. [10]
11. Will I always feel tired, even with treatment?
Fatigue is common in people with chronic blood disorders and can come from many causes: thick blood, sleep problems, mood changes, or drug side effects. Many patients feel better once hematocrit is controlled and other conditions like sleep apnea and depression are treated. However, some residual tiredness can remain, and pacing daily activities may still be needed. [11]
12. Can I play sports?
Most people can do moderate exercise such as brisk walking, cycling, or swimming after their doctor says it is safe. Extreme sports, heavy weightlifting, or activities with high dehydration risk may need limits. If you have had clots, chest pain, or severe breathlessness, you must get a personalized exercise plan from your care team. [12]
13. Does diet alone control my red blood cell count?
No food or diet pattern can “fix” the VHL gene mutation or fully control red blood cell production. A heart-healthy diet supports vessels and organs and helps prevent complications, but phlebotomy and, when needed, medicines are still required. Diet is a helper, not a replacement, for medical care. [13]
14. Can I take herbal or traditional medicines?
Many herbal products can interact with blood thinners, affect the liver, or change clotting. Some increase bleeding risk; others may contain hidden steroids or stimulants. Always show your doctor any herbal or traditional medicines before using them, and never stop prescribed drugs in favor of unproven treatments. [14]
15. What is the most important thing I should remember?
The most important point is that familial polycythemia caused by VHL mutation is manageable. With regular follow-up, safe hematocrit control, healthy lifestyle, and fast action when warning signs appear, many people live long, active lives. Stay informed, stay connected with your care team, and never hesitate to ask questions. [15]
Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.
The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members
Last Updated: January 25, 2025.
