Erythrocytosis: Causes, Thrombosis Risk, and What a High Hematocrit Means for Athletes

Key Takeaways

Erythrocytosis refers to an erythrocyte count above the sex-specific normal range and can be relative (reduced plasma volume) or absolute (increased erythrocyte mass).[1]
Erythrocytosis is a common reason for referral to haematology services and is usually secondary in origin.[2]
Common secondary causes include smoking, hypoxia, and diuretics, and testosterone or anabolic steroids are among the common drug causes.[2]
Polycythemia vera is rare, and a JAK2 mutation underlies 98% of PV cases.[1]
In the general population, each 5% increment of hematocrit was associated with a hazard ratio of 1.25 for venous thromboembolism.[3]
For secondary erythrocytosis, there is no definitive evidence of increased thromboembolism risk, and phlebotomy is not recommended routinely.[1]
Reduced plasma volume, high altitude and drugs such as erythropoietin, testosterone or anabolic steroids are listed causes of a raised hematocrit,[1][2] and altitude training can make athletes’ blood values harder to interpret.[4]
In my clinical experience, high hemoglobin and erythrocyte values are fairly common, whereas true polycythemia vera is rare, and in my practice testosterone is a much more frequent explanation than SGLT2 inhibitors.

Introduction: Erythrocytosis and the High Hematocrit Result

Erythrocytosis is often discovered incidentally on a routine blood test.[2] In Canada, up to 4% of ambulatory men and 0.4% of ambulatory women have erythrocytosis, based on hemoglobin levels greater than 165 g/L or 160 g/L, respectively.[1] Erythrocytosis is a common reason for referral to haematology services and is usually secondary in origin.[2] In other words, most people with a raised hematocrit do not have a bone marrow disease. Something else is driving the number up.

From a sports medicine perspective, erythrocytosis sits at an awkward intersection. Endurance athletes are often interested in “more red blood cells,” strength athletes may use testosterone or anabolic steroids, and many athletes train at altitude. At the same time, a higher hematocrit has been associated with a higher risk of venous thromboembolism in the general population.[3]

This article covers what erythrocytosis is, its main causes, how it is investigated, why it matters for thrombosis risk, and what is specific to athletes.

What Is Erythrocytosis?

Erythrocytosis refers to an erythrocyte count above the sex-specific normal range and can be subclassified into relative erythrocytosis, caused by a reduction in plasma volume (hemoconcentration), or absolute erythrocytosis, caused by increased erythrocyte mass.[1]

The terminology matters. In the past, the term polycythaemia was used synonymously with erythrocytosis; however, this is incorrect because polycythaemia implies an increase in all blood cells.[2]

Different thresholds are used depending on the context:

Referral thresholds: for iron replete patients, packed cell volume (hematocrit) persistently >0.52 in men and >0.48 in women.[2]
WHO 2016 diagnostic criteria for polycythemia vera: hemoglobin level >165 g/L in men, >160 g/L in women, or hematocrit >0.49 in men, >0.48 in women, or increased erythrocyte mass (one of three major criteria).[1]

Erythrocytosis is something I come across from time to time at my practice, although in my experience the erythrocyte count often gets a little less attention than hemoglobin. A patient may have small red cells but a high number of them while hemoglobin stays quite stable, and the opposite can also happen. In some cases of PV with iron deficiency, for example, erythrocytes are microcytic and the hemoglobin level is low or within normal limits.[1]

A single hematocrit value above the laboratory range is therefore a starting point, not a diagnosis.

Erythrocytosis Types: Primary, Secondary and Relative

Primary erythrocytosis refers to autonomous production of erythrocytes, typically from a myeloproliferative neoplasm (polycythemia vera [PV]).[1] Polycythemia vera is rare, with an incidence and prevalence of 0.84 and 22 per 100 000, respectively.[1] A gain-of-function mutation in Janus kinase 2 (JAK2) underlies 98% of PV cases.[1]

Secondary erythrocytosis is caused by a physiologically appropriate response to elevated serum erythropoietin levels.[1] Although its prevalence is difficult to estimate, it is higher than that of PV.[1] Common secondary causes include smoking, hypoxia, and diuretics,[2] and the drug-related causes listed in clinical reviews include testosterone or anabolic steroids and erythropoietin.[2]

Relative erythrocytosis results from any condition that reduces plasma volume, such as gastrointestinal fluid losses or diuretic use.[1] A related entity is apparent erythrocytosis (normal red cell mass but reduced plasma volume); factors associated with apparent erythrocytosis are obesity, alcohol excess, smoking, and hypertension.[2]

In my clinical experience, some erythrocytosis findings are entirely normal, while a small proportion may be malignant. Polycythemia vera is the one that often draws my attention. I have seen that these patients usually have a very high hemoglobin, so the condition tends to come to light even when no one looks at the erythrocyte count itself, and they are referred to haematology for assessment. I see high hemoglobin and high erythrocyte values fairly often, but true polycythemia vera I fortunately see quite rarely.

Common Causes of Secondary Erythrocytosis

Smoking

Heavy smoking has been described as a reversible cause of polycythemia. In an early case series, five smokers had erythrocyte masses sufficiently larger than normal to pose a problem in the differential diagnosis of polycythemia; all were found to have levels of carboxyhemoglobin sufficient to cause clinically significant hypoxemia, and in two patients the erythrocytosis improved when they stopped smoking.[5] Carboxyhemoglobinemia from tobacco smoking is also one of the causes of hypoxia that may present with a normal or falsely elevated oxygen saturation value.[1]

Obstructive Sleep Apnea: Less Clear Than Often Assumed

Obstructive sleep apnea (OSA) is often listed as a cause of erythrocytosis, and one review states that secondary erythrocytosis affects 2%–8% of patients with obstructive sleep apnea.[1] However, the direct data are more modest. A meta-analysis of eleven eligible studies with a total of 4608 patients with OSA found that hematocrit values were significantly higher in patients with OSA than in controls, but the elevation was modest and the hematocrit value is expected to be within the normal range; the authors concluded that OSA leads to slight increases in hematocrit but does not cause clinically significant erythrocytosis.[6]

In a study of 1604 consecutive veterans, 77.4% were diagnosed with OSA, yet few (1.6%) had clinical erythrocytosis. OSA severity defined by AHI was not associated with hematocrit, whereas awake and mean nocturnal oxygen saturation were inversely related to hematocrit. Active tobacco, increased alcohol ingestion and exogenous testosterone therapy were associated with higher hematocrit.[7] In that study, oxygen saturation, smoking, alcohol and testosterone were more closely linked to hematocrit than OSA severity itself.[7]

Testosterone

Testosterone is listed among the drug-associated causes of secondary erythrocytosis.[1] In a 20-year follow-up of 1073 adult trans men who started testosterone therapy, erythrocytosis occurred in 11% (hematocrit > 0.50 L/L), 3.7% (hematocrit > 0.52 L/L), and 0.5% (hematocrit > 0.54 L/L). Hematocrit increased most in the first year, from 0.39 L/L at baseline to 0.45 L/L after 1 year, and the probability of developing erythrocytosis was 10% after 1 year and 38% after 10 years.[8]

In another cohort of 282 people taking injectable testosterone cypionate (median dose 100 mg weekly), the cumulative incidence over the first 20 months was 12.6% for hematocrit >50.4%, 1.0% for hematocrit >52%, and 0.6% for hematocrit >54%.[9] Mild elevations are therefore common, while severe elevations are much rarer.

SGLT2 Inhibitors

Another drug-related cause is the sodium-glucose cotransporter 2 inhibitor (SGLT2i) class, which is widely used for type 2 diabetes, heart failure and chronic kidney disease.[10] In a cohort study of 269 064 propensity score–matched adult patients with type 2 diabetes, SGLT2i initiation was associated with a higher prevalence of erythrocytosis compared with dipeptidyl peptidase 4 inhibitors and glucagon-like peptide 1 receptor agonists, but erythrocytosis was not associated with an increased risk of arterial or venous thrombotic events.[10]

From time to time I have seen high erythrocyte values in patients on testosterone replacement therapy. In my experience, these patients are often already under a urologist’s care. When a reduction of the testosterone dose is sometimes considered, the situation is assessed as a whole, and the patient’s testosterone levels are also taken into account. In patients on SGLT2 inhibitors, I myself see clear erythrocytosis fairly rarely, and I have noticed that patients, and clinicians in general, rarely realise that the drug may be behind it. Testosterone-related erythrocytosis is much more common in my practice, and there the connection is often well known.

Why Erythrocytosis Matters: Viscosity and Thrombosis

Hematocrit is one of the major determinants of blood viscosity, and an increase in the hematocrit is associated with increased blood viscosity, reduced venous return and increased adhesiveness of platelets.[3]

One large set of general-population data comes from the Tromsø Study. In 26,108 subjects followed for a median of 12.5 years, there were 447 venous thromboembolic events. Multivariable hazard ratios per 5% increment of hematocrit were 1.25 for total venous thromboembolism and 1.37 for unprovoked venous thromboembolism. Men with a hematocrit in the upper 20th percentile (≥46%) had a 1.5-fold increased risk of total venous thromboembolism and a 2.4-fold increased risk of unprovoked venous thromboembolism compared to men whose hematocrit was in the lower 40th percentile.[3] This is an observational association, not proof that hematocrit itself causes the clots.

In polycythemia vera, the evidence is randomized. In the CYTO-PV trial, 365 adults with JAK2-positive polycythemia vera were assigned to a target hematocrit of <45% or 45 to 50%. After a median follow-up of 31 months, the primary end point (death from cardiovascular causes or major thrombotic events) was recorded in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the high-hematocrit group (9.8%).[11]

For me, as for many clinicians, the thrombosis risk is what usually raises concern in a patient with polycythemia vera, because it may be increased. I have often seen these patients using some form of blood-thinning medication, such as acetylsalicylic acid or another antithrombotic drug.

Secondary erythrocytosis is different. There is no definitive evidence that the risk of thromboembolism is increased in patients with secondary erythrocytosis, and phlebotomy is not recommended routinely.[1] In the SGLT2 inhibitor cohort above, new-onset erythrocytosis was likewise not associated with a higher risk of thrombotic events.[10] The risk attached to a high hematocrit may therefore depend on its cause.

Erythrocytosis is often discovered incidentally.[2] When symptoms are present, symptoms of hyperviscosity listed in clinical reviews include headache, fatigue, blurred vision, paraesthesia, myalgia and weakness, and chest and abdominal pain.[2] Two specific symptoms for myeloproliferative neoplasms are pruritus and erythromelalgia, and the pruritus is often aquagenic.[1]

Erythrocytosis in Athletes

Athletes add three special questions: normal adaptation, altitude, and doping.

In endurance athletes, training phases did not appear to change hemoglobin mass much. In 24 endurance athletes measured five times during a year, the effects of training volume and training phases on total hemoglobin mass (tHb-mass) were not significant, and tHb-mass showed very low individual oscillations during a training year (<6%), below the expected changes due to EPO application or blood infusion (~10%).[12]

Altitude complicates interpretation. Altitude training may affect an athlete’s hematological parameters in ways similar to those observed following blood doping, and current detection methods appear insufficient to differentiate between the two, which makes interpretation of an athlete’s biological passport difficult.[4]

Erythropoietin is listed among the drug-associated causes of erythrocytosis.[1] In a small study in healthy non-athlete subjects, rHuEpo treatment increased VO2max by 12.6 and 11.6% in weeks 4 and 11, and time-to-exhaustion at 80% VO2max increased by 54.0 and 54.3%. However, when the workload was normalized to the same relative intensity (only done at week 11), time-to-exhaustion was 26.8% lower than before rHuEpo administration.[13] In a double-blind, randomised, placebo-controlled trial in well trained but non-professional male cyclists aged 18–50 years, rHuEPO improved a laboratory test of maximal exercise, but submaximal exercise test performance and road race performance were not affected.[14]

In my experience, many athletes think it would be useful to have as high an erythrocyte count or hemoglobin as possible. In my view, a very high hemoglobin is not necessarily an advantage, and there seems to be a sweet spot: as erythrocytes or hemoglobin rise, so does blood viscosity, which may start to hinder the athlete. In a mouse study, exercise performance did not keep improving as hematocrit rose further, and the authors concluded that blood viscosity plays a critical role in limiting exercise capacity.[15] Because this was an animal experiment, the result cannot be transferred directly to humans.

Androgens are a common drug cause. Testosterone and anabolic steroids are listed among the common drug causes of erythrocytosis,[2] and clinical reviews recommend asking specifically about androgenic steroids, including testosterone.[1]

Reduced plasma volume can mimic erythrocytosis. Because relative erythrocytosis results from reduced plasma volume,[1] a sample drawn after fluid losses can show a higher hematocrit without any true increase in red cell mass.

Erythropoietin doping naturally increases the share of erythrocytes, but in doping a blood-thinning or plasma-expanding agent may be used alongside it to mask the change. For Finns, the familiar example is the 2001 doping case in the Finnish cross-country ski team, which many of us still remember as the Lahti scandal. The skiers used Hemohes (hydroxyethyl starch, HES) so that their hematocrit, hemoglobin and erythrocyte values would not look too high from the outside. Because of its masking properties, HES is prohibited by WADA, and in 2001 systematic doping in the Finnish cross-country ski team was detected with HES analysis techniques.[16] In other words, it was the HES use itself that was detected. HES has been used medically as a plasma expander for decades,[16] but in my view, when a cross-country skier uses it, doping is a fairly obvious reason for it. Perhaps this case has also left athletes with the idea that the bigger the number, the better.

How Erythrocytosis Is Investigated

Erythrocytosis is often discovered incidentally, and clinical reviews advise repeating the full blood count (minimum of one week interval) and checking whether earlier results were also raised; once-off borderline increases in packed cell volume often return to the normal range when patients are reviewed.[2]

The history focuses on tobacco smoking, medications (especially androgenic steroids, including testosterone), exposure to carbon monoxide and symptoms of obstructive sleep apnea.[1] Oxygen saturation less than 92% on room air by pulse oximetry suggests that erythrocytosis is secondary to hypoxic cardiopulmonary disease.[1] Serum ferritin is checked because iron deficiency can mask the degree of erythrocytosis.[2]

The serum erythropoietin level helps separate primary from secondary causes. In a cohort study of 125 patients, a low erythropoietin level (< 2.9 mU/mL) was specific (92%) and moderately sensitive (64%) for the diagnosis of PV, while a high erythropoietin level (> 15.1 mU/mL) was specific (98%) but had poor sensitivity (47%) for the diagnosis of secondary erythrocytosis.[1] In the primary care setting, where the probability of PV is low, clinical evaluation for secondary causes paired with a high erythropoietin level can rule out PV in most patients; JAK2 V617F mutation testing is used when PV is more likely.[1]

Some patients ask me what it means when their blood count shows erythrocytosis, that is, a raised erythrocyte count. In my experience, the answer depends on how high the value is. When it is only slightly above the reference range, I often tell patients to take it calmly and that the situation can be rechecked. At that point I also look at the hemoglobin. If hemoglobin is moderately raised and the erythrocyte count only slightly, I first look at the patient’s history: have earlier erythrocyte or hemoglobin values also been high? If it is typical for that patient that the values have run near the upper limit, I am used to simply following the situation. If the finding does not fit the history, rechecking it is usually my first step.

When I recheck, I usually order a full blood count. If the value is raised again, and especially if it is clearly raised, I may fairly readily consult a haematologist. In my experience, further investigations then usually take place at a hospital haematology outpatient clinic in specialist care, and the haematologists give clear instructions on how care should continue. For the differential diagnosis, I, like many clinicians, am also interested in the other cell lines, such as the white cell differential and platelets, to see whether the change involves only one cell line or several. In polycythemia vera, for example, patients often have mild to moderate leukocytosis and thrombocytosis rather than isolated erythrocytosis.[1]

How Management Depends on the Cause

Management follows the cause rather than the number alone. For secondary erythrocytosis, treatment should be directed at the underlying cause, and phlebotomy is not routinely recommended.[1] Reversible drivers matter: in the smoking case series, erythrocytosis improved in two patients when they stopped smoking,[5] and in the trans men cohort the authors described quitting smoking, switching to a transdermal administration route and, if BMI is high, losing weight as a reasonable first step.[8]

Polycythemia vera is managed by specialists. Most patients with PV are treated with low-dose acetylsalicylic acid and phlebotomy to achieve a target hematocrit value of less than 0.45, whereas patients at high risk for thrombosis may receive cytoreductive therapy.[1]

Practical Points

A single high hematocrit is a signal to repeat and interpret, not a diagnosis.[2]
Most erythrocytosis is secondary; polycythemia vera is rare.[1][2]
Smoking, hypoxia, diuretics, testosterone or anabolic steroids, and SGLT2 inhibitors are among the causes worth reviewing.[2][10]
OSA raises hematocrit only slightly on average; low oxygen saturation is the stronger signal.[6][7]
When interpreting an athlete’s result, reduced plasma volume, altitude exposure and drugs such as erythropoietin or androgens are worth considering.[1][2][4]
Thrombosis risk is clearly established for polycythemia vera, while evidence for secondary erythrocytosis is less certain.[1][11]

Conclusion

Erythrocytosis is a common reason for haematology referral, and it is usually secondary in origin rather than a sign of bone marrow disease.[2] In the general population, each 5% increase in hematocrit was associated with a hazard ratio of 1.25 for venous thromboembolism,[3] and in polycythemia vera, death from cardiovascular causes or major thrombosis occurred in 2.7% of patients with a hematocrit target below 45%, compared with 9.8% of those with a target of 45 to 50%.[11] For secondary causes, the evidence for thrombosis risk is weaker, and the cause itself is the main target.[1]

This matches what I see in practice: high erythrocyte and hemoglobin values are fairly common, true polycythemia vera is seen quite rarely, and when a value is only slightly raised and fits the patient’s earlier results, I am used to simply following the situation.

In my view, a high hematocrit in an athlete deserves a calm second look, with hydration, altitude exposure and possible use of testosterone, anabolic steroids or other substances all taken into account. Understanding the cause is what turns a worrying number into a manageable finding.

Erythrocytosis: Causes, Thrombosis Risk, and What a High Hematocrit Means for Athletes

Table of Contents

Key Takeaways

Introduction: Erythrocytosis and the High Hematocrit Result

What Is Erythrocytosis?

Erythrocytosis Types: Primary, Secondary and Relative