Approach to polycythemia

1. POLYCYTHEMIA
D I A G N O S T I C A P P R O A C H

2. INTRODUCTION
Erythrocytosis (also called polycythemia) refers to an increased hemoglobin concentration and/or
hematocrit in peripheral blood.
Diagnosing the specific cause of polycythemia is important for proper management of the patient

3. 5 MINUTE CLINICAL CONSULT 2023

4. 
TERMINOLOGY
Erythrocytosis – Erythrocytosis (polycythemia) is an abnormal elevation of hemoglobin (Hb) and/or
hematocrit (Hct) in peripheral blood.
Increased hemoglobin – >16.5 g/dL (10.3 mmol/L) in men or >16.0 g/dL (10.0 mmol/L) in women
Increased hematocrit – >49 percent in men or >48 percent in women
Relative polycythemia – Hemoconcentration, or an elevation of Hb and/or Hct due to a decrease in
plasma volume alone (ie, without an increase of the RBC mass) is referred to as relative polycythemia
Absolute polycythemia – Absolute polycythemia refers to an increase of RBC mass, which has multiple
causes (table 3) and can be categorized as either primary or secondary polycythemia.
Primary polycythemia – Primary polycythemia refers to an increase of RBC mass caused by mutation
RBC progenitor cells.
Secondary polycythemia – Secondary polycythemia refers to an increase of RBC mass caused by
elevated serum erythropoietin (EPO)

6. PHYSIOLOGY
Erythropoietin (EPO) is the primary driver of proliferation and differentiation of RBC progenitors in normal
physiology.
Ninety percent of circulating EPO in humans is produced by the kidneys as a physiologic response to
hypoxia.
EPO-producing renal cells detect hypoxic signals due to
reduced hemoglobin (anemia)
hypoxemia (eg, reduced oxygen saturation or release by hemoglobin)
impaired oxygen delivery to the kidney (eg, vascular occlusion).

7. SPURIOUS POLYCYTHEMIA
This occurs due to volume contraction rather than an increase in true RBC mass

Causes include :-
Severe dehydration due to isolated fluid loss: potentially seen in diarrhea and severe vomiting
Gaisbock syndrome: Usually seen amongst obese, hypertensive males. Smoking, excessive alcoho
use of diuretics are contributory.
TRUE/ABSOLUTE POLYCYTHEMIA
Low serum EPO levels (Primary polycythemia)
High/ Inappropritely normal serum EPO levels (Secondary polycythemia)
NEONATAL POLYCYTHEMIA
The increase in hematocrit is a normal compensatory mechanism in infants due to the relative tissue-level
hypoxia in the intrauterine environment. It is exacerbated by the high affinity of fetal hemoglobin for
oxygen

8. Resolution of polycythemia — If a repeat complete blood count (CBC) reveals resolution of polycythemia,
and no findings from the initial evaluation that suggest polycythemia vera (PV), other myeloproliferative
neoplasm (MPN), or other malignancy, no further evaluation is required. In many such cases, the initial
evaluation will identify a likely explanation for transient polycythemia. As examples:
Erythrocytosis resolved after management of dehydration from diarrhea or diuretic use; in this
setting, the diagnosis is relative polycythemia due to plasma volume contraction.
Erythrocytosis resolved in association with improvement of hypoxia after smoking cessation or
management of obstructive sleep apnea in a patient with elevated serum erythropoietin (EPO).
Suspected volume depletion — When hemoglobin (Hb) and/or hematocrit (Hct) are elevated
due to volume depletion, rather than an increase in RBC mass, the patient is considered to
have relative polycythemia. In this setting, evaluation and management are primarily focused on
identifying the underlying cause, managing symptoms, and correcting volume depletion, fluid
loss, and associated electrolyte abnormalities.oietin (EPO).

9. Identification of volume depletion is generally based on the initial clinical evaluation, because
direct methods for estimating blood volume are not widely available. Examples of clinical
findings that suggest volume depletion are thirst, postural dizziness, loss of skin turgor,
orthostatic hypotension, and elevated blood urea nitrogen (BUN)/creatinine, but these findings
are not always reliable in older individuals.
When volume depletion is suspected as the cause of relative polycythemia, a repeat CBC after
fluid restoration or reduction of diuretics should reveal improvement in Hb/Hct. No further
evaluation is required if polycythemia resolved and the initial clinical evaluation did not reveal
findings associated with PV/MPN (eg, constitutional symptoms, pruritus, erythromelalgia,
splenomegaly, or thromboses) or other cancer.

10. ABSOLUTE - PRIMARY
Primary polycythemia is caused by a mutation (either acquired or inherited) in RBC progenitor cells that
results in increased RBC mass.
Most commonly, primary polycythemia is caused by an acquired condition, such as polycythemia vera
(PV) or another myeloproliferative neoplasm (MPN) in association with JAK2 V617F or other mutation.
PV should be suspected in patients with MPN-related symptoms (eg, headache, dizziness, visual
disturbances, pruritus, early satiety) or complications (eg, thrombosis, bleeding); a blood smear that
reveals leukocytosis, increased eosinophils or basophils, immature white blood cell forms, an increased
number or abnormal appearance of platelets, or a leukoerythroblastic picture; or polycythemia in
association with low or absent EPO.
Polycythemia may also be a manifestation of differentials essential thrombocythemia (ET), primary
myelofibrosis, or chronic myeloid leukemia.

13. POLYCYTHEMIA VERA
Polycythemia vera (PV) is a BCR::ABL1-negative myeloproliferative neoplasm characterized by
excessive, clonal proliferation of erythroid cells.
PV is clinically manifested as an elevated red blood cell mass that is often accompanied by troublesome
pruritus, erythromelalgia (burning pain in feet or hands), and abdominal pain/fullness from splenomegaly.
PV is associated with an increased risk for thromboembolic events, leukemic transformation, and/or
myelofibrosis.
Epidemiology:-
Polycythemia vera shows a male preponderance in all races and ethnicities, with a male-to-female ratio of
approximately 2 to 1
The median age of presentation of PV is 60 years, with patients seldom seen before the age of 40
Polycythemia due to hemoglobinopathies and congenital cyanotic heart diseases is likely to be detected
in significantly younger patients.

14. PATHOPHYSIOLOGY - PV
LOW EPO LEVELS
The primary defect in nearly 95% of cases of polycythemia vera is an acquired mutation in exon 14 of the
tyrosine kinase JAK2 (V617F)
Mutations have also been described in exon 12 of JAK2
These mutations result in a loss of the auto-inhibitory pseudo-kinase domain of JAK2, resulting in its
constitutive activation
This constitutive activation results in both hypersensitivity to EPO and EPO-independent erythroid colony
formation.

15. HISTORY
Common presenting symptoms, usually non-specific, include fatigue, headache, dizziness, transient
blurry vision, amaurosis fugax, and other symptoms suggestive of transient ischemic attacks (TIAs).
Infrequently, patients may complain of pruritus after a warm water shower, particularly over the back.
A history of epistaxis, gastrointestinal (GI) bleeding, or easy bruising may be forthcoming.
Peptic ulcer disease commonly coexists, and patients may present with non-specific abdominal pain. Left
hypochondrial pain and early satiety should raise the suspicion of splenomegaly
Rarely, patients may present with a history of unexplained thrombotic complications, such as Budd-Chiari
syndrome or digital infarcts
It is vital to try and elicit etiology-specific history, such as a history of smoking, an extended stay at high
altitudes, and congenital cardiac disease, among others. Significant family history may be noted in
patients with hemoglobinopathies

16. PHYSICAL EXAMINATION
Abnormal facial ruddiness may be prominent.
Cyanosis and clubbing, along with the presence of a murmur on auscultation, provide strong evidence
favoring a congenital cyanotic heart disease.
Nicotine staining of the nails and teeth provides presumptive evidence of smoking, even in a non-
forthcoming patient.
Morbid obesity could raise the possibility of Pickwickian syndrome, whereas a barrel chest could suggest
obstructive lung disease
Examining the abdomen may lead to finding a palpable spleen or eliciting the bruit of renal arterial
stenosis in a thin-built individual

17. EVALUATION

HEMOGRAM

SERUM EPO LEVEL
Low EPO Level
EPO levels indicate primary polycythemia. Subsequent evaluation should be targeted toward the
detection of polycythemia vera
JAK2 mutation studies are virtually diagnostic for polycythemia vera (95% cases).
High EPO Level
High EPO levels indicate secondary polycythemia.

19. High EPO Level:-
Subsequent evaluation should be aimed at determining the cause. This should include, but not be limited to,
the following:
Measurement of arterial oxygen saturation levels using a pulse-oximeter: low levels would likely indicate a
pulmonary or cardiac cause
Normal saturation levels could require further evaluation, such as:
The use of a co-oximeter to rule out methemoglobinemia
Measurement of carboxyhemoglobin levels for smokers
Measurement of the P50 of Hb to detect high-affinity hemoglobinopathies
Relevant investigations to detect a possible EPO-secreting tumor

20. BONE MARROW EXAMINATION :-
Its utility largely remains restricted to cases where the clinical suspicion of polycythemia vera is high,
despite the absence of a JAK2 (V617F) mutation, or if facilities to test for the mutation are unavailable.
Differentials :- CML, PRIMARY MYELOFIBROSIS
Assessment of RENAL FUNCTION :-
Renal function abnormalities indicate a higher likelihood of secondary polycythemia. Uric acid levels are
often raised due to increased cell proliferation and subsequent turnover
Assessment of HEPATIC FUNCTION :-
Liver cirrhosis and inflammatory liver disease have been associated with secondary polycythemia and
increased RBC proliferation.

USG :- An ultrasound and Doppler study of the abdomen would help identify a secondary cause

21. ARE JAK2 TESTING/BONE MARROW EXAMINATION REQUIRED FOR ALL? -UPTODATE
We suggest not testing for JAK2 mutation and/or bone marrow examination in all patients with
polycythemia.
We selectively perform JAK2 mutation testing in the following settings:
Patients with clinical findings from the history and physical examination that suggest PV or other MPN
(eg, pruritus, erythromelalgia, arterial or venous thrombosis, unexplained bleeding/excessive bruising)
Patients with low or normal serum EPO and no evidence of volume contraction (ie, relative polycythemia
We perform a bone marrow examination only when there is clinical suspicion or molecular evidence for
PV or other MPN, as described above. In those settings, bone marrow biopsy is important for evaluation
of myelofibrosis, acute myeloid leukemia, or other complications of these disorders

22. TREATMENT / GENERAL MEASURES
Risk factors :- Patients >60years or with history of thrombosis are HIGH RISK

Age <=60 years and no history of thrombosis are LOW RISK
Phlebotomy and low dose aspirin therapy are first line therapy for all patients
Although not curative modern therapy for PV can relieve symptoms and prolong survival
Phlebotomy reduces blood hyperviscosity, improves platelet function, restores systemic pressures and
decrease risk of thrombosis. 1 unit 500ml of phlebotomy reduce HCT by 3 percent)
Other therapies
Maintain hydration
Pruritus therapy - H1, H2 Blockers, SSRI, Oatmealbaths eg Cyproheptadine 4-16mg OD
Uric acid reduction therapy - Allopurinol 300mg/day PO

23. TREATMENT / MANAGEMENT
The treatment of secondary polycythemia is directed at correcting the cause.
Polycythemia vera, available treatment modalities include
PHLEBOTOMY
Phlebotomy was established as the backbone of therapy, primarily based on the trial conducted by t
Polycythemia Vera Study Group (PVSG).
The rationale behind repeated phlebotomies was that cytoreduction would reduce hyperviscosity.
Additionally, it would induce a state of iron deficiency that would help retard red-cell proliferation
This is continued weekly until a target hematocrit of under 45% is obtained. Based on the findings o
CYTO-PV trial conducted in Italy
For secondary polycythemias, phlebotomy is usually reserved for the following conditions
Chronic lung diseases
Cyanotic heart diseases
Post-renal transplant patients with hypertension and erythrocytosis, not responding to
optimal doses of angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor
blockers (ARBs)

24. A standard one-unit phlebotomy (eg, 500 mL) typically reduces the hematocrit (Hct) by three percentage
points in an adult. Patients should be encouraged to maintain hydration and avoid vigorous exercise
within 24 hours of phlebotomy.
Most males tolerate removal of 1.5 to 2 units per week, whereas some females, older adults, and those
with low body mass (eg, <50 kg) or cardiopulmonary disease may only tolerate removal of 0.5 units per
week (eg, 7 mL/kg). Since phlebotomy controls polycythemia by producing a state of absolute iron
deficiency, iron supplementation should not be given.
Performed initially as every 2-3 days as Hematocrit normalises, phlebotomies of 250ml to 500ml are done
250- 350ml in elderly and patients with cerebrovascular disease.
Frail patients should have volume replaced with saline solution to avoid postural hypotension.
Complication of phlebotomy :- Chronic iron deficiency ( pica angular stomatitis glossitis) possible muscle
weakness / dysphagia as a result of esophageal web

25. LOW DOSE ASPIRIN
Original PVSG trial showed that, despite greater longevity, patients treated with phlebotomy alone
were at a greater risk of developing thrombosis during the first three years of therapy. This seemed to
suggest a potential benefit to concurrently using antiplatelet or anticoagulant agents. Initial trials
using higher doses of aspirin or dipyridamole showed unsatisfactory gastrointestinal hemorrhage.
However, subsequent studies found that lower doses of aspirin could be safely used.
Currently, aspirin is indicated when there is inadequate control of microvascular symptoms after
achieving the target hematocrit or in the presence of other cardiovascular risk factors
Aspirin, when indicated, is recommended to be used at low doses, ranging from 40 to 100 mg daily.
For all patients with PV, we suggest treatment with low-dose daily aspirin based on its efficacy for
alleviating microvascular symptoms, reducing deaths from CV and thromboembolic causes, and
safety.- UPTODATE

26. HYDROXYUREA
Hydroxyurea recommended for patients with High risk PV
Poor venous access
High phlebotomy requirement
When phlebotomy is not possible due to logistic reasons
Severe thrombocytosis
Intractable pruritus
Other indications
Standard daily doses range from 500 to 1500 mg per day.
Doses are adjusted to target platelet counts below 500,000/mcL. However, it is necessary to adjust
such that the absolute neutrophil count remains above 2000/microliters
Hydroxyurea can lead to skin ulcer, myelosuppression and higher risk of leukemic transformation

27. RUXOLITINIB
The JAK2 inhibitor ruxolitinib is used when patients are intolerant or unresponsive to hydroxyurea.
The COMFORT-I study compared the efficacy of Ruxolitinib with placebo therapy, whereas
COMFORT-II compared it with the “best available therapy.” Both trials showed a significant
reduction in splenomegaly, improvement in symptoms, and better survival.
However, despite this enhanced benefit, the use of ruxolitinib was associated with increased risks of
anemia, often dose-limiting, and thrombocytopenia.
Standard recommended dose for polycythemia vera is 10 mg twice a day
Dose reduction is required if hemoglobin drops to below 12 gm/dl.
A fall in hemoglobin to below 8 gm/dl indicates that dosing is to be temporarily interrupted.

28. Management of polycythemia vera in pregnancy
Standard therapeutic measures of phlebotomy and low-dose aspirin are appropriate in most cases.
Certain high-risk women may require the addition of pegylated interferon (IFN)-alpha
Hydroxyurea, alkylating agents, and warfarin are contraindicated in pregnant patients because of
potential teratogenicity
Pregnant patients with PV are at an increased risk for thromboses.
Prophylaxis – A decision to use prophylaxis should be individualized and made jointly with the
patient. No published studies have tested the safety and utility of thrombosis prophylaxis in
pregnant patients with PV.
Neonatal Polycythemia
Most patients do not need treatment. Exchange transfusion is occasionally required due to
hyperviscosity.

29. FOLLOW UP RECOMMENDATIONS
Monitor hct often and phlebotomize as needed to maintain target goal
PATIENT MONITORING
DIET
Avoid high sodium diet can caise fluid retention
Avoid iron supplementation, a permissive chronic state of iron defociency can help decrease blood
production
PATIENT EDUCATION
Perform leg and ankle excercise to prevent clots
Continuous education for possible complications and seeking treatment early for any change or increase
in symptoms
PROGNOSIS
PV cannot be cured but can be controlled with treatment
Survival is >15 years with treatment
Patients are at risk of developing PPMF and an increased risk of malignant transformation

30. 
COMPLICATIONS
Splenomegaly or hepatomegaly
Budd- Chiari syndrome

Vascular thrombosis - Major cause of death
Transformation to acute leukemia ( 5%)
Transformation to MF (10%)
Hemorrhage
Peptic ulcer
Uric acid stones
Secondary gout
Increased risk of conplication and mortality from surgical procedure. Assess risk/benefits and ensure
optimal control of disorder before any elective surgery.

31. FAMILIAL POLYCYTHEMIA
Familial polycythemia should be suspected when the onset of polycythemia is in childhood or there is a
positive family history of polycythemia.
A normal P50 in a patient with a familial polycythemia may be caused by a variety of rare syndromes
caused by inherited (germline) mutations. Examples include primary familial and congenital polycythemia,
which may be caused by an activating mutation of the EPO-receptor (EPOR) or other mutations; Chuvash
polycythemia
Laboratory investigation usually begins with the determination of the oxygen pressure at 50 percent Hb
saturation (P50)
A low P50 suggests a high oxygen affinity hemoglobinopathy, congenital methemoglobinemia,
bisphosphoglyceromutase deficiency, or other rare conditions.

32. PRIMARY FAMILIAL AND CONGENITAL POLYCYTHEMIA
Primary familial and congenital erythrocytosis/polycythemia (PFCP), also called benign erythrocytosis and
autosomal dominant erythrocytosis, is an uncommon cause of erythrocytosis that is caused by mutations
of EPOR (which encodes the EPO receptor).
Clinical/laboratory characteristics – PFCP is characterized by:
Elevated RBC mass
Low serum EPO
Normal Hb-O2 dissociation curve
Absence of progression to acute leukemia
Hypersensitivity of erythroid progenitors to EPO

33. Normal P50 value is 24-28mmhg

34. ABSOLUTE - SECONDARY
Secondary polycythemia refers to an increase of RBC mass caused by elevated serum EPO.
Most often, this is due to an appropriate physiologic response to tissue hypoxia, but secondary
polycythemia can also result from autonomous EPO production (eg, an EPO-secreting tumor)
Inherited - 
Germline mutation in oxygen sensors, high oxygen affinity hemoglobinopathy.
Acquired
Hypoxia associated.
Autonomous EPO production.

36. OXYGEN SENSORS
The major stimulus for EPO production is decreased oxygen (O2) delivery caused by anemia (reduced
RBC mass) or decreased O2 saturation of hemoglobin (hypoxemia)
Factors that regulate EPO transcription are referred to as a cellular oxygen sensor
Hypoxia inducible factors (HIFs) – Hypoxic stimulation of the O2 sensor signaling pathway increases
production of HIF-1 and HIF-2; HIF-2 is the principal regulator of EPO gene transcription. Protein levels of
HIF-1 and HIF-2 alpha subunits are stabilized by hypoxia, while they decay rapidly in normoxia
Above a critical oxygen concentration HIF-1-alpha is ubiquitinated and rapidly degraded in proteosomes.
This oxygen sensor in mammalian cells appears to be a proline hydroxylase (prolyl hydroxylase domain
proteins PHD1, PHD2, and PHD3) that adds a hydroxyl moiety in an oxygen- and iron-dependent manner
to P-564 of HIF-1-alpha; P-564 lies within a highly conserved region of HIF-1-alpha that binds the von
Hippel-Lindau (VHL) protein.
When P-564 hydroxylated HIF-1-alpha binds VHL, an ubiquitin E3 ligase complex is activated, leading to
ubiquitination and subsequent destruction of HIF-1-alpha

37. MANAGEMENT OF SECONDARY POLYCYTHEMIA
For patients with secondary polycythemia, the focus of management is amelioration of the underlying
cause and contributing factors to alleviate symptoms and reduce the risk of thrombosis
For patients who remain symptomatic, we empirically employ cautious phlebotomy (without a specified
hematocrit [Hct] target) rather than cytoreduction.
Lessen contributing factors – Remediable causes of secondary polycythemia should be addressed
whenever possible.
Examples include improving oxygenation in patients with pulmonary or heart disease,
providing continuous positive airway pressure for obstructive sleep apnea, correcting
renal artery stenosis, removing EPO-producing tumors, considering angiotensin
converting enzyme inhibitors for postrenal transplant syndrome, and re-evaluating the
need for drugs that may be causing erythrocytosis.
All patients with secondary polycythemia should be encouraged to discontinue
smoking.

38. Symptom relief – For patients with symptomatic secondary polycythemia, we suggest empiric,
cautious therapeutic phlebotomy rather than cytoreductive therapy
There is no specific target Hct for patients with secondary polycythemia. Rather, cautious phlebotomy
(eg, removal of 250 mL blood, replaced by an equal volume of crystalloid) may be evaluated for
symptom relief; however, reduction to Hct <55 percent is likely to exacerbate dyspnea or other hypoxic
symptoms.
Thrombosis prophylaxis – There is no persuasive evidence that prophylactic phlebotomy or
cytoreduction reduces the risk of thrombosis in patients with secondary polycythemia.
We offer once-daily low-dose aspirin to patients with cardiovascular risk factors, twice-daily low-dose
aspirin for patients with a history of arterial thrombosis, and systemic anticoagulation for those with a
history of venous thromboembolism

39. COMPLICATIONS SECONDARY PV
Secondary polycythemia is associated primarily with complications arising from hyperviscosity
Thrombosis: Due to hyperviscosity, there is a preponderance of both arterial and venous thrombosis.
Manifestations of arterial thrombosis include digital infarcts, and cerebral ischemic infarcts, particularly
in watershed territories. Venous thrombosis, such as Budd-Chiari syndrome, is also seen

40. Phlebotomy is not warranted for Chuvash erythrocytosis. Phlebotomy may increase the rate of
thrombotic complications because iron deficiency inhibits PHD2 and augments levels of HIFs, which
augment expression of prothrombotic factors [24,26-28]. In one report, the JAK2 inhibitor ruxolitinib
decreased phlebotomy requirements in patients with Chuvash erythrocytosis
CONGENITAL ERYTHROCYTOSIS
Management – Erythrocytosis is an appropriate physiologic response to a high O2 affinity Hb. Patients
with a high affinity Hb should not be phlebotomized, as it further decreases tissue O2 delivery.

41. 
OTHER CAUSES
SGLT2 inhibitors – SGLT2 (sodium-glucose cotransporter-2) inhibitors (eg, canagliflozin, empagliflozin,
dapagliflozin, ertugliflozin) are antidiabetic agents that are also used in patients with heart failure and
chronic renal disease. SGLT2 inhibitors are increasingly recognized as a cause of erythrocytosis.
Athletic performance enhancers – Polycythemia may be due to autologous blood transfusion ("blood
doping"), self-injection of recombinant EPO, or use of androgens or anabolic steroids as a technique for
enhancing athletic performance.
Cobalt – Cobalt toxicity has been associated with polycythemia, but the mechanism is poorly understood
POEMS syndrome – POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal
plasma cell disorder, Skin changes) is a paraneoplastic process that is occasionally associated with
polycythemia, but the mechanism is not well understood.

43. World Health Organization (WHO): Classification and
diagnostic criteria for myeloproliferative neoplasms –
Document summary and in-depth discussion, 2016
(published 2018)
Further reads

44. References
Uptodate - Topic 7106 Version 31.0
Topic 7075 Version 31.0
Topic 4517 Version 45.0
NCBI STATPEARLS https://www.ncbi.nlm.nih.gov/books/NBK526081/
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