erythrocytosis



Overview of Erythropoiesis

Erythrocytosis is defined as a condition in which hemoglobin and/or hematocrit in the peripheral blood exceeds the high limit of normal levels and is characterized by redness of the face and extremities, itching of the skin, and symptoms of the primary disease due to a decrease in plasma volume, an increase in the autopoiesis of erythrocytes, or an increase in EPO.PV is treated with general therapy, thromboprophylaxis, bloodletting, and cytotoxicity; the other major focus is on the elimination of the cause of the condition and the treatment of the primary disease.

Definition

Erythrocytosis is defined as peripheral blood hemoglobin (Hb) concentration and/or hematocrit (Hct) exceeding the high limit of normal levels.

Hb: >165 g/L in men, >160 g/L in women, and >160 g/L in children.

Hct: >49% in males, >48% in females, >55% in children or an absolute red cell volume of more than 35 ml per kilogram of body weight.

Classification

According to whether the number of red blood cells is increased or not and the reason for the increase

Absolute erythrocytosis: refers to an absolute increase in the number of red blood cells.

Primary erythrocytosis: includes true erythrocytosis (PV), familial erythrocytosis and congenital erythrocytosis.

Secondary erythrocytosis: increased erythropoietin release due to tissue hypoxia, renal tumors, and other causes of increased erythropoiesis.

Relative erythrocytosis: refers to a decrease in plasma volume and concentration of erythrocytes, resulting in a relative increase in the number of erythrocytes per unit volume and an increase in hematocrit.

Morbidity

The annual incidence of true erythrocytosis is approximately (0.4-1.6)/100,000, with an age range of 20-85 years, a median age of onset of 60 years, and more males than females.

Causes

Causes

Relative erythrocytosis

Reduced plasma volume due to diuretics, vomiting, or diarrhea causes a relative increase in red blood cells.

Smoking can cause a decrease in plasma volume and an increase in erythrocyte volume; these usually return to normal after cessation of smoking.

Pseudoerythrocytosis or stress erythrocytosis, seen in hypertensive patients who are stressed and anxious, will present with decreased plasma volume and increased erythrocytes without splenomegaly.

Absolute increase

Increased autonomous production of red blood cells

It is an increase in red blood cell volume caused by acquired or inherited mutations in erythroid progenitor cells, commonly seen in PV or other myeloproliferative tumors.

Inherited germline mutations that cause erythropoiesis include Chuvash erythropoiesis (VHL gene mutation), EPO receptor mutations, and other rare conditions.

Increased erythropoietin (EPO)

Hypoxia: Hypoxia causes an increase in EPO, leading to erythropoiesis.

Cardiopulmonary diseases such as chronic lung disease, cyanotic heart disease or obstructive sleep apnea, high altitude, carbon monoxide poisoning, etc.

Smoking: can cause hypoxia, carbon monoxide exposure, etc., leading to increased EPO production and erythrocytosis.

Renal diseases: renal artery stenosis, renal cysts, hydronephrosis, kidney transplantation and other renal diseases can reduce renal blood flow, the kidneys are stimulated by hypoxic signals, and EPO production is increased.

Tumor-induced: many kinds of tumors can produce EPO autonomously, resulting in paraneoplastic erythropoiesis. Commonly found in liver cancer, kidney cancer, hemangioblastoma, uterine smooth muscle tumor, etc.

Other causes

Autologous blood transfusion, use of EPO, after androgens or anabolic steroids, lead poisoning, etc. can cause increased erythropoiesis.

Symptoms

Common Symptoms

Skin changes

Red and purple skin on the face and extremities is the main symptom of erythrocytosis.

The lips, mouth and earlobes are cyanotic, and the conjunctiva of the eyes is congested.

Some of the skin is itchy, especially after warm baths or showers with intense itching sensations.

Some have pestle fingers.

Nervous system

Headache, dizziness, weakness and sweating.

Individuals with severe cases may have abnormalities such as transient blindness (transient blackouts), flashing dark spots and blurred vision.

Erythematous limb pain

Burning pain, whitening or cyanosis in the hands and feet.

Erythema is often seen.

Thrombosis

Erythrocytosis causes increased blood viscosity, leading to slow blood flow and the formation of emboli.

Arterial thrombosis can be seen, as well as venous thrombosis.

Thrombosis can lead to complications such as cerebral infarction and myocardial infarction.

Other Symptoms

Gastrointestinal symptoms

Epigastric discomfort, early satiety, bloating, lack of appetite, and constipation may occur.

Liver and spleen enlargement.

Bleeding

Rare.

Manifested by bleeding from the nose, bleeding gums and bruises and sloughs on the mucous membranes of the skin.

Bleeding is difficult to stop after injury.

Symptoms associated with decreased blood volume

Seen in relative erythrocytosis due to decreased blood volume.

Manifestations include thirst, postural dizziness, skin inelasticity, and upright hypotension.

Symptoms of cardiopulmonary disease

Dyspnea, cough, cyanosis.

Obstructive sleep apnea may present with snoring, waking sleepiness, nocturnal choking or wheezing.

Complications

Hyperuricemia.

Massive destruction of red blood cells can lead to hyperuricemia.

Kidney stones, renal impairment, and secondary gout can occur.

Hypertension

Due to the increase in blood volume, the pressure of blood vessel wall increases, and the manifestation of elevated blood pressure can occur.

Angina pectoris, myocardial infarction

Most of the erythrocytosis will have coronary artery thrombosis, which will trigger angina pectoris and myocardial infarction.

Consultation

Department of Medicine

Hematology

It is recommended to consult the Department of Hematology in case of redness and itching of the skin all over the body, headache, dizziness, sweating, or when the values of red blood cell count, hemoglobin, and hematocrit are higher than the reference values in routine blood tests.

Preparation

Preparation for Consultation: Registration, Preparation of Documents, Frequently Asked Questions

Tips for Consultation

Regular work and rest, balanced diet and relaxation are sufficient.

Preparation Checklist

Symptom list

Pay particular attention to the time of onset of symptoms, special symptoms, etc.

Is there any redness or purple coloring of the skin? How long did it last?

Is there any itching of the skin, especially after bathing?

Is there a burning sensation in the hands and feet?

Are there any symptoms of headache, dizziness, fatigue, sweating?

Are the hands and feet red and painful? Nature of pain? Does it turn white or purple?

Are there any symptoms of epigastric discomfort, bloating, or lack of appetite?

Medical History Checklist

Has there been any recent vomiting or diarrhea?

Is there any smoking?

Is there a history of hypertension?

Are there any myeloproliferative disorders?

Are there any cardiopulmonary diseases such as chronic lung disease or heart disease?

Has there been prolonged living at high altitude?

Has there been recent carbon monoxide poisoning?

Any kidney disease or kidney transplant?

Is there a history of tumors, such as liver cancer, kidney cancer, uterine smooth muscle tumors?

Have you been exposed to lead?

Have you received red blood cell transfusions?

Is there a family history of erythrocytosis?

Checklist

Test results from the last six months, which can be brought to the doctor’s office

Laboratory tests: blood tests, bone marrow cytology.

Imaging tests: liver, spleen, kidney and other abdominal ultrasonography, X-ray, CT, MRI, etc.

Medication List

Medications used in the last 3 months, if available in boxes or packages, can be brought to the doctor

Diuretics: hydrochlorothiazide, furosemide, amphotericin, amphotericin, etc.

Others: erythropoietin, androgens, anabolic steroids, etc.

Diagnosis

Diagnosis is based on

Medical history

Recent history of vomiting and diarrhea.

Recent history of treatment with diuretics, erythrocyte infusion, EPO, etc.

History of smoking or carbon monoxide poisoning.

History of hypertension, myeloproliferative disease, cardiopulmonary disease, renal disease or tumor.

History of high altitude travel.

Family history of erythrocytosis.

Clinical manifestations

Symptoms

Redness of the skin all over the body, itching after bathing.

Burning sensation on hands and feet, etc.

Headache, dizziness, weakness and sweating may occur.

Physical signs

Conjunctival congestion, venous congestion in the fundus.

Skin scratches: suggests the presence of itching.

Liver and spleen are enlarged.

Some patients may have a heart murmur.

Laboratory Tests

Blood counts

Know the red blood cell, white blood cell, and platelet counts for diagnosis of the disease.

Red blood cells, hemoglobin, and hematocrit are above the upper limit of normal.

There may be a corresponding increase in white blood cells and platelets.

Fasting is not required for routine blood tests.

Serum EPO

Helps to differentiate between primary and secondary erythrocytosis.

Primary erythrocytosis usually has a low or absent EPO; secondary erythrocytosis has an elevated EPO.

Bone marrow cytology

To clarify the presence of myeloproliferative disorders.

Bone marrow cytology may be abnormal in true erythrocytosis and myeloproliferative disorders.

It is done when there is clinical suspicion or molecular biological evidence of true erythrocytosis or other myeloproliferative disorders.

Genetic testing

Used to clarify the cause of the disease.

Mutations in the JAK2 V617F and JAK2 exon 12 genes are present in 95% of cases of true erythrocytosis.

Chuvash erythrocytosis will have a mutation in the VHL gene.

There will also be EPO receptor mutations, etc.

Blood biochemistry

These include serum electrolytes, liver function, kidney function, and blood uric acid measurement.

They are used to identify the presence of decreased blood volume, renal disease, tumor-related organ dysfunction, and hyperuricemia.

Urine routine

Used to clarify whether there is kidney disease.

Hematuria often indicates the presence of renal tumor or other abnormalities.

Imaging

Ultrasound

Used to assess whether the liver and spleen are enlarged.

Commonly seen in true erythrocytosis or other myeloproliferative disorders.

CT Abdomen

A clearer image of the liver and spleen with or without density changes.

In patients with true erythrocytosis, CT can often indicate an enlarged liver and spleen.

Diagnostic criteria

The 2016 WHO diagnostic criteria for true erythrocytosis are listed below:

Main diagnostic indicators

Hb >165 g/L in men and >160 g/L in women, or hematocrit >0.49 in men and >0.48 in women, or red cell volume (RCM) exceeding 25% of the mean normal predicted value.

Bone marrow biopsy suggests whole myeloid hyperplasia relative to age, including significant erythroid and granulocytic hyperplasia and proliferation of polymorphic, variably sized mature megakaryocytes.

Presence of JAK2 V617F mutation or mutation in JAK2 exon 12.

Secondary diagnostic indicator: serum EPO below normal.

The diagnosis of true erythrocytosis is made when 3 major criteria are met, or when the first 2 major and minor criteria are met.

Differential diagnosis

Since erythrocytosis can be clarified after routine blood tests, there is no need to differentiate it from other diseases.

Treatment

Aims of treatment: to relieve symptoms, control the progression of the disease, and prevent and minimize complications.

Principles of treatment

Relative erythrocytosis and secondary erythrocytosis: the main purpose is to remove the cause of the disease and treat the primary disease.

True erythrocytosis: low-risk group mainly take low-dose aspirin and bloodletting treatment; high-risk group in the first two treatments on the basis of the combination of cell-lowering therapy; intermediate-risk group need to determine the treatment program.

Relative erythrocytosis and secondary erythrocytosis

Rehydration

Mainly for diarrhea and diuretic-induced dehydration.

Commonly used rehydration solutions include: compound lactic acid sodium chloride solution, 0.9% sodium chloride solution, 5% dextrose, albumin, and plasma.

Smoking cessation

Relative erythrocytosis caused by smoking decreases Hct after a few days of smoking cessation.

Removal of the cause of the disease

Diuretic reduction

Relative erythrocytosis caused by diuretics can be reduced by tapering the diuretics.

Treating the primary disease

Caused by cardiopulmonary disease, renal disease, tumor, etc., the primary disease needs to be actively treated.

Oxygen therapy

Oxygen therapy may be given if caused by lung disease.

True erythrocytosis

General treatment

When the skin is itchy, reduce the frequency of bathing and avoid bathing with too hot water.

Venous bloodletting

This treatment is preferred in patients <50 years of age with no history of embolism.

It keeps blood cell volume in the normal range, reduces blood viscosity, lowers red blood cell volume to recommended levels, and improves headache symptoms.

The initial bloodletting volume is 400-500 ml/2-4 days, and the interval between bloodletting can be extended appropriately in the later stage to maintain the hematocrit <45%.

The amount of bloodletting should be reduced for patients weighing less than 50 kg, and patients with combined cardiovascular and cerebrovascular diseases should be bled in small amounts and many times.

Drug therapy

Aspirin

All patients with erythrocytosis can be used after excluding contraindications.

It is used for thromboprophylaxis.

For intolerance, disulfiram may be used.

Hydroxyurea

First-line drug for cytostatic therapy.

Indications: age > 40 years; inability to tolerate bloodletting or excessive frequency of bloodletting with uncomfortable symptoms; progressive splenomegaly; severe disease-related symptoms; PLT > 1500 x 109/L and progressive leukocytosis.

Combined venous bloodletting therapy (with erythrocyte monocentesis if necessary) reduces embolic complications.

Hydroxyurea should be used with caution in younger patients (<40 years).

Adverse reactions include fever, pneumonia, skin and mucosal damage.

IFN-a

First-line drug for hypocellular therapy.

Indications: patients intolerant or resistant to hydroxyurea.

Reduce erythrocyte and platelet counts, control Hct, relieve skin itching, improve splenomegaly symptoms.

Major adverse effects: flu-like symptoms, fatigue, musculoskeletal pain.

Rucotinib

JAK2 inhibitor for hypocellular therapy.

Indications: for use in patients with poor hydroxyurea efficacy or intolerance.

Adverse effects: anemia, thrombocytopenia and neutropenia.

Used as a second-line agent for cytostatic therapy.

Indications: for hydroxyurea resistance or intolerance.

Adverse reactions: Treatment-associated leukemia or myelodysplastic syndromes and neoplasms occur in the distant future.

Leukovorin

Second-line cytoreductive therapy.

Indications: For hydroxyurea resistance or intolerance. Intermittent oral leucovorin may be considered in elderly patients (>70 years).

Adverse effects: Severe myelosuppression.

Cyproheptadine

For relief of pruritus.

Prognosis

Cure.

Relative erythrocytosis and secondary erythrocytosis disappear when the cause is removed or the primary disease is treated.

True erythrocytosis progresses slowly, and patient survival is usually 10 to 15 years or more.

Prognostic factors

The prognosis of true erythrocytosis is mainly related to age, white blood cell count, and the presence of thrombosis.

Age: ≥67 years is 5 points; 57-66 years is 2 points.

Leukocytosis: a leukocyte count >15×109/L is 1 point.

History of venous thrombosis is 1 point.

Hazard stratification: low risk (0 points); intermediate risk (1 to 2 points); high risk (≥3 points).

Hazard

True erythrocytosis

Patients may experience headache, dizziness, tinnitus, nausea, and vomiting, affecting their quality of life.

Increased risk of thrombotic diseases, such as venous thrombosis, cerebral infarction, myocardial infarction, etc., which can be life-threatening in severe cases.

There is a tendency to bleed, which is life-threatening in severe cases.

Individuals may progress to acute leukemia or myelofibrosis, which is life-threatening.

Secondary Erythrocytosis and Relative Erythrocytosis

Erythrocytosis can cause redness and itching all over the body, affecting daily life and work.

Erythrocytosis can lead to thrombosis, which can be life-threatening.

The primary disease may cause breathing difficulties, dizziness and other symptoms, affecting the quality of life.

If the primary disease is tumor, it can be life-threatening if not treated actively.

Daily

Daily Management

Dietary management

Eat a balanced diet, less oily food, low salt and low fat diet.

Drink more water to ensure urine output and prevent hyperuricemia.

Prohibit alcohol.

Life Management

Stop smoking.

Regular work and rest.

Pay attention to skin care, reduce the frequency of bathing and avoid bathing in excessively hot water.

Maintain regular and moderate physical exercise, the intensity of which should be such that you do not feel tired after exercise.

Psychological support

Learn to reduce stress, communicate with others, relieve anxiety, and maintain a comfortable mood.

Disease monitoring

Observe whether there is any abnormality in limb movement, skin, etc., and closely monitor the change of blood pressure.

Follow-up

Follow the doctor’s instructions for regular follow-up.

Review items include: blood pressure, blood routine, uric acid, liver and kidney function, abdominal ultrasound and so on.

Prevention

Regular medical checkups should be conducted to detect abnormalities and seek medical attention in time.

Actively treat the primary disease and use medication as prescribed by the doctor.

Smoking cessation.