1. Aetiology
Blood consists of red cells, white cells and platelets suspended in liquid plasma. If the blood is allowed to separate into cellular and liquid phases then the cellular phase is in the range of 37 to 54 per cent of the total. This is the haematocrit also known as the packed cell volume.
The majority of cells are red cells, so the haematocrit is mainly a reflection of the quantity of red cells present. The haematocrit is a measure of the viscosity or 'thickness' of the blood. Because red cells are filled with haemoglobin, the level of the haematocrit is related to the level of haemoglobin.
The normal range for haematocrit is 0.45+/-0.05 in men and 0.41+/-0.05 in women. If raised above 0.52 in men or 0.48 in women this may be abnormal.
Because the haematocrit is the percentage of cells in the total blood volume, if the liquid phase is reduced then the haematocrit will appear higher. To show there is a true increase in red cells it may be necessary to measure the red cells' mass using a radioisotope dilution method. It has been shown that a haematocrit of 0.60 in men or 0.56 in women always reflects an increased red cell mass.
Erythropoietin drives red cell production. Hypoxia will lead to increased red cell production and so a raised haematocrit. There are therefore a number of causes secondary to alteration of erythropoietin levels for increased red cell production (see box).
In some patients the raised haematocrit is a primary phenomenon where the bone marrow has a clonal abnormality leading to the increased red cell production, and so a raised haematocrit, as part of a myeloproliferative disorder.
| Causes of erythrocytosis |
| Primary Secondary Acquired Erythropoietin-mediated hypoxia-driven:
Pathologic erythropoietin production:
Exogenous erythropoietin administration |
2. Making a diagnosis
Whenever an unexpected abnormal laboratory test is reported, it should be reviewed and repeated to confirm the abnormality.
With a confirmed elevated haematocrit, the first step is to take a careful history looking for secondary causes of erythrocytosis and symptoms of a primary myeloproliferative disorder, such as red face or itch.
Examination should look for features of secondary disease, such as respiratory or cardiac disease, and features suggesting myeloproliferation, such as splenomegaly.
Investigations
Laboratory investigation should be guided by the history and examination. Possible secondary causes should be confirmed or refuted. In a patient in whom a primary myeloproliferative disorder is suspected, the FBC and blood film should be examined.
Most patients with polycythaemia vera have clonal abnormalities in the JAK2 gene and these abnormalities are now part of the diagnostic criteria (see box). This test can be carried out on peripheral blood but should remain under the remit of haematologists. If positive it will confirm a diagnosis of polycythaemia vera without further laboratory tests.
Further investigations
Patients with a raised haematocrit and no secondary cause who are negative for a JAK2 mutation require further investigation. A red cell mass measurement to confirm an absolute erythrocytosis is the first step. Further investigations indicated are arterial oxygen; abdominal ultrasound; serum erythropoietin level; and bone marrow aspirate and trephine, with cytogenic analysis and bone marrow culture for the erythropoietin-independent colonies found in polycythaemia vera.
Specialist investigations may be required to look for other causes of erythrocytosis, including lung function studies or searching for rare mutations such as in the erythropoietin receptor gene.
| Diagnostic criteria for polycythaemia vera |
JAK2-positive polycythaemia vera A1. High haematocrit (>0.52 in men, >0.48 in women) OR raised red cell mass (>25% above predicted). JAK2-negative polycythaemia vera A1. Raised red cell mass (>25% above predicted) OR haematocrit >0.60 in men, >0.56 in women. Diagnosis requires A1+A2+A3+either another A or two B criteria. |
3. Management
After assessment, all ill patients with a raised haematocrit should have any necessary resuscitation carried out. Dehydration should be corrected and any lifestyle issues need to be addressed.
Primary cause
If the raised haematocrit is due to a primary haematological disorder of the bone marrow then the management issues that need to be considered are reduction of the haematocrit by venesection and intervention to reduce platelet 'stickiness' and, if cytoreduction is required, to return blood counts to the normal range.
The haematocrit should be reduced to below 0.45. The volume of blood removed should be commensurate with the patient's size and comorbidities.
Low-dosage aspirin has been shown to be effective in reducing the incidence of thromboembolic events in those with primary myeloproliferative disorders.
Treatment options
Options for cytoreduction include interferon, hydroxycarbamide (formerly known as hydroxyurea), anagrelide, radioactive phosphorus and busulfan.
The decision to use a cytotoxic and choice of agent depends on the risk group into which the patient falls.
Risk is determined by factors including age, previous thrombo- embolic history, presence of other factors such as hypertension and diabetes and level of blood counts. There is little evidence to support venesection to reduce the haematocrit in secondary cases of erythrocytosis.
There are instances where judicious venesection may be beneficial, particularly in some respiratory cases and in patients with cyanotic heart disease. These patients should be managed by experts in the medical area.
Referral
All patients who have primary myeloproliferative disorder such as polycythaemia vera should be managed by a haematologist. Specific investigations such as JAK2 mutation analysis should be under the auspices of a haematologist.
Secondary causes should be referred to a medical expert.
In some rare areas such as erythrocytosis due to cyanotic heart disease, patients should be managed by a consultant with specific expertise in that area of cardiac disease.
