Recommendation grades (A-C) and levels of evidence (Ia-IV) are defined at the end of the "Major Recommendations" field.
Diagnosis of Erythrocytosis
Patients with a persistently raised venous haematocrit (Hct) (>0.52 males, >0.48 females for >2 months) should, in general, be investigated by measurement of their red cell mass (RCM).
Red Cell Mass and Terminology
- Red cell mass (RCM) should be expressed in relation to surface area as recommended by the International Committee for Standardisation in Haematology (ICSH).
- The term 'relative erythrocytosis' should be reserved for states of dehydration.
- Apparent erythrocytosis should be used for those individuals who have a raised venous haematocrit but with a RCM within the reference range.
Investigation of Absolute Erythrocytosis
The classification of absolute erythrocytoses is shown in the table below. Once an absolute erythrocytosis has been confirmed it is desirable to identify the underlying aetiology, although this may not be possible either initially or after prolonged investigation. Nevertheless, the starting point is knowledge of the underlying causes of a secondary erythrocytosis (see table "Classification of the Absolute Erythrocytoses" below) and the diagnostic criteria of polycythaemia vera (PV) (see table "Modified Diagnostic Criteria for Polycythaemia Vera" below). Frequently, it can be difficult to prove conclusively that an erythrocytosis is either secondary or primary and dual pathologies resulting in an erythrocytosis should be considered, especially in the elderly.
Primary erythrocytosis
Polycythaemia vera
Secondary erythrocytosis
Congenital
High oxygen-affinity haemoglobin
2,3-Biphosphoglycerate mutase deficiency
Erythropoietin receptor-mediated
Chuvash erythrocytosis (VHL mutation)
Acquired
EPO-mediated
Hypoxia-driven
Central hypoxic process
Chronic lung disease
Right-to-left cardiopulmonary vascular shunts
Carbon monoxide poisoning
Smoker's erythrocytosis
Hypoventilation syndromes including sleep apnoea (high-altitude habitat)
Local renal hypoxia
Renal artery stenosis
End-stage renal disease
Hydronephrosis
Renal cysts (polycystic kidney disease)
Pathologic EPO production
Tumours
Hepatocellular carcinoma
Renal cell cancer
Cerebellar haemangioblastoma
Parathyroid carcinoma/adenomas
Uterine leiomyomas
Pheochromocytoma
Meningioma
Exogenous EPO
Drug associated
Treatment with androgen preparations
Postrenal transplant erythrocytosis
Idiopathic erythrocytosis
|
EPO, erythropoietin
Table: Modified 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)* |
| A2 |
Mutation in JAK2 |
| Diagnosis requires both criteria to be present |
| JAK2-negative polycythaemia vera |
| A1 |
Raised red cell mass (>25% above predicted) OR haematocrit >0.60 in men, >0.56 in women. |
| A2 |
Absence of mutation in JAK2 |
| A3 |
No cause of secondary erythrocytosis |
| A4 |
Palpable splenomegaly |
| A5 |
Presence of an acquired genetic abnormality (excluding BCR-ABL) in the haematopoietic cells |
| B1 |
Thrombocytosis (platelet count >450 × 109/liter) |
| B2 |
Neutrophil leucocytosis (neutrophil count >10 × 109/liter in non-smokers; >12.5·× 109/liter in smokers) |
| B3 |
Radiological evidence of splenomegaly |
| B4 |
Endogenous erythroid colonies or low serum erythropoietin |
| Diagnosis requires A1 + A2 + A3 + either another A or two B criteria |
*Dual pathology (co-existent secondary erythrocytosis or relative erythrocytosis) may rarely be present in patients with a JAK2-positive myeloproliferative disorder. In this situation, it would be prudent to reduce the haematocrit to the same target as for polycythaemia vera.
The diagnostic criteria will alter the number and sequence in which investigations need to be carried out. Start with a thorough history and examination, to identify most patients with a secondary cause and arrange confirmatory investigations. Then stage 1 initial screening tests will identify those with JAK2-positive clonal disease in whom there is no need to proceed further with further investigations:
Stage 1 Investigations
- History and examination
- Full blood count/film
- JAK2 mutation
- Serum ferritin
- Renal and liver function tests
Stage 2 Investigations
If the initial screening tests are negative for a JAK2 mutation and there is no obvious secondary cause then further investigations are indicated. A red cell mass is required first and if an absolute erythrocytosis is confirmed then the following tests are appropriate.
- Red cell mass
- Arterial oxygen saturation
- Abdominal ultrasound
- Serum erythropoietin level
- Bone marrow aspirate and trephine
- Cytogenetic analysis
- Erythroid burst-forming unit (BFU-E) culture
Stage 3 Investigations
For those patients who do not fulfil either set of criteria and who have erythrocytosis there are a number of specialised tests that may need to be considered. Some of these are listed below.
- Arterial oxygen dissociation
- Sleep study
- Lung function studies
- Gene mutations EPOR, VHL, EGLN1 (also known as PHD2)
Management of Polycythaemia Vera
The aims of treatment of PV are to:
- Reduce the risk of thrombosis and haemorrhage
- Minimise the risk of transformation to acute leukaemia and myelofibrosis
- Manage complications which may occur including thrombosis, haemorrhage and pruritus
- Manage pregnancy
Thrombotic Complications
Assessing Risk of Thrombosis
Pregnancy and Polycythaemia Vera
An overview of the literature does not enable confident management guidelines to be drawn up. These recommendations are based on current knowledge of PV, essential thrombocythaemia (ET) and the management of antiphospholipid syndrome, which all have placental dysfunction as a common pathogenic feature. Therapeutic strategies for PV in pregnancy are influenced by the patients' disease status and prior obstetric history. If any of the following factors are present, then the pregnancy is likely to be at high risk of complication to the mother and/or fetus:
- Previous venous or arterial thrombosis in mother (whether pregnant or not)
- Previous haemorrhage attributed to PV (whether pregnant or not)
- Previous pregnancy complication that may have been caused by PV; e.g.
- >3 first trimester or >1 second or third trimester pregnancy loss
- Birthweight <5th centile for gestation
- Intrauterine death or still birth (with no obvious other cause, evidence of placental dysfunction and growth restricted fetus)
- Significant ante- or postpartum haemorrhage (requiring red cell transfusion)
- Severe pre-eclampsia (necessitating preterm delivery <37 weeks) or development of any such complication in the index pregnancy
- Platelet count rising to >1000 X 109/l
Therapeutic options include antithrombotic treatment, venesection and cytoreductive agents, although the expected natural fall of the platelet count and Hct during pregnancy may anyway obviate or reduce the need for the latter. The Hct could be controlled with either careful venesection or cytoreductive therapy. The target Hct for a non-pregnant female has yet to be determined, but in pregnancy the Hct should be maintained within the normal range appropriate for gestation. There is currently no evidence for maintaining Hct less than this in pregnancy.
Cytoreduction should be avoided in pregnancy, particularly in the first trimester. None of the cytoreductive agents have a product licence for use in pregnancy. Where cytoreduction is deemed necessary (see above), IFN-alpha is the drug of choice.
Anagrelide is not recommended because of insufficient documentation of its use in pregnancy. Hydroxycarbamide or anagrelide should be gradually withdrawn 3 to 6 months prior to conception and IFN-alpha may be substituted if necessary.
The guideline authors recommend that, in the absence of clear contraindications, all patients should be on aspirin (initially 75 mg once daily) throughout the pregnancy and for 6 weeks after delivery (Grade C recommendation, Evidence level IV).
If the patient has had a previous venous or arterial thrombosis, then the use of low-molecular-weight heparin (LMWH) thromboprophylaxis is indicated during pregnancy. Use of unmonitored intermediate dose LMWH is widely used (e.g., enoxaparin 40 mg once daily) increased to 40 mg twice daily from 16 weeks, dropping to 40 mg/d for 6 weeks postpartum).
During the pregnancy the patient should be monitored regularly and management is summarised in Fig 1 of the original guideline document. It is important to discuss the implications of the use of thromboprophylaxis with the obstetric anaesthetist for epidural or spinal anaesthesia. During labour, dehydration should be avoided, attention should be given to the LMWH dose and the use of graded elastic compression stockings (GECS) should be considered. In the puerperium, the guideline authors recommend thromboprophylaxis with 6 weeks LMWH for all women with myeloproliferative disorders (MPD). Breast feeding is safe with heparin and warfarin (providing baby receives adequate vitamin K). Breast feeding is contra-indicated with the cytoreductive agents (IFN-alpha, anagrelide and hydroxycarbamide). The first 6 weeks postpartum are a high risk time for venous thrombosis; blood counts may rise rapidly, thus on-going haematological monitoring is important.
Apparent Erythrocytosis
Management of Apparent Erythrocytosis
- Confirm that the elevated Hct is persistent, with at least two measurements of the Hct under standardised conditions over a 3-month period.
- Advise reduction or elimination of factors which may contribute to apparent erythrocytosis (e.g., a reduction in smoking and alcohol intake and control of hypertension [without the use of a thiazide diuretic]).
- Consider venesection in the following circumstances:
- Patients with a recent history of thrombosis, or with additional risk factors for thrombosis.
- Patients whose Hct exceeds 0.54 (>3 standard deviations above the mean), based on the increased risk of thrombosis in idiopathic erythrocytosis and low incidence of normal individuals with a Hct >0.54.
- Untreated patients should be monitored to exclude a further rise in Hct and possible evolution to absolute erythrocytosis.
There is no data on which to base a target Hct for patients undergoing venesection, but a Hct <0.45 has been proposed based on data from patients with PV and idiopathic erythrocytosis (Pearson, 1991).
Grade C recommendation: Evidence level IV.
Idiopathic Erythrocytosis
High Oxygen Affinity Haemoglobins
Hypoxia
Hypoxic Pulmonary Disease (HPD)
- Patients with HPD who develop an erythrocytosis should be evaluated by a respiratory physician for consideration of long-term oxygen therapy or alternative therapy (Grade A recommendation: Evidence level 1A).
- Patients who are symptomatic of hyperviscosity or have a Hct >0.56 should have venesection to reduce this to 0.50 to 0.52 (Grade B recommendation: Evidence level III).
- There is limited evidence to suggest that therapy with drugs such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists could be used in patients who do not tolerate venesection (Grade B recommendation: Evidence level IIa)
Cyanotic Congenital Heart Disease (CCHD)
- Patients with CCHD and an erythrocytosis represent a complex management problem and should be managed primarily in a congenital heart disease unit so that advances in surgery, catheter interventional and medical management that may improve (rarely cure) the erythrocytosis are not missed. (Grade C recommendation: Evidence level IV)
- Isovolumic venesection should be performed when the patient has symptoms of hyperviscosity but no general target Hct can be suggested and treatment should be individualised (Grade B recommendation: Evidence level III).
- Excessive venesection may produce iron deficiency, which may compromise oxygen delivery and raise the viscosity for a given level of haemoglobin thereby causing a recurrence of symptoms. Iron therapy in this setting should be used judiciously as it may provoke a rapid rise in Hct (Grade B recommendation: Evidence level III).
Postrenal Transplant Erythrocytosis
Definitions:
Classification of Evidence Levels
Ia: Evidence obtained from meta-analysis of randomised controlled trials
Ib: Evidence obtained from at least one randomised controlled trial
IIa: Evidence obtained from at least one well-designed controlled study without randomization
IIb: Evidence obtained from at least one other type of well-designed quasi-experimental study*
III: Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case studies
IV: Evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities
Classification of Grades of Recommendations
Grade A: Requires at least one randomised controlled trial as part of a body of literature of overall good quality and consistency addressing specific recommendation (evidence levels Ia, Ib)
Grade B: Requires the availability of well conducted clinical studies but no randomised clinical trials on the topic of recommendation (evidence levels IIa, IIb, III)
Grade C: Requires evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality (evidence level IV)
*Refers to a situation in which implementation of an intervention is out of the control of the investigators, but an opportunity exists to evaluate its effect.
