What are the diagnostic criteria and treatment options for primary erythrocytosis in females?

Diagnostic Criteria for Primary Erythrocytosis in Females

The diagnosis of primary erythrocytosis (polycythemia vera) in females requires either meeting all 3 major criteria, or the first 2 major criteria and the minor criterion, with specific hemoglobin/hematocrit thresholds that are lower for women than men. 1

Diagnostic Criteria for Polycythemia Vera in Females

Major Criteria

1. Elevated red cell parameters (one of the following):

   • Hemoglobin >16.0 g/dL in women
   • Hematocrit >48% in women
   • Increased red cell mass (>25% above mean normal predicted value)

2. Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes

3. Presence of JAK2 V617F or JAK2 exon 12 mutation

Minor Criterion

• Subnormal serum erythropoietin level

Diagnostic Algorithm

1. Initial laboratory evaluation:

   • Complete blood count with peripheral smear
   • JAK2 V617F mutation testing (present in >95% of PV cases)
   • Serum erythropoietin level

2. If JAK2 V617F is negative but PV still suspected:

   • Test for JAK2 exon 12 mutations

3. Bone marrow examination:

   • While criterion #2 (bone marrow biopsy) may not be required in cases with sustained absolute erythrocytosis if major criterion #3 and the minor criterion are present, it is important to note that initial myelofibrosis (present in up to 20% of patients) can only be detected by performing a bone marrow biopsy 1
   • This finding may predict more rapid progression to overt myelofibrosis (post-PV MF)

4. Rule out secondary causes of erythrocytosis:

   • Hypoxia-driven causes (pulmonary disease, high altitude, smoking, sleep apnea)
   • Non-hypoxia-driven causes (renal cell carcinoma, uterine leiomyoma, pheochromocytoma)
   • Relative polycythemia (dehydration, diuretic use)

Important Considerations Specific to Females

1. Lower diagnostic thresholds: The hemoglobin threshold for diagnosing PV in females (>16.0 g/dL) is lower than in males (>16.5 g/dL) 1

2. Masked PV: Iron deficiency, which is more common in women of reproductive age, can normalize hemoglobin levels in PV, leading to "masked PV" 2

   • Consider PV in women with unexplained iron deficiency, especially with thrombotic events

3. Unusual site thrombosis: Splanchnic vein thrombosis or other unusual site thromboses should raise suspicion for PV in women, even with normal or borderline hemoglobin levels 2

4. Reproductive considerations: Women of childbearing age with PV require special consideration regarding pregnancy planning and management

Common Pitfalls in Diagnosis

1. Overlooking masked PV: Iron deficiency can normalize hemoglobin in PV, particularly relevant in women with menstrual blood loss 2

2. Misattributing to secondary causes: Thoroughly investigate before attributing erythrocytosis to common conditions like smoking or sleep apnea

3. Using outdated diagnostic criteria: The WHO criteria have evolved over time, with the most recent updates lowering the hemoglobin threshold for women to >16.0 g/dL 1

4. Neglecting bone marrow examination: While not always required, bone marrow biopsy provides valuable diagnostic and prognostic information 1

5. Failing to test for JAK2 mutations: JAK2 testing should be performed in all suspected cases, as it is present in >95% of PV cases 1

Evolution of Diagnostic Criteria

The diagnostic criteria for PV have evolved significantly over time:

• The 2008 WHO classification established the current framework with sex-specific hemoglobin thresholds 1
• The 2016 WHO revision maintained these thresholds while emphasizing the role of JAK2 mutations 1

By following these diagnostic criteria and being aware of the specific considerations for females, clinicians can accurately diagnose primary erythrocytosis in female patients and initiate appropriate management to reduce morbidity and mortality from thrombotic events and disease progression.