What conditions are associated with elevated white blood cell (WBC) count and elevated red blood cell (RBC) count?

Conditions Associated with Concurrent Elevation of WBC and RBC Counts

The most important condition to consider when both white blood cell (WBC) and red blood cell (RBC) counts are elevated is polycythemia vera, a myeloproliferative neoplasm characterized by JAK2 mutation-driven trilineage proliferation affecting red cells, white cells, and platelets. 1

Primary Myeloproliferative Neoplasm: Polycythemia Vera

Polycythemia vera is the classic disease presenting with concurrent elevation of both WBC and RBC counts, diagnosed by the presence of JAK2V617F mutation (present in >95% of cases) and characteristic bone marrow trilineage myeloproliferation. 1

Diagnostic Criteria

• Hemoglobin elevation >18.5 g/dL in men or >16.5 g/dL in women with concurrent WBC elevation is characteristic of polycythemia vera. 1
• The World Health Organization requires either both major criteria plus one minor criterion, or the first major criterion plus two minor criteria: JAK2V617F or JAK2 exon 12 mutation, bone marrow trilineage myeloproliferation, subnormal serum erythropoietin level, and endogenous erythroid colony growth. 1
• The JAK2V617F mutation is a major diagnostic criterion and is associated with increased risk of thrombotic events. 1

Clinical Significance of Elevated WBC in Polycythemia Vera

• Elevated WBC count >11 × 10⁹/L in polycythemia vera significantly increases thrombotic event risk (hazard ratio 2.35), independent of hematocrit control. 2
• Even when hematocrit is controlled at ≤45%, WBC count >12 × 10⁹/L remains significantly associated with thrombotic events (hazard ratio 1.95). 2
• The European Society for Medical Oncology recommends cytoreductive therapy with hydroxyurea when WBC >12 × 10⁹/L, even with controlled hematocrit, to reduce thrombotic risk. 1

Secondary Polycythemia with Reactive Leukocytosis

Secondary polycythemia can present with concurrent WBC elevation due to reactive leukocytosis from chronic hypoxemia and inflammation, particularly in cyanotic congenital heart disease. 1

Distinguishing Features

• Secondary polycythemia is distinguished from polycythemia vera by normal or elevated erythropoietin levels and absence of JAK2 mutation. 1
• The American Heart Association recommends evaluating cyanotic congenital heart disease for compensatory erythrocytosis with concurrent reactive leukocytosis. 1
• Chronic hypoxemia from any cause (chronic lung disease, high altitude, sleep apnea) can produce this pattern. 1

Chronic Myeloid Leukemia vs. Leukemoid Reaction

Chronic myeloid leukemia must be distinguished from leukemoid reaction when both WBC and RBC counts are elevated, based on Philadelphia chromosome t(9;22) and BCR-ABL transcripts. 1

Key Distinguishing Features

• Chronic myeloid leukemia is characterized by Philadelphia chromosome, BCR-ABL transcripts, basophilia, and bone marrow hypercellularity with granulocytic proliferation. 1
• Leukemoid reaction shows mature neutrophils, absence of blasts, and negative Philadelphia chromosome and BCR-ABL. 1
• Primary bone marrow disorders should be suspected when WBC counts are extremely elevated or concurrent abnormalities in RBC or platelet counts exist. 3

Critical Red Flags Requiring Urgent Evaluation

Weight loss, bleeding, bruising, hepatosplenomegaly, or lymphadenopathy with concurrent WBC and RBC elevation mandate immediate hematology referral for suspected malignancy. 4, 3

Emergency Situations

• WBC counts >100,000/mm³ represent a medical emergency due to risk of cerebral infarction and hemorrhage, requiring immediate cytoreductive chemotherapy. 4, 5
• Moderate or massive splenomegaly suggests an alternative cause beyond simple polycythemia vera and requires urgent evaluation. 6

Diagnostic Algorithm for Concurrent Elevations

Initial Evaluation

1. Obtain complete blood count with manual differential to assess all three cell lines (RBC, WBC, platelets) and identify trilineage proliferation. 6, 1
2. Review peripheral blood smear by a qualified hematologist to identify abnormalities inconsistent with polycythemia vera, such as schistocytes or leukocyte inclusion bodies. 6
3. Order JAK2V617F mutation testing as the primary diagnostic test for polycythemia vera. 1
4. Measure serum erythropoietin level to distinguish primary from secondary polycythemia (low in polycythemia vera, normal/elevated in secondary causes). 1

Secondary Testing Based on Initial Results

• If JAK2 mutation is positive with trilineage proliferation: diagnose polycythemia vera and initiate management. 1
• If JAK2 mutation is negative with elevated erythropoietin: evaluate for secondary causes including chronic hypoxemia, cyanotic heart disease, and chronic lung disease. 1
• If basophilia or immature cells are present: order Philadelphia chromosome and BCR-ABL testing to exclude chronic myeloid leukemia. 1
• If constitutional symptoms, splenomegaly, or lymphadenopathy are present: perform bone marrow examination with flow cytometry and cytogenetic testing. 6, 4

Management Approach

For confirmed polycythemia vera with elevated WBC, perform phlebotomy to reduce thrombotic risk and initiate cytoreductive therapy (hydroxyurea) when WBC >12 × 10⁹/L with controlled hematocrit. 1, 2

Specific Management Recommendations

• Target hematocrit ≤45% through phlebotomy to reduce thrombotic events (hazard ratio 1.84 when >45%). 2
• Control WBC count to <12 × 10⁹/L with hydroxyurea, as elevated WBC independently increases thrombotic risk even with controlled hematocrit. 1, 2
• For suspected secondary causes, evaluate and treat underlying chronic hypoxemia, infection, and medications causing leukocytosis, and perform therapeutic phlebotomy with equal volume replacement if hyperviscosity symptoms are present. 1

Common Pitfalls to Avoid

• Do not assume isolated polycythemia vera without checking all three cell lines—trilineage proliferation is the hallmark. 1
• Do not overlook the independent thrombotic risk from elevated WBC in polycythemia vera—both hematocrit and WBC require control. 2
• Do not delay hematology referral when splenomegaly, constitutional symptoms, or extreme leukocytosis (>100,000) are present. 4, 3, 5
• Do not confuse secondary polycythemia with polycythemia vera—erythropoietin levels and JAK2 mutation testing are essential for differentiation. 1