What causes elevated white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin, and hematocrit levels?

Causes of Elevated White Blood Cells, Red Blood Cells, Hemoglobin, and Hematocrit

The simultaneous elevation of both white blood cells and red blood cells (with elevated hemoglobin and hematocrit) most strongly suggests polycythemia vera, a myeloproliferative neoplasm characterized by clonal proliferation affecting multiple cell lines. 1

Primary Cause: Polycythemia Vera

Polycythemia vera is the most important diagnosis to consider when all three cell lines are elevated together, as this combination of findings—elevated WBC, RBC, hemoglobin, and hematocrit—represents a hallmark pattern of this myeloproliferative disorder. 1, 2

Diagnostic Criteria and Testing

• JAK2 mutation testing should be ordered immediately as the first-line diagnostic test, with JAK2V617F found in up to 97% of polycythemia vera cases. 1, 2

• The World Health Organization diagnostic criteria require either:

  • Both major criteria (hemoglobin >16.5 g/dL in women or >18.5 g/dL in men PLUS JAK2 mutation) plus one minor criterion, OR
  • First major criterion plus two minor criteria 1

• Minor criteria include bone marrow hypercellularity with trilineage growth, subnormal erythropoietin level, or endogenous erythroid colony formation. 1

Clinical Features Suggesting Polycythemia Vera

• Splenomegaly is a key physical finding that increases suspicion for primary bone marrow disorder rather than secondary causes. 3, 4

• Aquagenic pruritus (itching after water exposure) and erythromelalgia (burning pain in extremities) are characteristic symptoms that strongly suggest polycythemia vera. 1, 4

• Thrombocytosis and leukocytosis occurring together with elevated hemoglobin/hematocrit are strong indicators for polycythemia vera rather than secondary polycythemia. 4

Secondary Causes of Isolated Erythrocytosis

When WBC elevation is explained by infection or inflammation, the following can cause isolated elevation of RBC/hemoglobin/hematocrit:

Hypoxia-Driven Secondary Polycythemia

• Chronic obstructive pulmonary disease (COPD) causes tissue hypoxia that stimulates erythropoietin production, leading to compensatory erythrocytosis. 1

• Obstructive sleep apnea produces nocturnal hypoxemia that drives erythropoietin production and should be evaluated with sleep study if suspected. 1

• Smoking causes "smoker's polycythemia" through chronic carbon monoxide exposure, which creates tissue hypoxia and stimulates erythropoietin production; this resolves with smoking cessation. 1

• Cyanotic congenital heart disease with right-to-left shunting results in arterial hypoxemia, triggering compensatory erythrocytosis to optimize oxygen transport. 1

• High altitude residence causes physiological increases in hemoglobin levels, with specific adjustments needed based on elevation (e.g., +1.9 g/dL at 3,000 meters). 1

Non-Hypoxic Secondary Causes

• Testosterone therapy or abuse is a common cause of erythrocytosis in young adults and should always be considered in the differential diagnosis. 1

• Erythropoietin-producing tumors including renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma can cause elevated hemoglobin independent of hypoxia. 1

• Exogenous erythropoietin therapy directly causes elevated hemoglobin levels and should be identified in the medication history. 1

Relative Polycythemia (Plasma Volume Depletion)

• Dehydration is the most common cause of elevated hematocrit and should be assessed first by reviewing fluid intake history and recent losses. 2

• Diuretic use can cause plasma volume depletion leading to relative polycythemia without true increase in red cell mass. 1

• Stress polycythemia (Gaisböck syndrome) represents relative polycythemia from reduced plasma volume rather than increased red cell mass. 1

Causes of Isolated Leukocytosis

When RBC elevation is explained by the above causes, WBC elevation may be due to:

Benign Causes

• Infections and inflammatory processes are the most common causes of leukocytosis, typically showing increased polymorphonuclear leukocytes with left shift. 3

• Physical stress from seizures, anesthesia, or overexertion can elevate white blood cell counts. 3

• Emotional stress can also cause transient leukocytosis. 3

• Medications commonly associated with leukocytosis include corticosteroids, lithium, and beta agonists. 3

Serious Causes Requiring Immediate Evaluation

• Primary bone marrow disorders should be suspected when WBC counts are extremely elevated (>100,000/mm³ represents a medical emergency due to risk of brain infarction and hemorrhage). 3

• Concurrent abnormalities in other cell lines (thrombocytopenia, anemia) suggesting multiple cytopenias require immediate hematology referral. 2

• Lymphadenopathy or splenomegaly on examination mandates immediate referral to hematology/oncology. 2

Diagnostic Algorithm

Initial Laboratory Workup

• Complete blood count with red cell indices, reticulocyte count, and manual differential should be ordered immediately to characterize the elevations. 1, 2

• Serum ferritin and transferrin saturation are essential to evaluate iron status, as iron deficiency can coexist with erythrocytosis. 1

• C-reactive protein (CRP) helps identify inflammatory processes that may explain leukocytosis. 1

• Peripheral blood smear review by a qualified hematologist is essential to identify abnormal morphology and assess for left shift. 1, 2

Confirmatory Testing

• Repeat hemoglobin and hematocrit measurements are necessary, as a single measurement is not reliable for establishing diagnosis. 2

• JAK2V617F mutation testing should be ordered as first-line if polycythemia vera is suspected based on the combination of elevated WBC and RBC counts. 1, 2

• JAK2 exon 12 mutation testing should follow if JAK2V617F is negative but suspicion remains high. 2

• Erythropoietin level measurement helps differentiate primary (low EPO) from secondary (high EPO) causes of erythrocytosis. 1

Evaluation for Secondary Causes

• Oxygen saturation measurement and arterial blood gas if hypoxemia is suspected. 1

• Sleep study if nocturnal hypoxemia from obstructive sleep apnea is suspected. 1

• Chest imaging to evaluate for chronic lung disease if clinically indicated. 1

• Medication review specifically for testosterone, erythropoietin, corticosteroids, lithium, and beta agonists. 1, 3

Critical Thresholds and Red Flags

• Hemoglobin >20 g/dL and hematocrit >65% with symptoms of hyperviscosity (headache, visual disturbances, dizziness) requires urgent therapeutic phlebotomy after excluding dehydration. 1

• WBC >100,000/mm³ represents a medical emergency requiring immediate evaluation due to risk of leukostasis. 3

• Elevated total band count (>1500 cells/mm³) has the highest likelihood ratio (14.5) for detecting bacterial infection, even without fever. 2

• Left shift (≥6% band neutrophils) has likelihood ratio of 4.7 for bacterial infection and warrants further investigation. 2

Common Pitfalls to Avoid

• Do not assume dehydration without confirming with clinical assessment, as a near-normal hemoglobin value may actually suggest dehydration masking anemia. 5

• Do not overlook the possibility of coexisting iron deficiency in patients with erythrocytosis, as iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk. 1

• Do not perform aggressive phlebotomy without adequate volume replacement, as this can cause further hemoconcentration. 1

• Do not dismiss borderline elevations (hemoglobin 16.5-18.5 g/dL in men) if there is documented increase above individual baseline or associated features like thrombocytosis, splenomegaly, or aquagenic pruritus. 1

• Do not rely on automated differentials alone—obtain manual differential to assess band forms and immature cells, as automated differentials may miss critical findings. 2

Immediate Referral Indications

• Positive JAK2 mutation requires immediate hematology referral for management of polycythemia vera. 1

• Hemoglobin >20 g/dL with symptoms of hyperviscosity requires urgent hematology consultation. 1

• Unexplained splenomegaly with elevated blood counts mandates hematology evaluation. 1

• Weight loss, bleeding, bruising, or immunosuppression accompanying elevated counts increases suspicion for malignant bone marrow disorder. 3