What medical conditions can cause elevated white blood cells (WBCs) and red blood cells (RBCs) with normal platelet count?

Elevated WBC and RBC with Normal Platelets: Differential Diagnosis

The most critical diagnosis to exclude is polycythemia vera (PV), a clonal myeloproliferative disorder that characteristically elevates both red and white blood cells, though it typically also elevates platelets—making isolated WBC/RBC elevation with normal platelets an atypical presentation that warrants urgent hematology evaluation. 1, 2, 3

Primary Consideration: Hemoconcentration

Volume depletion is the most common cause of concurrent WBC and RBC elevation, as plasma volume contraction concentrates both cell lines simultaneously. 4 This occurs with:

• Dehydration from any etiology (vomiting, diarrhea, inadequate intake, fever) 4
• Diuretic use causing iatrogenic volume depletion 4
• Infection with volume depletion, where bacterial infection drives leukocytosis while concurrent fluid losses concentrate RBCs 4

Key diagnostic maneuver: Repeat CBC after adequate hydration—if elevations resolve, hemoconcentration was the cause. 4

Myeloproliferative Neoplasm: Polycythemia Vera

PV must be excluded urgently when both cell lines are elevated, even with normal platelets. 2, 3 While PV classically presents with trilineage proliferation (elevated RBC, WBC, and platelets), approximately 50% of patients show leukocytosis or thrombocytosis at presentation, meaning isolated RBC/WBC elevation can occur. 1

Diagnostic criteria for PV:

• JAK2V617F mutation present in >95% of cases 3
• Hemoglobin >18.5 g/dL (men) or >16.5 g/dL (women) with concurrent WBC elevation 3
• Subnormal serum erythropoietin level distinguishes from secondary polycythemia 3
• Bone marrow showing trilineage myeloproliferation 3

Red flags mandating hematology referral: 2, 3, 5

• Persistent elevation after rehydration
• Splenomegaly (moderate or massive)
• Constitutional symptoms (fever, weight loss, night sweats)
• Pruritus, especially after warm baths
• Thrombotic events (hepatic, portal, mesenteric vein thrombosis; erythromelalgia) 1, 6

Secondary Polycythemia with Reactive Leukocytosis

Chronic hypoxic conditions causing true polycythemia plus inflammatory leukocytosis:

• Chronic obstructive pulmonary disease (COPD): Chronic hypoxia drives erythropoietin-mediated RBC production while chronic inflammation elevates WBC 2
• Cyanotic congenital heart disease: Compensatory erythrocytosis with concurrent reactive leukocytosis from chronic hypoxemia 3
• Chronic smoking: Causes true polycythemia from carbon monoxide exposure AND persistent leukocytosis 1, 2

Distinguishing features from PV: 3

• Normal or elevated erythropoietin levels (not suppressed)
• Absence of JAK2V617F mutation
• Clinical context of chronic lung/heart disease

Infection-Driven Elevations

Bacterial infection is the leading cause of leukocytosis and should be systematically evaluated. 4, 2 When combined with volume depletion from infection, RBCs become concentrated:

Diagnostic markers of bacterial infection:

• Absolute band count ≥1,500 cells/mm³ 4
• Neutrophil percentage >90% 4
• Left shift ≥16% bands 4

Common bacterial sources to evaluate: 4

• Respiratory tract infections (pneumonia, bronchitis)
• Urinary tract infections
• Skin/soft tissue infections
• Gastrointestinal infections

Medication-Induced Causes

• Corticosteroid therapy: Causes neutrophilic leukocytosis and can unmask or exacerbate underlying polycythemia 2, 5
• Lithium therapy: Consistently causes leukocytosis (WBC <4,000/mm³ would be unusual on lithium) 2, 5

Critical Diagnostic Algorithm

Step 1: Obtain complete blood count with manual differential

• Assess absolute neutrophil count, band forms (left shift), and RBC indices 2
• Review peripheral blood smear for abnormal cells, toxic granulations, or immature forms 7, 5

Step 2: Assess clinical context systematically

• Fever, localizing symptoms, signs of sepsis suggest infection 4, 2
• Volume status assessment (orthostatic vitals, mucous membranes, skin turgor) 4
• Medication review (corticosteroids, lithium) 2, 5
• Smoking history and chronic lung/heart disease 2

Step 3: Site-specific evaluation if infection suspected

• Blood cultures if fever or sepsis present 4
• Chest X-ray for respiratory symptoms 4
• Urinalysis and culture for urinary symptoms 4

Step 4: Repeat CBC after hydration

• If elevations resolve: Hemoconcentration was the cause 4
• If elevations persist: Proceed to Step 5 2

Step 5: Evaluate for polycythemia vera

• JAK2V617F mutation testing (present in >95% of PV) 3
• Serum erythropoietin level (suppressed in PV, normal/elevated in secondary) 3
• Oxygen saturation and arterial blood gas (to exclude hypoxic drive) 1

Step 6: Urgent hematology referral if:

• JAK2V617F mutation positive 3
• Splenomegaly on examination 3, 6
• Constitutional symptoms present 3, 5
• Unexplained persistent elevation after excluding infection and hemoconcentration 2, 5
• WBC >100,000/mm³ (medical emergency due to hyperviscosity risk) 5

Common Pitfalls to Avoid

Do not assume dehydration alone without considering primary bone marrow disorders, especially if elevation persists after rehydration. 2 PV is a clonal disorder requiring specific treatment (phlebotomy, cytoreductive therapy) and carries significant thrombotic risk if untreated. 1, 3, 6

Do not overlook PV when platelets are normal—while trilineage proliferation is classic, isolated RBC/WBC elevation can occur early in disease course. 1

Do not delay hematology referral in patients with extreme leukocytosis (WBC >100,000/mm³), as this represents a medical emergency due to risk of brain infarction and hemorrhage from hyperviscosity. 5