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

Medical Conditions Causing Elevated RBCs and WBCs with Normal Platelets

The combination of elevated red blood cells and white blood cells with normal platelet counts most commonly suggests Adult-Onset Still's Disease (AOSD), secondary polycythemia with concurrent infection or inflammation, or a myeloproliferative disorder in transition, though the specific pattern requires systematic evaluation to distinguish between inflammatory, hypoxic, and primary bone marrow causes.

Primary Inflammatory Conditions

Adult-Onset Still's Disease (AOSD)

AOSD characteristically presents with marked leukocytosis (often >15-20 × 10⁹/L) due to neutrophilia, along with anemia of chronic disease that may mask concurrent processes, and reactive thrombocytosis—though normal platelet counts can occur. 1

• In AOSD, 50% of patients demonstrate peripheral leukocyte counts >15 × 10⁹/L, with 37% exceeding 20 × 10⁹/L, resulting from striking neutrophilia secondary to bone marrow granulocyte hyperplasia 1
• While reactive thrombocytosis is common in AOSD, normal platelet counts do not exclude the diagnosis, particularly in early or less active disease 1
• Anemia of chronic disease typically accompanies active AOSD, but if the patient has concurrent erythrocytosis from another cause (such as smoking or hypoxia), the typical anemia may be absent 1
• Additional diagnostic features include extremely elevated ferritin levels (4,000-250,000 ng/mL), elevated ESR and CRP, fever, characteristic salmon-pink rash, and arthritis 1

Myeloproliferative Disorders

Polycythemia Vera (PV)

Polycythemia vera can present with isolated erythrocytosis initially, but frequently evolves to include leukocytosis and eventually thrombocytosis as the disease progresses. 1, 2

• PV diagnosis requires either both major criteria (hemoglobin >18.5 g/dL in men or >16.5 g/dL in women AND JAK2 mutation) plus one minor criterion, OR the first major criterion plus two minor criteria 1, 2
• JAK2 mutation testing (both exon 14 V617F and exon 12) is essential, as up to 97% of PV cases carry this mutation 2
• Leukocytosis in PV results from clonal proliferation affecting multiple cell lines, though platelet elevation may lag behind RBC and WBC increases 1
• The absence of thrombocytosis does not exclude PV, particularly in early disease or when concurrent conditions suppress platelet production 1

Transitional Myeloproliferative States

• Patients may present with elevation of two cell lines before developing pan-myeloproliferation 1
• Bone marrow examination is critical to assess for proliferation patterns, megakaryocyte morphology, and reticulin fibrosis that would suggest myelofibrosis 1

Secondary Polycythemia with Concurrent Inflammatory/Infectious Processes

Hypoxia-Driven Erythrocytosis with Infection

Secondary causes of erythrocytosis (chronic hypoxia from smoking, COPD, sleep apnea, or cyanotic heart disease) can coexist with acute or chronic infections that drive leukocytosis. 2, 3

• Smoking causes "smoker's polycythemia" through chronic carbon monoxide exposure stimulating erythropoietin production, while concurrent chronic bronchitis drives persistent leukocytosis 2
• Obstructive sleep apnea produces nocturnal hypoxemia driving erythropoietin production, and patients often have concurrent upper respiratory infections or inflammatory conditions 2
• Cyanotic congenital heart disease results in compensatory erythrocytosis to optimize oxygen transport, and these patients are prone to recurrent infections 2
• COPD patients develop both hypoxia-driven erythrocytosis and chronic inflammatory leukocytosis 2

Stress-Induced Leukocytosis with Underlying Erythrocytosis

• Physical stress (surgery, trauma, exercise) or emotional stress can double the peripheral WBC count within hours due to demargination from bone marrow storage pools 3, 4
• If the patient has underlying erythrocytosis from any cause, acute stress-induced leukocytosis will create the pattern of elevated RBCs and WBCs with normal platelets 3, 4

Medication and Toxin-Related Causes

Testosterone Therapy or Abuse

Testosterone use causes dose-dependent erythrocytosis through direct stimulation of erythropoiesis, and can be associated with leukocytosis, particularly in the context of supraphysiologic dosing. 2

• Testosterone-induced erythrocytosis requires dose adjustment or temporary discontinuation when hematocrit exceeds 54%, with close monitoring 2
• This should be specifically considered in young adults with unexplained erythrocytosis and leukocytosis 2

Corticosteroid Use

• Corticosteroids commonly cause leukocytosis through demargination of neutrophils and can mask anemia, potentially revealing underlying erythrocytosis 3, 4
• Lithium therapy is associated with persistent leukocytosis 4

Diagnostic Algorithm

Initial Laboratory Evaluation

Order complete blood count with differential, reticulocyte count, peripheral blood smear review by a qualified hematologist, serum ferritin, transferrin saturation, CRP, and erythropoietin level. 2, 3

• Confirm true erythrocytosis by documenting hemoglobin >18.5 g/dL in men or >16.5 g/dL in women, or hematocrit >55% in men or >49.5% in women on repeated measurements 2
• Assess the WBC differential to determine if leukocytosis is neutrophilic (suggesting infection, inflammation, or myeloproliferation) versus lymphocytic (suggesting viral illness or CLL) 3, 4
• Peripheral smear review is paramount to identify abnormal cell morphology, left shift, toxic granulations, or dysplastic features 2, 3
• Elevated ferritin (particularly >1,000 ng/mL) with concurrent leukocytosis and fever strongly suggests AOSD 1

JAK2 Mutation Testing

• Test for JAK2 V617F and exon 12 mutations if PV is suspected based on persistent erythrocytosis 1, 2
• Positive JAK2 mutation with elevated hemoglobin/hematocrit confirms PV diagnosis and warrants immediate hematology referral 2

Evaluation for Secondary Causes

If JAK2 is negative, systematically evaluate for hypoxic and non-hypoxic secondary causes of erythrocytosis while investigating infectious or inflammatory sources of leukocytosis. 2, 3

• Obtain detailed smoking history and consider carbon monoxide level measurement 2
• Perform sleep study if nocturnal hypoxemia is suspected based on history of snoring, daytime somnolence, or obesity 2
• Evaluate for chronic lung disease with pulmonary function tests and arterial blood gas if clinically indicated 2
• Screen for cyanotic congenital heart disease with echocardiography if suggested by examination or history 2
• Measure erythropoietin level: low or inappropriately normal suggests PV, while elevated levels suggest secondary polycythemia 2
• Consider imaging (renal ultrasound, abdominal CT) to evaluate for erythropoietin-secreting tumors (renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma) if erythropoietin is elevated without clear hypoxic cause 2

Assessment for Inflammatory Conditions

• If ferritin is markedly elevated (>1,000 ng/mL) with fever, rash, arthralgia, or sore throat, strongly consider AOSD and measure additional inflammatory markers 1
• Evaluate for other autoimmune conditions (SLE, rheumatoid arthritis) with appropriate serologic testing if clinically suggested 1, 5
• Consider HIV and hepatitis C testing, as these infections can cause complex hematologic abnormalities 1

Bone Marrow Examination Indications

Perform bone marrow aspirate and biopsy with flow cytometry if: age >60 years, systemic symptoms present, JAK2 negative with unexplained persistent elevations, or if splenectomy is being considered. 1

• Bone marrow examination helps differentiate between reactive processes, myeloproliferative disorders, and early myelodysplastic syndromes 1
• Flow cytometry can identify occult lymphoproliferative disorders (CLL) that may present with cytopenias or cytoses 1

Critical Management Considerations

When to Refer to Hematology

Immediate hematology referral is indicated for: positive JAK2 mutation, hemoglobin >20 g/dL with symptoms of hyperviscosity, unexplained splenomegaly, or WBC count >100 × 10⁹/L. 2, 4

• WBC counts >100 × 10⁹/L represent a medical emergency due to risk of brain infarction and hemorrhage from leukostasis 4
• Therapeutic phlebotomy is indicated only when hemoglobin >20 g/dL and hematocrit >65% with symptoms of hyperviscosity, after excluding dehydration 2

Common Pitfalls to Avoid

• Do not assume isolated erythrocytosis excludes PV—the disease can present with sequential elevation of cell lines rather than simultaneous pan-myeloproliferation 1
• Do not overlook coexisting iron deficiency in erythrocytosis—iron-deficient RBCs have reduced oxygen-carrying capacity and deformability, increasing stroke risk 2
• Do not perform aggressive phlebotomy without volume replacement—this causes further hemoconcentration and increases thrombotic risk 2
• Do not ignore the possibility of AOSD in patients with marked leukocytosis and fever—extremely elevated ferritin levels (>5,000 ng/mL) are highly suggestive 1
• Do not use standard PV diagnostic thresholds at high altitude without adjustment—physiologic adaptation can increase hemoglobin by 0.2-4.5 g/dL depending on elevation 2

Treatment Principles

• For confirmed PV, maintain hematocrit strictly <45% through phlebotomy to reduce thrombotic risk, and initiate low-dose aspirin (81-100 mg daily) 2
• For secondary erythrocytosis, treat the underlying condition: smoking cessation, CPAP for sleep apnea, management of COPD, or testosterone dose adjustment 2
• For AOSD, treatment typically involves corticosteroids, with consideration of immunosuppressive agents for refractory disease 1
• If infection is identified as the cause of leukocytosis, appropriate antimicrobial therapy should resolve the WBC elevation 3, 4