What are the other causes of thrombocytosis beyond Chronic Obstructive Pulmonary Disease (COPD)?

Causes of Thrombocytosis Beyond COPD

Thrombocytosis is predominantly a secondary phenomenon, with tissue injury, infection, chronic inflammatory disorders, and iron deficiency anemia representing the major causes, while primary myeloproliferative neoplasms account for only 12.5% of cases. 1

Primary Thrombocytosis (12.5% of cases)

Myeloproliferative Neoplasms:

• Essential thrombocythemia is the most common primary cause, with 86% of primary thrombocytosis patients having at least one molecular marker (JAK2V617F, CALR, or MPL mutations) indicative of myeloproliferative neoplasms 1, 2
• Polycythemia vera frequently presents with thrombocytosis, though approximately half of patients display this finding 3
• Primary myelofibrosis can manifest with elevated platelet counts 2
• Chronic myeloid leukemia and other myeloproliferative disorders less commonly present with thrombocytosis 3, 2

Key distinguishing features: Primary thrombocytosis demonstrates significantly higher median platelet counts and increased incidence of thrombosis compared to secondary causes 1. Patients with essential thrombocythemia are more likely to have extreme thrombocytosis (>800 × 10⁹/L) and prolonged elevation (>1 month) 4.

Secondary Thrombocytosis (83.1% of cases)

Tissue Injury and Inflammation (32.2% of secondary cases)

Acute tissue damage:

• Post-surgical states, particularly major orthopedic or abdominal procedures 1
• Trauma with significant tissue destruction 1
• Burns 1

Chronic inflammatory conditions (11.7% of secondary cases):

• Inflammatory bowel disease (Crohn's disease, ulcerative colitis) 1, 5
• Rheumatoid arthritis and other connective tissue diseases 1, 5
• Vasculitis 1

Infectious Causes (17.1% of secondary cases)

Infection represents nearly half of all secondary thrombocytosis cases in hospitalized patients 4:

• Bacterial infections: pneumonia, urinary tract infections, osteomyelitis, abscess formation 1, 4
• Viral infections 1
• Fungal infections in immunocompromised hosts 4

Clinical clues suggesting infectious etiology: fever, tachycardia, weight loss, hypoalbuminemia, neutrophilia, leukocytosis, and anemia 4. Demographic risk factors include inpatient status, quadriplegia/paraplegia, indwelling prostheses, dementia, and diabetes 4.

Important prognostic note: Patients with infection-related thrombocytosis demonstrate more rapid platelet count normalization but higher mortality risk than those with non-infectious secondary causes 4.

Hematologic Causes

Iron deficiency anemia (11.1% of secondary cases):

• Chronic iron deficiency is a well-established cause of reactive thrombocytosis 1, 5
• Clinical predictors include lower MCV, lower ferritin, and microcytic anemia 5

Hemolytic anemia:

• Chronic hemolysis can trigger reactive thrombocytosis 1

Post-hemorrhagic states:

• Acute or chronic blood loss stimulates platelet production 6

Anatomic and Surgical Causes

Splenectomy or functional asplenia:

• Surgical splenectomy causes persistent thrombocytosis due to loss of splenic platelet sequestration 6, 5
• Congenital isolated spleen agenesis can mimic essential thrombocythemia; Howell-Jolly bodies on peripheral smear and abdominal ultrasonography are diagnostic 6
• Functional asplenia from sickle cell disease or other conditions 6

Malignancy-Associated Thrombocytosis

Active malignancy is strongly associated with secondary thrombocytosis 5:

• Solid tumors: lung, gastrointestinal, ovarian, renal cell carcinoma 1, 5
• Lymphoproliferative disorders 3, 1
• Mechanism involves cytokine production (IL-6, thrombopoietin) by tumor cells 1

Cardiovascular and Pulmonary Causes

Cyanotic congenital heart disease:

• Thrombocytopenia is more common, but mild thrombocytosis (100,000-150,000/μL) can occur due to polycythemia and hyperviscosity triggering platelet consumption, with platelet counts inversely correlating with hematocrit 3

Pulmonary hypertension:

• Chronic myeloproliferative disorders are listed among causes of pulmonary arterial hypertension, though thrombocytosis is a feature rather than cause 3

Medication and Toxin-Related

Drug-induced thrombocytosis:

• All-trans retinoic acid (ATRA) therapy 1
• Epinephrine and other catecholamines (transient) 1
• Minocycline 1

Diagnostic Algorithm to Differentiate Primary from Secondary Thrombocytosis

Step 1: Assess clinical context 5

• Favor secondary causes if: active malignancy, chronic inflammatory disease, recent surgery/trauma, splenectomy, iron deficiency, acute infection, or indwelling prostheses present
• Favor primary causes if: history of arterial thrombosis, absence of inflammatory conditions

Step 2: Evaluate laboratory parameters 5

• Favor essential thrombocythemia if: higher hemoglobin, higher MCV, elevated RDW, increased MPV, platelet count >800 × 10⁹/L, duration >1 month
• Favor secondary thrombocytosis if: higher BMI, leukocytosis, neutrophilia, anemia, hypoalbuminemia, low ferritin

Step 3: Examine peripheral blood smear 6, 5

• Look for Howell-Jolly bodies (suggests asplenia/hyposplenia)
• Assess for microcytosis (iron deficiency)
• Evaluate for abnormal white cells or red cell fragments

Step 4: Molecular testing indications 5

• Reserve JAK2V617F, CALR, and MPL mutation testing for patients WITHOUT clear secondary causes
• Overall yield of molecular testing is 52.4%, with 92.1% being JAK2, CALR, or MPL mutations 5
• Avoid costly molecular testing when clinical and laboratory features strongly suggest secondary thrombocytosis 5

Step 5: Bone marrow evaluation 2

• Required when molecular markers are negative but clinical suspicion for myeloproliferative neoplasm remains high
• Essential for distinguishing among different myeloproliferative disorders 2

Critical Pitfalls to Avoid

Do not assume thrombocytosis is benign: While secondary thrombocytosis is more common, missing primary thrombocytosis increases thrombotic risk significantly 1, 2.

Do not overlook infection as a cause: Infection accounts for nearly half of secondary thrombocytosis in hospitalized patients and carries higher mortality 4.

Do not forget to check for asplenia: Congenital spleen agenesis can perfectly mimic essential thrombocythemia; always verify spleen presence on imaging when splenomegaly is absent 6.

Do not order molecular testing reflexively: A practical clinical approach identifying secondary causes (malignancy, inflammation, iron deficiency, splenectomy) reduces unnecessary expensive testing 5.

Do not ignore iron deficiency: Even with elevated platelets, iron deficiency anemia accounts for 11.1% of secondary thrombocytosis and requires specific treatment 1, 5.