Continuing Education Activity

Reactive thrombocytosis, defined as an abnormally high platelet count in the absence of chronic myeloproliferative disease, secondary to an infection, inflammation, and hemorrhage. Secondary thrombocytosis is usually identified in routine laboratory testing, as most patients are asymptomatic. This activity highlights the role of the interprofessional team in the evaluation and management of secondary thrombocytosis.

Objectives:

• Describe the etiology of secondary thrombocytosis thus improve outcomes.
• Identify the workup of secondary thrombocytosis.
• Review the differential diagnosis of secondary thrombocytosis.

Introduction

Platelets are a component of blood produced in the bone marrow that plays a vital role in the blood clotting process. The normal platelet count in adults and children is 150,000/microL to 450,000/microL (150 to 450 x 10/L), but the normal range may vary in different clinical laboratories. Thrombocytosis is a condition where the platelet count exceeds 450,000/μl.[1] It is also referred to as thrombocythemia. Thrombocytosis can be divided into two groups:  primary thrombocytosis and secondary (or reactive) thrombocytosis.[2] 

This distinction between primary and secondary thrombocytosis is important as it carries implications for evaluation, prognosis, and treatment. Primary thrombocytosis is due to the unregulated abnormality of platelet production of bone marrow progenitor cells.[3] They are usually associated with the myeloproliferative neoplasms group. Primary thrombocytosis, especially essential thrombocythemia and polycythemia vera, have an increased risk of thrombosis and bleeding compared to secondary thrombocytosis.[4]

Secondary thrombocytosis, also known as reactive thrombocytosis defined as an abnormally high platelet count due to underlying events, disease, or the use of certain medications. Secondary thrombocytosis is the more common type and is usually identified in routine laboratory results. Among individuals with thrombocytosis, 80% to 90% are known to have secondary thrombocytosis.[5] Reactive causes of thrombocytosis include transient processes such as acute blood loss, acute infection, or sustained forms of reactive thrombocytosis include iron deficiency, asplenia, cancer, chronic inflammatory, or infectious diseases. Secondary thrombocytosis (reactive thrombocytosis) is a laboratory anomaly that resolves when the underlying causative condition is addressed.

In most cases, the symptoms are due to an underlying disorder and not the thrombocytosis itself. Extreme thrombocytosis may rarely result in thrombotic events such as acute myocardial infarction, mesenteric vein thrombosis, and pulmonary embolism.[6] Even though secondary thrombocytosis is benign, the underlying etiology of thrombocytosis (e.g., malignancy, connective tissue disorders, chronic infections) can be associated with an increased risk of adverse outcomes.

Etiology

Common causes of secondary thrombocytosis 

• Infections (acute bacterial and viral infections/chronic infections like tuberculosis)
• Inflammation
• Functional and surgical asplenia
• Hemorrhage/ iron deficiency
• Drugs- aztreonam, ceftazidime, ibuprofen, epinephrine, glucocorticoids
• Rheumatoid arthritis, IBD (Inflammatory bowel disease), sarcoidosis
• Hemolysis
• Metastatic cancer/lymphoma
• Allergic reactions
• Exercise[7]

Epidemiology

Secondary thrombocytosis (reactive thrombocytosis) is a common condition compared to primary thrombocytosis. Around 75% of individuals without any prior myeloproliferative disorders developed thrombocytosis after splenectomy.[6] The prevalence of reactive thrombocytosis in iron deficiency anemia was around 30%. According to a Chinese study around (25.9%), children developed platelet ≥500 × 10/L  with respiratory tract infections.[8] In an Italian study of children 1 to 24 months old who were hospitalized for community-acquired infections, 50% of them developed thrombocytosis.[9] 

Race, sex, and Age-related demographics: No race, sex, or age predilection exists for secondary thrombocytosis (reactive thrombocytosis).

Pathophysiology

In the bone marrow, stem cells transform into very large cells known as megakaryocytes. Megakaryocyte forms cell fragments known as platelets and each megakaryocyte can produce anywhere between 5,000 to 10,000 platelets. The pathophysiology of secondary thrombocytosis may differ, depending on the cause of thrombocytosis. Thrombocytosis is driven by overproduction of thrombopoietin, interleukin-6, other cytokines, or catecholamines in inflammatory, infectious, or neoplastic conditions or in situations of stress.[10][11]  Megakaryocyte proliferation is the reason for elevated platelet count in iron deficiency anemia. While in asplenia, decreased platelet sequestration is the reason for thrombocytosis.

History and Physical

Most patients are asymptomatic and are usually identified on routine laboratory results. History should evaluate the condition that may have precipitated the thrombocytosis or complications of thrombocytosis:

• Prior trauma or surgery
• History of splenectomy or hemolysis
• Findings suggesting infection or inflammation
• History of bleeding (e.g., menorrhagia, gastrointestinal) or iron deficiency
• History of arterial or venous thrombosis
• Medications
• Smoking and alcohol consumption
• Prior diagnosis of a chronic hematologic disorder
• Unexplained fever, sweats, weight loss, fatigue, or other systemic complaints suggesting malignancy

No distinguishing features of secondary thrombocytosis (reactive thrombocytosis) are found on physical examination but should look for 

• Cutaneous or mucosal bleeding/bruising
• Lymphadenopathy
• Hepatosplenomegaly
• Signs of arterial or venous thrombosis

Evaluation

The laboratory workup  of secondary thrombocytosis (reactive thrombocytosis) includes the following:

• Complete blood count shows an increased platelet count
• Peripheral Blood Smear 
• Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)
• Antinuclear antibody (ANA), rheumatoid factor (RF)
• Iron studies (serum iron, serum ferritin)

If the clinical condition does not differentiate between primary and secondary thrombocytosis, further tests like genetic testing and a bone marrow biopsy may be indicated.

Treatment / Management

Secondary thrombocytosis has no specific treatment, but the identification of reactive conditions and appropriate therapy of the underlying disorder is most relevant.[12] For example, the normalization of platelet counts can be achieved by iron supplementation in inflammatory bowel patients.[13][14] 

Treatment with anti-platelets like aspirin is usually not indicated as the risk of thrombosis is very low in secondary thrombocytosis. Still, it can be considered for patients with platelets more than 1,000,000/μL, and complications of thrombocytosis are present, or to be at risk of developing complications.[15] The platelet-reducing effect of the plateletpheresis is done in patients with evidence of thrombosis and active bleeding. Though plateletpheresis is temporary, it helps in the rapid reduction of the platelet count.

Differential Diagnosis

• Familial essential thrombocythemia
• Myelodysplastic syndrome
• Polycythemia vera
• Chronic myeloid leukemia
• Myelofibrosis
• Spurious thrombocytosis 
• Pseudothrombocytosis

Prognosis

Secondary thrombocytosis is usually transient and resolves when the underlying condition is addressed. The overall prognosis depends on the primary causative condition. The presence of thrombocytosis is considered poor prognosis in certain disorders like COPD, GI cancers like esophageal and colorectal cancer.[16]

Complications

 Physicians need to be familiar with the complications associated with thrombocytosis. However, the complications due to secondary thrombocytosis are rare.

• Arterial and venous thrombosis leading to stroke, myocardial infarction, mesenteric ischemia
• Bleeding
• Spontaneous abortion
• IUD- intrauterine death/ intrauterine growth retardation
• Transformation to AML and primary myelofibrosis

Enhancing Healthcare Team Outcomes

Platelets are acute-phase reactants, and secondary thrombocytosis can occur due to underlying infection (typically acute), tissue damage, chronic inflammatory disorders, and malignancy. A complete history and physical examination should be performed to exclude common causes of reactive thrombocytosis.[4] 

In patients with secondary thrombocytosis (reactive thrombocytosis) for whom the underlying causative condition has not been identified, a thorough workup should be done to exclude occult disorder (e.g., malignancy). Thrombocytosis occurs in a variety of clinical situations and can have diverse underlying etiologies. In certain patients differentiating primary from secondary causes of thrombocytosis can be difficult, yet the distinction has important therapeutic and prognostic implications. In those conditions, expert opinion from a hematologist is recommended. Patient education is essential and regular followup should be emphasized.