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Secondary Thrombocytosis
Introduction
Once referred to ignobly as "blood dust," platelets are a component of blood produced in the bone marrow that have a vital role in the blood clotting process.[1] The average platelet count in adults and children is usually between 150,000 and 450,000/μL (150 to 450 x 10/L), although the normal range may vary in different clinical laboratories. Thrombocytosis, or thrombocythemia, occurs when the platelet count exceeds 450,000/μL of blood.[2]
Thrombocytosis can be classified into primary and secondary (or reactive) thrombocytosis.[3] This distinction is essential as it carries implications for evaluation, prognosis, and treatment. Primary thrombocytosis results from an unregulated abnormality in platelet production by bone marrow progenitor cells and is usually associated with myeloproliferative neoplasms.[4] Primary thrombocytosis, especially in conditions such as essential thrombocythemia and polycythemia vera, carries an increased risk of thrombosis and bleeding compared to secondary thrombocytosis.[5]
Secondary thrombocytosis, also known as reactive thrombocytosis, is characterized by an abnormally high platelet count due to underlying events, infections or diseases, or certain medications. Secondary thrombocytosis, which is more common than primary thrombocytosis, is typically identified through routine laboratory studies. In most cases, secondary thrombocytosis symptoms are due to an underlying disorder rather than the thrombocytosis itself. Rarely, extreme thrombocytosis may lead to thrombotic events such as acute myocardial infarction, mesenteric vein thrombosis, and pulmonary embolism.[6]
Although secondary thrombocytosis is typically benign, the underlying causes—such as malignancy, connective tissue disorders, and chronic infections—can be associated with an increased risk of adverse outcomes. Approximately 80% to 90% of individuals with thrombocytosis are known to have secondary thrombocytosis.[7] Causes of secondary thrombocytosis include transient conditions like acute blood loss or infection, as well as sustained factors such as iron deficiency, asplenia, cancer, chronic inflammation, or infectious diseases. Reactive thrombocytosis is a laboratory anomaly that generally resolves once the underlying causative condition is addressed.
Etiology
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Etiology
The common factor among the various underlying causes of secondary thrombocytosis is the presence of inflammatory compounds, such as interleukin 6 (IL6), which enhance thrombopoietin secretion and subsequently increase megakaryocyte production.[8] Secondary thrombocytosis etiologies are often categorized under the "5 I's"—inflammation, ischemia, infection, infarction, and iron deficiency.
Infection
Acute bacterial, viral, or chronic infectious conditions (eg, tuberculosis) can cause secondary thrombocytosis due to increased production of IL6—an inflammatory component that enhances thrombopoietin synthesis. Approximately 75% of pediatric patients with reactive thrombocytosis have an infectious etiology.[9] Clinical features associated with reactive thrombocytosis include fever, tachycardia, weight loss, hypoalbuminemia, leucocytosis, and anemia. Secondary thrombocytosis is less common in COVID-19 and is considered a poor prognostic sign; instead, thrombocytopenia typically occurs secondary due to a direct effect of antibodies or immune complexes on megakaryocytes in the bone marrow.[10] During a COVID-19 infection, a hyperinflammatory cytokine storm releases large amounts of inflammatory compounds (eg, IL1B, IL12, interferon (IFN)-gamma, and IL6). IL6 causes prominent thrombopoiesis through its stimulatory effect on thrombopoietin, subsequently increasing megakaryocyte proliferation.
Functional and Surgical Asplenia
The major functions of the spleen are immune activity and blood filtration.[11] The white pulp is responsible for immune activity against pathogens (eg, Neisseria meningitides, Streptococcus pneumonia, and Hemophilus influenza type b). The red pulp, composed of matrices of sinuses and cords, filters the blood, removing old or defective erythrocytes (ie, hemocatheresis). Up to 90% of splenectomized patients experience thrombocytosis postoperatively due to the loss of splenic sequestration.[12][6][13] A hyposplenic or asplenic functional state can also lead to an elevated platelet count, as the thrombocytes bypass the modulating effect of the spleen. Other morphological effects can be seen in peripheral blood smears, including Howell-Jolly bodies (nuclear remnants), pitted erythrocytes with Pappenheimer bodies (iron deposits), and Heinz bodies (hemoglobin aggregates).[11]
The risk of thrombosis is as high as 5% in the few weeks following splenectomy and can result in acute myocardial infarction, portal vein thrombosis, splenic vein thrombosis, mesenteric vein thrombosis, or pulmonary embolism.[14][6][15] Platelet counts greater than 800,000/μL can be observed in patients, with a normalizing gradual decrease occurring within weeks to years.[16] Some experts recommend thromboprophylaxis in the immediate postoperative period as a preventative strategy, while others advocate the use of hydroxycarbamide chemotherapy due to its cytoreductive effect.[11][17][18] Additionally, all patients with a functional splenic defect should be fully vaccinated.
Iron Deficiency
Reactive thrombocytosis accompanying iron deficiency anemia can occur independently or in association with erythropoietin or as an additive event related to cytokines.[19][20] Erythropoietin levels increase in this type of anemia, stimulating erythropoietin receptors on megakaryocyte progenitors and leading to increased production of platelets. When iron deficiency anemia coexists with a comorbid condition, inflammation and cytokine effects (eg, IL6 or thrombopoietin) may further elevate a high platelet count.[21] This can result in extreme thrombocytosis or a thrombotic event in approximately 6% of cases.[5] However, repletion of iron stores typically normalizes the platelet count, and clinicians should consider other etiologies if counts do not respond. Additionally, large von Willebrand multimers can be absorbed when platelet counts exceed a million, leading to an acquired von Willebrand disease.[5]
Drugs
Drug-induced thrombocytosis can result from various causative factors.[22] One proposed mechanism is that certain drugs can cause the release of cytokines, particularly IL6, leading to thrombocytosis.[23] The increased IL6 would then lead to thrombocytosis. Many drugs can induce thrombocytosis, with varying propensities to do so. Examples include low molecular weight heparin, vincristine, epinephrine, all-trans retinoic acid (ATRA), beta-lactam antibiotics, gemcitabine, and clozapine.[24][23] Antibiotics such as ciprofloxacin, tazobactam, piperacillin, augmentin, and ceftazidime can produce significantly high thrombocytosis, but the platelet count usually normalizes once the drug is discontinued.[25][26][27]
Inflammatory Conditions
Rheumatoid arthritis, inflammatory bowel disease, sarcoidosis, and autoimmune antibody-mediated illnesses can cause thrombocytosis through inflammatory effects, particularly involving IL6.[28] Several diseases, such as rheumatic disease, celiac disease, polyarteritis nodosa, and giant cell arteritis, can present with a fever of unknown origin and an increased platelet count.[29][30] Furthermore, a survey noted that thrombocytosis in these conditions has been associated with cancer in approximately 11% of cases.[31] Although sarcoidosis can affect many organ systems, especially the lungs, bone marrow involvement can result in thrombocytosis.[31] In these patients, a high mean platelet volume correlates with active inflammatory disease and typically resolves with the treatment of sarcoidosis.
Platelets can also mediate allergic inflammation using immunoglobulin E (IgE) receptors and dependent processer on their surfaces.[32][33] Platelets can migrate out of the vasculature and into the airways, contributing to allergic reactions.[34][35] Alongside allergic reactions, chronic inflammation also increases the platelet count.[36] A high mean platelet volume reflects the presence of young platelets released from the body's reserve.
Hemolysis
Most diseases with antibody-mediated hemolysis manifest thrombocytopenia. Conversely, some conditions, including cold agglutinin disease (CAD), cause thrombocytosis. Although classically associated with Mycoplasma pneumoniae, CAD is also linked to Epstein-Barr virus, cytomegalovirus, COVID-19, and malignant or lymphoproliferative diseases.[37][38] Mycoplasma-associated hemolysis is due to cold agglutinins, the antibodies against the I antigen found on erythrocytes and respiratory endothelial cells.[39][37] The IgM cold agglutinins bind to complement factor C1 and initiate the classic complement pathway.[37]
Hemolysis itself has the propensity to cause endothelial dysfunction, leading to platelet activation and, thereby, the coagulation cascade.[40] Recent case studies have shown that thrombocytosis can exist in the setting of CAD; however, there was concern that the patient may have had an increased platelet count due to a concurrent infection.[39] Due to the increased thrombotic risk, thromboprophylaxis is recommended for acute hemolysis and patients considering splenectomy.[40] Other sources recommend checking for antiphospholipid antibodies as well.[41]
Metastatic Cancer and Lymphoma
Platelets have an established association with malignancies.[42] Cases of acute promyelocytic leukemia treated with ATRA can release cytokines (eg, IL6), resulting in platelet counts exceeding a million. Thrombocytosis predicts a decrease in disease-free survival and overall survival in patients being treated for gastric cancer.[43] The presence of thrombocytosis correlates with advanced disease stages and frequent lymphatic and renal involvement. Thrombocytosis has also been observed in patients with ovarian cancer undergoing chemotherapy.[44] Additionally, thrombocytosis commonly occurs with colon, lung, kidney, esophagus, stomach, pancreas, ovarian, breast, cervical, and endometrial cancers.[44][45]
Tumors can directly cause cytokine release, particularly IL6, which increases the liver's thrombopoietin (mRNA) production, leading to reactive thrombocytosis.[46] Tumors can also establish their blood supply via an angiogenic process regulated by platelets through alpha granules.[47] These tumors contain proangiogenic proteins, including vascular endothelial growth factor, for which platelets are the blood's largest repository.[48] Subsequently, by utilizing platelets, tumors increase and sustain their metastatic networks.
Exercise
A patient's exercise regimen can influence platelet release, activation, and function. Studies have confirmed that acute exercise leads to a transient increase in platelet count, partially due to hemoconcentration and mobilization from the liver, lungs, and spleen. However, regular exercise training reduces platelet adhesion and aggregation, thereby exerting an antithrombotic effect.[49][50][51]
Epidemiology
Secondary thrombocytosis is more common than primary thrombocytosis. Approximately 75% of individuals without prior myeloproliferative disorders develop thrombocytosis after splenectomy.[6] In cases of iron deficiency anemia, the prevalence of reactive thrombocytosis is about 30%. Additionally, a Chinese study found that around 25.9% of children with respiratory tract infections had a platelet count of more than or equal to 500 × 10/L.[52]
In an Italian study, 50% of children aged 1 to 24 months who were hospitalized for community-acquired infections developed thrombocytosis.[53] Typically, preterm infants have lower platelet counts at birth, while term and late-preterm infants often experience thrombocytosis that peaks shortly after birth and then declines within the first month.[54] High platelet counts in young children are commonly associated with respiratory infections and, less frequently, autoimmune diseases.[55] A specific race, sex, or age has not been found to have an increased prevalence of secondary thrombocytosis.
Pathophysiology
In the bone marrow, stem cells differentiate into large cells called megakaryocytes, which then produce platelets. Each megakaryocyte can generate between 5000 and 10,000 platelets. The pathophysiology of secondary thrombocytosis can vary depending on its underlying cause. Animal studies have demonstrated a connection between inflammation and thrombus formation through IL6 and platelets.[56][57]
Inflammation augments the release of IL6, which, in turn, stimulates proplatelet production by megakaryocytes and enhances hepatic thrombopoietin production. These mechanisms contribute to thrombocytosis, which can lead to thrombosis. Thrombocytosis may be driven by overproduction of thrombopoietin, IL6, other cytokines, or catecholamines in inflammatory, infectious, or neoplastic conditions or secondary to stress.[58][59] In iron deficiency anemia, elevated platelet counts result from increased megakaryocyte proliferation, while in asplenia, decreased platelet sequestration is the primary cause of thrombocytosis.
History and Physical
Clinical Symptoms
Secondary thrombocytosis is primarily an incidental laboratory finding and typically does not directly cause symptoms. However, symptoms may arise due to the underlying cause of the reactive thrombocytosis. Clinicians should take a focused history to investigate potential causes or complications of thrombocytosis, including:
- Prior trauma or surgery
- History of splenectomy or hemolysis
- Symptoms suggestive of infection, inflammation, or malignancy (eg, fever, sweats, weight loss, and fatigue)
- History of bleeding (eg, menorrhagia or gastrointestinal), iron deficiency, or chronic hematologic disorder
- History of arterial or venous thrombosis
- Medications
- Smoking and alcohol consumption
Physical Examination Findings
Findings from the physical examination consistent with reactive thrombocytosis may include:
- Cutaneous or mucosal bleeding or bruising
- Lymphadenopathy
- Hepatosplenomegaly
- Signs of arterial or venous thrombosis
Evaluation
Thrombocytosis, or thrombocythemia, is diagnosed through a complete blood count showing a platelet count greater than 450,000/μL.[2] Additional laboratory tests may be performed to differentiate between primary and secondary thrombocytosis in patients with this finding.[3] Because primary thrombocytosis results from unregulated platelet production in the bone marrow, the following laboratory diagnostic studies can help identify the underlying cause:
- Peripheral blood smear
- Erythrocyte sedimentation rate as an inflammatory gauge
- C-reactive protein as an inflammatory gauge
- Antinuclear antibody and rheumatoid factor
- Iron studies (eg, serum iron, total iron-binding capacity, and serum ferritin) [4]
However, additional tests such as genetic testing and a bone marrow biopsy may be considered if laboratory studies do not clarify whether the thrombocytosis is primary or secondary.
Treatment / Management
Secondary thrombocytosis resolves with treatment of the underlying etiology. Therefore, appropriate management should be initiated once the reactive condition, the causative factor, has been identified.[60] For example, the normalization of platelet counts can be achieved by iron supplementation in inflammatory bowel patients.[61][62] (A1)
Antiplatelet treatments, such as aspirin, are generally not indicated in secondary thrombocytosis due to the very low risk of thrombosis. However, antithrombotic therapy may be considered for patients with platelet counts exceeding 1,000,000/μL, those experiencing complications from thrombocytosis, or those at risk of developing such complications.[63] Plateletpheresis may be considered for patients with evidence of thrombosis or active bleeding; although its effects are temporary, it can rapidly reduce platelet counts.
Differential Diagnosis
Differential diagnoses for secondary thrombocytosis include:
- (Familial) Essential thrombocythemia: The presence of JAK2, CALB, and MPL favors this diagnosis.[64]
- Myelodysplastic syndrome (rare)
- Polycythemia vera
- Chronic myeloid leukemia
- Myelofibrosis
- Spurious thrombocytosis: Results from nonplatelet entities being counted as platelets.[5]
- Pseudothrombocytosis: Akin to spurious thrombocytosis; falsely elevated platelet count due to disease entities or compounds.[65][66][67][68]
Prognosis
Secondary thrombocytosis is usually transient and resolves when the underlying condition is addressed. The overall prognosis depends on the primary causative condition. In some disorders, such as chronic obstructive pulmonary disease and certain gastrointestinal cancers (eg, esophageal and colorectal cancer), the presence of thrombocytosis may indicate a poorer prognosis.[69]
Complications
Complications specifically associated with secondary thrombocytosis are rare. However, clinicians should be familiar with the general complications of thrombocytosis, including:
- Arterial and venous thrombosis, which leads to stroke, myocardial infarction, and mesenteric ischemia (platelet counts >1,000,000/μL increase the risk of thrombosis) [70][71]
- Bleeding
- Spontaneous abortion
- Intrauterine death or intrauterine growth retardation
- Transformation to acute myeloid leukemia and primary myelofibrosis
Deterrence and Patient Education
Patients should be advised that although secondary thrombocytosis is typically an incidental finding, addressing the underlying etiology is still essential, as thrombocytosis can lead to complications such as thrombosis. In addition, patients should also be informed that reactive thrombocytosis is a laboratory anomaly that resolves when the underlying causative condition is addressed. Therefore, compliance with treatment recommendations and follow-up appointments is essential for effective management.
Enhancing Healthcare Team Outcomes
Platelets act as acute-phase reactants, and secondary thrombocytosis can occur due to acute underlying infections, tissue damage, chronic inflammatory disorders, and malignancies. An interprofessional healthcare team comprising primary care providers, internists, surgeons, emergency room staff, pathologists, and laboratory technicians should collaborate to identify and treat patients with this secondary thrombocytosis. A thorough history and physical examination are essential to exclude common causes of reactive thrombocytosis.[5]
For patients with secondary thrombocytosis where the underlying cause remains unidentified, a comprehensive evaluation is necessary to rule out occult disorders such as malignancies. Thrombocytosis can arise in various clinical contexts with diverse underlying etiologies. In certain patients, differentiating primary from secondary causes of thrombocytosis can be challenging, yet this distinction is crucial for appropriate treatment and prognostic implications. In such cases, consulting a hematologist is recommended. Patient education and regular follow-up are also essential components of effective management.
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