Thrombocytosis

Synonym: thrombocythaemia

Thrombocytosis is defined as a platelet count above the upper limit of the normal range (450 x 10⁹/L in adults)¹.

This article aims to outline diagnosis, investigation and management of patients with thrombocytosis and to highlight possible complications. It is important to distinguish between true haematological disease causing thrombocytosis and secondary or reactive thrombocytosis caused by an exaggerated physiological response to a primary problem.

There are a number of haematological diseases causing thrombocytosis. Primary thrombocytosis is a chronic myeloproliferative disorder. However, there are other haematological diseases which can cause thrombocytosis, including other myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDS) and overlap syndromes. MPNs such as primary thrombocytosis (essential thrombocythaemia), polycythaemia vera and myelofibrosis are Philadelphia-negative clonal disorders of the bone marrow².

A study published in the British Journal of General Practice highlighted the potential significance of thrombocytosis. There was an increased incidence of cancer in those with raised platelet counts. The increase in cancer incidence increased with age, and a higher platelet count. Lung and colorectal cancers were the most commonly diagnosed cancers in the thrombocytosis cohort. Approximately 1/3 of those subsequently diagnosed with these two types of cancer had no symptoms suggestive of cancer³.

Aetiology

There are broadly two types of thrombocytosis:

Haematological disease including primary thrombocytosis

Primary thrombocytosis (also referred to as essential thrombocytosis, essential thrombocythaemia and primary thrombocythaemia) is due to a failure to regulate the production of platelets (autonomous production) and is a feature of a number of myeloproliferative disorders. Features include a platelet count greater than 600 x 10⁹/L, megakaryocyte hyperplasia, splenomegaly and a tendency to both thrombosis and haemorrhage. Platelet survival is normal but function is not.

Other haematological diseases which cause thrombocytosis are myeloproliferative, myelodysplastic or a combination of both. It includes some leukaemias.

Secondary or reactive thrombocytosis

This can be secondary to a number of conditions. It is an exaggerated physiological response to a primary problem, such as an infection. The trigger factor (eg, infection) results in the release of cytokines which mediate an increase in platelet production. It is often a transient phenomenon which disappears when the underlying cause is resolved.

Genetics⁴

Mutations in the key regulators of thrombopoietin, the thrombopoietin receptor MPL and JAK2, are found in 50-60% of patients with essential thrombocythaemia or primary myelofibrosis and in 10-20% of hereditary thrombocytosis. When present in a heterozygous state the JAK2-V617F mutation preferentially stimulates megakaryopoiesis and in most cases manifests as essential thrombocythaemia. Homozygous JAK2-V617F reduces megakaryopoiesis in favour of increased erythropoiesis, resulting in polycythaemia vera and/or myelofibrosis.

Epidemiology

Primary thrombocytosis⁵

• Essential thrombocytosis is the most common type of myeloproliferative neoplasm.

• The prevalence has been reported to be 38 to 57 per 100,000, with females more often affected.

• The incidence of essential thrombocytosis increases with age, with most patients presenting between 50 and 60 years.

Secondary thrombocytosis

The incidence is highest during the first three months of life, and preterm infants are more prone than term infants.

Presentation

Primary thrombocytosis

The clinical features can relate to an increased bleeding tendency and, rather oddly, an increased tendency to thrombosis. The mechanisms that cause these two phenomena are poorly understood but are thought to relate to a decrease in aggregation, hyper-aggregation, and the presence of high molecular weight von Willebrand factor multimers (substances released by tissue when coagulation is required).

• About a third of patients are asymptomatic at the time of diagnosis.

• Most symptomatic patients have vasomotor symptoms or symptoms related to small or large vessel thrombosis. Some present with bleeding.

• Between 20% and 30% of patients have constitutional symptoms that usually include sweating, low-grade fever and pruritus. Weight loss is unusual.

• On examination, 40-50% of patients have splenomegaly at presentation and 20% have hepatomegaly. Clinical findings are otherwise unremarkable.

• Clinical features can include:
  

  • Neurological symptoms:
    

    • Headache (the most common neurological symptom).

    • Burning pain and dusky appearance of the extremities (erythromelalgia).

    • Transient ischaemic episodes and paraesthesiae.

    • Other transient symptoms (including dizziness, dysarthria, syncope, migraine, seizures, etc).

  • Arterial thrombosis:
    

    • Cardiac, renal and leg arteries (possible).

    • Pain or gangrene of the toes and fingers.

  • Venous thrombosis:
    

    • Splenic, hepatic, or leg and pelvic veins may be involved.

    • Priapism is rare.

    • Pulmonary hypertension (may result from thromboembolism).

  • Bleeding:
    

    • Primarily gastrointestinal (GI) - often simulates duodenal ulcer following duodenal arcade thrombosis.

    • May also involve eyes, gums, skin, urinary tract, joints and brain.

    • Bleeding is usually not severe (only rarely requires transfusion).

    • Bleeding is unusual unless the platelet count exceeds 1,000 x 10⁹/L.

  • Complications in pregnancy:
    

    • Spontaneous abortions (usually first trimester).

    • Placental infarctions (causing intrauterine growth restriction and fetal death).

    • Excessive bleeding during delivery - this is rare.

Secondary thrombocytosis

• A history of the primary condition may be elicited (eg, infection) but sometimes the causative factor is not obvious.

• Symptoms prevalent in primary thrombocytosis are notably absent.

• There are no specific clinical findings on examination.

Differential diagnosis⁶

• Primary haematological:
  

  • Primary thrombocytosis (essential thrombocytosis).

  • Polycythaemia vera (haematocrit is also raised).

  • Primary myelofibrosis.

  • Myelodysplasia with del(5q).

  • Refractory anaemia (with ring sideroblasts associated with marked thrombocytosis).

  • Chronic myeloid leukaemia.

  • Chronic myelomonocytic leukaemia.

  • Atypical chronic myeloid leukaemia.

  • MDS/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U).

• Secondary or reactive thrombocytosis:
  

  • Infection (common infective causes are meningitis, infections of the upper and lower respiratory tract, urinary tract infections, gastroenteritis, septic arthritis, osteomyelitis, and generalised sepsis).

  • Inflammation (eg, rheumatoid arthritis, Kawasaki disease, Henoch-Schönlein purpura, inflammatory bowel disease).

  • Tissue damage (eg, burns, trauma, fracture).

  • Hyposplenism.

  • Postoperative.

  • Haemorrhage.

  • Iron deficiency.

  • Malignancy (especially soft-tissue sarcoma, osteosarcoma).

  • Haemolysis.

  • Drug therapy - eg, corticosteroids; adrenaline (epinephrine).

  • Cytokine administration (eg, thrombopoietin).

  • Rebound following myelosuppressive chemotherapy.

  • Rebound from other causes - eg, with iron-deficiency anaemia, recovery phase of idiopathic thrombocytopenic purpura (ITP).

  • Post-splenectomy.

  • Renal disorders (eg, nephrotic syndrome, nephritis).

  • Low birth-weight/preterm infants.

These should be further differentiated from spurious thrombocytosis⁶.

Investigations

The diagnosis of primary thrombocytosis is essentially one of exclusion. Some or all of the following investigations may be necessary:

FBC

• The hallmark of essential thrombocytosis is a sustained thrombocytosis. This is usually greater than 600 x 10⁹/L.

• Other findings may include leukocytosis, erythrocytosis, and mild anaemia.

• Immature precursor cells (eg, myelocytes, metamyelocytes) may occasionally be seen.

• Large platelets (thrombocytes) may also be identified on routine peripheral blood smear.

• Mild basophilia and eosinophilia sometimes occur.

Bone-marrow aspiration

• Hypercellularity in 90% of cases.

• Megakaryocytic hyperplasia is common.

• Giant megakaryocytes are seen.

• Hyperplasia of granulocyte and reticulocyte precursors may be seen.

• An increase in bone-marrow reticulin is detected.

• An absence of myelofibrosis is notable (this would raise the suspicion of agnogenic myeloid metaplasia).

• Iron stores may be absent.

Clotting and platelet aggregation studies

• Prothrombin time and activated partial thromboplastin time studies are usually normal.

• The bleeding time is sometimes prolonged.

• Platelet aggregation studies are abnormal and show impaired platelet aggregation (to adrenaline (epinephrine), adenosine diphosphate (ADP) and collagen but not to ristocetin and arachidonic acid).

• Some patients may have spontaneous platelet aggregation.

Red blood cell mass

• This is normal in primary thrombocytosis.

• It is raised in polycythaemia vera.

Biochemistry

• Elevated uric acid and vitamin B12 levels are found in 25% of patients.

• Occasionally there are elevated levels of potassium, phosphate and acid phosphatase.

• Antiphospholipid antibodies increase the risk of thrombosis.

Genetic studies
Philadelphia chromosome is absent (it is present in chronic myeloid leukaemia).

Imaging

• CXR and abdominal ultrasound may be indicated to exclude undetected sources of infection or malignancy. Ultrasound may also be useful to assess the spleen, especially when it is not palpable. To be palpable it must be at least twice the normal size.

Management

Primary thrombocytosis

Management requires an assessment of the individual's risk and, where possible, taking remedial action.

Patients with essential thrombocythaemia are considered at high risk of thrombosis if they are older than 60 years or have a previous history of thrombosis and at high risk of bleeding if platelet counts are above 1,500 x 10⁹/L. Patients with low-risk essential thrombocythaemia are usually managed with low-dose aspirin, whereas treatment of high-risk essential thrombocythaemia is based on the use of cytoreductive therapy, with hydroxyurea as the drug of choice and interferon alfa (IFN-α) being reserved for young patients or pregnant women⁷.

Assess risk factors

• Those over 60 years of age are at greater risk than younger patients and so merit more aggressive treatment. In younger patients the decision whether or not to treat should take into account the presence or absence of other risk factors. Previous thrombosis and raised cholesterol are notable risks.

• History of thrombosis requires attention to prophylaxis.

• Platelet count in excess of 1,500 x 10⁹/L, is paradoxically associated with an increased risk of GI tract bleeding in young women.

• Obese patients should be advised to lose weight.

• Cardiovascular risk factors, such as smoking, hypertension and hypercholesterolaemia, should be corrected.

• Markers of hypercoagulability, such as factor V Leiden and antiphospholipid antibodies, demand more aggressive treatment.

Consider therapeutic options

• In patients with low risk, simple observation may be justified. They tend not to have a high risk of complications of surgery or pregnancy.

• Where there are symptoms of microvascular occlusion such as erythromelalgia, low-dose aspirin may be very effective. The cost and risk of such treatment may make it suitable for all low- and medium-risk patients.

• In high-risk patients, including those with very high platelet counts, the platelets must be reduced.

• Possible treatments include hydroxyurea, anagrelide or IFN-α.

• When there are acute complications, plateletpheresis may achieve a rapid decrease in platelet count.

• If patients require elective surgery and are not at very low risk, cytoreductive therapy should be employed to reduce the risk of both thrombosis and haemorrhage. Splenectomy increases the risks of both thrombosis and haemorrhage.
  

Treatments

• Hydroxyurea is an antimetabolite that acts as a false precursor and is a very effective treatment.

• Anagrelide is an imidazoquinazoline drug that inhibits platelet aggregation but it also decreases platelet production.

• IFN-α is a biological response modifier. It does not cross the placenta, making it safe for use during pregnancy and there is no known teratogenicity. However, platelet counts tend to rebound after treatment is stopped.

• Busulfan, an alkylating agent, is reported in a number of case reports to control the platelet count⁶.

• Phosphorous-32 irradiates the bone marrow.

• Pipobroman is a bromide derivative of piperazine and acts as a metabolic competitor of pyrimidine bases. It is an alkylating agent. It is not available in the UK but can be obtained on a named patient basis. It has been used in the treatment of primary thrombocytosis for over 30 years⁶.

• Platelet counts are reduced to less than 600 x 10⁹/L in 90% of cases after three months of treatment. The dose is adjusted to achieve a platelet count within the target range of less than 450 x 10⁹/L.

Secondary thrombocytosis

Platelet counts well above 1,000 x 10⁹/L can occur in reactive thrombocytosis⁶. Despite high platelet counts patients rarely have symptoms. Usually the thrombocytosis resolves once the underlying condition has been treated. However, sometimes the thrombocytosis does not occur at the same time as the underlying condition.

There are differences of opinion on management of the thrombocytosis⁶. Reactive thrombocytosis has been considered as transient and self-limiting with often no treatment being necessary. Consideration should certainly be given to the use of aspirin 75 mg, although there is no evidence to support this practice.

However, careful evaluation of these patients is required, as the thrombocytosis can put patients at risk of complications and may need treatment along with treatment of the causative condition. A comprehensive assessment involving clinical and laboratory investigations is required⁶.

Complications

Primary thrombocytosis

• Thrombosis may be serious and fatal. Splanchnic vein thrombosis may be difficult to diagnose.

• Bleeding is usually from the GI tract and is usually far less serious.

• Transformation to acute myeloid leukaemia (AML) occurs in 0.5-5% of patients. In a series of 2,316 cases retrospectively collected in Italy, the rate of transformation to AML or MDS was 1% in patients left untreated. Use of IFN-α and hydroxyurea brought similar results but transformation occurred in 4% of patients treated with alkylating agents. Phosphorus-32 also has a higher rate of transformation.

Secondary thrombocytosis

Complications can arise from the platelet abnormality but are more usually a consequence of the primary disorder.

Prognosis

Primary thrombocytosis

Life expectancy in patients with essential thrombocythaemia is significantly worse than that of the control population. Leukocytosis is an adverse risk factor⁸.

Secondary thrombocytosis

The prognosis will usually be determined by the primary disorder. Thrombocytosis is an adverse prognostic factor in many types of cancer, including breast cancer, ovarian and other gynaecological cancers, renal cell carcinoma and lung cancer⁹.