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Thrombocytosis is defined as a platelet count above the upper limit of the normal range (450 x 109/L in adults).
This article aims to outline diagnosis, investigation and management of patients with thrombocytosis and to highlight possible complications. Until recently there have been no guidelines on how to diagnose and manage thrombocytosis. 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 marrow.
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.
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.
- The prevalence in the general population is approximately 30/100,000.
- The median age at diagnosis is 60 years but it can occur at any age and up to 20% of patients are younger than 40 years. It is rare in children.
- There is an equal sex ratio in the more common older group but, in younger patients, there is a female preponderance. Overall, the female-to-male ratio is about 2:1.
- There are usually no genetic factors but a thrombopoietin production or receptor abnormality can cause familial disease.
The incidence is highest during the first three months of life, and preterm infants are more prone than term infants. One meta-analysis found that 3-13% of hospitalised paediatric patients had a platelet count of more than 500 x 109/L.
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).
- 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.
- Neurological symptoms:
- 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.
- 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).
- Iron deficiency.
- Malignancy (especially soft-tissue sarcoma, osteosarcoma).
- 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).
- Renal disorders (eg, nephrotic syndrome, nephritis).
- Low birth-weight/preterm infants.
These should be further differentiated from spurious thrombocytosis.
- Establish whether the platelet count really is raised:
- Check with the laboratory to exclude artefactual reading.
- Repeat to confirm.
- Proceed to differentiate between primary thrombocytosis and secondary thrombocytosis.
- Take a history:
- Establish whether there are any symptoms of primary thrombocytosis.
- Note whether there is any history of a condition likely to cause secondary thrombocytosis.
- Examine the patient:
- Note whether there is any hepatosplenomegaly (suggestive of primary thrombocytosis).
- Note whether there are signs of any disease likely to cause secondary thrombocytosis.
- Draw up a differential diagnosis:
- It is often possible to determine from history and examination whether the thrombocytosis is primary or secondary.
- If primary - confirm and define exact diagnosis. This is a process of exclusion and may involve some or all of the investigations below.
- If secondary - confirm and define the causative disease. The following are likely to be raised in secondary thrombocytosis:
- Erythrocyte sedimentation rate (ESR).
- C-reactive protein (CRP).
- Fibrinogen level.
- Factor VIII procoagulant activity.
- Von Willebrand antigen level.
The diagnosis of primary thrombocytosis is essentially one of exclusion. Some or all of the following investigations may be necessary:
- 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.
- 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.
- 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.
Philadelphia chromosome is absent (it is present in chronic myeloid leukaemia).
- 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 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 women.
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.
- 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 count.
- 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 years.
- 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.
Platelet counts well above 1,000 x 109/L can occur in reactive thrombocytosis. 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 thrombocytosis. 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 required.
- 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.
Complications can arise from the platelet abnormality but are more usually a consequence of the primary disorder.
Life expectancy in patients with essential thrombocythaemia is significantly worse than that of the control population. Leukocytosis is an adverse risk factor.
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 cancer.
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Further reading & references
- Skoda RC; Thrombocytosis. Hematology Am Soc Hematol Educ Program. 2009:159-67. doi: 10.1182/asheducation-2009.1.159.
- Guideline for investigation and management of adults and children presenting with a thrombocytosis; British Committee for Standards in Haematology (April 2010)
- Gowin K, Mesa R; Management of thrombocythemia. F1000Res. 2014 Sep 29 3:227. doi: 10.12688/f1000research.5361.1. eCollection 2014.
- Briere JB; Essential thrombocythemia. Orphanet J Rare Dis. 2007 Jan 8 2:3.
- Harrison CN, Donohoe S, Carr P, et al; Patients with essential thrombocythaemia have an increased prevalence of antiphospholipid antibodies which may be associated with thrombosis. Thromb Haemost. 2002 May 87(5):802-7.
- Cervantes F; Management of essential thrombocythemia. Hematology Am Soc Hematol Educ Program. 2011 2011:215-21. doi: 10.1182/asheducation-2011.1.215.
- Barbui T, Finazzi G; Treatment indications and choice of a platelet-lowering agent in essential thrombocythemia. Curr Hematol Rep. 2003 May 2(3):248-56.
- Wolanskyj AP, Schwager SM, McClure RF, et al; Essential thrombocythemia beyond the first decade: life expectancy, long-term complication rates, and prognostic factors. Mayo Clin Proc. 2006 Feb 81(2):159-66.
- Voutsadakis IA; Thrombocytosis as a prognostic marker in gastrointestinal cancers. World J Gastrointest Oncol. 2014 Feb 15 6(2):34-40. doi: 10.4251/wjgo.v6.i2.34.
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