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Thrombocytosis

Essentials

  • Blood platelet, or thrombocyte, concentrations vary between individuals but remain rather constant in each individual.
  • Thrombocytosis can be classified into two categories: primary thrombocytosis, i.e. thrombocytosis related to myeloproliferative diseases, and secondary or reactive thrombocytosis.
  • Most cases of thrombocytosis are reactive. In such cases, platelets rarely cause problems, and treatment of the underlying disease will correct platelet levels.

Causes of thrombocytosis

  • The reference range for platelets in adults is 150-360 × 109 /l. The reference range follows the Gaussian curve, i.e. 95% of healthy people have platelet levels within the range. A few per cent of healthy people have platelet levels slightly exceeding the reference range.
  • Thrombocytosis can be classified into primary thrombocytosis (associated with clonal dyscrasia) and secondary or reactive thrombocytosis (see table T1).
  • Most, about 80%, of all cases of thrombocytosis are secondary.
  • Thrombocytosis not related to a blood dyscrasia is most often associated with essential thrombocythaemia (ET).
    • Essential thrombocythaemia is a chronic myeloproliferative haematological disease characterized by accelerated platelet production and gradually worsening thrombocytosis.
    • Aetiology unknown
    • Number of new cases 1-2/100 000 per year
    • 3 times more common in women
    • Life expectancy quite similar to reference population. In a few per cent of patients, the disease may turn into myelofibrosis and in rare cases to acute leukaemia, with significantly decreased life expectancy.

Classification and causes of thrombocytosis

Primary
Secondary
  • Acute or chronic haemorrhage
  • Over-compensation in the recovery phase of thrombocytopenia Thrombocytopenia (e.g. during recovery from ITP or from cytotoxic therapy)
  • Iron deficiency
  • Haemolytic anaemia Haemolytic Anaemia
  • Sequelae of operations
  • Connective tissue and rheumatic disorders (active stages)
  • Infections
  • Childbirth
  • A sequel of splenectomy
  • Neoplastic diseases
  • Intense physical exercise

Symptoms and findings

  • In reactive thrombocytosis, even high platelet levels rarely cause symptoms.
  • Essential thrombocythaemia (ET), too, is often asymptomatic and found incidentally, but it involves an increased risk of vascular occlusion and haemorrhage.
  • In some patients, ET is detected when examining the cause of a complication or a symptom.
    • Arterial or venous thrombosis
      • ET should be kept in mind particularly when investigating the aetiology of abdominal or cerebral venous thrombosis.
    • Cerebrovascular accident, headache
    • Peripheral ischaemic symptoms (erythromelalgia)
    • Major haemorrhage
    • Complication of pregnancy

Workup

  • As most thromboses are reactive, investigations should be chosen depending on the symptoms and findings (table T1).
  • If thrombocytosis is found incidentally in an asymptomatic patient, the situation should be checked in primary health care in 1-2 months.
    • If there is no indication of secondary causes, investigation of primary thrombocytosis should be started in primary health care by abdominal ultrasonography and, depending on the regional task division, possibly also by testing driver mutations (JAK2, CALR and MPL). The practice regarding mutation tests varies: all these mutations (or JAK2 alone) can be tested according to locally agreed practice either in primary health care or in specialized care.
    • Check also local policies and practices
  • Patients meeting any of the following criteria should be referred for examination in specialized care:
    • symptomatic (vascular occlusion, haemorrhage) thrombocytosis (emergency referral)
    • platelet level exceeding 1 000 x 109 /l (urgent referral)
    • platelets repeatedly exceeding 450 x 109 /l for six months or more, and reactive causes excluded
    • detected driver mutation (or for the examination of such mutations).
  • Bone marrow tests required for differential diagnosis of primary thrombocytosis are done in specialized care, at an outpatient clinic for internal diseases or haematology.

Treatment and follow-up

Secondary thrombocytosis

  • Treatment of the primary cause (such as iron deficiency) will correct thrombocytosis.

Essential thrombocythaemia (ET)

  • The diagnosis and treatment plan should be made in specialized care but subsequent follow-up of young, asymptomatic patients can often be done in primary health care.
  • The central aim of treatment is to reduce the risk of vascular occlusion associated with the disease.
    • The essential drug is ASA, started in all except young triple-negative patients (with none of the 3 driver mutations mentioned above) with no cardiovascular risk factors.
    • Cardiovascular risk factors should be surveyed and actively treated. Smoking cessation is important.
  • Follow-up of asymptomatic patients
    • The blood count should be checked once or twice a year.
    • Good treatment of cardiovascular risk factors should be ensured.
    • The size of the spleen should be assessed at intervals of a few years by palpation of the entire abdomen. Follow-up by routine ultrasonography of the spleen is unnecessary but ultrasonography should be performed if the spleen feels enlarged on palpation.
  • If after diagnosis further follow-up was transferred to primary health care, another referral to specialized care (outpatient clinic for internal diseases or haematology) for starting pharmacotherapy is appropriate
    • when the patient turns 61
    • if the platelet level exceeds 1 500 x 109 /l
      • If the patient is taking ASA, the possibility of acquired von Willebrand disease should be kept in mind if the platelet level exceeds 1 000 x 109 /l. This may increase the risk of haemorrhage and require starting medication to lower platelet levels. Consultation regarding further treatment of these patients is indicated even earlier, when the platelet level rises to about 1 000 x 109 /l.
    • if the patient has vascular occlusion
    • if the patient is going to undergo an operation (preoperative assessment of the need for platelet-lowering medication)
    • if the patient has symptoms associated with the disease (such as frequent headaches, bleeding symptoms)
    • if platelet levels increase, granulocyte precursors appear in the blood count or the spleen becomes enlarged
    • already when planning pregnancy.
      • Pregnancy in patients with ET involves an increased risk of complications, and follow-up during pregnancy should therefore be carried out in specialized care, at an outpatient clinic for haematology or internal diseases, as well as at an antenatal outpatient clinic.
  • The most common medicines used to treat ET are hydroxyurea and anagrelide.
    • The use of interferon, which was previously used to treat younger patients in particular, is restricted by the lack of reimbursement. Local policies may vary.
    • Very elderly patients can be treated with busulfan or radiophosphorus, both of which have been associated with a possible increase in the risk of leukaemia.

    References

    • Edahiro Y, Kurokawa Y, Morishita S, et al. Causes of Thrombocytosis: A Single-center Retrospective Study of 1,202 Patients. Intern Med 2022;61(22):3323-3328 [PubMed]
    • Hsieh RW, Ravindran A, Hook CC, et al. Etiologies of Extreme Thrombocytosis: A Contemporary Series. Mayo Clin Proc 2019;94(8):1542-1550 [PubMed]
    • Nordic MPN Study Group. Nordic care program for patients with essential thrombocythemia, polycythemia vera and primary myelofibrosis. 4th version, March 2017 http://nmpn.org/index.php/guidelines/17-nmpn-care-program-2017/file
    • Schafer AI. Thrombocytosis. JAMA 2015;314(11):1171-2 [PubMed]
    • Barbui T, Vannucchi AM, Buxhofer-Ausch V, et al. Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia. Blood Cancer J 2015;5(11):e369 [PubMed]
    • Harrison CN, Butt N, Campbell P, et al. Diagnostic pathway for the investigation of thrombocytosis. Br J Haematol 2013;161(4):604-6 [PubMed]
    • Sulai NH, Tefferi A. Why does my patient have thrombocytosis? Hematol Oncol Clin North Am 2012;26(2):285-301, viii [PubMed]
    • Bleeker JS, Hogan WJ. Thrombocytosis: diagnostic evaluation, thrombotic risk stratification, and risk-based management strategies. Thrombosis 2011;2011():536062 [PubMed]