Thrombocytosis

This is defined as a platelet count exceeding 450,000 per mL.¹
There are two types of thrombocytosis:

• Primary Thrombocytosis - this is due to a failure to regulate the production of platelets (autonomous production) and is a feature of a number of myeloproliferative disorders. About a third of patients are asymptomatic at the time of diagnosis.² It is also referred to as essential thrombocythaemia.
• Secondary Thrombocytosis - this can be secondary to a number of conditions. The trigger factor (e.g. 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.

Primary Thrombocytosis²

• Myelofibrosis with myeloid metaplasia
• Polycythemia vera
• Chronic myelocytic leukemia
• Familial essential thrombocythemia.

Secondary Thrombocytosis¹

• Infection - common infective causes are meningitis, infections of the upper and lower respiratory tract, urinary tract infections, gastroenteritis, septic arthritis, osteomyelitis, and generalised sepsis
• Chronic inflammations and vasculitis - rheumatoid arthritis, Kawasaki syndrome, Henoch-Schönlein purpura, inflammatory bowel disease
• Tissue damage - Postsurgical, burns, trauma, fracture
• Rebound thrombocytosis - Iron deficiency anemia, bleeding, cancer chemotherapy, recovery phase of idiopathic thrombocytopaenic purpura (ITP)
• Postsplenectomy
• Haemolytic anemia - sickle cell disease, thalassemia, and other haemolytic anaemias
• Renal disorders - nephrotic syndrome, nephritis
• Malignancy - soft tissue sarcoma, osteosarcoma
• Low birth weight/ preterm infants.

Primary Thrombocytosis

The prevalence in the general population is approximately 30/100,000. The median age at diagnosis is 65 to 70 years, but the disease may occur at any age. The female to male ratio is about 2:1.³

Secondary Thrombocytosis

The incidence is highest during the first 3 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 thrombocyte count of more than 500,000 per mL. ¹

Primary Thrombocytosis

The clinical features mainly related 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, hyperaggregation, and the presence of high molecular weight von Willebrand factor multimers (substances released by tissue when coagulation is required).
History

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

• Neurological symptoms These may include headache, pain or gangrene of the toes and fingers causes digital pain, gangrene, burning pain and dusky appearance of the extremities (erythromelalgia). Transient ischaemic episodes and paraesthesiae may develop, as well as other transient symptoms including:
  • Unsteadiness
  • Dysarthria
  • Dysphoria
  • Vertigo
  • Dizziness
  • Migraine
  • Syncope
  • Scotoma
  • Seizures.
• Arterial thrombosis Cardiac, renal and leg arteries may be involved.
• Venous thrombosis Splenic, hepatic, or leg and pelvic veins may be involved and pulmonary hypertension may develop.
• Bleeding This is primarily gastrointestinal but may also involve eyes, gums, skin and brain.

Secondary Thrombocytosis

History

A history of the primary condition may be elicited (e.g. infection) but sometimes the causative factor is not obvious. Symptoms prevalent in primary thrombocytosis are notably absent.
Examination

There are no specific clinical findings.

Primary Thrombocytosis

• Agnogenic myeloid metaplasia with myelofibrosis (this is a clonal disorder arising from the neoplastic transformation of early hematopoietic stem cells)
• Chronic myelogenous leukemia
• Myelodysplastic syndrome
• Polycythemia vera
• Secondary thrombocytosis.

Secondary Thrombocytosis

• Chronic lymphocytic leukemia
• Chronic Myelogenous Leukemia
• Polycythemia vera
• Thrombotic thrombocytopenic purpura.

The investigation of thrombocytosis is firstly concerned with differentiating between primary thrombocytosis and secondary thrombocythaemia. A full history and examination may be sufficient in strongly suspecting secondary thrombocytosis. If it is not, the following are all likely to be raised:

• 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:

• Full blood count (FBC) The hallmark of essential thrombocytosis is a sustained thrombocytosis. This is usually greater than 600,000 per mL. 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.
• Bone marrow Aspiration This may show:
  • Hypercellularity
  • Megakaryocytic hyperplasia
  • Giant megakaryocytes
  • Hyperplasia of granulocyte and reticulocyte precursors
  • An increase ins bone marrow reticulin
  • An absence of myelofibrosis (this would raise the suspicion of agnogenic myeloid metaplasia)
  • Iron stores may be absent in the bone marrow.
• Platelet Aggregation Studies There is an increase in platelet aggregation.
• Red Blood Cell Mass This is normal in primary thrombocytosis, but raised in polycythaemia vera.
• Genetic Studies Philadelphia chromosome is absent (it is present in chronic myeloid leukaemia).
• Imaging Chest Xray and abdominal ultrasound may be indicated to exclude undetected sources of infection or malignancy.

Primary Thrombocytosis²

• Risk Factor Reduction Individualised modification of risk factors should be considered in high risk patients to reducing the risk of thrombotic or haemorrhagic events. Risk factors include:
  • Age of 60
  • Obesity
  • Platelet count greater than 1.5 million per mL (paradoxical increased risk of gastro-intestinal bleeding in young women)
  • Cardiovascular risk factors - smoking, hypertension, hyperlipidaemia
  • Markers of hypercoagulability such as factor V Leiden and antiphospholipid antibodies.
• Cytoreductive drugs Drugs commonly used to reduce the platelet count include hydroxycarbamide (formerly known as hydroxyurea), anagrelide, interferon alfa, or phosphorous-32.^5,6 Hydroxycarbamide is considered to be a suitable compromise between effectiveness and long-term adverse effects.³
• Low-Dose Aspirin - this may be useful in treating patients with symptoms of microvascular occlusion (eg, erythromelalgia).
• Plasmapheresis Blood is removed, filtered to reduce the platelet count, and then transfused back into the circulation. This is used to rapidly reduce platelet count in patients with thrombosis or acute thrombocytosis.

Secondary Thrombocytosis¹

This condition is usually transient and self-limiting, and no treatment is required. Rarely, patients with a pre-existing thrombotic condition such as Kawasaki syndrome, may require aspirin if they develop a reactive thrombocytosis.

In both primary and secondary adult thrombocytosis, a normal lifespan is expected. However, this statement should be considered cautiously in children, as long-term survival studies of children with primary thrombocytosis have not yet been completed. The threat to long-term survival is principally from thrombosis and haemorrhage.