Primary Thrombocytosis

Synonyms: essential thrombocythaemia, essential thrombocytosis, primary thrombocythaemia.

Primary thrombocytosis is a chronic myeloproliferative disorder. There is sustained megakaryocyte proliferation that causes an increased number of circulating platelets. It was seen as a monoclonal disorder that involved pluripotent stem cells but recent studies suggest that in some patients it may be polyclonal. Features include a platelet count greater than 600x10⁹/L, megakaryocyte hyperplasia, splenomegaly and a tendency to both thrombosis and haemorrhage. Platelet survival is normal but function is not.

Other causes of raised platelets include as a reaction to stress, especially haemorrhage and as a component of polycythaemia rubra vera.

• An American study has reported an incidence of 2.38 cases per 100,000 population per year.¹
• The median age at diagnosis is 60 years but up to 20% of patients are younger than 40.
• 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.
• There are usually no genetic factors but a thrombopoietin production or receptor abnormality can cause familial disease.

• Between a quarter and a third of patients have no symptoms at diagnosis.
• The remainder report vasomotor symptoms or complications from thrombosis or haemorrhage.
• Most symptomatic patients have symptoms related to small or large vessel thrombosis. Some present with bleeding.
• It can present with neurological symptoms or complications of pregnancy.

Thrombotic symptoms

• Thrombosis of large veins and arteries is common and may cause occlusion of the leg, coronary and renal arteries. Other arteries may also be involved.
• Venous thrombosis of the splenic, hepatic, leg and pelvic veins may occur. Priapism is rare.
• Pulmonary hypertension may result from thromboembolism.

Haemorrhage

• The gastrointestinal tract is the commonest site to be involved. Around 40% of the patients have duodenal arcade thrombosis that causes sloughing of the duodenal mucosa, simulating a duodenal ulcer.
• Other sites of bleeding include the skin, eyes, gums, urinary tract, joints and brain.
• Bleeding is usually not severe and only rarely requires transfusion.
• Bleeding is unusual unless the platelet count exceeds 1000x10⁹/L.

Neurological symptoms

• Headache is the commonest neurological presentation.
• Occlusion of tiny vessels in the digits causes digital pain, gangrene, or erythromelalgia. Erythromelalgia produces a burning pain and dusky extremity congestion.
• The pain is aggravated by heat and relieved by cold. A single aspirin may provide relief for several days.
• Patients also report paraesthesia and episodes of transient ischaemic attacks. Transient neurological symptoms include the following:
  • Unsteadiness
  • Dysarthria
  • Dysphoria
  • Vertigo
  • Dizziness
  • Migraine
  • Syncope
  • Scotoma
  • Seizures

Constitutional symptoms

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

Complications of pregnancy

• There is a predisposition to spontaneous abortions.
• Placental infarctions may cause intrauterine growth retardation and fetal death.
• Most fetal loss is during the first trimester.
• A history of spontaneous abortion is the greatest risk factor for further spontaneous abortions.
• Excessive bleeding during delivery is rare.
• Patients with successful pregnancies show a decrease in platelet count.

Examination

Between 40 and 50% of patients have splenomegaly and 20% have hepatomegaly. Otherwise there are no common findings unless as a result of complications.

• Reactive thrombocytosis (or thrombocythaemia)
• Polycythaemia rubra vera (haematocrit is also raised)

Full blood count

• The essential feature is a sustained, unexplained thrombocytosis.
• Leukocytosis, erythrocytosis and mild anaemia may be found.
• The peripheral blood may show occasional immature precursor cells (e.g. myelocytes, metamyelocytes). Large platelets (thrombocytes) are typically identifiable on routine peripheral blood smear.
• Mild basophilia and eosinophilia sometimes occur.

Bone marrow

• Around 90% show an increase in bone marrow cellularity.
• Megakaryocytic hyperplasia is common.
• Giant megakaryocytes are common. Clusters of megakaryocytes may be seen but significant dysplasia of the megakaryocytes is unusual.
• Hyperplasia of granulocyte and reticulocyte precursors is common.
• Bone marrow reticulin is usually increased but collagen fibrosis is uncommon.
• Iron stores may be depleted. This may from gastrointestinal bleeding or menorrhagia. However in this as in other myeloproliferative disorders, bone marrow iron stain results may be negative even when other studies do not support the diagnosis of iron deficiency.

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, ADP and collagen but not to ristocetin and arachidonic acid.
• Some patients may have spontaneous platelet aggregation.

Biochemistry

• About a quarter of patients have elevated uric acid.
• About a quarter of patients have elevated vitamin B12 levels.
• There may be elevated levels of potassium, phosphate and acid phosphatase.
• Anti-phospholipid antibodies increase the risk of thrombosis.²

Imaging

Ultrasound may be useful to assess the spleen, especially when it is not palpable. To be palpable it must be at least twice the normal size.

Other tests

• Elevated C-reactive protein and fibrinogen suggest secondary thrombocytosis as they are acute-phase reactants.
• Red cell mass is elevated in polycythaemia vera but normal in primary thrombocytosis.

Risk factors

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

• Those over 60 years old are at greater risk than younger patients and so merit more aggressive treatment.³ 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.⁴
• History of thrombosis requires attention to prophylaxis.
• Platelet count in excess of 1500x10⁹/L, is paradoxically associated with an increased risk of GI tract bleeding in young women.
• Obesity needs attention.
• 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.

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, interferon alfa, or phosphorous-32.
  In emergencies, plateletphoresis 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.⁵
• Anagrelide is an imidazoquinazoline drug that inhibits platelet aggregation but it also decreases platelet production.
• Interferon alfa 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.
• Phosphorous-32 irradiates the bone marrow.
• Platelet counts are reduced to less than 600x10⁹/L in 90% of cases after 3 months of treatment. The dose is adjusted to achieve a platelet count within the target range of less than 450x10⁹/L.

• Thrombosis may be serious and fatal.
• Bleeding is usually from the gastrointestinal tract and is usually far less serious.
• Transformation to acute myeloid leukaemia occurs in 0.5 to 5% of patients. In a series of 2316 cases retrospectively collected in Italy, the rate of transformation to AML or myelodysplastic syndrome was 1% in patients left untreated. Use of interferon 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.

Patients with primary thrombocytosis have a 10 year survival rate of between 64%⁶ and 80%⁷ which may not be significantly different from that of the age-matched general population. Death occurs from thrombotic complications.
In young women there seems little that can be done to affect the pattern of recurrent miscarriage but the prognosis for life and health of the woman is remarkably benign.⁸