Myeloproliferative disorders

Myeloproliferative disorders occur due to uncontrolled proliferation of a precursor cell. They are forms of bone marrow cancer.

There are specifically 3 myeloproliferative disorders to concern ourselves with:

1. Essential thrombocytosis/thrombocythaemia - proliferation of megakaryocytes.
2. Primary myelofibrosis - proliferation of haematopoietic stem cells (HSCs).
3. Polycythaemia vera - proliferation of erythroid cells.

We have discussed polycthaemia vera separately (click the hyperlink above to access the notes for it). We shall cover essential thrombocytosis and primary myelofibrosis in this CCC.

ESSENTIAL THROMBOCYTOSIS/THROMBOCYTHAEMIA

Essential thrombocytosis is the myeloproliferative disorder resulting from megakaryocyte proliferation → platelet overproduction.

Pathophysiology

The causes of essential thrombocytosis are unclear still. However some important genetic mutations to remember include:

Megakaryocytes derive from HSCs and are produced primarily in the liver, kidney, spleen, and bone marrow in response to thrombopoietin (TPO) but TPO is not necessary. Instead cytokines such as GM-CSF, IL-3, IL-6, IL-11 and even EPO may also trigger proliferation and differentiation of megakaryocytes.

The lineage is as such: HSC → megakaryoblast → megakaryocyte → thrombocyte (platelets).

😷 Presentation

Over 50% of patients are asymptomatic and are diagnosed incidentally.

• Headache
• Dizziness/syncope - due to hyperviscosity.
• Arterial or venous thrombosis - this is sometimes the presenting complication. Manifestations include stroke, MI, PE, DVT.
• Haemorrhage - common sites being intracranial and gastrointestinal. It may seem paradoxical but it is similar to DIC. It usually occurs after a previous bleed, with a mechanism similar to DIC where there is hyperactivation of platelets due to the excess which then leaves a deficiency and increases risk of bleeds. It is also associated with the use of aspirin in large doses (>325mg/day).
• Erythromelalgia - a tender or painful burning sensation ± redness in fingers, palms, heels, toes. It is accompanied with red/blue discolouration of the extremities as well. Pain increases with heat exposure and improves with cold.
• Splenomegaly - causing abdominal discomfort.
• Livedo reticularis - a purple, lace-like rash that gives a mottled purplish discolouration to the skin. It may be blanching or non-blanching. It occurs due to fibrin deposition at the periphery of arterioles.

🔍 Investigations

1. 🥇 FBC - this is the first-line investigation. It will show a platelet count of >450. A platelet count of over >600 is more suggestive of essential thrombocytosis.
1. A repeat test should be performed with a peripheral blood smear included. The peripheral blood smear may show precursor cells or large thrombocytes.
2. 🏆 Bone marrow biopsy - gold-standard to confirm diagnosis if there is thrombocytosis without an identifiable cause. The aspirate is usually dry due to scar tissue buildup.
3. Genetic testing - for JAK2, MLP, CALR are not necessary but may aid the management.

🧰 Management

Management of essential thrombocytosis:

• Antiplatelet therapy
• Aspirin (75mg OD) is usually the first-line option to reduce thrombotic risk.
• Cytoreduction
• Hydroxycarbamide - is the preferred agent to reduce platelet count. It is first-line for high-risk patients.
• Interferon alfa 2b or peginterferon alfa 2a is second-line. It is often used in younger patients

PRIMARY MYELOFIBROSIS

Primary myelofibrosis (PMF) is another myeloproliferative disorder. It is a clonal malignancy thought to originate with HSCs.

Pathophysiology

The causes of PMF are unknown. It is once again linked to mutations of JAK2, MPL and CALR.

Myelofibrosis occurs due to proliferation of marrow fibroblasts. These increase the deposition of reticular fibres (a type of connective tissue fiber) and replace bone marrow. This is due to the response to cytokines such as PDGF and TGF-ß that promote these fibroblasts. TGF-ß also promotes osteoprotegrin formation and inhibits osteoclast proliferation → osteosclerosis.

Bone marrow fibrosis will lead to leukopenia and anaemia but will trigger extramedullary haematopoiesis → hepatomegaly (which can further lead to portal hypertension) and splenomegaly.

There is an increase in bone marrow angiogenesis due to an increase in VEGF and this is another finding

⚠️ Risk factors

• Radiation exposure
• Benzene, toluene and industrial solvent exposure

😷 Presentation

• Constitutional symptoms - such as weight loss, night sweats, low-grade fever, cachexia, fatigue and pruritus. This is due to anaemia and the hypercatabolic state.
• Splenomegaly - this is the cardinal sign. Almost every patient has splenomegaly to some degree but usually quite substantial. It can lead to early satiety, abdominal discomfort.
• Hepatomegaly - present in about 50% of patients.
• Portal hypertension - may occur due to increased hepatic blood flow coupled with decreased vascular compliance. It may lead to ascites, gastric or oesophageal varices, GI bleeding, hepatic encephalopathy.
• Pulmonary extramedullary haematopoiesis - may lead to pulmonary hypertension. This form of extramedullary haematopoiesis is rare and almost exclusively linked to myelofibrosis.
• Joint and bone pain - due to osteosclerosis.
• Bleeding - due to thrombocytopenia.
• Infections - due to leukopenia.

🔍 Investigations

1. 🥇 FBC - this is our first-line investigation. It may indicate anaemia which warrants a peripheral blood smear.
2. Peripheral blood smear - presents with tear-drop poikilocytes on a blood film.
3. Bone marrow aspiration - will be unable to aspirate, leading to a “dry-tap”.
4. 🏆 Bone marrow biopsy - will show bone marrow fibrosis.

🧰 Management

Management of symptomatic PMF:

• If a patient is symptomatic and <50 years old the first-line treatment is myeloablative stem cell transplant. Myeloablative simply means that the transplant uses high-dose chemotherapy to kill cells in the bone marrow including the cancer cells.
• if a patient is symptomatic and >50 years old the first-line treatment is non-myeloablative stem cell transplant.

If unsuitable for stem cell transplant, we have the following options:

• Ruxolitinib - first-line option.
• Thalidomide and prednisolone - second-line option.
• Interferon alfa 2b - in pregnancy when thalidomide is contraindicated.