Primary myelofibrosis

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Primary myelofibrosis is a condition characterized by the buildup of scar tissue (fibrosis) in the bone marrow, the tissue that produces blood cells. Because of the fibrosis, the bone marrow is unable to make enough normal blood cells. The shortage of blood cells causes many of the signs and symptoms of primary myelofibrosis.

Initially, most people with primary myelofibrosis have no signs or symptoms. Eventually, fibrosis can lead to a reduction in the number of red blood cells, white blood cells, and platelets. A shortage of red blood cells (anemia) often causes extreme tiredness (fatigue) or shortness of breath. A loss of white blood cells can lead to an increased number of infections, and a reduction of platelets can cause easy bleeding or bruising.

Because blood cell formation (hematopoiesis) in the bone marrow is disrupted, other organs such as the spleen or liver may begin to produce blood cells. This process, called extramedullary hematopoiesis, often leads to an enlarged spleen (splenomegaly) or an enlarged liver (hepatomegaly). People with splenomegaly may feel pain or fullness in the abdomen, especially below the ribs on the left side. Other common signs and symptoms of primary myelofibrosis include fever, night sweats, and bone pain.

Primary myelofibrosis is most commonly diagnosed in people aged 50 to 80 but can occur at any age.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Mutations in the JAK2, MPL, CALR, and TET2 genes are associated with most cases of primary myelofibrosis. The JAK2 and MPL genes provide instructions for making proteins that promote the growth and division (proliferation) of blood cells. The CALR gene provides instructions for making a protein with multiple functions, including ensuring the proper folding of newly formed proteins and maintaining the correct levels of stored calcium in cells. The TET2 gene provides instructions for making a protein whose function is unknown.

The proteins produced from the JAK2 and MPL genes are both part of a signaling pathway called the JAK/STAT pathway, which transmits chemical signals from outside the cell to the cell's nucleus. The protein produced from the MPL gene, called thrombopoietin receptor, turns on (activates) the pathway, and the JAK2 protein transmits signals after activation. Through the JAK/STAT pathway, these two proteins promote the proliferation of blood cells, particularly a type of blood cell known as a megakaryocyte.

Mutations in either the JAK2 gene or the MPL gene that are associated with primary myelofibrosis lead to overactivation of the JAK/STAT pathway. The abnormal activation of JAK/STAT signaling leads to overproduction of abnormal megakaryocytes, and these megakaryocytes stimulate another type of cell to release collagen. Collagen is a protein that normally provides structural support for the cells in the bone marrow. However, in primary myelofibrosis, the excess collagen forms scar tissue in the bone marrow.

Although mutations in the CALR gene and the TET2 gene are relatively common in primary myelofibrosis, it is unclear how these mutations are involved in the development of the condition.

Some people with primary myelofibrosis do not have a mutation in any of the known genes associated with this condition. Researchers are working to identify other genes that may be involved in the condition.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is generally not inherited but arises from gene mutations that occur in early blood-forming cells after conception. These alterations are called somatic mutations.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Primary myelofibrosis is a rare condition that affects approximately 1 in 500,000 people worldwide.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormality of bone marrow cell morphology · Very frequent (99-80%)

An anomaly of the form or number of cells in the bone marrow.

Abnormal megakaryocyte morphology · Frequent (79-30%)

Any structural anomaly of megakaryocytes. Mature blood platelets are released from the cytoplasm of megakaryocytes, which are bone-marrow resident cells.

Abnormality of blood and blood-forming tissues · Frequent (79-30%)

An abnormality of the hematopoietic system.

Anemia · Frequent (79-30%)

A reduction in erythrocytes volume or hemoglobin concentration.

Constitutional symptom · Frequent (79-30%)

A symptom or manifestation indicating a systemic or general effect of a disease and that may affect the general well-being or status of an individual.

Fatigue · Frequent (79-30%)

A subjective feeling of tiredness characterized by a lack of energy and motivation.

Hepatomegaly · Frequent (79-30%)

Abnormally increased size of the liver.

Hepatosplenomegaly · Frequent (79-30%)

Simultaneous enlargement of the liver and spleen.

Other findings in the same source

From: Orphanet

Additional reported features include Pallor (Frequent (79-30%)); Splenomegaly (Frequent (79-30%)); Thrombocytopenia (Frequent (79-30%)); Abnormal bleeding (Occasional (29-5%)); Abnormal thrombosis (Occasional (29-5%)); Anorexia (Occasional (29-5%)); Arterial thrombosis (Occasional (29-5%)); Bone marrow hypercellularity (Occasional (29-5%)); Easy fatigability (Occasional (29-5%)); Ecchymosis (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Primary myelofibrosis is Oncology, with a oncologist and relevant organ specialist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics; Relevant organ specialist / Surgical Oncology as indicated.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Has the exact tumour type been confirmed, and is staging relevant?
• What is the goal of each proposed treatment option?
• How will side effects, daily function and supportive care be addressed?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Primary myelofibrosis. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.