Myelofibrosis (MF)

Myelofibrosis (MF) is a rare, hematological malignancy belonging to a group of blood cancers called myeloproliferative neoplasms (MPNs). It is characterized by abnormal development and function of bone marrow cells, which leads to an excessive accumulation of fibrous tissue in the bone marrow.¹

MF can develop on its own (primary MF) or may be secondary to other diseases, such as polycythemia vera (PV) and essential thrombocythemia (ET), in which case it is called post-PV/ET MF.² Although the ages and symptoms of patients presenting with primary MF (PMF) vary widely, the vast majority are older than 60 years and have anemia and symptoms of extramedullary hematopoiesis.³ Other symptomatic complications may arise related to disease progression, such as hepatomegaly, splenomegaly, portal hypertension, osteosclerosis, and thromboembolic complications.  

Extramedullary Hematopoiesis 

In extramedullary hematopoiesis, hematopoietic cells develop beyond the bone marrow medullary space.⁴ In PMF, extramedullary hematopoiesis usually develops in the spleen, liver, and the lymph nodes. Other, less common sites are the central nervous system, adrenal glands, kidneys, perirenal soft tissues, breasts, peritoneum, and gastrointestinal tract.^4,5 

It is hypothesized that the constitutive mobilization of CD34+ cells into the peripheral circulation is related to the pathophysiology of extramedullary hematopoiesis. The seeding of extramedullary locations is most likely the result of this dysregulation of hematopoietic stem cell trafficking.⁵

The symptoms associated with extramedullary hematopoietic masses develop when the masses compress adjacent structures or cause an affected organ to malfunction. Depending on the location of the masses, bleeding in the gastrointestinal system, spitting or coughing up blood, seizures, or spinal cord compression may develop.^1,2

Read more about MF signs and symptoms

Hepatomegaly and Splenomegaly 

Hepatomegaly and splenomegaly are considered the 2 primary manifestations of MF, caused primarily, but not entirely, by extramedullary hematopoiesis. Splenomegaly may be caused by the sequestration of immature myeloid cells in the spleen or by other processes that are unclear. More than 80% of people with MF have palpable, sometimes massive splenomegaly, which can cause a variety of physical symptoms, such as generalized abdominal discomfort, left upper quadrant or subcostal pain, and early satiety. With worsening of splenomegaly, severe generalized abdominal pain may develop, and the clinical picture resembles one of acute abdomen. In some cases, splenic infarcts develop.⁶

In various studies, hepatomegaly has been reported in 39% to 65% of patients with MF at diagnosis. Hepatomegaly can lead to abnormal levels of liver enzymes, features of coagulopathy, and abdominal complaints.⁶ 

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Portal Hypertension

In myelofibrosis, the liver is a principal site of extramedullary hematopoiesis. Noncirrhotic portal hypertension, which presents as ascites and/or variceal hemorrhage, is a significant clinical symptom of hepatic extramedullary hematopoiesis. Microvascular or macrovascular clot, injury, and loss of small and large portal veins are thought to be the causes of portal hypertension.⁷ 

MF is the most common cause of massive splenomegaly and may lead to portal hypertension due to increased hepatic blood flow (or intrahepatic venous obstruction/stasis). This complication, which affects approximately 7% of patients with MF, can manifest as ascites or as esophageal or gastric varices. Variceal bleeding can result in catastrophic hemorrhage.⁶

Read more about MF life expectancy

Bleeding and Thromboembolic Complications

As MF progresses, thrombocytopenia develops, and impaired platelet function can cause easy bleeding. This is especially important if any surgical procedure is being contemplated.⁸ 

One-fourth of patients with PMF experience bleeding, which can range from mild cutaneous petechiae to fatal gastrointestinal bleeding. Acquired factor V deficiency, disseminated intravascular coagulation, esophageal varices, and peptic ulcer disease may also occur, and these contribute to bleeding as well.⁹

The risk of thromboembolic events tends to be lower in patients with MF (especially primary MF) than in those with PV or ET. However, cardiovascular, thromboembolic, and hemorrhagic events are frequent in patients with MF. In fact, according to multiple researchers, thromboembolic and hemorrhagic events are among the leading causes of mortality in patients with MF.⁶ Overt thromboembolism is a frequent presentation of PMF, particularly in uncommon sites.¹⁰ 

Read more about MF risk factors

Osteosclerosis

Inflammation of the connective tissue surrounding the bones and hardening of the bone marrow can develop as a consequence of MF and cause excruciating pain and tenderness in the bones and joints.¹ 

Osteosclerosis, a diffuse condition that affects the entire axial and appendicular skeleton, is seen in 30% to 70% of cases of PMF. Endosteal sclerosis causes cortical thickening in the long bones. Periosteal reaction is uncommon, and when it does occur, it is typically seen at the metaphyses of the distal femur and proximal tibia.¹⁰ 

Osteosclerosis in patients with PMF can progress to bone marrow failure, with many disease-related complications.¹¹

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Acute Myeloid Leukemia

Myelofibrosis, and especially PMF can transform into acute myeloid leukemia, which carries a poor prognosis. According to studies, this happens in 5% to 10% of all cases and in 20% of patients with PMF over a 10-year period.¹² 

In the largest single series of patients with PMF reported to date, leukemic change developed in 91 of 2333 consecutive patients (3.9%). Most frequently, leukemic transition occurs within the first 10 years after diagnosis. It should be noted that given the abnormal blood cell counts, morphologic abnormalities, and severe bone marrow fibrosis found in all patients with PMF, leukemic transformation may be challenging to diagnose. In these situations, the diagnosis is based on bone marrow biopsy showing an increase in blasts of 20% or more or biopsy of extramedullary leukemic deposits.³ 

The probability that leukemia (mostly secondary acute myeloid leukemia) will develop tends to increase with time, and patients with secondary acute myeloid leukemia have a dismal prognosis. Rarely, leukemic transformation can appear as granulocytic sarcomas (also known as chloromas) at any anatomical site.⁶ 

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​​Gout

In gout, uric acid (a byproduct of purine metabolism that is naturally present in the body) forms needle-like crystals in the joints, causing sharp joint pain, swelling, and inflammation. The body makes uric acid when it breaks down foods like organ meats, seafood, and steak. Patients with MF make more uric acid than normal. This build-up can lead to uric acid crystallization and symptoms of gout. ^1,13 

Immunodeficiency and Infections

One-half of patients with primary MF have abnormalities of humoral immunity. A spectrum of autoantibodies and circulating immune complexes can be seen, and amyloidosis may also develop. Immune dysfunction may lead to infections, most often pneumonia.⁹ 

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References

1. Myelofibrosis facts. Leukemia & Lymphoma Society. Accessed December 31, 2022.
2. Primary myelofibrosis. National Organization for Rare Disorders (NORD). Accessed December 31, 2022.
3. Abdel-Wahab OI, Levine RL. Primary myelofibrosis: update on definition, pathogenesis, and treatment. Annu Rev Med. 2009;60:233-245. doi:10.1146/annurev.med.60.041707.160528
4. Yassin MA, Nashwan A, Mohamed S. Extramedullary hematopoiesis in patients with primary myelofibrosis rare and serious complications. Blood. 2016;128 (22):5490. doi: https://doi.org/10.1182/blood.V128.22.5490.5490
5. Mohyuddin GR, Yacoub A. Primary myelofibrosis presenting as extramedullary hematopoiesis in a transplanted liver graft: case report and review of the literature. Case Rep Hematol. 2016;2016:9515404. doi:10.1155/2016/9515404
6. Mughal TI, Vaddi K, Sarlis NJ, Verstovsek S. Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes. Int J Gen Med. 2014;7:89-101. doi:10.2147/IJGM.S51800
7. Sherman MS, Samore WR, Pratt DS. Myelofibrosis and portal hypertension: the case for primary variceal screening. ACG Case Rep J. 2020;7(2):e00333. doi:10.14309/crj.0000000000000333 
8. Myelofibrosis. Mayo Clinic. Accessed December 31, 2022.
9. Lal A. Primary myelofibrosis clinical presentation. Medscape. Updated September  21, 2022. Accessed December 31, 2022.
10. Oon SF, Singh D, Tan TH, et al. Primary myelofibrosis: spectrum of imaging features and disease-related complications. Insights Imaging. 2019;10:71. https://doi.org/10.1186/s13244-019-0758-y
11. Karagianni A, Ravid K. Myeloproliferative disorders and their effects on bone homeostasis: the role of megakaryocytes. Blood. 2022;139(21):3127-3137. doi:10.1182/blood.2021011480
12. Mannelli F. Acute myeloid leukemia evolving from myeloproliferative neoplasms: many sides of a challenging disease. J Clin Med. 2021;10(3):436. doi: 10.3390/jcm10030436
13. Myelofibrosis complications. WebMD. Reviewed October 30, 2020. Accessed December 31, 2022. 

Reviewed by Debjyoti Talukdar, MD, on 12/31/2022.

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Harshi Dhingra, MD

Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.