Myelofibrosis (MF)

Myelofibrosis (MF) is a rare, clonal, hematopoietic stem cell disorder characterized by excessive bone marrow fibrosis, pathological myeloproliferation, disruption of erythropoiesis, and extramedullary hematopoiesis.¹ 

Several somatic mutations occurring in hematopoietic stem cell genes have been identified in patients with MF, including the Janus kinase 2 (JAK2) gene, the calreticulin (CALR) gene, and the myeloproliferative leukemia virus (MPL) oncogene.^2,3 

Although the underlying cause of these somatic mutations is unknown, increased risk is associated with exposure to radiation, contrast agents, and industrial solvents.²

Patients diagnosed with MF present with a diverse heterogeneity of disease manifestations, including severe anemia that may become transfusion dependent, thrombocytopenia or thrombocytosis, leukopenia or leukocytosis, leukoerythroblastosis, and splenomegaly and/or hepatomegaly, each with its own pathogenesis. 

Pathophysiology of Anemia and Hepatosplenomegaly in MF

The pathogenesis of MF-related anemia is not fully understood. While the displacement of medullary erythropoietic tissue with fibrotic scar tissue plays a central role in the pathophysiology of MF-related anemia, it is no longer viewed as the only contributing factor.¹ 

As erythropoietic tissues are driven out of the bone marrow and migrate to the spleen, liver, and other extramedullary sites to continue to produce erythrocytes via extramedullary hematopoiesis, these new sites provide suboptimal environments for erythrocyte production and maturation. This causes inefficient compensation for bone marrow failure and enlargement of the compensating organs.¹ 

Splenomegaly induced by extramedullary hematopoiesis drives splenic sequestration and destruction of circulating erythrocytes, which worsens the already existing anemia. Additionally, increased spleen size corresponds with increased plasma volume, resulting in dilutional anemia.¹

Upregulation of cytokines within the bone marrow induces local and systemic proinflammatory environments, disrupting erythrogenesis in any remaining functional bone marrow cells and causing upregulation of circulating hepcidin. Hepcidin impedes normal iron metabolism, which also further exacerbates anemia.¹

Lastly, certain MF treatments, such as Jakafi® (ruxolitinib), may induce or worsen pre-existing anemia.¹

Patients with MF who are triple negative for CALR, JAK2, and MPL somatic mutations demonstrate an increased likelihood of developing MF-related anemia compared to patients with CALR or MPL mutations.¹

Read more about MF genetics

Pathophysiology of Thrombocytopenia in MF

Thrombocytopenia occurs in patients with MF with an incidence of around 26%, and between 11% and 16% are severe cases.⁴

Thrombocytopenia related to MF also has multiple causative factors similar to those of anemia, including splenic sequestration, treatment-related side effects, and ineffective hematopoiesis.⁵

The number of patients with MF presenting with thrombocytopenia tend to have certain genetic mutations, such as U2AF1 Q157, SRSF2, or TP53 mutations, a deletion at 20q, multiple (3 or more) mutations, or high-risk karyotypes. However, researchers found that while thrombocytopenia in MF may be caused by different underlying genetic mechanisms, these pathophysiologic factors are not uniformly high risk and may not necessarily correlate with worse prognosis. They proposed that patients with MF-related thrombocytopenia could be risk stratified, depending on specific genetic and hematologic factors, such as SRSF2 or TP53 mutations and low serum albumin levels.⁶

Dysfunctional platelets and progressive thrombocytopenia caused by bone marrow failure may increase bleeding risk among patients with MF.⁷ 

Read more about MF risk factors

Pathophysiology of Thrombocytosis and Thrombosis in MF

The underlying pathophysiologic mechanism of MF-related thrombosis is not yet fully understood; however, research suggests that some of the key factors contributing to MF-associated thrombosis include platelet activation resulting in platelet-leukocyte adherence, endothelial activation, and initiation of the coagulation cascade, which also occurs in the two other classic myeloproliferative neoplasms: polycythemia vera (PV) and essential thrombocythemia (ET). PV and ET may progress to secondary MF.⁷ 

Patients with primary MF exhibit higher levels of soluble and platelet P-selectin expression and a higher percentage of platelet-monocyte complexes, indicative of heightened platelet activation. Factors such as CD11b overexpression, increased plasma concentrations of clotting biomarkers (F1+2), and platelet membrane abnormalities may contribute to increased platelet activation. CD11b overexpression, increased F1+2 plasma levels, and alterations in platelet production by megakaryocytes all correlate with JAK2 V617F mutations.⁷

Knock-out murine model experiments analyzing the pathogenesis of thrombosis in ET have shown that platelets produced by altered megakaryocytes are prothrombotic, have increased ability to migrate, and demonstrate increased reactivity to various agonists that prompt platelet aggregation. These ET experiments must be repeated to confirm these aspects of the possible pathogenesis of thrombosis in MF.⁷

Counterintuitively, higher platelet counts may also cause increased bleeding risk. Higher platelet counts promote thrombosis formation, which causes deficient numbers of circulating platelets in the peripheral blood, leading to the inability to effectively repair damaged endothelial blood vessel walls.⁸

Read more about MF etiology

Pathophysiology of Leukocytosis in MF

The development of persistent neutrophilic leukocytosis or persistent absolute monocytosis is a sign of progressing MF, either of primary MF or progression of PV or ET to secondary MF.^9,10 

Two factors promote leukocytosis in patients with MF. The increased production of white blood cells is a normal response of the bone marrow to inflammation, which is progressively heightened due to the upregulation of cytokines in patients with MF.^1,11 Additionally, abnormalities within the bone marrow found in patients with myeloproliferative disorders such as MF trigger leukocytosis.¹¹

Extremely severe leukocytosis rarely occurs in patients with primary MF and is often associated with genetic mutations in RAS, KIT, and EZH2.¹²

Leukocytosis may emerge as a treatment side effect, such as that seen with JAK inhibitors.¹³

Read more about MF prognosis

Pathophysiology of Leukoerythroblastosis in MF

Leukoerythroblastosis, as evidenced on peripheral blood smears by the presence of circulating nucleated red blood cells and myelocytes, occurs in patients with primary MF due to extramedullary hematopoiesis. This happens when nonmarrow organs, such as the liver and spleen, compensate for progressively fibrosing bone marrow.¹⁴ 

Blast transformation and fibrosis progression as seen in leukoerythrocytosis also indicate the progression of PV and ET as they transform into secondary MF.¹⁵

Read more about MF types

References

1. Naymagon L, Mascarenhas J. Myelofibrosis-related anemia: current and emerging therapeutic strategies. Hemasphere. 2017;1(1):e1. doi:10.1097/HS9.0000000000000001
2. Lal A. Primary myelofibrosis: etiology. Medscape. Updated September 21, 2022. Accessed December 30, 2022.
3. Zahr AA, Salama ME, Carreau N, et al. Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies. Haematologica. 2016;101(6):660-671. doi:10.3324/haematol.2015.141283
4. Masarova L, Alhuraiji A, Bose P, et al. Significance of thrombocytopenia in patients with primary and postessential thrombocythemia/polycythemia vera myelofibrosis. Eur J Haematol. 2018;100(3):257-263. doi:10.1111/ejh.13005
5. Sastow D, Mascarenhas J, Tremblay D. Thrombocytopenia in patients with myelofibrosis: pathogenesis, prevalence, prognostic impact, and treatment. Clin Lymphoma Myeloma Leuk. 2022;22(7):e507-e520. doi:10.1016/j.clml.2022.01.016
6. Kuykendall AT, Mo Q, Sallman DA, et al. Disease-related thrombocytopenia in myelofibrosis is defined by distinct genetic etiologies and is associated with unique prognostic correlates. Cancer. 2022;128(19):3495-3501. doi:10.1002/cncr.34414
7. Kc D, Falchi L, Verstovsek S. The underappreciated risk of thrombosis and bleeding in patients with myelofibrosis: a review. Ann Hematol. 2017;96(10):1595-1604. doi:10.1007/s00277-017-3099-2
8. Platelet disorders: thrombocythemia and thrombocytosis. National Heart, Lung, and Blood Institute. Updated March 24, 2022. Accessed December 30, 2022.
9. Geyer JT, Margolskee E, Krichevsky SA, et al. Disease progression in myeloproliferative neoplasms: comparing patients in accelerated phase with those in chronic phase with increased blasts (<10%) or with other types of disease progression. Haematologica. 2020;105(5):e221-e224. doi:10.3324/haematol.2019.230193
10. Ronner L, Podoltsev N, Gotlib J, et al. Persistent leukocytosis in polycythemia vera is associated with disease evolution but not thrombosis. Blood. 2020;135(19):1696-1703. doi:10.1182/blood.2019003347
11. Abramson N, Melton B. Leukocytosis: basics of clinical assessment. Am Fam Physician. 2000;62(9):2053-2060. 
12. Shah S, Talati C, Al Ali N, et al. Investigating patient characteristics and outcomes of myelofibrosis patients with hyperleukocytosis. Blood. 2018;132(Suppl 1):3041. doi:10.1182/blood-2018-99-117834
13. Vasic R, Shi Y, Arruda A, et al. Clinical significance of emergent leukocytosis in patients with myelofibrosis receiving JAK inhibitor therapy. Blood. 2020;136(Suppl 1):22. doi:10.1182/blood-2020-139936
14. Liesveld J. Primary myelofibrosis. MSD Manual Professional Edition. Updated September 2022. Accessed December 30, 2022.
15. Cerquozzi S, Tefferi A. Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors. Blood Cancer J. 2015;5(11):e366. doi:10.1038/bcj.2015.95

Reviewed by Hasan Avcu, MD, on 1/4/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.