During initial stages of the disease, thrombocytosis accounts for symptoms like thrombosis and thromboembolism. Poikilocytosis with teardrop-shaped erythrocytes may also be detected.

As the disease progresses, blood cell depletions and consequences of anemia, immune deficiency and coagulation disorders manifest, and this still happens before considerable bone marrow fibrosis becomes evident. Thus, patients may present with symptoms associated with either of those conditions. The following list may provide some guidance to this end:

• Patients suffering from mild to moderate anemia may report fatigue and weakness, problems with concentration and reduced performance as well as headaches. Dyspnea, tachycardia and dizziness are experienced in case of severe anemia.
• Disturbances in leukopoiesis render the patient prone to infections, e.g., to upper respiratory infection and urinary tract infection. Consequently, they may present with fever, night sweats and chills.
• PMF patients may claim a tendency to bleed. Gastrointestinal hemorrhages, hematochezia and melena, are commonly reported.

Hepatosplenomegaly may cause upper abdominal pain, portal hypertension and ascites. In some cases, gastrointestinal symptoms like feelings of fullness in the epigastric region and early satiety may prompt the patient to seek medical attention.

Hyperuricemia, gout and nephrolithiasis have been observed in PMF patients and may be considered consequences of increased extramedullary hematopoiesis or symptoms of tumor lysis syndrome [9].

In general, laboratory analyses of blood samples are carried out in order to clarify the causes of persistent fatigue, recurrent infections, thrombosis or bleeding diathesis, hepatosplenomegaly or any other of the aforementioned symptoms. During early stages of the disease, increased blood cell counts may be observed, and they correspond to the hypercellulary stage of the disease [9]. In contrast, pancytopenia is a common result in patients suffering from advanced PMF. Serum concentrations of lactate dehydrogenase are usually elevated. CD34+ cell counts are highly diagnostic, but they are not generally realized. Thus, although the aforementioned findings may be highly suspicious of PMF, it is often difficult to rule out differential diagnoses like other chronic myeloproliferative disorders. Histopathological analysis of a tissue sample obtained by bone marrow biopsy are required to support the tentative diagnosis of myelofibrosis. Such examinations may also be helpful to distinguish primary from secondary myelofibrosis.

Further diagnostic measures may be applied to reinforce the diagnosis of PMF. Plain radiography, for instance, typically reveals osteosclerotic lesions. Increased bone density may not be observed evenly in all parts of the skeleton or over whole bones. More complex imaging techniques, especially magnetic resonance imaging, allow for the depiction of bone marrow fibrosis. However, and as has been indicated above, myelofibrosis only develops during late stages of the disease. The degree of fibrosis observed in the proximal femur is generally considered a good measure of disease severity.

Molecular diagnostic techniques may allow for the detection of the underlying gene defect, but genes may be similarly affected in different chronic myeloproliferative diseases.

Advances with regards to the disease' etiology have allowed for the development of therapeutic agents for PMF patients. Since the majority of affected individuals shows a mutation of the gene encoding for JAK2, they may benefit from inhibitors of the corresponding pathway. Ruxolitinib, a Janus kinase inhibitor, has been approved to this end. But although ruxolitinib treatment may slow down disease progression and improve life quality by relieve of symptoms [10], myelofibrosis cannot be reversed by means of drug therapy. According to current knowledge, this can only be achieved by realizing hematopoietic stem cell transplantation. Non-myeloablative stem cell transplantation may be considered for patients aged 55 years and older.

In case the latter a stem cell transplantation not feasible, supportive therapy can be provided:

• Low-dose corticosteroid therapy or application of immunomodulators like lenalidomide may ease symptoms associated with PMF.
• If patients claim pain, analgesics should be prescribed.
• Infections may be treated with antimicrobial compounds.
• Transfusion of blood products should be considered in case of anemia or thrombocytopenia.
• Splenectomy may be indicated in case of portal hypertension or splenic infarction. Of note, intractable anemia may also result from splenomegaly and thus, splenectomy may be the therapeutic approach of choice in these cases.
• In general, extramedullary hematopoiesis may be reduced by means of radiation therapy.

Of note, watchful waiting is often recommended for asymptomatic patients.

PMF is associated with a reduced life expectancy. About 50% of PMF patients are expected to live beyond five years after diagnosis, only about 20% beyond a decade. However, the mean age of PMF patients - the disease is typically diagnosed in the elderly - has to be taken into account when interpreting this data. Common causes of death are infections and cardiovascular failure that do, in turn, result from bone marrow failure. Leukemic transformation, i.e. progression to acute myeloid leukemia, has also been reported.

The prognosis may vary depending on the underlying genetic defect. For instance, the above mentioned insertion of about 50 base pairs into the CALR gene is presumably related to longer survival times than a deletion of 5 base pairs in that same gene. In general, an abnormal karyotype, evidence of neoangiogenesis, severe anemia, leukopenia or leukocytosis as well as thrombocytopenia are considered poor prognostic factors. Patients who present with more than one of those conditions may live for less than one year; those who present neither may live for more than ten years.

High incidence rates among survivors of the atomic bombings hint at radiation as a possible etiologic factor [2], but the precise trigger of hematopoietic stem cell transformation is still unknown. However, genome analyses revealed certain anomalies that are frequently shown by PMF patients.

A determined somatic mutation of the gene encoding for cytoplasmic Janus kinase 2 (JAK2) may be encountered in about two-thirds of PMF patients. This gene is located on the short arm of chromosome 9, and the aforementioned mutation causes the substitution of valine for phenylalanine at position 617. This change in the amino acid sequence of JAK2 alters its susceptibility to regulatory mediators, which eventually leads to an uncontrolled proliferation of the affected stem cell and its clones. Of note, other, less frequent mutations of that gene have been described in PMF patients.

Furthermore, considerable shares of PMF patients present somatic mutations of the gene encoding for the thrombopoietin receptor. This proto-oncogene is generally referred to as myeloproliferative leukemia protein (MPL), and the respective mutation provokes constitutive activation of the receptor and subsequent formation of increased quantities of megakaryocytes. These cells may release growth factors that contribute to the pathogenesis of PMF [1].

Those patients that do neither present mutations of JAK2 nor MPL are likely to show a defect concerning the gene encoding for calreticulin (CALR) [3] [4]. In general, mutations are located in exon 9 of this gene, and they may consist in either deletions or insertions of several base pairs. Distinct mutations have been described, whereby an insertion of about 50 base pairs seems to be the most common one. Calreticulin interacts with thrombopoietin receptors and thus has pathophysiological consequences similar to those described in the previous paragraph.

Besides, mutations of JAK2, MPL and CALR have also been observed in patients suffering from other myeloproliferative disorders, e.g., essential thrombocytosis and polycythemia vera.

Other mutations have been related to PMF, too. They are listed elsewhere [5].

The annual incidence of PMF has been reported to be less than 1 per 100,000 inhabitants [6]. The disease is most commonly diagnosed in Caucasians, males and the elderly. Few PMF patients are younger than 50 years and if pediatric patients are affected, symptom onset usually occurs in infancy. Interestingly, gender predilection seems to reverse in the younger population.

Particularly high incidence rates have been reported for survivors of the atomic bombings in Japan; Ashkenazi Jews are generally prone to develop myeloproliferative malignancies [5].

Release of cytokines by clones of the degenerated stem cell, particularly by megakaryocytes, is a central pathophysiological process underlying bone marrow fibrosis. Besides bFGF and PDGF, transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) are produced by these cells and alter gene expression and signaling pathways in fibroblasts and endothelial cells, among other cell types.

• Stimulation of fibroblast proliferation, synthesis of extracellular matrix components and inhibition of collagenase lead to myelofibrosis. This process is further aggravated by a reduction of matrix metalloproteinase activity and by increase of concentrations of tissue inhibitors of metalloproteinases [7].
• TGF-β does not only contribute to the aforementioned events, but also induces an increased production of osteoprotegerin and hinders osteoclast proliferation and this eventually causes osteosclerosis.
• Neoangiogenesis can also be observed and primarily results from VEGF release. Although neoangiogenesis is not considered the main feature of PMF, it is generally detectable before fibrosis sets in.

In the long term, symptoms of bone marrow failure manifest, i.e., patients become susceptible to infections, develop anemia and tend to show hemorrhages. This broad range of complications is the result of disturbances in erythropoiesis, leukopoiesis and thrombopoiesis.

Abnormal hematopoietic stem cell trafficking, homing to peripheral organs and proliferation in these organs are intermediate steps leading to extramedullary hematopoiesis, which can be observed in advanced stages of PMF [8]. This behavior is only shown by degenerated stem cells, by clones of that cell that presents with gene defects. Thus, extramedullary hematopoiesis does by no means compensate for bone marrow deficits. It typically occurs in sites of fetal hematopoiesis, e.g., in liver and spleen. In case those organs are affected, the patient presents with hepatosplenomegaly. However, local mass effects due to excess proliferation of degenerated cells may also occur elsewhere in the body, and may provoke compression of nervous tissue, blood or lymphatic vessels. Symptoms vary depending on the affected organ and may range from portal or pulmonary hypertension and effusion to neurological deficits.

No specific measures can be recommended to prevent PMF.

Primary myelofibrosis (PMF) is a chronic myeloproliferative disorder and thus pertains to the same group of diseases as chronic myeloid leukemia, essential thrombocytosis and polycythemia vera, among others [1]. These disorders are characterized by transformation and subsequent proliferation of a hematopoietic stem cell that shows an altered susceptibility to regulatory growth factors. Accordingly, they are classified as clonal hematopoietic malignancies. PMF is the most severe, but fortunately also the rarest chronic myeloproliferative disease.

Transformed stem cell clones release a variety of growth factors, e.g., basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF). This is the pathophysiological basis of PMF symptoms like myelofibrosis and thrombocytosis. As a consequence of the altered microenvironment in the bone marrow, stem cells are mobilized, reach the circulation and peripheral organs. They subsequently colonize these organs, mainly liver and spleen, which results in extramedullary hematopoiesis and hepatosplenomegaly.

Knowledge about the disease's etiology acquired during recent years has allowed for the development of drugs that permit a causative therapy. The respective compounds inhibit those enzymes that are overexpressed owing to gain-of-function mutations. Such treatment relieves symptoms and decelerates disease progression. Nevertheless, stem cell transplantation is often required in later stages of PMF and is the only treatment option with a potential for cure. Still, the disease significantly reduces the patient's life expectancy and mean survival times are about five years.

Primary myelofibrosis (PMF) is a chronic disease characterized by excess proliferation of hematopoietic stem cells, extramedullary hematopoiesis, progressive fibrosis of the bone marrow and possible failure of peripheral organs. PMF is a hematopoietic malignancy that shows certain similarities to diseases like chronic myeloid leukemia and polycythemia vera.

The aforementioned events occur in distinct stages of the disease:

• Malignant degeneration of a hematopoietic stem cell is the initial event. Owing to mutations, this cell loses its susceptibility to regulatory mediators and starts to divide in an uncontrolled manner.
• Hugh quantities of stem cell clones release cytokines like basic fibroblast growth factor and platelet-derived growth factor, and these substances mediate stem cell mobilization (and subsequent colonization of peripheral organs like liver and spleen) and fibroblast proliferation (which leads to bone marrow fibrosis).
• Hematopoiesis in the bone marrow becomes increasingly insufficient and patients develop anemia, recurrent infections and coagulation disorders.
• Liver, spleen and other organs may swell and cause local mass effects, e.g., upper abdominal pain and ascites.

Transplantation of hematopoietic stem cells is often required to reverse bone marrow fibrosis, and is indeed the only treatment option with a potential for cure. It may, however, not be feasible in the elderly. Here, drug therapy and symptomatic treatment of PMF-associated symptoms are indicated. These may comprise administration of ruxolitinib and immunomodulatory compounds, transfusion of blood products, surgical removal of the spleen and radiation therapy.

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