Primary Myelofibrosis

Primary myelofibrosis (PMF) is a chronic myeloproliferative disease caused by unknown abnormal hematopoietic stem cells; marked bone-marrow fibrous-tissue hyperplasia and extramedullary hematopoiesis are the pathologic basis of PMF.

Common Symptoms

Coma; lymphadenopathy; ascites; disturbance of consciousness; abdominal pain; paraplegia; fatigue; raised intracranial pressure; emaciation; proteinuria

Causes and Pathogenesis

(A) Etiology: In animal experiments MF can be induced by certain chemicals, drugs and viruses; anti-marrow serum injection also successfully establishes MF models. But human PMF cause is unknown. Some PMF patients were exposed to toluene, benzene or ionizing radiation; populations in the Japanese atomic-bomb radiation zone have 18-fold PMF incidence vs unexposed. (B) Pathogenesis: PMF is a clonal blood disease originating from a single pluripotent stem cell. PMF hematopoietic cells express one type of G-6PD isoenzyme (either A or B). X-linked RFLP analysis and calcitonin-gene methylation on chromosome 11 prove peripheral blood cells are clonal. In advanced PMF, N-ras codon-12 mutation and p53 suppressor-gene inactivation are found. In vitro stem-cell culture shows markedly increased megakaryocyte progenitors (CFU-MK) in peripheral blood and marrow; other progenitors (CFU-GM, CFU-E, BFU-E, CFU-GEMM) are also elevated to varying degrees; some report 10-20-fold increase. Combined with clinical transformation to other MPDs and to AML/ALL, these support IMF as clonal hematopoietic-stem-cell disease. Marrow fibrosis is not neoplastic: in fibroblast culture, patient CFU-F equals normal; non-hematopoietic cells including fibroblasts express both G-6PD isoenzymes without clonal chromosomal abnormalities. Thus abnormal fibroblast proliferation is a secondary reaction to clonal hematopoietic proliferation. Also, MF may disappear after allogeneic BMT, long-term chemotherapy or alpha-interferon. In primary MF, marrow megakaryocytes are markedly hyperplastic; growth factors synthesized/stored in alpha granules - PDGF, EGF, ECGF, bFGF, beta-TGF and calmodulin - promote fibrous hyperplasia. PDGF is key (mitogenic, drives fibroblasts into cycle, stimulates proliferation and collagen secretion). Recent studies show beta-TGF is the main regulator of collagen deposition in PMF. Platelet factor 4 (PF4) released by megakaryocytes reduces collagen degradation by inhibiting collagenase. Thus megakaryocyte hyperplasia and released cytokines are important in PMF pathogenesis; early PMF marrow slides invariably show marked megakaryocyte hyperplasia. TNF-alpha/TNF-beta and IL-1 released by marrow cells also stimulate fibroblast proliferation. Immune abnormalities mediate fibrous hyperplasia: some PMF sera contain autoantibodies (ANA, RF, anticardiolipin); Coombs positive; circulating immune complexes, complement and immunoglobulins elevated; marrow plasmacytoid lymphocytes increased; glucocorticoids have some efficacy. A few reports of MF with SLE, polyarteritis nodosa, scleroderma and amyloidosis. Some think immune complexes bind platelets via Fc receptors, triggering PDGF release and fibrous hyperplasia - thus some PMF is an immune disorder unrelated to clonal stem-cell disease, called autoimmune myelofibrosis. Extramedullary hematopoiesis mechanism: early literature emphasized marrow fibrous hyperplasia gradually reduces hematopoietic cells; as compensation, fetal hematopoietic organs (spleen, liver, nodes) take over hematopoiesis. Pathology confirms hematopoietic function; splenic venous CFU-GM is higher than splenic arterial/peripheral blood. But compensatory theory cannot explain myeloid metaplasia when PMF early hematopoiesis is normal or even hyperplastic. Some authors propose extramedullary hematopoiesis results from abnormal hematopoietic cells escaping marrow and lodging in other organs. Morphology confirms massive type-IV collagen deposition/fibrosis in marrow sinusoids, destroying sinus wall integrity. Moreover, extramedullary hematopoiesis never dominates even in late PMF.

Treatment

Drug therapy, supportive therapy

Preventive Measures

1. Avoid radiation and chemicals such as benzene/lead; occupationally exposed workers must strictly follow protection. 2. Strengthen nutrition with protein and vitamins; eat kidney-nourishing/blood-enriching foods such as walnuts, jujube and peanuts - suitable for anemia, weakness and post-chemo marrow suppression. 3. Regular lifestyle, balance work/rest, moderate diet; avoid excessive fried/grilled/burnt/processed foods.

Department to Visit

It is recommended to visit the Hematology department; an appointment can be booked on this platform before the visit.

Warm reminder: The above information is for health science reference only and cannot replace professional medical diagnosis. If you have related symptoms, please seek medical attention at a regular hospital promptly.