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Primary Myelofibrosis pathogenesis and clinical findings

Primary Myelofibrosis: Pathogenesis and clinical findings Legend: Published March 30, 2019 on www.Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications thecalgaryguide.com Author: Tony Gu Reviewers: Naman Siddique Sonia Cerquozzi* Man-Chiu Poon* * MD at time of publication Definitions: Constitutive activation – Constant expression of gene Extramedullary hematopoeisis – red blood cell production outside of bone marrow Somatic mutations in genes that drive cancerous replication (e.g., JAK2, CALR, MPL) within hematopoietic stem cells Non-driver mutations in other myeloid genes (e.g., LNK, CBL, TET2, ASXL1, IDH) Constitutive activation of cellular proliferation pathways ↑ cell signaling ↑ gene transcription and expression Cellular proliferation and resistance to apoptosis Proliferation of abnormal megakaryocytes ↑ neutrophil engulfment by megakaryocytes ↑ growth factor release by megakaryocytes Stimulation of fibroblasts Stimulation of endothelial cells New blood vessel formation ↑ osteoprotegerin Unbalanced osteoblast proliferation Osteosclerosis Fibrosis of the bone marrow Anemia Bleeding and bruising Infections Fatigue and pallor Bone pain Increased cell turnover Tumor lysis syndrome Cachexia, night sweats, fever/chills, malaise Expanding marrow pushing against bone Extramedullary hematopoiesis Hepatomegaly Portal hypertension Splenomegaly ↑ LDH Thrombocytosis Leukocytosis Secretion of coagulation inducing cytokines Arterial and venous thromboembolism ↓ blood cell production & leukoerythroblastosis Thrombocytopenia Leukopenia ↑ K+, PO4 2-, uric acid ↓ Ca2+ Bone pain Periostitis Immature granulocyte and erythroid precursors with blasts ↑ cytokine production (+) ↑ sequestration of blood cells Disseminated intervascular coagulation (see MAHA slide) Definitions: Periostitis – Inflammation of the membrane surrounding bone Osteosclerosis – Abnormal hardening and increased in density of bone