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26 Cards in this Set
- Front
- Back
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Polycythemia vera overview
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Clonal disorder
RBC production is independent of erythropoietin and its receptor -Do not need Epo to form RBCs -Blocking Epo receptor does not “turn off” RBC production -The Epo receptor has no mutations -Epo level will be low (feedback) |
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Regulation of normal RBC production
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Hypoxia:
-HIF-1a is not degraded -HIF-1a/HIF-1b bind to Epo gene -Stimulate transcription of Epo Normoxia: -vHL protein targets HIF-1a for destruction by proteosomes (ubiquitination) -No HIF-1a/HIF-1b complex -Epo gene not transcribed |
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Polycythemia vera: Jak-2 mutation
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>80% of PV patients
Valine substituted for phenylalanine at amino acid position 617 of JAK-2 (Janus activating kinase-2) Results in constituitively active tyrosine kinase activity Promotes cytokine hypersensitivity, or cytokine independent growth Causes erythrocytosis |
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Polycythemia vera laboratory values
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Elevated hemoglobin and hematocrit
Elevated RBC mass ~60% of patients will have a platelet count > 400K ~40% of patients will have a WCC > 12K Bone marrow overall cellularity is increased Lower M:E ratio |
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Polycythemia vera clinical symptoms
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“Congestion”:
-HA, visual changes -Dizziness -Paresthesias -Facial plethora Pruritis after a warm bath Bleeding, bruising Thrombosis: -MI, DVT, PE, CVA, Budd-Chiari syndrome Hepatosplenomegaly Erythromelalgia |
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Polycythemia vera diagnosis
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Increased red blood cell mass
-Isotopic studies -“Very much” increased Hb and Hct Other causes of polycythemia are ruled out And one or more of the following: -Platelet count > 400K -WCC > 12K -Low Epo levels -Bone marrow biopsy: --Prominent erythroid and megakaryocytic proliferation --Fibrosis |
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Polycythemia vera natural history
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Thrombotic events:
-MI, CVA, DVT, PE --Risk increases with age and white cell count (marker) Risk of transformation: -Myelofibrosis -AML --Depending on age and previous treatments |
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Polycythemia vera treatment
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Phlebotomy
-Goal Hct < 45% for males; < 42% for females -Eventually they become iron deficient Hydroxyurea Aspirin 81 mg |
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Essential thrombocytosis overview
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Clonal disorder
Independent of thrombopoietin or its receptor (c-Mpl) TPO levels are normal or elevated -Decreased clearance JAK2 mutation seen in ~50% of ET patients |
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Essential thrombocytosis diagnosis
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Sustained platelet count ≥450K
Hyperplasia of megakaryocytes on bone marrow biopsy Absence of t(9;22) and other causes of secondary thrombocytosis |
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Essential thrombocytosis blood counts
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Elevated platelet count
Normal white blood cell count Normal hemoglobin |
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Essential thrombocytosis natural history
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Bleeding due to abnormal platelet function
Thrombosis -CVA, TIA, MI, priapism Splenomegaly Erythromelalgia Risk for progression to myelofibrosis or AML |
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Essential thrombocytosis treatment
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Hydroxyurea
Aspirin |
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Chronic eosinophilic leukemia overview
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Clonal disorder
Excess number of circulating eosinophils Some patients will respond to Gleevec (imatinib) |
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Chronic idiopathic myelofibrosis overview
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“Scarring” of the bone marrow
Reticulin and/or collagen fibrosis Decreased cellularity of bone marrow Often have “dry taps” JAK2 mutations also seen in ~50% of patients Risk of leukemic transformation -Usually myeloid -Can be lymphoid, erythroid, megakaryocytic, or mixed lineage |
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Chronic idiopathic myelofibrosis clinical presentation
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Marked splenomegaly
Hepatomegaly present as well Extramedullary hematopoiesis can be found in unusual places: -Pleural effusions -Pericardial effusions -Ascites -Central nervous system |
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Chronic idiopathic myelofibrosis blood counts
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Leukoerythroblastic picture:
-Pseudo-Pelger-Huet cells -Giant platelets -All signs of marrow replacement Patients are usually anemic WCC and platelet count may be high or low |
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Chronic idiopathic myelofibrosis treatment
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Palliative
-Hydroxyurea -Splenectomy -Appropriate acute leukemia treatments with transformation (prognosis worse than de novo leukemia patients) Jakafi |
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Plasma cell dyscrasia overview
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Genetic mutation results in increased numbers of plasma cells with increased amounts of antibody production
Excess antibodies can cause end organ dysfunction Get continuum of disorders depending on amount of excess protein present Continuum from MGUS to Multiple Myeloma to Plasma Cell Leukemia |
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Plasma cell dyscrasias: diagnosis
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To measure the number of plasma cells:
-Bone marrow biopsy and aspirate To measure the amount of protein (antibody) -Comprehensive panel --Total protein elevated in excess of albumin -Serum quantitative immunoglobulins -Serum protein electrophoresis -Serum immunofixation -Serum free light chains |
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SPEP: Normal
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Albumin
Alpha-1 peak: -Alpha-1 antitrypsin, etc Alpha-2 peak: -Haptoglobin, etc Beta peak: -Transferrin -Some immunoglobulins Gamma peak: -Most immunoglobulins -Not just IgG! |
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SPEP: Monoclonal Gammopathy
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Clonal disorder
One narrow peak All the proteins are the same so they travel the same distance on the electrophoresis gel Quantitates the M spike -0.40 g/dl, for example Can we tell if this is IgG (or IgA or IgM)? |
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Immunoelectrophoresis (IEP): Monoclonal Gammopathy
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Run patient’s serum on gel
Stain for different antibodies using specific reagents Confirms clonality Tells us which antibody is in excess -IgG kappa, for example |
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Serum free light chains
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Get quantification of amount of light chains in the serum
Free kappa, serum: Free lambda, serum: Free kappa/lambda ratio: (normal 2:1) |
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Plasma cell dyscrasia end organ damage
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Increased osteoclast activation
Leads to lytic lesions in the bones -Calvarium -Spine -Ribs -Pelvis -Long bones Kidneys Bone Marrow -Increased numbers of plasma cells in the marrow -Normochromic normocytic anemia -Circulating plasma cells usually only seen with plasma cell leukemia -Classic changes seen on peripheral smear Electrolytes -Hypercalcemia --Due to osteoclast activation --Contributes to renal dysfunction -“Stones, bones, groans, and moans” -Stones: kidney stones -Bones: increased bone rebsorption -Groans: constipation -Moans: psychiatric issues |
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Plasma cell dyscrasias: treatment
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Depends on where the patient falls along the continuum
Observation Oral chemotherapy Intensive IV chemotherapy |
