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62 Cards in this Set
- Front
- Back
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Myeloproliferative Disorders
(Definition and List Disorders) |
Clonal proliferation of a cell line derived from the myeloid stem cell
1. Polycythemia Vera 2. Essential Thrombocythemia 3. CML 4. Chronic Eosinophilic Leukemia 5. Chronic Idiopathic Myelofibrosis |
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Appropriate causes of Erythrocytosis
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1. COPD (Hypoxia)
2. Right to left cardiac shunts (Hypoxia) 3. Sleep apnea/ Pickwickian syndrome (Hypoxia) 4. High altitude (Hypoxia) 5. Chronic carbon monoxide poisoning (CO high affinity for Hb) |
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After what type of transplant can you have erythrocytosis and why?
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After a renal transplant, when the native kidneys continue to secrete EPO
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What are mutations that cause Polycythemia and why?
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1. High oxygen affinity Hb mutants (Shifts curve to left)
2. 2,3 DPG deficiency (Shifts curve to left) 3. von Hippel Lindau mutation (Doesn’t bind HIF-1a) 4. Congenital methemoglobinemia (Hb with Fe+3 > Fe+2) 5. Primary familial & congenital polycythemia (Varied) |
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Which malignancies secrete EPO?
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1. Renal cell carcinoma
2. Hepatocellular carcinoma 3. Hemangioblastoma 4. Uterine fibroids |
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Polycythemia Vera
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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 (b/c kidney realizes that EPO does not need to be secreted) |
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Polycythemia Vera
JAK-2 Mutation |
- 80% of PV patients have this mutation
- There is constant phosphorylation that results in EPO cascade always being on --> ERYTHROCYTOSIS |
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JAK-2 Mutation
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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 |
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Polycythemia Vera
Laboratory Values |
- 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 |
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Polycythemia Vera
Signs and Symptoms |
- Blood "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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Facial Plethora
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red, flushed face
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Erythromelalgia
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painful red hands
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Polycythemia Vera
WHO Criteria for Diagnosis |
- 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 & megakaryocytic proliferation - Fibrosis |
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Polycythemia Vera
Progression and risks |
- Risk for thrombotic events increases with age and white cell count (marker of aggressiveness of dz)
- Risk of Tranformation into: - Myloefibrosis - AML (depends on age and previous treatments) |
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Polycythemia Vera
Treatment |
- Phlebotomy to acheive goal Hct
- Hydroxyurea - Aspirin 81 mg (thrombosis prophylaxis) |
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What is the goal Hct for a male and female with polycythemia vera?
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- Hct <45% for males
- Hct <42% for females |
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Essential Thrombocythemia
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- Clonal disorder of platelets
- Independent of thrombopoietin or its receptor (c-Mpl) - TPO levels are normal or elevated (because of decreased clearance) - JAK2 mutation seen in ~50% of ET patients |
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Essential Thrombocythemia
Diagnosis |
- 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 Thrombocythemia
Blood Counts |
- Elevated platelet count
- Normal white blood cell count - Normal hemoglobin |
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Essential Thrombocythemia
Treatment |
- Hydroxyurea
- Aspirin |
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What are sustained processes that cause thrombocytosis?
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- Iron deficiency
- Hemolytic anemia - Asplenic state - Chronic inflammatory or infectious diseases - Cancer |
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What are transient processes that cause thrombocytosis?
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- Acute blood loss
- Recovery from thrombocytopenia - Acute infection or inflammation - Response to exercise - Drug reactions |
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Essential Thrombocytosis
Natural History |
- Bleeding due to abnormal platelet function
- Thrombosis (CVA, TIA, MI, priapism) - Splenomegaly - Erythromelalgia - Risk for progression to myelofibrosis or AML |
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Chronic Eosinophilic Leukemia
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- Clonal disorder of eosinophils
- Excess number of circulating eosinophils - Some patients will respond to Gleevec (imatinib) |
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Chronic Idiopathic Myelofibrosis
Bone Marrow |
- “Scarring” of the bone marrow
- Reticulin and/or collagen fibrosis - Decreased cellularity of bone marrow (b/c of fibrosis) - Often have “dry taps” |
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Chronic Idiopathic Myelofibrosis
Clinical Presentation |
- 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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Why do you have HSM in chronic idiopathic myelofibrosis?
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because the spllen and liver take over blood cell production
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Chronic Idiopathic Myelofibrosis
Blood Counts |
- LEUKOERYTHROBLASTIC picture:
- Pseudo-Pelger-Huet cells - Giant platelets - All signs of marrow replacement * these are present because bone marrow is pushing cells out quickly because there is not enough space - Patients are usually anemic - WCC and platelet count may be high or low |
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Pseudo-Pelger-Huet cells
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a neutrophil with only 2 segments
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Chronic Idiopathic Myelofibrosis
mutations |
JAK-2 mutation seen in ~50% of patients
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Chronic Idiopathic Myelofibrosis
Risk of Transformation |
Risk of LEUKEMIC transformation
- Usually myeloid - Can be lymphoid, erythroid, megakaryocytic, or mixed lineage |
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Chronic Idiopathic Myelofibrosis
Treatment |
PALLATIVE
- Hydroxyurea - Splenectomy - Appropriate acute leukemia treatments with transformation (prognosis worse than de novo leukemia patients) |
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Why is there so much fibrosis in Chronic Idiopathic Myelofibrosis?
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because the megakaryocytes are secreting something that makes the fibroblasts secrete too much collagen
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Whyic myeloproliferative disorders may have a JAK-2 mutation?
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1. Polycythemia Vera
2. Essential Thrombocytosis 3. Chronic Idiopathic Myelofibrosis |
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Myelodysplastic Syndromes
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- INEFFECTIVE HEMATOPOIESIS
- Cells do not progress through the normal stages of maturation - Peripheral blood: CYTOPENIAS - Bone marrow: HYPERCELLULAR (b/c of ineffective maturation), with abnormal cells |
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How do patients with myelodysplastic Syndromes present?
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as a result of their CYTOPENIAS
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Myelodysplastic Syndromes
Clinical Presentation |
- Recurrent infections (b/c lack neutrophils)
- Fatigue, pallor (b/c lack RBCs) - Bleeding (b/c lack platelets) - Usually don’t have splenomegaly (unlike myeloproliferative disorders) |
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How is a dx of Myelodysplastic Syndrome made?
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Take a bone marrow biopsy and aspirate and look for:
- dysplastic cells (nucleus/cytoplasm dyssynchrony) - an increased number of blasts (6-19% blasts) ...both are sufficient for dx...only need 1 |
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Why do you evaluate chromosomes in Myelodysplastic Syndrome?
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helps with prognosis
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How do you determine the aggressiveness of myelodysplastic syndromes?
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more aggressive with:
- more cytopenias - more blasts |
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Myelodysplastic Syndrome and Prognosis
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Two greatest risk factors for developing AML from MDS are:
- Age - IPSS score |
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How does the WHO Classification Scheme classify myelodysplastic syndromes?
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based on prognosis
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How does IPSS classify myelodysplastic syndromes?
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determines risk based on :
- karyotype - bone marrow blasts - cytopenias |
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5q- Syndrome
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- a myelodysplastic syndrome
- Clinical course tends to be relatively more benign - Overall more responsive to certain treatments - Thalidomide - Lenalidomide |
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Myelodysplastic Syndrome
Treatment |
Supportive care
- Antibiotics, transfusions - Growth factors: EPO, GCSF - Iron chelators (Exjade [deferasirox]) - Binds iron which gets excreted in urine and bile Chemotherapy - Different from AML chemotherapy Monitor for transformation to AML - Remember outcomes are worse for patients with AML arising from MDS |
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Plasma Cell Dyscrasias
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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 |
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What is the Plasma Cell Dyscrasias Continuum?
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MGUS (Monoclonal Gammopathy of Undetermined Significance)
--> Multiple Myeloma --> Plasma Cell Leukemia (as you follow the continuum, there are increased numbers of plasma cells and protein production .: more aggressive) |
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Plasma Cell Dyscrasias
Diagnosis |
- measure the number of plasma cells:
- Bone marrow biopsy and aspirate - measure the amount of protein (antibody) - Comprehensive panel (determine total protein elevated in excess of albumin) - Serum quantitative immunoglobulins - Serum protein electrophoresis - Serum immunofixation - Serum free light chains |
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Quantitative Immunoglobulins
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Tells us how much immunoglobulin a patient has
(does not tell us monoclonal vs. polyclonal) |
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SPEP
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graphically reveals amount with peaks:
- albumin - alpha 1 peak - alpha 2 preak - beta peak - gamma peak |
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Which peaks of SPEP have information on immunoglobulins?
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- beta peak
- gamma peak |
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What do you see with a monoclonal gammopathy on SPEP?
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- one narrow peak (result of the clonal disorder); all the proteins are the same so they travel the same distance on the electrophoresis gel
- quantitation of the M spike (you cannot distinguish between IgG, IgA and IgM at this point) |
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What is an IEP?
What does an IEP show us? |
- IEP is when the serum is run on the gel
- Antibdoies are stained for by using specific reagents - IEP confirms clonality and tells us which heavy and light chains are in excess |
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Serum Free Light Chains
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- quantification of amount of light chains in the serum
- gives kappa to lambda ratio |
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What is a normal kappa/lambda ratio?
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2 kappa : 1 lambda
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Plasma Cell Dyscrasias
Treatment |
Depends on where the patient falls along the continuum
- Observation - Oral chemotherapy - Intensive IV chemotherapy * bisphosphonate (bonetta) can help with hypercalcemia |
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What systemic damages (by end organ damage) are seen with Plasma Dyscrasias?
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Bone
Kidneys Bone Marrow Electrolytes |
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What happens are a result of hypercalcemia?
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Stones, Bones, Groans and Moans
Stones: Kidney Stones Bones: Increased Bone Resorption Groans: Constipation Moans: Psychiatric Issues |
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Electrolytes in Plasma Dyscrasias
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- Hypercalcemia due to osteoclast activation
- Contributes to renal dysfunction (Ca excretion in urine) |
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Bone Marrow and Plasma Dyscrasias
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- Increased numbers of plasma cells in the marrow
- Normochromic normocytic anemia - Circulating plasma cells usually only seen with plasma cell leukemia - Rouleaux on peripheral smear |
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Kidneys and Plasma Dyscrasias
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- Deposition of immunoglobulin in the kidney leads to cast nephropathy
- High Serum Calcium leads to kidney stones - Kidney is infiltrated by plasma cells |
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Bones and Plasma Dyscrasias
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Increased osteoclast activation, leads to lytic lesions in the bones:
- Calvarium - Spine - Ribs - Pelvis - Long bones |
