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3 Cards in this Set
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POLYCYTHEMIA
A laboratory finding with increased RBCs with accompanying increase in hematocrit and hb conc in peripheral blood
These parameters depends on plasma volume and total red cells mass (RCM
Relative polycythemia - an isolated decrease in plasma volume can elevate hb, hct, and RBC count without increasing RCM
Absolute polycythemia - erythrocytosis; increased RCM; primary and secondary
Primary polycythemia - by acquired or inherited mutation leading to abnormality in RBC progenitor: include polycythemia Vera and other familial variants
Secondary polycythemia - caused by circulating factor stimulating erythropoiesis ie Epo: most often due to Epo induced hypoxia or Epo secreting tumor
Combined polycythemia - Increased RCM and reduced plasma volume; mostly in smokers
Inapparent polycythemia- RCM and plasma volume equally increased while hb, hct and RBC count normal; detected via blood volume studies
Erythropoiesis
Epo synthesized by kidneys in response to hypoxia Hypoxic signals Anemia: hypoxemia ; decreased oxygen release from hb, reduced delivery to kidney eg vascular occlusion
Negative feedback inhibition down regulates Epo production with increasing oxygen delivery ie
Epo independent erythrocytosis as in PV suppress renal Epo production: associated with low serum Epo conc
Epo driven erythropoiesis eg in hypoxia or tumor characterize secondary erythrocytosis is associated with high or normal serum Epo conc
Causes of polycythemia Autonomous increase in Epo - inappropriate high serum Epo
pheochromocytoma, uterine fibroids
Epo producing renal lesions eg cysts, hydronephrosis,renal artery stenosis
Appropriate increase in Epo- appropriately high serum Epo Epo producing neoplasm eg renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma, pheochromocytoma, uterine fibroids Epo producing renal lesions eg cysts, hydronephrosis,renal artery stenosis Appropriate increase in Epo- appropriately high serum Epo Hypoxemia secondary to; chronic pulmonary disease,right left shunts, sleep apnea, massive obesity, high altitude Germ line and somatic mutational cause eg PV- JAK2 mutations , Epo receptor mutation , Chuvash polycythemia- VHL gene Congenital methemoglobinemia ,Idiopathic familial polycythemia, High oxygen affinity Hbs 2,3 BPG mutase deficiency PHD2, HIF-2 mutations Miscellaneous causes eg use of androgens, diuretics, blood doping,self Epo injection, POEMS syndrome Red cell defects eg congenital methemoglobinemia, chronic CO poisoning, cobalt |
EVALUATION
Initial Evaluation
History and physical examination Pulse oximetry and arterial oxygen saturation at rest and after exercise CBC with differential RBC indices Urinalysis Liver function studies Chest x-ray
History
Symptoms due to underlying polycythemia related to hyperviscosity of blood; eg chest pain, myalgia, fatigue, headache, blurred vision, paraesthesia, slow mentation
Symptoms suggesting underlying pulmonary disease eg shortness of breath, dyspnea on exertion, chronic cough, cyanosis, sleep disordered breathing, hypersomnolence with unintentional sleep
Physical examination
General Pulse oximetry, cyanosis, finger clubbing, murmurs
Others Plethoric faces, dilated lingual or retinal veins, painful erythema Hepatosplenonegaly
Diagnostic approach
Laboratory
Hct> 48% in females or > 49% in men Hb> 16g/dl in female or >16.5g/dl in men RBC count less often used
The type of polycythemia via blood volume measurements
Pulse oximetry: hypoxia present at rest, following mild exercise or sleep
Serum Epo; primary or secondary
Caveats and other finding ie apply sex and age related references Thalassemia minor ie high RBC count, low Hb, low MCV Low MCV, high WBC and or high platelets is PV Microscopic hematuria; RCC Hyperglycemia and electrolytes imbalance eg functional endocrine tumors Abnormal LFTs eg in hepatocellular carcinoma CO poisoning via direct blood testing Chest x-ray |
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CLINICAL MANIFESTATIONS AND DIAGNOSIS OF POLYCYTHEMIA VERA
POLYCYTHEMIA VERA
Polycythemia ribra vera, primary polycythemia and essential polycythemia
BCR-ABL1 negative myeloproliferative neoplasm with peripheral erythrocytosis with or without leukocytosis or thrombocytosis
Essential features
Increased RBC production with RBC count and Hb not proportional to Epo production (usually markedly decreased Epo levels)
Diagnosis require 3 or 2 major criteria and minor criterion
JAK2 V617F (exon 14, valine to phenylalanine) and JAK2 exon 12 mutation in 95% of cases and 5% respective
Three phases ie prodormal/ pre polycythemia Overt polycythemic Post polycythemic myelofibrosis
Less than 10% in post polycythemic phase undergo blast transformation
Epidemiology
Annual incidence increase with advancing age Slight male predominant Median age is 61yrs
Sites
Peripheral blood and bone marrow Spleen and liver in extra medullary hematopoiesis in later stages
Pathophysiology
Clonal hematopoietic stem cell disorder Point mutation in JAK2 gene at 9p24 results in constitutional activation of transcription factors of STAT family, promote growth factor independent proliferation and survival
Mechanism of thrombosis and bleeding due to increased circulating RBCs and elevated platelets
Three phases
Prodormal: characterized by borderline to mild erythrocytosis
Overt polycythemic - significant increase in red cells mass
Post polycythemic myelofibrosis - cytopenia including anemia, associated with ineffective hematopoiesis, bone marrow fibrosis, extra medullary hematopoiesis and hypersplenism
Etiology
Cause idiopathic Genetic predisposition, ionizing radiation and occupational toxin exposure
Clinical features
Related to hypertension or vascular abnormalities due to increased red cells mass
Plethora characterized by excess blood and turgescence due to increased red cells mass
Common complaints are headache, dizziness, visual disturbances, Angina pectoris, tinnitus , paraesthesia, pruritus, intermittent claudication, gout, erythromelalgia
Venous thrombosis eg hepatic portal vein thrombosis, Budd Chiari syndrome or mesenteric vein thrombosis
Arterial thrombosis, myocardial ischemia, transient Ischemic attack
Symptoms of altered microcirculation eg peptic ulcers due to micro thrombi, increased histamine or decreased gastric pH
Early satiety due to massive splenomegaly in later stages
Abdominal pain secondary to Ischemic bowel
Hepatosplenonegaly
Erythromelalgia ( Increased skin temperature, burning sensation, redness)
Diagnosis
All 3 major or first 2 major and minor criterion
Major criteria
H >16.5 in men, >16 in women Hct>49% in men, >48% in women Increased red cells mass above 25% mean normal
Bone marrow biopsy with hypercellular for age with trilineage growth/panmyelosis including prominent erythroid, granulocytic and megakaryocytic proliferation with pleomorphic, mature megakaryocytes
Presence of JAK2 V617F or JAK2 exon 12 mutation
Minor criteria
Subnormal serum Epo ; normal= 4.1-19.5mU/ml
Sustained absolute erythrocytosis rules out major 2
Hb levels>18.5, hct 55.5% in men; or 16.5, hct 49.5% in women if major 3 and minor criterion present
Approximately 20% of PV patients show myelofibrosis with may progress rapid to overt myelofibrosis
Diagnosis by polycythemia Vera study group ( PVSG)
Require all 3 category A or that criterion A1,A2 and any two category B criteria are present
Category A
A1- total red cells mass greater or equal to 36mL/kg in males, 32ml/kg female
A2 arterial oxygen saturation greater or equal to 92%
A3 splenomegaly
Category B
Thrombocytosis with platelets count greater 400,000/dl Leukocytosis with WBC greater 12,000 Leukocyte alkaline phosphatase greater 100U/l in absence of fever or infections Serum vitamin B12 greater 900 pg/ml or binding capacity greater 2200pg/ml
Other present findings
Subnormal Epo Endogenous erythroid colony formation Detection of JAK2 V617F or JAK2 exon 12 mutation
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MORPHOLOGICAL FEATURES
Bone marrow in pre myelomonocytic and overt
Hypercellular ( mean 80%,range 37-100% Panmyelosis with erythroid and megakaryocytic predominant Complete and and progressive maturation of all three lineage Abnormal megakaryocytic morphology ue hyperlobulated, not as pronounced in essential thrombocytopenia Minimal or absent reticulin fibrosis Decreased iron stores or absence
Post PV
Leukoerythroblastosis Overt marrow reticulin and collagen fibrosis Prominent osteosclerosis Less than 20% increase in blasts Declined in hematopoietic cells Dilated sinuses with intrasinusoidal hematopoiesis
Peripheral blood in pre and overt
Normochromic, normocytic RBC or microcytic hypochromic when iron deficient
Erythrocytosis with increased Hb or hct Red cell morphology unremarkable except if irons deficit
Deep basophilic reticulocytes or rare normoblast Mild neutrophilic leukocytosis with rare left shift
Mild basophilia Thrombocytosis predominant in prodormal phase or exaggerated by iron deficiency
Peripheral blood in Post PV
Myeloid metaplasia with erythroblastosis Poikilocytosis with tear drop red cells >10% blasts or significant myelodysplasia is unusual 20% or more blast considered AML
DIFFERENTIAL DIAGNOSIS
MPD MDS MDS/MPD AML
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Myelodysplastic syndromes Essential features
Heterogeneous group of malignant stem cell disorders with dysplastic ineffective blood cells production and variable risk of transformation to Acute Leukemia
Variable reduction in RBC production, platelets and mature granulocytes with functional defects
Pathogenesis
Stepwise acquisition of oncogenic mutations denovo or after exposure to certain form's of chemotherapy, benzene, radiation
Epidemiology
Crude annual incidence of 4.1 per 100,000 Older adults with median age 65 years Male predominance Earlier age than 50 is unusual but can occur in children
Predisposing factors
Heritable
Downs syndrome, trisomy 8 mosaicism, familial monosomy 7, neurofibromatosis 1, germ cell tumors eg embryonic dysgenesis, congenital neutropenia DNA repair deficiency eg Fanconi anemia, Ataxia telangiectasia, Bloom syndrome, xeroderma pigmentosa
Acquired
Senescence Mutagen exposure Aplastic anemia Paroxysmal nocturnal hemoglobinuria Polycythemia Vera Obesity
Clinical features
Signs and symptoms at presentation nonspecific Asymptomatic at diagnosis until anemia, neutropenia and thrombocytopenia in blood count Features of previous unrecognizable cytopenia eg infection fatigue Complications of autoimmune abnormalities Results in anemia, bleeding and increased risk of infection Pathogenesis Stepwise acquisition of oncogenic mutations denovo or after exposure to certain form's of chemotherapy, benzene, radiation
Epidemiology Crude annual incidence of 4.1 per 100,000 Older adults with median age 65 years Male predominance Earlier age than 50 is unusual but can occur in children Predisposing factors Heritable Downs syndrome, trisomy 8 mosaicism, familial monosomy 7, neurofibromatosis 1, germ cell tumors eg embryonic dysgenesis, congenital neutropenia DNA repair deficiency eg Fanconi anemia, Ataxia telangiectasia, Bloom syndrome, xeroderma pigmentosa Acquired Senescence Mutagen exposure Aplastic anemia Paroxysmal nocturnal hemoglobinuria Polycythemia Vera Obesity Clinical features Signs and symptoms at presentation nonspecific Asymptomatic at diagnosis until anemia, neutropenia and thrombocytopenia in blood count Features of previous unrecognizable cytopenia eg infection fatigue Complications of autoimmune abnormalities Pathologic features CBC Macrocytic or normocytic Anemia with low reticulocyte count Neutropenia and thrombocytopenia variable Pancytopenia at diagnosis in 50% Cytochemistry and immunocytochemistry Iron staining for ringed sideroblasts PAS staining for erythroblasts to assess dyserythropoiesis Peroxidase or Sudan black to confirm myeloid blasts Nonspecific or double esterase to discern abnormal granulocytes and monocytic forms Immunocytochemistry m Exclude lymphoid origin of primitive blasts Distinguish erythroid precursor by antibodies specific for glycophorin CD235a or transferrin receptor CD71 Quantify myeloid blasts and progenitor using antibodies CD34, CD117,CD13, CD14,CD33 Detect dysplastic or immature megakaryocytes via antibodies specific for Von Willebrand factor VIII, CD41,CD61, HPI-ID monoclonal antibody Detect lineage infidelity Flow cytometry For scoring dyspoiesis in MDS Genetics Via PCR, FISH, to distinguish between MDS, AML Determine prognosis and classification and therapy
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Diagnostic criteria
Require
Unexplained quantitative changes in one or more of blood and bone marrow elements Values Hb less than 10 g/dl(100g/dl) Absolute neutrophils less than 1.8×10'9(less than 1800/ microL) Platelets less than 100×10'9/ microL( less than 100,000/microL)
Failure to meet threshold for cytopenia does not rule out MDS if there is morphological evidence of dysplasia
Morphological evidence of dysplasia Ie more than or equal to 10% of erythroid precursor, granulocytes or megakaryocytic,upon visual inspection in absence of other causes of dysplasia
In absence of morphological evidence of dysplasia, presumptive MDS diagnosis can be made with otherwise unexplained refractory cytopenia in presence of other genetics abnormalities
Differential diagnosis
MPD MDS MPD/ MDS AML
FAM CLASSIFICATION OF MDS
Refractory anemia Less than 5 % blast
Refractory anemia with ringed sideroblasts Less than 6% blasts, 15% ringed sideroblasts
Refractory anemia with excess blasts 5:20% blasts 60% chance transformation to AML
Refractory anemia with excess blasts in transformation 21-29% blasts Auer rods 60-100% chance to AML
Chronic myelomonocytic Leukemia 20% Blasts Monocytosis |
