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New-Onset Cytopenias: A Discussion of Etiologies and Evaluation
Garth A. Aasen M.D.
Disclosure Statement
I have no relevant financial interests to disclose.
Learning Objectives
• Review the complete blood count and how hemogram data is obtained
• Discuss select cytopenias including possible etiologies with a focus on macrocytic anemia and peripheral smear findings
• Integrate laboratory and morphologic findings in classifying myelodysplastic syndromes
Overview
• The CBC and how hemogram data is obtained
• Select cytopenias with a focus on macrocytic anemia
• The classification and diagnosis of MDS
Case Presentation
• History: – 79-year-old, Caucasian female presented to the ED with
lightheadedness and weakness – No chest or abdominal pain – No fever, night sweats, headaches, dizziness, other
neurological symptoms
• Past Medical/Surgical History: – Atrial fibrillation – Hypothyroidism – Hypertension – Pulmonary nodules (stable on CT) – Hip arthroplasty 2013
Case Presentation
• Family History: – N/A
• Social History: – Lives at home and is cared for by her sister – No alcohol, tobacco, or illicit drug use
• Medications – Iron supplement – Hydrochlorothiazide 25mg – Synthroid 50 mcg – Warfarin 2-3 mg
• Allergies – NKDA
• ROS is otherwise negative
Case Presentation
• Physical Exam:
– Dry mucus membranes
– Shortness of breath
– Bradycardia
– Pallor
– Regular heart rate and rhythm
• Initial Labs…
The Complete Blood Count: A Review
The Complete Blood Count: RBCs
The Complete Blood Count: RBCs
The Complete Blood Count: RBCs
• Coulter Principle- electrical impedance
– Suspended cells drawn through small aperture
– Cells displace solution creating impedance of electrical current
– Voltage proportional to size
The Complete Blood Count: RBCs
(Constantino, 2011)
The Complete Blood Count: RBCs
(Constantino, 2011)
The Complete Blood Count: Platelets
Platelet Histogram
The Complete Blood Count: WBCs
• Volume: Impedance
• Conductivity (complexity): Radiofrequency
• Light Scatter (cytoplasmic granularity): Flow cytometry
(beckmancoulter.com)
The Complete Blood Count: A Review
• Spectrophotometer: Hemoglobin
• RBCs:
– Directly measured: RBC, MCV, Hgb
– Calculated:
• Hct (MCV x RBC)
• MCHC (Hgb/Hct x 100)
• RDW
• Platelets (manual confirmation if low)
• WBCs: automated (reflex manual) differential
Case Presentation- CBC CBC: Patient Normal Range WBC 1.9 4.5 - 11.0 K/uL
RBC 2.23 3.8 - 4.8 M/uL Hgb 7.8 12.0 - 15.0 gm/dL Hematocrit 23.9 36-46 % MCV 106.8 83.0 - 101.0 fL MCHC 32.5 31.5 - 36.0 % RDW 13.9 11.5 - 14.5 % Platelets 125 150 - 400 K/uL Differential: % Abs Normal Range Neutrophils 48 0.9 1.8 - 7.7 K/uL Lymphocytes 37 0.7 1.0 - 4.8 K/uL Monocytes 6 0.1 0.2 - 1.0 K/uL Eosinophils 9 0.2 0.0 - 0.5 K/uL Basophils 0 0 0.0 - 0.5 K/uL
Case Presentation- CBC CBC: Patient Normal Range WBC 1.9 4.5 - 11.0 K/uL
RBC 2.23 3.8 - 4.8 M/uL Hgb 7.8 12.0 - 15.0 gm/dL Hematocrit 23.9 36-46 % MCV 106.8 83.0 - 101.0 fL MCHC 32.5 31.5 - 36.0 % RDW 13.9 11.5 - 14.5 % Platelets 125 150 - 400 K/uL Differential: % Abs Normal Range Neutrophils 48 0.9 1.8 - 7.7 K/uL Lymphocytes 37 0.7 1.0 - 4.8 K/uL Monocytes 6 0.1 0.2 - 1.0 K/uL Eosinophils 9 0.2 0.0 - 0.5 K/uL Basophils 0 0 0.0 - 0.5 K/uL
Anemia
• Decreased RBC count or hemoglobin in relation to normal ranges
• Systematic Approach to Evaluation
– Assess clinical parameters (family history, onset, underlying illnesses, etc.)
– Integrate CBC data and morphology
– Develop differential diagnosis and pursue with additional testing
Classification of Anemias
• MCV based differential diagnosis – Microcytic
– Normocytic
– Macrocytic
• Pathogenesis based differential diagnosis – Production defect
– Nuclear maturation defect
– Cytoplasmic maturation defect
– Survival defect (destruction)
– Blood Loss
Classification of Anemias • Microcytic
– Iron deficiency – Thalassemia – Anemia of chronic disease – Lead toxicity
• Normocytic – Anemia of chronic disease – Chronic renal disease – Hemolysis – Blood loss – Bone marrow disorder (infiltration,
aplasia)
• Macrocytic – B12 deficiency – Folate deficiency – Drug effect – Excessive alcohol use – Hypothyroidism – Copper deficiency – Myelodysplasia
Macrocytic anemia
(Green and Dwyre, 2015)
What are Megaloblastic Changes?
• Impaired DNA synthesis
– Decreased thymidine synthesis
– Defective nuclear maturation
– Delay/block in cell division
– Decreased cell division
– Normal RNA and protein synthesis (normal cytoplasmic maturation)
– Associated morphologic changes
Megaloblastic Changes- Morphology
• Peripheral Smear
– Ovalocytes
– Hypersegmented neutrophils
(Foucar, 2016)
Megaloblastic Changes- Morphology
• Bone Marrow
– Marrow hyperplasia
– Nuclear to cytoplasmic dyssynchrony
– Giant metamyelocytes/ bands
(Foucar, 2016)
Megaloblastic Macrocytic Anemia
• DDx:
– B12 deficiency
– Folate deficiency
– Drugs
Reticulocytosis
• Increased RDW
• DDx: hemolysis, blood loss, etc.
Normal Reticulocyte Count
• Alcohol
• Hypothyroidism
• Myelodysplastic syndromes
• Liver disease
• Drugs
• Aplastic anemia
• Copper deficiency
• Congenital disorders
Normal Reticulocyte Count
• Myelodysplastic syndromes
• Liver disease
• INSERT PHOTOS
Neutropenia
• Neutropenia – Decreased absolute neutrophil count
• Children: infection • Adults: drugs, toxins • Other:
– Race-related variations – Neoplasms
• T-cell large granular lymphocytic leukemia • MDS
– Aplastic anemia – Levamisole (contaminated cocaine)
Thrombocytopenia
• Decreased production
• Increased consumption
• Destruction/sequestration
• Artifactual
Pancytopenia
• Anemia, neutropenia, and thrombocytopenia – Drugs – Aplastic anemia – Paroxysmal nocturnal
hemoglobinuria – Copper, B12, folate deficiency – Metastasis – Leukemia – Myelodysplastic syndrome – Congenital (Fanconi anemia, etc.) – Autoimmune – Infection
• INSERT PHOTOS HERE – Normal marrow – Hypocellular marrow
Case Presentation- LabS
Patient RR
Folate: 24.5 >5.9
RBC Folate: 640 >236.9
Vitamin B12: 900 180-914
TSH: 3.48 0.34-5.6
Free T3: 2.7 2.1-3.7
Free T4: 1.17 0.58-1.64
Case Presentation- Peripheral Smear
Diagnosis of Myelodysplastic Syndrome
• Clonal stem cell diseases:
– Cytopenia(s)
– Dysplasia
– Ineffective hematopoiesis
– Increased risk of AML
Myelodysplastic Syndromes
Myelodysplastic Syndromes
• Dyserythropoiesis
Myelodysplastic Syndromes • Dysgranulopoiesis
Myelodysplastic Syndromes
• Dysmegakaryopoiesis
Myelodysplastic Syndromes
Myelodysplastic Syndromes
Myelodysplastic Syndromes
Myelodysplastic Syndromes
Myelodysplastic Syndromes
• Cytogenetic abnormalities
– Not sufficient for diagnosis: +8, -Y, del(20q)
– Found in 50% of diagnosed patients
Myelodysplastic Syndromes
• “Idiopathic cytopenias of undetermined significance”
– Provisional WHO category
– Persistent cytopenia without explanation
– No dysplasia
– No specific cytogenetic abnormality
– No evidence of clonality
Case Presentation- Bone Marrow
Case Presentation- Bone Marrow
Case Presentation- Bone Marrow
Case Presentation- Ancillary Studies
• Flow:
• Florescent in situ hybridization: No deletion 5q
• Cytogenetics: 46,XX [20]
Case Presentation- Diagnosis
• Findings:
– No megaloblastic changes
– No dysplasia
– No increase in blasts
– No bone marrow replacement
– Normal molecular studies
• Differential Diagnosis:
– Drugs
– Aplastic anemia
– Hypothyroidism
– Idiopathic cytopenias of undetermined significance
Summary
• The CBC and how hemogram data is obtained
• Select cytopenias with a focus on macrocytic anemia
• The classification and diagnosis of MDS
References
• Constantino BT. The red cell histogram and the dimorphic red cell population. Lab Medicine. 2011;42:300-308.
• Green R and Dwyre DM. Evaluation of macrocytic anemia. Seminars in Hematology. 2015;52:279-286.
• Santini V. Anemia as the main manifestation of myelodysplastic syndromes. Seminars in Hematology. 2015;52:348-356.
• Foucar K. Overview of anemia. Expertpath.com. 2016. • Vardiman JW et al. The 2008 revision of the World Health
Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937-951.
• Malcovati L and Cazzola M. The shadowlands of MDS: idiopathic cytopenias of undetermined significance (ICUS) and clonal hematopoiesis of indeterminate potential (CHIP). Hematology. 2015;299-307.
• Kaferle J and Strzoda CE. Evaluation of macrocytosis. American Family Physician. 2009;79:203-208.