New-Onset Cytopenias: A Discussion of Etiologies and ... · • Review the complete blood count and...

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


• Coulter Principle- electrical impedance

– Suspended cells drawn through small aperture

– Cells displace solution creating impedance of electrical current

– Voltage proportional to size


(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

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


• Dyserythropoiesis

Myelodysplastic Syndromes • Dysgranulopoiesis


• Dysmegakaryopoiesis


• Cytogenetic abnormalities

– Not sufficient for diagnosis: +8, -Y, del(20q)

– Found in 50% of diagnosed patients


• “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- 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.

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