L3 - Hematopoiesis Diseases

What are Hyperplasia, Hypoplasia, and Aplasia?

Hyperplasia:

• Increased hematopoietic cellularity affecting one or more marrow lineages

Hypoplasia

• Reduced hematopoietic cellularity affecting one or more marrow lineages

Aplasia

• Near-complete or complete absence of hematopoietic cells in one or more marrow lineages

What are Pancytopenia and Myelophthisis?

Pancytopenia:

• Concurrent anemia, neutropenia, and thrombocytopenia in peripheral blood

Myelophthisis:

• Displacement or disruption of normal hematopoietic marrow by infiltrative tissue or fibrosis, impairing blood cell production

What are Myelodysplasia, Myelofibrosis, Myelonecrosis, and Myelitis?

Myelodysplasia:

• Abnormal morphology and maturation of hematopoietic cells

Myelofibrosis:

• Increased deposition of reticulin and/or collagen fibers in bone marrow

Myelonecrosis:

• Necrosis of hematopoietic cells and supporting marrow tissue

Myelitis:

• Inflammation of bone marrow

What is Ineffective Hematopoiesis?

Inadequate production of mature blood cells despite the presence of marrow precursors → due to defective maturation or premature precursor destruction

What are the Major Indications for Bone Marrow Evaluation?

1. Persistent, unexplained cytopenias

2. Diagnosis or staging of hematopoietic or metastatic neoplasia

3. Investigation of selected infectious diseases

4. Unexplained systemic abnormalities, including fever, hypercalcemia, weight loss, or hyperproteinemia

5. Suspected storage diseases

Which Cytopenias are the Primary Indications for Bone Marrow Sampling?

Key: Cytopenias should generally be persistent and unexplained

• Anemia

• Neutropenia

• Thrombocytopenia

• Any combination of these abnormalities

Why is Isolated Lymphopenia Not Typically an Indication for Bone Marrow Sampling?

Lymphocytes can proliferate in lymphoid tissues and circulate between blood and tissues

• Therefore, lymphopenia does not necessarily indicate impaired bone marrow production.

Which Neoplastic Diseases May Require Bone Marrow Evaluation?

• Lymphoproliferative diseases

• Myeloproliferative diseases, including leukemia and MDS

• Multiple myeloma

• Histiocytic sarcoma

• Mastocythemia

• Metastatic neoplasia

Which Infectious Diseases May Require Bone Marrow Evaluation?

• Viral: FeLV, parvovirus, equine infectious anemia

• Bacterial: Ehrlichia canis, Anaplasma phagocytophilum, mycobacteria

• Fungal: Histoplasmosis, invasive mold infections

• Protozoal: Leishmaniasis.

What is the Difference between Reduced and Ineffective Hematopoiesis?

Reduced hematopoiesis:

• Too few precursors are present in the affected lineage

Ineffective hematopoiesis:

• Precursors are present, sometimes increased, but defective maturation or destruction prevents adequate mature blood cell production

What Conditions Can Cause Reduced Hematopoiesis?

• Hypoplasia

• Aplasia

• Myelofibrosis

• Myelonecrosis

• Infiltration or replacement of normal marrow

What Conditions Can Cause Ineffective Hematopoiesis?

• Myelodysplastic syndrome (MDS)

• Precursor immune-mediated anemia (PIMA)

• Secondary dysplastic changes associated with infections or other marrow injuries

Why can Hypercellular Bone Marrow Still Have Hypoplasia of a Specific Lineage?

Overall marrow cellularity and individual lineage cellularity are different measurements

• EX: granulocytic or megakaryocytic hyperplasia may increase total marrow cellularity while erythroid precursors remain decreased

What are the Major Categories of Bone Marrow Pathology?

• Neoplastic

• Inflammatory or infectious

• Immune-mediated

• Degenerative

• Toxic

• Idiopathic

What were the Major Clinical and Bone Marrow Findings in Elliot?

Clinical findings:

• Persistent, progressive anemia

Bone Marrow Findings:

• Hypercellular bone marrow

• Trilineage dysplasia

• Granulocytic left shift

• Mild plasmacytosis

• Dx: Myelodysplastic syndrome (MDS)

What Abnormal Granulocytic Morphology was identified in Elliot?

These findings support abnormal granulocytic development

• Giant band neutrophils: Abnormally large band forms

• Ring-shaped nuclei: Abnormal nuclear morphology in dogs

• Myeloblasts: Immature myeloid cells identified in the marrow

What Erythroid and Megakaryocytic Dysplastic Changes were identified in Elliot?

• Erythroid: Nuclear-cytoplasmic maturation asynchrony

• Megakaryocytic: Dwarf megakaryocytes, which are abnormally small megakaryocytes with relatively mature cytoplasm.

What is Trilineage Dysplasia?

Abnormal morphology or maturation affecting all three hematopoietic lineages

1. Erythroid

2. Granulocytic

3. Megakaryocytic

What is Myelodysplastic Syndrome (MDS)?

A PRIMARY clonal neoplastic myeloid disorder characterized by:

• Ineffective hematopoiesis

• Dysplastic hematopoietic cells

• Abnormal maturation

• Chronic or progressive peripheral cytopenias, and often hypercellular bone marrow

Why Does MDS Cause Peripheral Cytopenias Despite Hypercellular Bone Marrow?

Abnormal precursors proliferate but fail to mature appropriately and may die prematurely

• Therefore, numerous marrow precursors produce too few functional mature blood cells

What Blast Percentage is Associated with MDS?

Less than 20% blasts

• The lecture uses 20% as the threshold separating MDS from acute leukemia

What is the Main Takeaway from Elliot's Case?

• A hypercellular marrow does not necessarily indicate effective hematopoiesis

• Elliot demonstrates ineffective hematopoiesis caused by primary myelodysplastic syndrome

What were the Major Clinical and Bone Marrow Findings in Mama?

Clinical findings:

• Persistent anemia

• Neutropenia

• Thrombocytopenia

• Persistent fever

• FIV-positive status

Bone marrow findings:

• Marked hypercellularity

• Granulocytic hyperplasia with marked left shift and mild dysplasia

• Moderate erythroid hypoplasia

• Mild megakaryocytic hyperplasia and dysplasia

What does a marked Granulocytic Left Shift Indicate in Bone Marrow?

An increased proportion of immature granulocytic cells relative to mature cells → This indicates abnormal maturation or increased immature cell production

What is the Difference between Primary Myelodysplasia and Secondary Dysmyelopoiesis?

Primary myelodysplasia (MDS):

• Clonal neoplastic disease characterized by abnormal hematopoietic maturation

Secondary dysmyelopoiesis:

• Abnormal marrow development associated with another disease or reactive process

What are Common Causes of Secondary Dysmyelopoiesis?

• Immune-mediated: IMHA, ITP

• Infectious: FeLV, FIV, Leishmania

• Drugs/toxins: Chemotherapy, folate antagonists, estrogen, phenobarbital, heavy metals

• Other marrow diseases: Lymphoma, myelofibrosis.

What is the Main Takeaway from Mama's Case?

• Dysplasia does not automatically indicate MDS

• Secondary diseases can cause dysplastic changes

• Hypercellular marrow can contain hypoplasia of a specific lineage

• FIV positivity alone does not prove the cause of every marrow abnormality

What were the Major Clinical and Bone Marrow Findings in Daisy?

Clinical:

• Chronic, suspected immune-mediated anemia

Bone marrow:

• Moderate to marked hypercellularity

• Erythroid hyperplasia

• Erythroid left shift

• Erythrophagocytosis

• Mild plasmacytosis

• Megakaryocytic left shift

• Mild dysplasia

What is Precursor Immune-Mediated Anemia (PIMA)?

An immune-mediated disorder in which the immune system targets developing erythroid precursors, typically late-stage precursors, within bone marrow → This prevents adequate production of mature circulating red blood cells

What are the Characteristic Findings of PIMA?

• Non-regenerative anemia

• Erythroid hyperplasia

• Erythroid left shift or maturation arrest

• Erythrophagocytosis may be observed

What is Erythrophagocytosis, and How is It Recognized in Bone Marrow?

Engulfment of erythrocytes or erythroid precursors by macrophages

• Morphologic finding: Red blood cells or erythroid precursors visible within macrophage cytoplasm.

Why does PIMA Cause Erythroid Hyperplasia and a Left Shift?

1. Immune destruction of erythroid precursors contributes to anemia

2. Anemia causes tissue hypoxia

3. Kidneys increase EPO production

4. EPO stimulates erythroid precursor proliferation

5. Continued precursor destruction prevents normal maturation

Result: Erythroid hyperplasia with accumulation of immature cells

What is the Main Takeaway from Daisy's Case?

• Peripheral anemia does not necessarily indicate reduced erythroid precursor production

• Daisy demonstrates ineffective erythropoiesis caused by immune-mediated destruction of developing erythroid cells

What were the Major Clinical and Bone Marrow Findings in Bailey?

Clinical:

• Severe anemia and thrombocytopenia

Bone marrow:

• Myelofibrosis

• Marked hematopoietic hypoplasia

• Focal myelonecrosis and myelitis

• Multifocal hemosiderosis

What is Myelofibrosis, and How Does It Cause Cytopenias?

Excessive deposition of reticulin and/or collagen fibers within bone marrow

• Fibrous tissue replaces or disrupts normal hematopoietic tissue, reducing blood cell production and potentially causing marrow failure

How is Myelofibrosis Recognized in Bone Marrow Images?

• Increased fibrous matrix replacing normal hematopoietic tissue

• Reduced hematopoietic cellularity

• Collagen appears pink in routine histologic sections

• Special stains highlight collagen as blue fibrous material in the lecture images

Why is a Core Biopsy Preferred over an Aspirate for Evaluating Myelofibrosis?

Aspirate:

• Often nondiagnostic because fibrotic marrow yields few cells

Core biopsy:

• Preserves marrow architecture and reveals collagen deposition and loss of hematopoietic tissue

What is the Difference between Primary and Secondary Myelofibrosis?

Primary:

• Neoplastic disorder associated with marrow fibrosis

  • Very rare in veterinary medicine

Secondary:

• Reactive fibrosis associated with chronic inflammation, toxic injury, necrosis, immune-mediated disease, or other marrow injuries

What is the Main Takeaway from Bailey's Case?

• Bailey demonstrates reduced hematopoiesis caused by structural damage to bone marrow

• Unlike Elliot and Daisy, whose marrows contain abundant but ineffective precursors, Bailey's marrow has reduced hematopoietic tissue because of fibrosis

QUESTION 1: Why can hypercellular marrow coexist with anemia? 

ANSWER → Precursors may fail to mature or be destroyed before release

• Alternatively, overall hypercellularity may conceal hypoplasia of the erythroid lineage

QUESTION 2: Does dysplasia prove MDS?

ANSWER → No

• Secondary infectious, immune, drug-related, toxic, and other marrow disorders can produce dysplasia

QUESTION 3: Which findings should you recognize in images?

ANSWER →

• Dysplasia: Abnormal nuclear or cellular maturation

• Erythrophagocytosis: Macrophages engulfing erythroid precursors

• Fibrosis: Increased fibrous matrix with reduced hematopoietic tissue

• Infection: Intracellular infectious organisms.

Bone Marrow Terminology SUMMARY

Term	Definition	Key Distinction
Hyperplasia	Increased hematopoietic cellularity	More cells
Hypoplasia	Decreased hematopoietic cellularity	Fewer cells
Aplasia	Near-complete or complete absence of hematopoietic cells	Almost no cells
Pancytopenia	Concurrent anemia, neutropenia, and thrombocytopenia	All three cell lines decreased in blood
Myelophthisis	Replacement/disruption of marrow by infiltrative tissue or fibrosis	Normal marrow displaced
Myelodysplasia	Abnormal morphology and maturation	Abnormal cell development
Myelofibrosis	Excess reticulin/collagen deposition	Fibrous tissue replaces marrow
Myelonecrosis	Death of marrow cells and supporting tissue	Tissue necrosis
Myelitis	Inflammation of bone marrow	Marrow inflammation

Reduced vs. Ineffective Hematopoiesis SUMMARY

Feature	Reduced Hematopoiesis	Ineffective Hematopoiesis
Definition	Too few precursors are present	Precursors are present but fail to produce adequate mature cells
Bone Marrow	Decreased precursors in affected lineage	Often increased precursors
Main Problem	Insufficient cell production	Defective maturation or premature destruction
Peripheral Blood	Cytopenias	Cytopenias
Common Causes	Hypoplasia, aplasia, fibrosis, necrosis, infiltration	MDS, PIMA
Clinical Example	Bailey (myelofibrosis)	Elliot (MDS), Daisy (PIMA)
Key Concept	Not enough cells are made	Cells are made but do not mature or survive appropriately

Important: Overall marrow hypercellularity does not exclude hypoplasia of a specific lineage, as demonstrated in Mama's case.

Clinical Case Comparison SUMMARY

Feature	Elliot	Mama	Daisy	Bailey
Disease	MDS	FIV-positive, secondary dysplastic changes	PIMA	Myelofibrosis
Mechanism	Neoplastic	Infectious/systemic disease association	Immune-mediated	Fibrosis
Marrow Cellularity	Hypercellular	Hypercellular	Hypercellular	Hypoplastic
Key Findings	Trilineage dysplasia, granulocytic left shift	Granulocytic hyperplasia, erythroid hypoplasia, dysplasia	Erythroid hyperplasia, left shift, erythrophagocytosis	Excess collagen, hypoplasia, necrosis
Hematopoiesis	Ineffective	Mixed lineage responses	Ineffective	Reduced
Main Takeaway	Abundant abnormal precursors fail to produce mature cells	Dysplasia does not always indicate MDS	Immune destruction of erythroid precursors	Fibrosis disrupts normal marrow production

Remember:

• Elliot: Neoplastic dysplasia.

• Mama: Secondary dysplastic changes.

• Daisy: Immune-mediated precursor destruction

• Bailey: Fibrosis replacing hematopoietic tissue

Recognizing Bone Marrow Abnormalities SUMMARY

Abnormality	What to Look for in Images	Associated Disease/Case
Dysplasia	Abnormal nuclear or cellular morphology, giant bands, ring-shaped nuclei, dwarf megakaryocytes	Elliot (MDS)
Granulocytic left shift	Increased immature granulocytes relative to mature neutrophils	Elliot, Mama
Erythroid left shift	Increased immature erythroid precursors	Daisy (PIMA)
Erythrophagocytosis	Macrophages containing engulfed erythrocytes or erythroid precursors	Daisy (PIMA)
Fibrosis	Excess fibrous matrix replacing normal hematopoietic tissue	Bailey (myelofibrosis)
Infection	Infectious organisms within marrow cells, such as macrophages	Leishmaniasis

Image recognition tips:

• Dysplasia: Look for abnormal cell shapes and nuclear maturation

• Erythrophagocytosis: Look for erythroid cells inside macrophages

• Fibrosis: Look for collagen replacing normal marrow cells; collagen appears blue in the special-stain images

• Infection: Look for intracellular organisms

Primary vs. Secondary Bone Marrow Disorders SUMMARY

Disorder	Primary	Secondary
Myelodysplasia	MDS: Clonal neoplastic disease causing ineffective hematopoiesis	Dysmyelopoiesis associated with infection, immune disease, drugs, or toxins
Myelofibrosis	Neoplastic marrow fibrosis; very rare in veterinary medicine	Reactive fibrosis associated with inflammation, toxic injury, necrosis, or immune-mediated disease
Key Difference	Primary disease process	Develops in association with another underlying disorder

Important distinction: Dysplasia alone does not prove MDS. Clinical history, peripheral blood findings, and other possible causes must be considered