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HEMATOLOGY 2 PRELIMS LECTURE 2: ANEMIA OF BONE MARROW FAILURE AND SYSTEMIC DISORDER

Bone Marrow failure is associated with the failure to replace the damaged cells, which are damage because of normal
apoptosis or hemolysis. BM failure also has the reduction or cessation of the production of cells (mostly Erythroid lineage but
still can affect WBCs and Platelets)

Patients with Bone Marrow Failure will always have Pancytopenia occurring.

PATHOGENESIS IN BM FAILURE (GENERAL) - Any of the following:

 Destruction of hematopoietic stem cells (could be because due to injury or exposure to drugs or chemicals)
 Premature senescence and apoptosis of hematopoietic stem cells (there might be mutation that is happening
for that specific cell)
 Ineffective hematopoiesis (may be because of the deficiency of Vitamin B12 and Folate)
 Disruption of the bone marrow microenvironment (reversible at sometimes through bone marrow transplant)
 Decrease production of hematopoietic growth factors or related hormones
 Loss of normal hematopoietic tissue (because the malignant/ abnormal cells are able to infiltrate the bone
marrow)

3 GENERAL TYPES OF ANEMIA (Aplastic Anemia, Pure Red Cell Aplasia, Myelophthisic Anemia)
A. APLASTIC ANEMIA
Either Acquired or Inherited - (Most common is acquired)
General View of Aplastic Anemia:
 Anemia
 Neutropenia
 Thrombocytopenia
*The term aplastic anemia is misleading because we think the problem is the Anemia, but the primary problem is the
Neutropenia and Thrombocytopenia. If there is Neutropenia there is a recurrent bacterial infection while having
Thrombocytopenia is a possibility of having hemorrhage
Aplastic Anemia is characterized by:
 Pancytopenia
 Hypoplastic or Aplastic BM (underdevelopment of the Bone Marrow or reduction of cells in the organ or tissue)
 According morphology: Normocytic, Normochromic
 Decreased Reticulocyte Count and RPI (Reticulocytopenia)
*Reticulocyte Normal Value: 0.5-2% for Adults
 Absence of Immature Cells (BM is unable to compensate) and Absence of Splenomegaly
*If the patient is having Anemia, Splenomegaly, and Lymphadenopathy then you could rule out Aplastic Anemia
(because AA has no Splenomegaly and Lymphadenopathy)
PRIMARY: Inherited or Congenital (Fanconi’s Anemia)
SECONDARY: Acquired
Pathogenesis of Aplastic Anemia:
 Defective CFU-S Stem Cell Population
*CD-34 expresses hematopoietic stem cells, individuals with AA has decrease CD-34 Values
*Also having an increase number of FAS Receptor - which mediates apoptosis in the cell which result to increased
number of premature cell death thus leadingto anemia
 Altered microenvironment for normal stem cell production (still reversible through BM transplant)
 Absent humoral and cellular stimulators for hematopoiesis
 Excessive suppresion of hematopoiesis by T-Lymphocytes (particularly the T-Suppresor Cells)
 Immunologic mechanisms that suppresses hematopoiesis
*Administering immunosuppresive drugs may alleviate the problem
 Premature senescence and apoptosis causes increased FAS Receptors
*BM Aspirate/Biopsy as the sample from the posterior iliac crest as the common site, sometimes from the sternum.
Needles used: Jamshidi Bone Marrow Aspiration Needle and Illinois Sternal/Illiac Aspiration Needle
*Bone Marrow Aspirate - To get the cells from the bone marrow by making a smear
*Bone Marrow Core Biopsy/ Trephine Biopsy - To get a 1-2 cm intact bone marrow in which is reflective of the cellularity of
the BM
*Myeloid:Erythroid (M:E) Ratio - Numerical expression of demonstrating or comparing the relative number of granulocytic
precursors with the erythroid precursors
Normal Reference Values = 2:1-4:1; Average = 3:1 (3:1 because granulocytic precursors to erythroid precursors)

Granulocytic Precursors: Erythroid Precursors: 10%


Neutrophil - 20%
Eosinophil - 8% 30%:10% = 3:1
Basophil - 2%; Total = 30%
*In a bacterial infection, there will be an increase in N:E Ratio with 6:1 Ratio but in Leukemia, it has a higher N:E Ratio with
25:1
*For the cellularity of the BM: it should be 50:50 (Fats and Active Hematopoietic Cells); if fat is increased it will cause a
decrease hematopoiesis of the BM

SECONDARY APLASTIC ANEMIA (Acquired)


*Usually due to Drugs and Chemicals
- Chloramphenicol - Usual drug associated with AA
- Exposure to Benzene (Fixative for Histopathology in the past), Hydantoins (Anti-convulsant), Sulfonamides (Wide range of
Antibiotics)
- Insecticides/ Pesticides
*Can also because of exposure to Radiation (causes damage to the stromal cells of the bone marrow), Viruses (ex. EBV,
Hepatitis Virus, HIV, and Human Parvovirus which invades the Eythroid replicating cells), and Miscellaneous Etiology
(coexistence of paroxysmal nocturnal hemoglobinuria and pregnancy)
*Possible Immune Mechanism - Because of the involvement of the Lymphocytes or Humoral Factors (Seen from syngeneic
transplant - expect that there is no rejection that will happen because the donor of the patient will be his/her identical twin;
but there was an instance of rejection of the patient and they used Cyclophosphamide, which is an immunosuppressive drug,
there was no rejection happened) Thus, they found out there is an immune mechanism occurring in AA

- Antithymocyte Globulin - Suppresses action of the Lymphocytes


ex. NK Cells which kills the target cell and also shown that it is able to suppress hematopoiesis by mediating Lymphocyte
Mediated Aplasia
- Abnormal T Cell subsets in BM (Overexpression of ex. T3 or T11) which suppress hematopoiesis
- Humoral Inhibitors of Stem Cell Growth (Associated with Systemic Lupus Erythematosus or exposure to Quinidine or can be
Idiopathic

Secondary Aplastic Anemia symptoms are directly related to Pancytopenia

CLINICAL PRESENTATION
*Aside from striking hypoplastic marrow
 Pancytopenia  Hemorrhage (from Thrombocytopenia)
 Pallor, wekaness, fatigue  Lack of palpable spleen (absence of Splenomegaly)
 Decreased Neutophil (recurrent bacterial infection)
LABORATORY FINDINGS
Peripheral Blood Smear:
 Decreased total Leukocytes  Normal Red Cell Morphology (Normocytic and
 Lymphocyte is normal to slightly decreased (SD when Normochromic)
administering immunosuppressive drug)  Decreased Reticulocyte count in PB
 No Immature Cells in PB
Bone Marrow:
 Hypoplastic/Aplastic  No increase number of immature cells
 Lymphocyte and Plasma Cells are present  With patchy areas of cellularity
 Megakaryocytes are absent

*Treatment for Secondary AA - Below 40 years old: Bone Marrow Transplant;


Above 40 years old: Immunosuppressive Drugs
PRIMARY APLASTIC ANEMIA (Inherited)
*Fanconi’s Anemia - Most common type of AA that is inherited; as known as Familial Aplastic Anemia
- Autosomal Recessive as mode of congenital type of inheritace. It is a type of Chromosomal instability disorder having Aplastic Anemia, Physical
Abnormalities, and Cancer Susceptibility

CLINICAL FINDINGS
 Short stature  Microcephaly (causing retardation)
 Brown skin pigmentation  Low Birth weight
 Hypogonadism (Failure to develop secondary sexual  Internal Strabismus
characteristic)  Increased levels of Fetal Hemoglobin and small “i”
 Malformation of organs antigen (iAg)
 Mental Retardation
Fanconi’s Anemia (Phenotype)
 Growth retardation and Abnormal development  1000 Fold Risk of Cancer
 Stem Cell Failure
*FA is a chromosomal instability disorder which mean there is random breakage of chromosome; Culture cells (from patient with FA) are
challenged with the addition of Alkylating/DNA Cross Linking Agent (2 most common types: Mitomycin and Diepoxybutane [DEB]); They
observed chromosomal breakage when the agents were added
*15 reported genes that are associated in FA (15 Genes are found in Rodak’s)
Remember: Most common gene present in FA is the FANCA Gene or known as Fanconi’s Anemia Complement Group A Gene
LABORATORY FINDINGS
 Pancytopenia (Thrombocytopenia precedes other  Macrocytic RBCs (First detected abnormality)
Cytopenia)  Increased HbF and iAg
 Reticulocytopenia  Chromosomal Breakage
 Hypoplastic BM  Increase OFT and ESR result
Treatment: Due to Hypogonadism, it is administered with Androgen and Corticosteroid to stimulate Hematopoiesis
Dyskeratosis Congenita (Zinsser-Engman-Cole Syndrome)- Characterized by Mucocutaneous abnormalities, BM failure, and
Pancytopenia. It is a rare, inherited BM failure
Triad of Clinical Findings: Abnormal Skin Pigmentation (other references: Reticulated skin hyperpigmentation), Dystrophic
Nails, Oral Leukoplakia (whitish patch in the tongue, can’t be removed
- Patient is predisposed to Epithelial malignancies and Acute Myeloid Leukemia
Laboratory Findings: Macrocytic RBCs, Pancytopenia, Increase HbF
*This is differentiated from FA which has chromosomal breakage; DC has none
*Shwachman-Bodian-Diamond Syndrome - Combination of Pancreatic enzyme insufficiency and Neuropenia (or
Endocrine-Pancreatic insufficiency and Neuropenia)

B. PURE RED CELL APLASIA (Acquired)


*Occuring in individuals older than 40 years old:
 Severe anemia  Severe decrease in Erythroid element (Problem in
 Normal BM Cellularity Erythroid precursors)
 Normal to Slightly Decreased WBC and Platelet Count
2 Mechanisms Involved:
A. Idiopathic - no known cause
B. Immune Mechanism - (ex. Patient’s serum was incubated plus marrow cells, there was suppression of hematopoietic activity; 2nd
experiment: only the marrow cells was incubated and there was hematopoietic activity) Thus, what is present in the serum of the patient
inhibits the action of hematopoiesis
*Acquired PRCA is secondary to etiologic agent: Benign Thymoma (tumors present in Thymus)
CLINICAL PRESENTATION
 Extreme pallor
 Splenomegaly or Hepatomegaly (or both) - Consequence of frequent transfusion of Packed RBC to the patient (not in Aplastic
Anemia)
*Transient Erythroblastopenia of Childhood (TEC) - Occurring in childhood due to history of viral illness and with increased HbF
LABORATORY FINDINGS
 Normocytic and Normochromic  BM is normal (Extreme decrease/absence of Erythroid
 Markedly decreased Reticulocyte count precursors)
 WBC and Platelet counts are normal

DIAMOND BLACKFAN ANEMIA


- Inherited/Congenital Pure Red Cell Aplasia
- Evident by 1 year of age
- No Renal Abnormality
- Decreased Erythroid Precursors
- Normal WBCs and Platelets
*Studies show that patients with this are unresponsive to Erythropoietin (EPO) thus decreased Erythroid Precursors
Steininger: Normocytic, Normochromic; Rodak: Macrocytic, Normochromic BUT FOLLOW STEIN
- 25% of patients have mutation in:
(40s) RPS7, RPS10, RPS17, RPS19, RPS24, RPS26 (RPS - Small Ribosomal Protein) (RPS19 is the most common)
(60s) RPL5, RPL11, RPL35A (RPL - Large Ribosomal Protein)
*No noted inhibition when serum is present (differentiate from acquired PRCA)
Patient with DBA, only one erythroid precursor is seen in BM and the is Pronormoblast
Treatment: BM Transplant and Corticosteroid
C. MYELOPHTHISIC ANEMIA
- Infiltration of malignant cells into BM (associated with metastatic cacinoma)
*Compensated via Extremedullary hematopoiesis (the blood cell production does not come from the BM, but the HSC migrates to the Spleen and
Liver)
CLINICAL FINDINGS
 Cytopenia
 Releases immature hematopoietic cells
 Stem and progenitor cells migrate to the Spleen and Liver
 Mild to Moderate Anemia
 Reticulocytopenia (Not enough number of reticulocytes)
Peripheral Blood Smear: Teardrop Cells (Dacryocyte), Nucleated RBCs, Immature Myeloid Cells, and Megakaryocyte Fragments
*same with Leukoerythroblastic Reaction because of nRBCs and Immature Myeloid Cells but LR has no anemia present

ANEMIA OF SYSTEMIC DISORDERS

ANEMIA OF CHRONIC RENAL DISORDERS


- Often seen in Chronic Renal Failure
*Problem is inadequate stimulation or production of Erythropoietin (EPO) because the problem is in the Kidneys
*Increased BUN, Creatinine; Decreased Hematocrit (Artifactual Decrease: considered as anemia)
*Normocytic and Normochromic
- Dialysis should be consistent, Chronic Blood Loss (because of consistent dialysis) and patient will have Iron and Folate Deficiency
- Uremia along with Burr Cells (pathologic) because of increased BUN, same appearance with Echinocytes (artifactual) due to prolonged storage

ANEMIA OF ENDOCRINE DISORDERS


- Hypothyroidism
- Decreased Metabolic Rate: Decreased need for oxygen
*When 2,3 DPG is measured, decreased levels is detected because there is no stimulation of oxygen
- Decreased Plasma Volume (masking of anemia)

- Hypopituitarism - the pituitary controls the adrenal gland, gonads, and thyroid. So if there is a problem it causes hypothyriodism and there would
be no production of the hormones: Growth Hormone, Thyroxine, and Prolactin (directly stimulate Erythropoiesis) so there is no stimulation of
Erythropoiesis
- Adrenal Abnormalities (Decreased Plasma Volume)
- Hypergonadism (Low Androgen: Low Testosterone thus there would be no stimulation of Erythropoiesis)
- Poikilocyte observed is Acanthocyte

ANEMIA OF PREGNANCY
- Relative anemia
- Starting at 8th Week of Gestation, increasingly slowly stable at 32 to 34th week
- Dilutional effects
*During pregnancy there would always be expansion of RCM and PV
*RCM expands because it is a protective mechanism of females because there is a chance for blood loss during childbirth or delivery
*PV is still anemia because PV expansion is more prominent/pronounced causing dilutional effect