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PREFI Hema
PREFI Hema
PREFI Hema
Science Program
OBJECTIVES
At the end of the lecture, students are expected to articulate
the:
• Basic and Fundamentals of anemia
• Different types of anemia
• Pathophysiology of each type of anemia
• Mechanisms involved in each type of anemia
I. ANEMIA CAUSED BY DEFECTS IN
DNA METABOLISM
➢ Impaired DNA production
Folate
(5 Methyl
(THF) CYTOPLASM
FOLATE TRAP
Folate M homocysteine methionine
(5 Methyl
(THF) Methionine
B12 synthase
Dihydrofolate THF
reductase
B12
THF
DHF Thyymidylate Serine
syntthsase serine hydroxymethyl
transferase
M
dITP dTMP dUMP M 5,10 methylene THF B6
glycine
I. ANEMIA CAUSED BY DEFECTS IN
DNA METABOLISM
Pathophysiology:
• Vitamin B12 → THYMIDINE NUCLEOTIDE production
• Folate – Direct effect
• When vitamin B12 is deficient, Folate becomes trapped as 5 METHYL THF → FOLATE TRAP
I. ANEMIA CAUSED BY DEFECTS IN
DNA METABOLISM
Thymidine
Uridine
NONFUNCTION
DNA
I. ANEMIA CAUSED BY DEFECTS IN
DNA METABOLISM
➢ RNA production is
not affected
because it uses
URACIL instead of
thymidine.
NUCLEO-CYTOPLASMIC
ASYCHRONY
I. ANEMIA CAUSED BY DEFECTS IN
DNA METABOLISM
➢ MYELODYSPLASTIC SYDROMES (MDS)
✓ Delayed cytoplasmic and nuclear maturation
✓ Vacuoles
✓ Multinucleation
➢ Bone marrow
✓ Confirmatory test for diagnosis of MEGALOBLASTIC APPEARANCE
✓ Asynchrony of the POLYCHROMATOPHILIC NORMOBLASTS
I. ANEMIA CAUSED BY DEFECTS IN
DNA METABOLISM
➢ Assays
✓ ANTI-INTRINSIC FACTOR – autoantibodies against parietal cells, IF and
ANTI-INTRINSICFACTOR
cobalamin IF, important in the diagnosis of PERNICIOUS
PERNICIOUSANEMIA
ANEMIA
✓ SERUM
SERUM GASTRIN
GASTRIN – determines ACHLORHYDRIA measures the pH,
and the method used is CHEMILUMINISCENSE IMMUNOMETRIC ASSAY
No dietary and
Intrinsic Factor
Deficiency
No bacterial
overgrowth
I. ANEMIA CAUSED BY DEFECTS IN
DNA METABOLISM
SCHILLINGS TEST
Fourth Stage
Ingestion of
Increased RB12
Radiolabeled
(Pancreatic
cyanocobalamin
insufficiency)
+ pancreatic
enzymes
Free B12 R
Pepsin Free B12
IF IF
Chief cells protease R
I. ANEMIA CAUSED BY DEFECTS IN
DNA METABOLISM
• Treatment: Oral Vitamin B12 and Folic Acid
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
➢ Cessation or reduction of RBC destruction
➢ Common manifestation is PANCYTOPENIA
➢ Reasons:
✓ Hematopoietic stem cell destruction
o Drugs, Injury, Chemicals, Viruses, Radiation
✓ Premature senescence and apoptosis
o Genetic mutations
✓ Ineffective erythropoiesis
o Stem cell mutations
o B12 and Folate deficiency
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
✓ Disruption of bone marrow microenviroment
✓ Decreased growth factors and hormones
✓ Loss of normal hematopoietic tissue due to abnormal cells
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
•Aplastic anemia:
➢ Rare, fatal syndrome
➢ Pancytopenia, reticulocytopenia, and HYPOCELLULAR MARROW
➢ Two types:
✓ ACQUIRED
✓ INHERITED HUMAN PARVOVIRUS
EPSTEIN BARR VIRUS
HIV
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
Acquired
• Pathophysiology:
➢ Quantitative and Qualitative deficiency of hematopoietic stem cells
➢ Decreased CD 34 cells, Increased Fas RECEPTORS
➢ Stromal cells in the bone marrow of patient are normal
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
➢ Related to immune damage (drugs, chemicals, viruses or other agents)
✓ Increased CD8+ , T lymphocytes
✓ Increased cytokines (IFN ɣ and TNF α)
✓ Upregulation of T-bet IFN ɣ
✓ Increased TNF α receptor
✓ Improvement of cytopenias after immunosuppression
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
➢ Shortened TELOMERES
TELOMERASE
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
• Clinical Findings:
➢ Insidious onset anemia
➢ Pallor, fatigue, weakness
• Laboratory Findings:
➢ .PANCYTOPENIA
➢ Hemoglobin <10 g/dL
➢ Decreased Reticulocyte count
➢ Can be Macrocytic or normocytic
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
➢ Increased liver enzymes
➢ Paroxysmal Nocturnal Hemoglobinuria
•Bone marrow
➢ Fat cells predominate
➢ .PATCHY MARROW CELLULARITY
➢ Decreased progenitor cells
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
•Treatment:
➢ Identify the causative agent
➢ Blood product replacement
➢ .HSCT (Hematopoietic Stem Cell Transplant) <40 years old px
Fibroblast cells
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
Prognosis:
➢ 40% develop bone marrow failure
➢ 1/3 develop MDS and AML
➢ Squamous cell carcinoma
Treatment:
➢ Transfusion
➢ HSCT
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
Dyskeratosis congenita
➢ Rare inherited bone marrow failure and pancytopenia
• Clinical Findings:
➢ Triad
✓ Abnormal skin pigmentation
✓ Dystrophic nails
✓ Oral leukoplakia
➢ Pulmonary Fibrosis
➢ Liver disease
➢ Short stature
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
•Pathophysiology:
➢ very short telomeres
➢ inherited defect telomere complex
➢ Genetic:
✓ X linked autosomal dominant
✓ Autosomal dominant
✓ Autosomal recessive
➢ Mutations in the long arm of the X CHROMOSOME on the DKC1 GENE DYSKERIN
TERC
Elongation of
Premature apoptosis telomeres
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
• Laboratory Findings
➢ Pancytopenia, macrocytic RBCs
➢ Increased Fetal Hemoglobin
➢ FISH – to identify short telomeres has been proposed
• Prognosis:
➢ Mean survival : 42 years
➢ Deaths due to bone marrow failure
• Treatment:
➢ Androgen therapy
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
•Shwachman-Bodian-Diamond Syndrome
➢ Inherited multisystem disorder characterized
➢ , PANCREATIC INSUFFICIENCY cytopenia, skeletal abnormalities and
genetic predisposition to hematologic malignancies
•Clinical Findings:
➢ Delayed bone maturation, failure thrive and short stature.
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
• Laboratory Findings:
➢ Peripheral blood cytopenia, decreased pancreatic enzyme secretion
➢ Nearly all have neutropenia
• Pathophysiology:
➢ Autosomal recessive disorder
➢ Biallelic mutations in the SBDS genes
➢ Quantitative and Qualitative Deficiencies in CD34+ cells
➢ Dysfunctional bone marrow cells
➢ Increased apoptosis
➢ MITOTIC SPINDLE destabilization in hematopoietic cells
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
➢ short telomeres
➢ Increased FECAL FAT SECRETION
➢ Decreased TRYPSINOGEN and ISOMYLASE
➢ Similar with CYSTIC FIBROSIS except for the NORMAL SWEAT CHLORIDE RESULT
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
•Treatment:
➢ Some cases requires no treatment
➢ Enzyme replacement and G CSF administration is recommended for some
cases.
➢ .ALLOGENEIC BONE MARROW TRANSPLANTATION
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
•Other forms of Bone marrow Failure:
➢ Pure Red Cell aplasia: selective and severe decrease in erythrocyte
precursors in an otherwise normal bone marrow.
✓ Acquired Pure Red Cell Aplasia:
o Children or Adults
o Acquired or Chronic
o Idiopathic or autoimmune
o Secondary PRCA – associated with, THYMOMA hematologic malignancies,
solid tumors and infection
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
Auto-antibodies, natural killer
(NK) cell-mediated or T
lymphocyte-mediated
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
o TRANSIENT ERYTHROBLASTOPENIA OF CHILDHOOD : immune
mechanism that targets red cell production following a history of viral
infection
II. ANEMIA CAUSED BY BONE
MARROW FAILURE
✓ Diamond-Blackfan (Congenital)
o Congenital erythroid hypoplastic disorder of early infancy
o RPS7, RPS10, RPS17, RPS19, RPS24, and RPS26 in the 40S subunit and RPL5,
RPL11, RPL35A in the 60S subunit.
✓ Trauma
✓ Prosthetic hear valves
✓ Parasites
III. ANEMIA CAUSED BY INCREASED
DESTRUCTION OF ERYTHROCYTES
B1
HG
CD163 receptor
HEMOPEXIN B2
Urobilinogen
III. ANEMIA CAUSED BY INCREASED
DESTRUCTION OF ERYTHROCYTES
• Clinical Findings:
➢ Cholelithiasis
➢ Kernicterus in newborns
➢ Splenomegaly (chronic macrophage mediated hemolysis)
III. ANEMIA CAUSED BY INCREASED
DESTRUCTION OF ERYTHROCYTES
•Laboratory Findings:
➢ Fragmentation hemolysis:
✓ Macroscopic analysis: COFFEE BROWN COLOR of plasma. ROOT
ROOTBEER
BEER COLOR
urine.
MATRIPTASE 2
Iron will not be
absorbed
HEPCIDIN
IV. ANEMIA CAUSED BY DISORDERS OF
IRON KINETICS AND HEME METABOLISM
• Pathophysiology:
• Three stages:
➢ Stage 1 (STORAGE IRON DEPLETION)
✓ No evidence of iron deficiency
✓ Low serum ferritin
✓ Patient appears healthy without any signs and symptoms
IV. ANEMIA CAUSED BY DISORDERS OF
IRON KINETICS AND HEME METABOLISM
➢ Stage 2 (TRANSPORT IRON DEPLETION)
✓ Exhaustion of stored iron
✓ Anemia is still not evident
✓ Hemoglobin begins to drop
✓ RDW starts to increase
✓ Decreased Serum Ferritin and Iron
✓ Increased TIBC and % transferrin
✓ FEP starts to accumulate
IV. ANEMIA CAUSED BY DISORDERS OF
IRON KINETICS AND HEME METABOLISM
➢ Stage 3 (Frank anemia)
✓ Low hemoglobin and hematocrit
✓ RBC precursors are affected
✓ .MICROCYTIC AND HYPOCHROMIC CELLS
✓ .INCREASED ERYTHROPOIETIN AND DECREASED HEPCIDIN
✓ Increased TIBC and % transferrin
✓ Decreased Serum Ferritin and Iron
✓ Manifestation of signs and symptoms
IV. ANEMIA CAUSED BY DISORDERS OF
IRON KINETICS AND HEME METABOLISM
•Laboratory Findings:
➢ Complete Blood Count:
✓ Anisocytosis, poikilocytosis, microcytosis and hypochromia
✓ Decreased RBC indices (MCV, MCH, MCHC)
✓ . DECREASED RBC COUNT
✓ .LOW RETICULOCYTE COUNT
✓ .THROMBOCYTOSIS
IV. ANEMIA CAUSED BY DISORDERS OF
IRON KINETICS AND HEME METABOLISM
➢ Iron studies:
✓ Low Ferritin, Serum Iron
✓ High TIBC, FEP, % Transferrin
➢ Treatment:
✓ Treat the cause of deficiency
✓ Oral supplements (ferrous sulfate)
IV. ANEMIA CAUSED BY DISORDERS OF
IRON KINETICS AND HEME METABOLISM
•Anemia of Chronic Inflammation
➢ Commonly associated with systemic diseases:
✓ rheumatoid arthritis, chronic infections and malignancies
➢ Role of acute phase reactants:
✓ HEPCIDIN – APR that is produced by the liver. It causes the degradation
of . FERROPORTIN
➢ Hereditary or acquired
IV. ANEMIA CAUSED BY DISORDERS OF
IRON KINETICS AND HEME METABOLISM
➢ Acquired:
✓ Lead poisoning: Lead affects the central nervous system and the
hematologic system. Interferes with. PORPHYRIN SYNTHESIS.
o Normocytic, normochromic (microcytic hypochromic in chronic exposure)
o . BASOPHILIC STIPPLING
IV. ANEMIA CAUSED BY DISORDERS OF
IRON KINETICS AND HEME METABOLISM
LEAD
POISONING
PORPHYRIA.
IV. ANEMIA CAUSED BY DISORDERS OF
IRON KINETICS AND HEME METABOLISM
✓ Porphyrias: impaired production of the porphyrin component of heme.
Psychosis is a prominent clinical feature.
PORPHYRIN: is harmful
to the skin and brain .
V. ACQUIRED NON-IMMUNE ANEMIAS
OF INCREASED RBC DESTRUCTION
•Microangiopathic Hemolytic Anemia
➢ Fragmentation and thrombocytopenia
➢ Decreased hemoglobin, increased reticulocyte count increased lactate
dehydrogenase, increased serum indirect bilirubin, urine urobilinogen.
➢ .INTRAVASCULAR HEMOLYSIS
➢ Thrombocytopenia
V. ACQUIRED NON-IMMUNE ANEMIAS
OF INCREASED RBC DESTRUCTION
•Thrombotic Thrombocytopenic Purpura (TTP)
➢ Low Von Willebrand Factor cleaving factor ADAMTS 13
➢ . IDIOPATHIC, SECONDARY OR INHERITED
➢ PENTAD (FATRN)
✓ Fever, Anemia, thrombocytopenia, renal disease, neurologic symptoms
V. ACQUIRED NON-IMMUNE ANEMIAS
OF INCREASED RBC DESTRUCTION
Platelet Plug
Increased
Thrombi
V. ACQUIRED NON-IMMUNE ANEMIAS
OF INCREASED RBC DESTRUCTION
• Hemolytic Uremic Syndrome
➢ Acute renal failure
➢ Atypical and typical
➢ : SHIGA TOXIN
E.coli O157:H7, Shigella
C3 to C9
VII. INTRINSIC DEFECTS LEADING TO
HEMOLYSIS
•Paroxysmal Nocturnal Hemoglobinuria
➢ rare, chronic intravascular disorder
➢ LACKS
. GPI (CD55 AND CD59)
.
➢ PHENOTYPIC MOSAICISM
CD55,59
GP1
GP1 CD55,59
VI. ACQUIRED IMMUNE ANEMIAS OF
INCREASED RBC DESTRUCTION
➢ Hemolytic anemia, thrombosis, and bone marrow failure
➢ Hemoglobinemia, hemoglobinuria
➢ DAT negative
➢ Bone marrow: normocellular and hypocellular
➢ Tests: FLOW CYTOMETRY, SUGAR WATER TEST, HAM TEST
➢ Treatment: ECULIZUMAB
VI. ACQUIRED IMMUNE ANEMIAS OF
INCREASED RBC DESTRUCTION
SUGAR WATER TEST
PX CONTROL
SICKLE CELL ANEMIA
➢ Inherited a sickle (S) gene from one parent and S,C, or Ɓ-thalassemia from
the other.
➢ Homozygous SS = severe manifestations
➢ α2 Ɓ2 6Glu->Val
➢ Eight genotypes that cause disease: Hb SS, Hb S-Ɓºthal, severe Hb S- Ɓ+thal,
Hb SD- Punjab, Hb SO-Arab, Hb SC-Harlem, Hb CS-Antilles, Hb S-Quebec-
CHORL
SICKLE CELL ANEMIA
•Clinical Findings:
➢ no symptoms to a potentially lethal state
➢ Hallmark: VASOOCCLUSIVE CRISIS
➢ Acidosis, hypoxia, dehydration, infection, and fever
➢ Related with G6PD deficiency
SICKLE CELL ANEMIA
Rigid and
Sticky
Hgb SA
SICKLE CELL ANEMIA
•Laboratory Diagnosis:
➢ Associated with chronic hemolytic anemia
➢ Normocytic, normochromic
➢ Marked poikilocytosis
➢ Increased RDW, MCV
➢ Increased thrombocytes
➢ Increased Immunoglobulin A
➢ HPLC, Hemoglobin electrophoresis, capillary electrophoresis, Isoelectric
focusing
SICKLE CELL ANEMIA
• Treatment:
➢ .SUPPORTIVE THERAPY
REFERENCES
• Lotspeich-Steininger, C. A., Stiene-Martin, E. A., & Koepke, J. A. (1992). Clinical
hematology: Principles, procedures, correlations. Philadelphia: Lippincott.
– Rodak, B. F., Fritsma, G. A., & Keohane, E. M. (2012). Hematology: clinical
principles and applications. 4th ed. St. Louis, Mo.: Elsevier Saunders.
– Turgeon, M. L. (2012). Clinical hematology: Theory and procedures (5th ed.).
Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins.
END