HEMATOLOGY PHYSIOLOGY

396

Normal Myelogram: 1% Blasts (increased in acute leukemia, up to 20%), 2-3%

Promyelocytes, 12% Myelocytes, 50% Metamyelocytes, Bands, Neutrophils, 25-30%
Erythroid, 5% Lymphocytes, Plasma Cells, Monocytes (increased in multiple
myeloma), Myeloid-Erythroid (M:E) ratio: 3:1, decreases in anemia because more
erythrocytes produced to compensate for anemia

397

plasma cells blasts

398

399
❖ Describe the emergence of hemoglobin in embryos:
- In first few weeks of gestation → HB is formed in yolk sac and contain ζ, ϵ
chain (Gower, Portland)
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 - At week 8, HBF begins to appear and replace all the Hb by week 14 when
eryhtopoeisis in liver and spleen established
- After birth, HbA replace the fetal Hb and this process is completed by 6
months

400
ABO Hemolytic Disease of the Newborn (ABO HDN) –
- maternal IgG antibodies to ABO blood group proteins cross placenta and cause
hemolysis of fetal RBCs, resulting in anemia and HDN,
- in contrast to Rh HDN, half of ABO HDN cases occur during 1st pregnancy, and ABO
HDN does not worsen with successive pregnancies,
- causes:
1.) Environmental Exposure: anti-A and anti-B antibodies usually IgM which cannot
cross placenta, but some mothers naturally have IgG versions, esp. type O
mothers (association of type A or B fetus with type O mothers in 15% of cases),
2.) Fetal-Maternal Transmission: mother exposed to fetal blood and produces
antibodies against it,
3.) Blood Transfusion: very rare due to preventative tests,
Rh Hemolytic Disease of the Newborn (Rh HDN) ---
mechanism:
1st Pregnancy: where mother is Rh⊖ and fetus is Rh⊕, during birth, embryonic
chorion which normally separates maternal and fetal blood breaks, fetal
erythrocytes leak into maternal blood, maternal B cells activated, produce large
numbers of anti-Rh antibodies, Rh⊖ mothers only have anti-Rh (anti-D) IgG
antibodies if previously exposed to Rh⊕ blood,

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2nd Pregnancy: fetus again is Rh⊕, memory B cells reactivate, secrete anti-Rh (anti-D)
IgG antibodies, which cross placenta and attack fetal erythrocytes, fetal splenic
macrophages phagocytose IgG-coated RBCs
serious complication is Erythroblastosis Fetalis: extravascular destruction of fetal RBCs
resulting in severe anemia, high output cardiac failure, extramedullary
hematopoiesis, severe ascites and edema (hydrops fetalis), and death

❖ What is the indication of anti Rh antibodies & its mechanism :

- Women at 28 weeks gestation & immediate postpartum period must
administer Anti-D IgG which bind to the fetal RBCs that pass to the
maternal circulation → bind to them → destroyed by spleen
- The amount of the IgG are small, not cause significant hemolysis of fetal BV
when transplacental transferred

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❖ Despite the pathology of HBS , HBC are similar, HBS is more severe, lethal:
- HB is highly compact due to non polar hydrophobic residues in the
interior and charged polar residues on the surface
- SCD → substitution of glutamate with Valine (non polar) lead to formation
of hydrophobic pocket → interact with another non polar residues on HB
molecule → polymerization of HBS molecules → sickling
- HBC → substitution lead to Lysine (polar) with no hydrophobic interaction
occur, just slowing in electrophoresis

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Factor Identity
1 Fibrinogen
2 Prothrombin
3 Tissue Factor (TF)
4 Calcium
5 Proaccelerin, labile factor
6 -
7 Proconvertin, serum prothrombin, conversion accelerator, stable factor,
shortest half-life, fasted depleted in liver disease
8 Antihemophilic factor
9 Christmas factor, plasma thromboplastin component
10 Stuart-Prower factor
11 Plasma thromboplastin antecedent
12 Hageman (contact) factor
13 Fibrin stabilizing factor

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 HEMATOLOGY PHYSIOLOGY
404
Stomatocyte – slit-like area of central pallor, Polychromasia – increased reticulocyte
seen in liver disease, acute alcoholism, count (normal 0.5-1.5%)
malignancies, Hereditary Stomatocytosis,
may be an artifact of the collection
process

Schistocytes – fragmented helmet or Pappenheimer Bodies – inclusion bodies

triangle-shaped RBCs, seen in
Microangiopathic Hemolytic Anemia
(including DIC/TTP/HUS, HELLP Syndrome),
mechanical (artificial valves), uremia,
malignant hypertension, severe burns
formed by phagosomes that have
engulfed excessive amounts of iron,
seen in Sideroblastic Anemia, hemolytic
anemia, and SCD

Schizont – RBC with many organisms inside, Poikilocytosis – RBC morphology (shape)
seen in Malaria variation
- Increased central pallor … upper arrow
- Poikilocyte … lower arrow

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 Anisocytosis – RBC size variation Anisopoikilocytosis – variation in RBC size
and shape

406

❖ What is the effect of iron administration on patients with Iron Deficiency

Anemia:
- Normally; patients should experience Hb level ↑↑ ~ 2g/dL weekly for the first
3 weeks
- The ↑↑ is in mature RBCs and reticulocytes → after ~ one day the retics →
RBCs
❖ L/M of reticulocytes: immature RBCs that is slightly larger and bluer than
mature RBC, lack nucleus but retain basophilic, reticular network of residual
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 rRNA
❖ What is the role of Hepcidin in iron transport & storage:
- Hepcidin is the central regulator of iron homeostasis
- It interact with ferroportin (on the enterocytes) to degrade it and prevent
excess iron absorption in the intestine
- Gastric acid production: direct gastrin action on the parietal cells are less
significant than its effect in ECL cells

❖ What are the regulators of Hepcidin release:

- Stimulated by: high iron levels and inflammatory conditions (APR form liver)
- Inhibited by: hypoxia and ↑↑ erythropoiesis
❖ What is the fate absorbed iron :
- Iron is absorbed in the proximal small intestine facilitated by divalent metal
transporter 1 (DMT) with 2 pathways:
1) Fe bind to ferritin and remain stored in the enterocytes → sloughting of
intestinal cells help to get rid of the excess iron
2) By ferroportin, Fe enter the circulation where it transported in blood by
transferrin → stored in tissues as ferritin

❖ Role of HFE gene in iron transport & hemosiderosis:

• HFE protein form a complex with transferrin receptor (which uptake the
iron-transferrin complex & sense the free iron pool in the liver)
• When free iron pool reach the desired level & sensed by transferrin –HFE →
liver produce hepcidin which inhibit DMT1 (divalent metal tansporter) on
the intestinal surface → ↓↓ iron absorption.
• In hemochromatosis, defective HFE gene → defective sensing the hepatic
iron pool → ↓↓ hepcidin, ↑↑ DMT1 → ↑↑ iron absorption ➔ ↑↑ ferritin
(storage protein), ↑↑ transferrin saturation (iron transporter I the plasma)

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407
❖ Clinical characters of thalassemia minor:
- β → more in adults of Mediterranean descent while α → more in Asian
descent
- microcytic anemia with normal iron profile, blood smear → Spherocytes &
target cells
- ↑↑ HBA2 (α2δ 2), +/- ↑↑ HBF
- Mutation in β chain DNA affect transcription, translation of mRNA →
aberrant precursor of mRNA splicing or premature chain temrination
❖ Blood smear findings in patient with thalassemia:
1- Microcytes
2- Anisopoikilocytosis
3- Target cells
4- Teardrop cells
5- Nucleated precursors
6- Basophilic stippling

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❖ Mention the differential diagnosis of drug induced PN:
- Vitamin B12 deficiency:
o vitamin B12 need 4 -5 years of absence of intake to occur, as body can
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 store 1000 times the daily need for vitamin B12
o the longer the deficiency → the less likely to be reversible
- vitamin B6 deficiency:associated with chelosis, stomatitis, atrophic glossitis,
sideroblastic anemia, PN
- phenytoin → only cause PN after chronic use > 1 year
❖ Hematological changes in response to injecting vitamin B12 in pernicious
anemia:
- Erythrocyte recursor begin to change from megaloblasts to normoblasts
- Immature reticulocytosis are released to blood stream → begin rising within 3
– 4 days and peaks within 1 week
- The reticulocytes that are present in the circulation take longer time o mature
to form mature erythrocytes (cause left shift)
- Hemoglobin level ↑↑ by rate of 1 g/week, anemia typically take 8
weeks to correct

Pernicious Anemia –
type of vitamin B12 deficiency anemia (megaloblastic) due to autoantibodies that prevent
vitamin B12 absorption,
caused by autoimmune attack of gastric mucosa,
3 types of antibodies (diagnostic, not causative, damage to intestinal lining thought to be
T-cell mediated – T4, leading to autoantibody production):
1.) Type 1: blocks binding of vitamin B12 to intrinsic factor, 75% of patients,
2.) Type 2: prevents binding of vitamin B12-intrinsic factor complex to ileal receptor,
3.) Type 3: binds to α and β subunits of gastric proton pump, non-specific finding,
also occurs in Idiopathic Chronic Gastritis, older adult (60), esp. Scandinavian or Caucasian,
associated with other autoimmune disorders, esp. thyroiditis and adrenalitis,
histology:
1.) GI: diffuse chronic gastritis, fundic gland atrophy (diminished chief cells, absent parietal
cells), goblet cell metaplasia (intestinalization), megaloblastic epithelial cells, atrophic
glossitis (tongue becomes shiny, glazed, beefy),
2.) CNS: demyelinization of dorsal and lateral spinal tracts producing spastic paraparesis,
sensory ataxia, and severe lower limb paresthesias, may also occur in posterior DRGs
and peripheral nerves,

409

Degradation of Heme and Bilirubin – system designed to remove Hb from degraded RBCs,
process happens in spleen (RBCs destroyed), liver (bilirubin conjugation), GI
(conversion via normal gut flora), heme is insoluble, bound to albumin in blood,
2 types of bilirubin:
1.) Direct: conjugated, glucuronate group added, soluble,
2.) Indirect: unconjugated, glucuronate group not yet added, insoluble,
urobilinogen gives urine yellow color,
stercobilin gives feces brown color (blocked bile duct results in no stercobilin in feces,

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which makes it clay, i.e. white/pale colored)

❖ Effect of extra-medullary hematopoiesis on cells

- Charcterised by accumulation of erythroid precursor cells in the liver, spleen
due to EPO stimulated hyperplastic marrow cell invasion of extra-medullary
organs
- Expansion of the mass of the progenitor cells → BM thinning and impaired
bone growth, pathoglogical fractures & chipmunk facies

❖ Commonest cause of Aplastic anemia: is idiopathic by direct toxic insult or T-

cell response leading to apoptosis of stem cells (parvo virus don’t cause aplastic
anemia, it only cause aplastic crisis in hemoglobinopathy)

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Aplastic Anemia –
BM stem cell failure results in pancytopenia,
circulating cells may have normal morphology,
causes:
1.) Idiopathic: primary stem cell defect, likely immune-mediated, may follow acute
hepatitis,
2.) Infection: Parvovirus B19 (infects RBCs and progenitor myelocytes), EBV, CMV,
hepatitis, VZV, HIV,
3.) Inherited: Fanconi Anemia (autosomal recessive defect in DNA repair, early marrow
failure, hypoplasia of kidneys, spleen, and some bones, CBC may show macrocytosis,
presents with short stature, café-au-lait spots, thumb/radial defects, increased
incidence of tumors/leukemia),
4.)Radiation,
5.) Chemicals: Benzene, insecticides (e.g. DDT, parathion),
6.) Drugs (Dose-Related): alkylating agents, antimetabolites, Chloramphenicol, inorganic
arsenicals, anticonvulsants (e.g. Carbamazepine),
7.) Drugs (Idiosyncratic): Chloramphenicol, Phenylbutazone, organic arsenicals,
Methylphenylethylhydantoin, Streptomycin, Chlorpromazine

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• Myelophthisic Anemia –
- displacement of functioning hematopoietic BM tissue with fibrosis, tumors (esp.
metastatic), or granulomas,
- caused by chronic myeloproliferative disease (e.g. myelofibrosis), leukemia,
lymphoma, metastatic carcinoma or myeloma,
- cytokines in these settings stimulate fibroblastic proliferation and fibrosis of
marrow,
- associated with chronic idiopathic myelofibrosis,
- common sources of metastasis are small-cell lung cancer, breast cancer, and
prostate cancer,
- presents with anemia with extramedullary hematopoiesis in liver and spleen,
- peripheral smear shows nucleated RBCs, teardrop-shaped RBCs (dacryocytes), or
immature myeloid precursors (leukoerythroblastosis, distinguish from Aplastic
Anemia, where RBCs are not produced or visible),
- diagnose with BM biopsy, which shows significant replacement of normal BM with
fibrosis, malignancy or other infiltrative process,
- treat underlying illness
• Pure Red Cell Aplasia –
rare BM failure involving only RBC development (WBC and platelet lineages remain
normal),
causes:
1.) Thymoma, so any case of PRCA must undergo chest CT
2.) Parvovirus B19 Infection: destroys RBC precursors, may lead to aplastic crisis in
patients with pre-existing RBC deficiency (e.g. Hereditary Spherocytosis, β-
Thalassemias),
3.) Autoimmune: anti-EPO antibodies may develop after prolonged EPO
administration,
4.) Congenital: Diamond-Blackfan Anemia,
5.) Idiopathic: likely anti-erythroid autoimmune reaction,
Normocytic non hemolytic anemia → BM show absence of eythroid progenitors with
preserved megakaryocytes & myeloid cells
for all causes, serum shows normocytic anemia with corrected reticulocyte count <3%,
if associated with thymoma, removal of mass is curative

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❖ L/M of Spherocytes: 2/3 diameter of normal RBCs more densely Hb at
the periphery with lack of central zone of pallor
❖ Laboratory findings of hereditary spherocytosis:

❖ Osmotic fragility test is done by incubation of RBCs in hypotonic saline with

glycerol → positive = Hb release

❖ Why fetal Hb has more affinity to O2 than HbA:

- It is all about 2,3 BPG; normally, it bound to a pocket between 2 β chains of
deoxygenated Hb.
- This pocket is positively charged formed due to abundance of histidine and
lysine in this pocket which attach to the negatively charged 2,3 BPG → ↓↓
affinity to O2
- In HBF, histidine residue is replaced by serine, less attached to 2,3, BPG →
more affinity to O2
❖ Mechanism of anemia in pyruvate kinase deficiency :
- Pyruvate kinase → produce ATP from conversion of PEP → pyruvate , main
metabolite for glycolysis in RBCs is lactate.
- Most of ATP used in transport cation, when absent → loss of H2O &
potassium → echinocyte formation → hemolysis
- Damaged RBCs are removed in the red pulp of spleen

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❖ Pathogenesis of PNH & cause of its clinical picture :
- Due to acquired mutation in PIGA gene → ↓↓ synthesis of GPI anchor which
hold CD55( DAF), CD95 (MAC inhibitory protein)
- Thrombosis: due to release of free Hb, other prothrombotic factors from
lysed RBCs
- Hemolysis: occur at low level throughout the day, but more often occur at
night as complement more activated at low PH, which occur at night
- Pancytopenia: due to autoimmune attack against GPI antigens on stem cells
❖ Mention the Initiators of sickling and pathogenesis:
- Under anoxic conditions → polymerization of HBS form gel → meshwork of
fibrous polymers → distortion & sickling
- Occur in low O2 state, ↑↑ acidity, dehydration, more in the organs with slow
blood flow as it has lower O2& acidity
- Organs with high O2 demand → more O2 unloading → promote sickling

❖ Clinical picture and diagnosis of sickle cell trait:

- HB electrophoresis usually show HbA > HbS throught the patient life with
normal RBCs inices
- usually asymptomatic with incidence of hematuria, priapism, uti, splenic
infarction at high altitude
- relative protection(not immunization) to P. falciparum due to rapid
removal of the infected RBCs by spleen & sickling of the infected cells
❖ why SCD is treated by hydration ☺
- calcium dependent (Gardos) potassium channel → regulate transport of K,
H2O from the RBCs, when blocked → efflux of K, H2O is reduced → #
dehydration of RBCs → ↓↓ polymerization of Hb S
❖ Clinical picture of dactylitis (hand foot syndrome) in SCD:
- It usually occur in the first few years of life as the bine still contain
hemopoetic BM
- Result from small infarctions in the bones of the extremities, these infarctions
cause bilateral swelling, tenderness when slight touch, warmth
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❖ Clinical picture of acute chest syndrome in SCD:
- Vaso-occlusive crisis localized to the pulmomary vasculature, usually
precipitated by pulmonary infection.
- Occur by severe chest pain, fever
- The spleen may demonstrate brownish discoloration due to extensive
ingestion of RBCs

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411
❖ Mention the difference between cold and warm agglutinin:
• Cold agglutinin:
 The IgM formed bind to RBCs stongly at lower blood temperature (either
invitro or in vivo)
 Occur at areas with below core body temperature (far from lymphoid tissue)
→ intravascular hemolysis due to complement activation
 The presence of cold agglutinin can be assessed bedside by drawing blood on
anticoagulated tubes, immerse the tube in iced water for several seconds →
clumping of blood which relieve as the tube warm

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❖ Porphyria cutenea tarda (PCT):
- It is the most common disorder of heme synthesis mostly due to acquired
deficiency of uroporphyrinogen decarboxylase
- The disease manifesting more in presence of iron, halogenated
hydrocarbon, alcohol, smoking, HCV, HIV
- Accumulation of porphyrinogens in the skin → rect with O2 o excitation by
UV rays ➔ photosensitivity; preset as vesicle, blister formation on sun
exposed area, edema, pruritis, pain
❖ Acute intermittent porphyria:
- Clinical picture of Acute intermittent porphyria:
• AD disease, presented with severe abdominal pain & neurological
manifestation (this occur in any deficiency of early heme synthetizing
enzyme)
• The most characteristic findings is→ reddish urine that become very
dark on exposure and long standing due to oxidation of excess PBG
- Treatment of Acute intermittent porphyria:
• Avoid of CYT P450 inducers (which induce δ ALA synthetase), smoking,
alcohol
• Acute treatment is IV dextrose which ↓↓ALA synthetase activity

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❖ Shortest and longest half life of coagulation factors :
- Shortest half-life : factor VII, protein C
- Longest half-life : factor II (prothrombin)
❖ What is the role of Vitamin K in activation of coagulation factors.
- Vitamin K is an essential cofactor for γ glutamyl carboxylase → responsible
for converting glutamyl residues to γ carboxy-glutamates
- Carboxylation → allow for creation of calcium binding sites which attract the
clotting factors to the negatively charged phospholipids
- Due to neonatal deficiency of vitamin K, all neonates must be given IM
vitamin K at birth
415
❖ Describe the mechanism of ristocetin aggregation test:
- ristocetin activate GP Ib receptor on platelets → make them available for vWF
binding
- positive test = either Bernarnd Soliuer disease or VWD → differentiated by
mixing test
- When normal plasma mixed with the blood (sufficient vWF):
o aggregation = VWD
o failure to aggregate = Bernard soliuer

❖ Causes of ITP and different presentations in adults vs. children:

- It is due to Ig autoantibodies against GP IIa/IIIb protein
- Primary ITP: isolated ↓↓ platelets within normal blood smear. Adults:
insidious and chronic, while in children → acute and self limited.
- Secondary ITP : may be associated with HIV, HCV

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416
❖ Compare and contrast between HUS/TTP and DIC:

❖ Prevelance of VTE in factor V leiden :

- Inherited causes of hypercoagulability must be considered in all patients < 50
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 years with non obvious explanation for prothrombotic state
- Heterozygotes → 5 – 10 ↑↑ in VTE (9% of population)
- Homozygous → 50 – 100% risk of VTE

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❖ L/M of Burkitt’s lymphoma:
- Due to ↑↑ C-MYC → ↑↑ transcription factor → highly mitotic activity
(measured by high Ki-67 fraction approaching 100%)
- It appear as diffuse medium sized deeply basophilic lymphocytes
- Normal macrophage which phagocyte the resulting cellular debris
(tangible body macrophage)

❖ What is the genetic abnormalities in Burkitt’s lymphoma: T(8:14), T(2:8),

T(8:22)

❖ L/M of follicular lymphoma :

- 2nd most common NHL, with typical fluctuating (waxing and waning)course
- They are composed of aggregates of packed follicles that obscure the normal
architecture of the lymph nodes
- Consists of centrocytes (small cleaved cells) mainly, with some centroblasts
(large noon cleaved cells)

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❖ How to detect malignancy in reactive lymph nodes:
- Pleomorphism, ↑↑ mitoses, nuclear changes are associated with any reactive
hyperplastic lymph nodes (sign of ↑↑ growth)
- The best indicator of malignancy is mono-clonality
- Reactive lymph nodes → polyclonal with proliferation of many different
cell types within the lymph nodes
- Malignant transformation → monoclonal proliferation which result from
unchecked proliferation of single genetically unique cell
 Monoclonality can be tested by PCR. In case of T-cell → examine the
rearrangement of TCR (especially V-region of the TCR), in case of B-cell →
examine the rearaangement of genes for immunoglobulin variable regions
❖ Describe different types of reactive hyperplasia of lymph nodes
 Broad term encompasses al benign, reversible enlargement of LN
- Follicular hyperplasia: ↑↑ number & size of the lymphoid follicles
- Sinus hyperplasia: sinuses enlarge and fill with histiocytes.
- Diffuse hyperplasia: diffusely effaced nodal architecture by sheets of
lymphocytes
- Malignant transformation → distorted or effaced architecture of lymph nodes,
which may be follicular or diffuse

419
❖ Mechanism of bony lesions in patients of MM: neoplastic cells ↑↑ IL-1, IL-6
→ activate osteoclasts → bone resorption → osteopenia
❖ Diagnostic studies for diagnosis MM: M protein (monoclonal Ig) in the
serum , Bence Jones protein (monoclonal light chain) in urine, ↑↑ Igs
→ Rouleaux formation → ↑↑ ESR, BM show > 30% plasma cells
❖ Treatment of multiple myeloma & mechanism of this treatment :
- Due to its high activity of plasma cells to synthetize new protein → they are
particulary susceptible to proteasome inhibitor
- Treatment is bortezomib → boronic acid containing dipeptide
- Inhibiton of proteasome → a) accumulation of toxic misfolded proteins b)
accumulation of proapoptotic proteins → these two mechanisms lead to
apoptosis of plasma cells
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❖ What is the genetic abnormalities in acute promyelocytic leukemia:
- T[15:17] → gene of retinoic acid receptor α (RARα) is transformed from
chromosome 17 to chromosome 15 where it fuses with promyelocytic
leukemia gene (PML) → PML/RAR which is inactive
❖ LM of atypical lymphocytes present in mononucleosis:
- Much larger cells than normal lymphocytes, abundant blue cytoplasm
- Basophilic rim is very characteristic
- Eccentrically placed nucleus
- Cell membrane appear to conform to the borders of the neighboring cells.
- The presence of abundant cytoplasm and lack of bizarre nuclear
changes distinguish it from blast cells

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❖ Immunophenotying of precursor lymphoblastic leukemia:
- Both show TdT positive cells with PAS positive material
- Precursor B-cells:CD10, CD19
- Precursor T-cells: CD2, CD3, CD4, CD5, CD7, CD8, +/- CD1a
❖ L/M of Acute myeloid leukemia:
- Several myeloblasts (very large cells (compared to RBCs), abundant
basophilic cytoplasm, bilobed / folded nucleus, multiple nucleoli)
- Contain Auer rods (stain +ve for peroxidase) → intracytoplasmic needle
shaped (rod ) fused lysosomal granules

❖ Lab characters of leukomoid reaction :

- LAP may be normal (not usually ↑↑)
- Smear show Dohle bodies → light blue peripheral granules in neutrophils
due to ribososmes bound to RER, seen in toxic systemic diseases, MDS, burn
- Some other findings include: Toxic granulations and cytoplasmic vacuoles

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❖ Genetic abnormalities in M4Eo (eosinophilic) subtype of AML: inversion occur
at chromosome 16 [inv(16)]
❖ Genetic abnormalities in CLL may include deletion of 13q segment
❖ Definition & Causes of leukomoid reaction
Benign leukocytosis > 50,000 due to severe infection, hemorrhage, solid tumor
or acute hemolysis
❖ DD leukomoid reaction & acute leukemia
In leukomoid reaction → ↑↑ bands, early mature neutrophil precursors
(myelocytes), while in acute leukemia → ↑↑ immature cells (promyelocytes,
myeloblasts)

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• Absolute vs. relative erythrocytosis: Hb content or HCT value are not
accurately used, instead RBCs mass should be measured
• Primary vs. secondary: measurelevel of erythropoietin levels (↓↓ in
primary, ↑↑ in secondary)
• Hypoxic vs. other causes of secondary: the threshold is SO2 < 92%
(PO2 < 65 mmHg)

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❖ Pathogenesis & treatment of primary myelofibrosis:
- Caused by hyperplasia of atypical megakaryocytes → stimulate fibroblast
proliferation → replacement of the BM bby dense collaen deposition ➔ HSM
due to extra-medullary hematopoiesis with tear drop & nucleated RBCs
- Due to mutation of JAK2 pathway, so JAK2 inhibtors can treat myelofibrosis
→ ruxolitinib

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 HEMATOLOGY PHARMACOLOGY
423
❖ Action of LMWH & fondaparinaux, reversibility:
- LMWH act more on factor Xa, not thrombin
Unfractionated heparin contain large polysaccharide wich can bind to
both thrombin & factor X equally, while LMWH has short polysaccharide
which bind mainly to factor Xa
- Fondaparinaux act only on factor Xa (as it is pentasaccharide Factor Xa
inhibitor)
- Protamine is used in bleeding for both however it cannot completely
reverse the anti-Xa activity
- FFP never be used in heparin overdose as it contain anti-thrombin III →
potentiate effect of heparin

❖ Difference between effect of heparin and rivaroxaban on coagulation profile:

- Heparin: ↑↑ aPTT, ↑↑ thrombin time (TT), normal PT
- Rivaroxaban: ↑↑ aPTT, ↑↑ PT, normal TT
- TT prolong only if the drug directly or indirectly inactivate thrombin

424
 Warfarin inhibit epoxide reducatse which is responsible for regeneration of
vitamin K
 Treatment of warfarin induced skin necrosis is by administration of FFP,
protein C concentrate

427
❖ What is the effect of MTX on cells when administered:
- MTX is an analogue of folic acid competitively inhibit DHF reductase, once
enter the cells → undergo polyglutamation, so accumulation of folic acid,
DHF polyglutamate inside the cells.
- Folinic acid is therapeutic reduced form of THF
❖ What is the difference between MTX & 5FU , and effect of folic acid on them:
- MTX: prevent reduction of folic acid to THF, + Leucovorin (reduced THF) →
rescue the MTX BM suppression
- 5FU: bind to THF, thymidine synthetase in stable reaction, so + leucovorin →
↑↑ action and toxicity

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