Medicine II Disorders of hemoglobin

HEMATOLOGY - Definition
Midterm Coverage – Dr. Tuy o Inherited disorders of α- or β-globin biosyntheis
AMS 204 o reduced supply of globin  ↓ production of
hemoglobin tetramers  microcytic anemia
Coverage of Midterm Examination: o unpaired α- or β-globin chain
I. Disorders of Granulocyte and Monocyte - Generally affect two properties of the hemoglobin:
II. Myeloproliferative Disorders o Solubility
III. Leukemias o Ability to release oxygen
IV. Lymphoid Malignancies - Take note that the globin synthesis is always in pair.
V. Plasma cell disorders o Adult hemoglobin = alpha paired with beta
 Hgb A (α2β2)
- Unpaired globin chain will precipitate and form Heinz
bodies which can cause hemolysis (ineffective
DISORDERS OF HEMOGLOBIN
hematopoiesis).
- In the normal adult blood, there are three forms of
There are diseases that either involves the alteration in the
hemoglobin that are normally found.
structure of the hemoglobin or those diseases that affects the
rate of synthesis of the globin chains. These diseases possess
various forms. It could present as a hemolytic condition
(Thalassemia) and it could also present as a vaso-occlusive
phenomenon (Sickle cell anemia), etc. Some of these are not really
common and some are quite prevalent in our country especially the
Thalassemia. o Hemoglobin A (HbA)
 Predominant
To understand the different hemoglobin diseases, we must review  Composed of alpha and beta
the structure of the hemoglobin and the way the hemoglobin is o Hemoglobin A2 (HbA2)
synthesized.  Small amount
 Composed of alpha and delta
o Fetal hemoglobin (HbF)
 Small amount
 Composed of alpha and gamma
- The genes that code for the different globin chains are
found in several gene clusters

Hemoglobin
- The hemoglobin is composed of a paired dimer of alpha
and beta chain.
- It is composed of 4 globin chains. Attached to each globin
chain is the heme component.
- It is a globular molecule. The outer surfaces are said to be
hydrophilic which are important in the solubility of the
hemoglobin in the red cell. The inner area (crevices) is
where the heme component is found is hydrophobic
which is important in the ability of the red cell to release
oxygen to the tissue.
o Heme – hydrophobic; 1 heme binds 4 molecules
of oxygen
o Alpha/ Alpha like gene– found in chromosome
16
o Beta/ Beta like gene – found in chromosome
11
- The different globin genes are arranged sequentially
according to the time that they are expressed.
- Take note that each pair of alpha gene cluster you have
one copy of beta gene which is the primitive or embryonic
alpha like gene and two copies of alpha gene which
encodes for alpha chain. While in the beta like gene
cluster, for each pair of chromosomes you have one copy
of epsilon which encodes for the primitive beta like globin
gene. This is primarily expressed during the embryonic
period and is paired with alpha like chain.
- There are two variants of gamma chain that differentiates
in the 136th position of the chain where one form have
lysine in that position and the other would have alanine in
that position (Agamma and Bgamma).
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 - We have two genes for the gamma chain for each paired
chromosome.
- There is one copy of delta and one copy of beta.
Summary: Alpha gene is duplicated as compared to beta gene. For
each individual there are 4 alpha genes and 2 beta genes both
coming from either the mother and father. The genes are arranged
according to the sequence of expression (embryonic  fetal 
adult). Each of the globin gene are turned off or on depending on the
stage of development.
Hemoglobin gene clusters
Note: Embryonic globin chains: beta and epsilon. This is called as
Gower 1. Alpha chain is expressed throughout life (Embryonic
period (small amount)  birth to adult life (predominant)). In
comparison to beta light chain, epsilon for the embryonic period and
during the fetal period the predominant beta light chain is gamma.
The combination of alpha and gamma produces the fetal
hemoglobin. During the fetal stage, the predominant is gamma.
After birth, approximately 3-6 months, there is a switch from gamma
predominance to beta predominance. 6 months onwards, the
predominant type of hemoglobin is a combination of alpha and beta.
(HbA)
Clinical implication
- The alpha chain is crucial for life. Without alpha, life is not
possible even in utero
- Most structural hemoglobinopathies, those that involve the
alteration of hemoglobin actually involves the beta chain
(clinically significant). Structural abnormalities involving the
alpha are not compatible with life (not seen clinically).
Individuals with alpha chain alterations are incompatible
with life.
Disorders of hemoglobin are either inherited structural alteration in
one of the globin chains which is called hemoglobinopathies
(Hemoglobinopathy is an inherited structural alteration in one of the
globin chains) and those disorders of hemoglobin that affects the rate
of synthesis in one or more of the globin chains are called
thalassemias.
Thalassemias
- Those with this disorder are considered the most prevalent
monogenic disorder and affects about 7% of the world’s
population. It is estimated to be about 7-15% Filipinos are
afflicted with Thalassemia. It is a very important genetic
disorder. They are propagated during evolution because
they are said to confer advantage on the human species. It
protects the human species against malaria. Those
countries with prevalence of thalassemia and
hemoglobinopathies are those countries where malaria is
not prevalent. It is a protective mechanism.
These are the different clinical syndromes that are produced by
hemoglobin abnormalities:
- Hemolysis
o if the hemoglobin is not soluble it precipitates and
forms Heinz bodies
- It could be expressed as Thalassemia if it involves a
reduction in the synthesis in one or more of the Globin
chains.
o Usually alpha or beta
o Rarely, both are involved
- It could cause familial or inherited polycythemia when
you have altered oxygen affinity for the hemoglobin.
o Example: congenital methemoglobinemia –
patients are cyanotic because the hemoglobin
will not release the oxygen to the tissues.
- Acquired form
o Example: acquired types of methemoglobinemia
Geographical Distribution of Hemoglobinopathies
Note: Asians will generally have higher incidence of alpha
thalassemia as compared to Mediterranean. In the Philippines, there
is hemoglobinopathy E (Hb E). Sickle cell is not that prevalent
because it is predominantly found in African continents.
Thalassemia Syndromes
- Most important disorders of hemoglobin
- “Thala” – sea; referring to the Mediterranean sea
- Inherited disorder of alpha or beta globin chain synthesis
o There is a reduction in the synthesis of globin
chain leading to a production of low levels of
hemoglobin tetramers. As a consequence of
which, there is development of microcytic type of
anemia.
o The clinical consequence of the disease is
dependent on the amount of unpaired globin
chain. The unpaired portion is the one that
causes the anemia because it precipitates and
form Heinz bodies.
 More unpaired alpha  worse
hemolysis
- Microcytic anemia
- Unbalanced accumulation of alpha and beta globin chain
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Note: Thalassemia is an inherited defect in the rate of synthesis of - Hemoglobin H is only seen in Alpha-Thalassemia
one or more of the globin chains. It is the most prevalent disorder syndromes.
affecting more than 70% of the world’s population and 15% of Filipino - Most of the other deletions involving the alpha
population thalassemias, will generally not manifest with thalassemia
3 or thalassemia minors.
Clinical Classification of Thalassemia - Alpha are generally secondary to deletions of the whole or
- There are various categories of the clinical expression of part of the alpha genes.
Thalassemia ranging from asymtptomatic to the very
severe. Beta-Thalassemia syndromes
o Thalassemia minor - Either no B-chain (B0) or small amounts are synthesized
 Especially those with beta3 (B+)
thalassemia 3 will only have: - Excess alpha chain precipitate
 mild anemia - Production of gamma chains helps to “mop up” excess
 microcytic hypochromic type alpha chains
of red cell morphology o the ability of the bone marrow to produce red cell
 Not transfusion dependent that could produce the gamma chain will help
o Thalassemia intermedia mop up the excess alpha.
 Not transfusion dependent - Majority are due to point mutations
 Moderate anemia compared to minor
o Thalassemia major Note: There are only two beta genes: one from the mother and one
 Express very few globin chains from the father. Unlike the alpha thalassemia, the beta thalassemias
 Have severe anemia are generally secondary to point mutations within the beta globin
 Transfusion dependent genes. Alpha are generally secondary to deletions of the whole or
 If not treated with stem cell transplant, part of the alpha genes. The clinical consequence of beta
they will succumb to complications of thalassemia is related to the excess alpha chain.
repeated blood transfusion.
 Consequences of repeated Case: Adult with beta thalassemia, the excess alpha will bind to
blood transfusion: delta and alpha. Beta-like chains are alpha, gamma, and delta
o Iron overload
o Exposure to Hallmark: Elevation in Hemoglobin A2
transfusion-
transmitted Severe type: Expressed as some form of anemia
diseases
o Hemoglobin H Pathophysiology (Beta thalassemia - Thalassemia Major)
 Condition where in three of the alpha - Secondary to excess unpaired alpha chain  produce
chains are deleted. hemolysis ineffective erythropoiesis (increased iron
 This will produce severe anemia absorption in the GIT) Heinz bodies (B and G6PD) 
 Patient is transfusion dependent. spleen in overactive  splenomegaly  increase fraction
of red cells sequestered  anemia  splenectomy (>6
Alpha-Thalassemia syndromes y/o)
- “golf-ball” like red cells upon request of reticulocyte count
Note: the consequence is secondary to the excess of unpaired alpha
Note: Different forms of Alpha Thalassemias: chain. This excess unpaired alpha chain could produce hemolysis or
- If an adult lack alpha chains, there will be excess unbound ineffective erythropoiesis because they precipitate as Heinz bodies
beta which will bind to another beta forming a beta tetramer (which can also be seen in G6PD hemolysis). If there are Heinz
called Hemoglobin H if the patient has deletion of three bodies, the macrophage will recognize them as abnormal and
alpha genes. destroy the red blood cells. Because of the presence of the Heinz
- If the patient only has 1 deletion, he or she is a silent bodies, the spleen will be overactive as it tries to remove the
carrier. I abnormal hemoglobin. This will lead to splenomegaly. The
splenomegolary perse will increase the fraction of red cells that are
Case: Person A has 2 deletions of alpha genes on the same side sequestered and this will aggrevate the patient’s anemia. One of the
and married Person B with one deletion. The risk for having treatment for severe thalassemia or beta thalassemia will be the
Hemoglobin H is higher if it is cis compared if it is trans (cis>trans) removal of the spleen. This is not done until the patient reaches the
age of 6 years.
Note:
- If there is a single deletion  silent If this is a major form of beta thalassemia, there will be a
- If there are two deletions  mild anemia corresponding response by the bone marrow so that you would have:
- If there are three deletions  hemoglobin H where the - Expansion of the marrow cavities as they try to produce
beta genes bind to each other. This abnormal globin chain more red cells.
appears as “golf ball” like red cells. - If it is a thalassemia major, those expansion could cause
skeletal deformities. Classic picture of thalassemia

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 patients: malapad ang noo and maxillaries because the
marrow tries to compensate to the degree of anemia.
Note: Patients with Beta thalassemia major or thalassemia major are
usually treated by transfusion. They are given repeated transfusions
and usually the target is hemoglobin which is higher than usual. This
is called as hypertransfusion. This repeated transfusions will
predispose the patient to iron overload. In patients with ineffective
erythropoiesis, as in thalassemia, for some reason, there is an
increase iron absorption in the GIT. This will further aggrevate the
pateint’s iron overload.
Patient
- Stunted
- Develop various complications: infection, thrombosis,
cardiac, shortened lifespan if not treated adequately
- Treatment: hematopoietic stem cell transplantation
Note: A patient with Cooley’s anemia is described as a stunted
individual with malapad na noo, skull deformity. Because of repeated
blood transfusion, they develop various complications like cardiac,
endocrine, predisposed to thrombosis, infection, and others. All of
these will lead to a shortened lifespan if they are not treated
adequately. Patients have chipmunk facie due to the expansion of
the marrow cavities. When these patients receive repeated blood
transfusions at the same tiem they are given iron chelating agent in
order to remove excess iron which is very expensive
(75,000pesos/month). Hematopoietic stem cell transplantation can
also be offered. Thalassemia screening is now part of newborn
screening.
Treatment:
- Regular blood transfusion
o In one unit of blood, assuming there is 1mg of
iron/1ml of packed RBC or packed red cells,
there is 250-300mg iron per unit of blood.
o Goal is higher than usual in order to suppress
marrow red cell production in order to prevent
skeletal deformities.
- Folic acid supplement – because they are in a state of
hyperproliferation
- Iron chelation therapy
o Rule: For every 20 units of blood transfused 
near iron overload  give ICT
o Together with blood transfusion, you should
chelate the patient.
- Splenectomy
o the patient must at least be 6 y/o
o Consequence: predisposed to infection:
pneumococcal sepsis, and to some extent even
H.influenza
- Endocrine therapy
o As a consequence of iron overload
- Immunization
- Allogenic stem cell transplantation
o expensive
Sickle cell syndromes
- Among the hemoglobinopathies (structural abnormalities in
the hemoglobin), the sickle cell anemia is the most
important. In the Philippines, it is not prevalent.
Definition:
- Caused by the mutant sickle cell hemoglobin (HbS)’
- There is an abnormal hemoglobin S involving the beta
chain where there is an exchange or a replacement of
glutamic acid for valine in the 6th position of the beta chain.
Pathophysiology
- Hemoglobin easily release O2  hemoglobin forms
polymer fibers  red cell assumes sickling phenomenon
(irreversible)
Note: Hemoglobin S easily releases the oxygen. As a result of which,
the hemoglobin forms polymer fibers and will become deoxygenated.
As a result of the formation of the polymer fibers, the red cells
assume the sickling phenomenon. Originally, the sickling
phenomenon is reversible. Eventually, as the red cell passes through
a hypoxic environment, the sickling becomes permanent. This sickle
cell has special propensity to adhere to the endothelial tissues.
Clinical Features of Sickle cell anemia (Homozygous type SS)
- Vaso-occlusive phenomenon
- Chronic hemolysis
Vaso-occlussive complications:
- Painful episodes
- Stroke (at a very young age)
- Acute chest syndrome (may be related to repeated
pulmonary embolism)
- Priapism (persistent and painful erection of penis)
- Liver disease
- Splenic sequestration (repeated infarction of the spleen at
a very young age resulting to photosplenectomy. By the
time they become adult, they are in a state of asplenia
which predisposes them to different infections)
- Spontaneous abortion
- Leg ulcers
- Osteonecrosis
- Proliferative retinopathy
- Renal insufficiency (as the red cell blocks the endothelial
component of the glomerulus)
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 WBC DISORDERS
Two categories:
- Non-neoplastic or Benign conditions of WBC
- Neoplastic conditions of WBC
Phagocytes and Immune Cells
- Several types of WBC
o Granulocytes – contain granules
o Neutrophils – predominant form
Segmented cells o Eosinophils – with golden-brown granules
o Basophils – heavy granules of purple material
that obscure the nuclear details of the cells.
o Mononuclear cells – includes the monocytes and
lymphocytes.
 Monocyte – large cell with abundant
cytoplasm usually containing multiple
granules. Usually described as “ground
glass” appearance. Nuclear material
would assume various shapes: with
indentations, U-shape or shoe shape
 Lymphocyte – small cell with very high
nucleo-cytoplasmic ratio (larger
nucleus compared to the cytoplasmic
material where in the cytoplasm almost
hugging the nuclear material). There
are three types of lymphocytes:
 B cell
 T cell
 NK cell
Note: For practical purposes, when we refer to the segmenters, we
are referring to the neutrophils. But all of these (granulocytes,
neutrophils, eosinophils, and basophils) are segmented. They are
also called as polymorphonuclear cells, not to say that they have
multiple nuclei, but the nuclear material is divided into lobes. They
are also called granulocytes because they contain granules. PMNs
are phagocytic cells that primarily remove pus-forming
microorganisms while the eosinophils and basophils participate in
allergic reactions. Basophils release the mediators of allergy and
anaphylaxis while the eosinophils act as reactant cells. In addition to
this, the eosinophils have the ability to remove the phagocytosed
helminthes.
The normal leukocyte count
- Enumeration of white blood cells is part of complete blood
count. There are two values: Total white cell count and
Differential count.
Note: In the traditional way of getting the differential count is
counting 100 cells or through eyeballing. You should always interpret
white cell count by relating the total white cell count with the
differential count in order to derive the absolute count. When you
interpret the white cell values, you must think of absolute count. The
absolute neutrophil counts are obtained by adding the number of
neutrophils plus the stabs and then multiply it with the total white cell
count.
Example: WBC - 1 x 109 andthe differential count is 0.10 neutrophil
and the absolute neutrophil count is (10% of 1000) is 100. If there are
stabs, add the stabs.
Note: If we think of neutropenia, we are referring to the absolute
count. We are not referring to the differential count alone.
Formation of neutrophil and monocyte
o Granulocyte and monoctyte  tissue-bound;
stay shortly in the blood
Note: The granulocyte and monocytes have a common progenitor
cells. From the common myeloid they differentiate and give rise to
the common granulocyte monocyte progenitor cell. From the bone
marrow, they move to the tissues. The granulocytes and monocytes
are predominantly tissue-bound blood cells. Unlike red cells and
platelets these are only found in the circulation. The granulocytes
and monocytes are tissue-bound so they stay only for a short time
within the blood. For the granulocytes, it stays for about 6-7 hours
(transient) and ends up in the tissues. When the monocytes enter the
tissues, it becomes a highly specialized cell called as macrophage
which is the major phagocytic cells hence the term “macrophages” in
comparison to neutrophils which are termed as “microphages”.
Granulocyte maturation
Stages of the maturation of granulocytes
Note: From the most primitive granulocyte termed as the myeloblast,
it matures to become promyelocyte. At this stage, it cannot be
distinguished morphologically on whether they are neutrophils,
eosinophils, or basophils. It only becomes clear when they reach the
stage of myelocyte. When the granulocyte reaches the myelocytic
state, they lose their capacity to divide and they become mature
cells. In the blood, the predominant granulocytes are the neutrophils.
As the granulocytes mature, they express various forms of granules.
Within the hematopoietic system, the granulocytes are said to exist in
several compartments:
- Dividing pool within the bone marrow
- Non-dividing pool
Note: This is called as the storage pool, from the most primitive
precursor to the more mature types of cells. There are small amounts
of stem cells that give rise to the myeloid cell line. Within the storage
pool it enters the blood.
In the blood, there are two pools when it comes to the granulocytes:
- Marginated cells – cells adherent to the endothelial cells
- Cells bound freely in the blood
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Note: When you request for CBC, the one you measure are the
granulocytes which are in the blood and not the marginated cells.
When you tap the vessels or when you give certain drugs like
steroids, there will be a release of cells in the marginated pool and
this would paradoxically increase the white cell count.
Myeloid differentiation
All granulocytes are derived from the pluripotent stem cells that
differentiate in to the common myeloid stem cells. There are
cytokines that are necessary for the maturation of the granulocytes.
Among these, the most important is the Granulocyte-Colony
Stimulating Factor (G-CSF) which in its recombinant form is used to
treat neutropenia secondary to chemotherapy or myelosuppression.
Clinical Applications of G-CSF
- Post-chemotherapy, radiotherapy, or stem cell
transplantation
o It is used to rescue the patient from the
myelosuppressive effects of chemotherapy and
radiotherapy or even during the process of stem
cell transplant.
- Severe neutropenia
o Either acquired or congenital
- Severe infection
o In order to accelerate the maturation of the
neutrophils
- Peripheral blood stem cell harvesting
o Used to harvest the stem cell because when G-
CSF is given the stem cells found in the bone
marrow are released or detached from their
microenvironment and enters the systemic
circulation. From the systemic circulation, you
can harvest the stem cells.
Monocytes-reticuloendothelial system: distribution of monocytes
- Different types of monocytes when they enter the tissues or
different organ systems become specialized cells which are
termed as macrophages. Different organ systems have
different macrophages. Example: Brain  microglial cells
Note: Traditionally, the brain is devoid of inflammatory cells. Other
organs that are devoid of inflammatory cells include: eyes, testis
(called as immunologically privileged sites). Paradoxically, if the
patient has leukemia, these are the sites where the leukemic cells
are found.
Disorders of granulocytes and monocytes:
- Qualitative
o Chemotaxis
o Phagocytosis
 Inability to phagocytose red cells
because of the lack of certain enzymes
which is also the underlying
mechanism when your granulocytes
and monocytes have killing and
digesting defect
o Killing and digestion
- Morphologic abnormalities
- Quantitative
Note: What are important in the clinics are the morphologic
abnormalities and the quantitative abnormalities.
Morphologic abnormalities of neutrophils
- Hypersegmentation of nuclear material
o Seen in megaloblastic anemias
- Hyposegmentation
o Granules that are seen in those with rare
disorders
Note: Toxic granules are cytoplasmic vacuolations. Dohle bodies
are seen in patients with infections like toxic granules.
Quantitative abnormalities
- Common is leukocytosis predominantly of the neutrophils
so there is absolute neutropenia. Common causes are:
o Bacterial infections (common)
o Inflammation and tissue necrosis (common)
o Metabolic disorders
 Uremic patients
o Neoplasms
 Either as part of the leukemoid reaction
or as part of a hematologic neoplasm
o Acute hemorrhage and hemolysis
 Or even in states of dehydration the
white cells tend to be elevated 
neutrophil leukocytosis
o Drugs – steroids  increase white blood cells
 The most important that causes
neutrophilic leukocytosis is steroids
(increases white cell count)
o Myeloproliferative disorders
o Asplenia
 If you remove a patient’s spleen, there
is removal of sequestered granulocytes
that will cause an elevation in the
granulocyte count
o Leukemoid reaction
Leukoerythroblastic reaction
- There is elevation in neutrophils and there is a shift to the
left in the differential count so immature cells are seen and
the presence of nucleated RBCs.
- When this is accompanied by the presence of tear-drop
cells there is myelofibrosis
- This can also be seen in other conditions.
- Causes of LER
o Metastatic neoplasm in the marrow
 The most common malignancy
infiltrating the bone marrow is the
small cell carcinoma.
o Primary myelofibrosis
o Acute and chronic leukemia
Neutropenia
- There is an absolute decrease in the neutrophil count.
Clinically, the neutrophil count must be at least 1 x 109 in
order to prevent opportunistic infections. As the absolute
neutrophil count drops below 1,000 the predisposition to
infection correspondingly increases. Until you reach a
critical level <200
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 Absolute Neutrophil Count Clinical Significance undergo apoptosis, there is replacement of normal marrow cells by
>1,500/mm3 Normal clonal population of neoplastic cells.
1,000-1,500 No significant risk for infection
500-1,000 Some risk for infection Epidemiology of blood neoplasms
<500 Significant risk for infection - In terms of prevalence and incidence, the hematologic
<200 Absence of inflammatory response neoplasms comprises <10% of the total malignancies in
both males and females.
Note: In very severe aplastic anemia, the absolute neutrophil count o Male - Prostate 24%
is <200. There is no inflammatory response. This is usually seen in o Female - Breast
patients receiving chemotherapy especially those with acute
leukemia. Risk factors for hematologic neoplasm
- Inherited factors
Clinical features of severe neutropenia o Like in solid tumors, there are also inherited
- Associated with infections of mouth and throat – painful component. There is inheritance of the risk and
ulceration not the disease itself.
- Skin and anus may be affected - Environmental factors
- Septicemia o Chemicals
 benzene
Note: Patients with neutropenia because of chemotherapy will have o Drugs
stomatitis (painful canker sores). Sometimes, these are also seen in  Anti-cancer drugs
the anal cavity. o Radiation
 Nuclear accidents
Causes of monocytosis (Elevated monocytes) - Infection – there are microorganisms that have been
- Chronic bacterial infection associated with hematologic neoplasms.
o Monocytosis is usually a hallmark of chronic o Viruses (most)
bacterial infection o Bacteria (few)
- Connective tissue diseases o Protozoa*
- Protozoan infections (or parasitic infections)
- Hodgkin lymphoma, AML, and others (hematologic Infections associated with hematopoietic neoplasms
malignancies) Infection Neoplasms
- Chronic myelomonocytic leukemia Virus
- Acute bacterial  infectious mononucleosis - HTLV 1 Adult T cell leukemia/lymphoma
- EBV Burkitt’s and Hodgkin lymphoma; PTLD
Note: this can also be seen in autoimmune diseases - HHV8 Primary effusion lymphoma; Castleman disease
- HIV-I High-grade B cell lymphoma
Causes of eosinophilia (absolute increase in eosinophils >500)
- Allergic disease Bacteria
- Parasitic infections - H.pylori Gastric lymphoma (MALT)
- Recovery from acute infection
- Dermatologic infection Protozoa?
- Malaria Burkitt’s lymphoma
Note: Eosinophilia is commonly secondary to allergy and parasites.
These two should be ruled out first before considering the rare Note: HTLV1 – Human Lymphotrophic virus causes a unique type of
causes of eosinophilia like hypereosinophilic syndrome or chronic leukemia called the adult T cell leukemia/lymphoma that are seen
eosinophilic leukemias (uncommon). predominantly in certain areas of Japan and Carribean island. PTLD
is Post-transplant lymphoproliferative disease. Organ recipients are
HEMATOPOIETIC NEOPLASM also at risk for hematopoietic neoplasms especially certain types of
Neo-plastic diseases of the blood lymphomas because they are receiving immunosuppressive agents.

Definition Genetics of blood neoplasms

- Clonal diseases that derive from a single cell in the marrow
(leukemia) or peripheral lymphoid tissue (lymphoma) that
has undergone genetic alteration (usually in the
protooncogene and in the tumor suppressor gene leading
to proliferative advantage of the stem cell)
Note: Clonal diseases – originate from a single abnormal stem cell.
Just like other malignancies, the hematopoietic neoplasm begins with
a single abnormal cell that gains proliferative advantage over the
normal hematopoietic tissues either marrow or lymphoid. Over a
period of time, depending on their doubling rate or their ability to
- Malignant transformation occurs as a result of the
accumulation of genetic mutations in cellular genes
Note: Just like any malignancy, blood neoplasms are thought to
occur because of a transformation of a single cell because of a
genetic alteration in two broad genes: protoocogene  oncogene
and tumor suppressor gene. In some cases, it may involve enzymes:
especially tyrosine kinase enzymes that are responsible for
phosphorylation in certain chemical reactions.
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Proto-oncogene Hematopoietic neoplasms are classified broadly by the WHO.
- Normal within our genome The operational classification of hematologic neoplasms:
- When altered (either by mutation or translocation) - Leukemia
become highly altered  becomes oncogene  - Lymphoma
oncogenes gain function so that is causes excess
proliferation of cells Note: They are classified based on the origin of the clone either as
myeloid or lymphoid neoplasms. Myeloid neoplasms generally
Note: Protooncogenes are factors that regulate proliferation and presents as leukemias or myeloproliferative disorders. Lymphoid
apoptosis. neoplasms would present as leukemia and lymphoma and
sometimes they present as plasma cell disorders. Different
Tumor suppressor gene hematopoietic neoplasms based on either they are leukemia,
- Counteracts the effects of protooncogene. lymphoma, or plasma cell disorders
- The most common tumor suppressor gene that is
associated with malignancy is P51 LEUKEMIA
- When there is mutation of the tumor suppressor gene there Acute leukemia
is a loss of function and this will prevent apoptosis of cells
and will result in accumulation of malignant cells. Definition:
- This mechanism is seen in different abnormalities in some - Group of disorders characterized by accumulation of
of the hematologic neoplasms. malignant blood cells in the bone marrow and blood
- Leukemic cells are frequently present in the/invade the:
Common genetic abnormality in hematopoietic neoplasms o Peripheral blood
Disease Genetic abnormality Oncogenes o Invade the reticuloendothelial tissues, spleen,
involved liver, and lymphnode
CML T(9,22) BCR-ABL  Primitive organs of hematopoiesis; It
Secondary AML 11Q23 translocation MLL capitulates otogeny
- May also invade other tissues
Note: CML is the first malignancy where a specific cytogenetic - Untreated, eventually causes death
abnormality has been identified. They have a translocation involving o Death within 3-6 months of diagnosis in the
chromosome 9 and 22 resulting in a production of a unique gene absence of effective therapy
known as BCR-ABL gene. What is important for these different
genetic abnormalities is that you can assay for them and it will help Note: There is heterogeneity within the leukemic diseases. When it is
classify the disease or confer certain risk factors for special groups of acute, it is characterized as accumulation of malignant cells in the
individuals. bone marrow. Bone marrow is replaced by a monotonous population
of mononuclear cells. Some leukemias, chronic types of leukemia,
Multistep clonal development of malignancy and clonal may be compatible with life (late onset of leukemia ex.80 y/o).
progression
- Malignancy is said to occur because of clonal expansion Classification
and progression - Classified according to cell type – with regard to both:
- Theory is that it originates from a single cell that gains o Cell maturity – used to distinguish between
proliferative advantage over the other cells. As these clone acute and chronic leukemia
of cells proliferate, they gain other genetic abnormalities  If malignant cells are immature – acute
that makes them more resistant to chemotherapy and  If the cells are arrested at
evade immune tumor surveillance and eventually these either the blast or at the
abnormal clones will dominate or replace that particular promyelocytic phase
tissues.  More blast (according to
WHO it should be at least
Genetic abnormality that may lead hematopoietic malignancies 20% blast in the peripheral
- Point mutation blood or in the bone marrow;
- Translocation between chromosomes; exchange of if it is more than 20% in the
material bone marrow or peripheral
o Example: Philadelphia chromosome blood it is classified as acute
- Partial chromosomal deletion leukemia otherwise they are
o Myelodysplastic syndrome chronic leukemias or
- Chromosome duplication myeloproliferative
o Especially when the disease progress neoplasms)
- DNA methylation or deacetylation of histones that covers  Rapidly aggressive
the chromosomes  Predominantly mature – chronic
 If the cells are able to
Note: All of these will predispose the individual to the development of generate enough mature
malignancies. cells.
 Slow or indolent course
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 o Cell lineage – based on their origin they could
either be:
 Myeloid – (granulocytic, monocytic,
megakaryocytic, and erythrocytic)
 Lymphoid
cytogenetic or molecular genetic abnormalities which are
part of the WHO classification.
Note: What differentiates acute from chronic leukemia is the number
of blast cells. Chemotherapy can be done in acute leukemia.

Note: Leukemias are classified based on the degree of maturation of Morphologic approach to classification
the cell either it is acute or chronic, or based on their cell lineage Traditionally, the acute leukemia are differentiated by the morphology
either myeloid or lymphoid. of the blast either as a myeloid or as a lymphoid.
Feature AML ALL
Categories of Leukemias Auer rods Present in 60-70% of cases Not present
- ALL (Acute Lymphoid Leukemia)
- AML (Acute Myeloid Leukemia) or ANLL (Acute Blast size Larger, usually uniform Variable, small to
nonlymphoblastic leukemia) medium size
- CML (Chronic myeloid leukemia) Nucleoli 1-4 often prominent Absent or 1-2, often
- CLL (Chronic lymphocytic leukemia) indistinct

Comparison of acute and chronic leukemia Note: Auer rods are pathognomonic of AML. Blast classification is
Acute Chronic important but not in the immunologic classification of leukemias.
Age All ages Adults
Clinical onset Sudden Insidious Type I myeloblast
Course (untreated) <6 months 2-6 years Type III blast
Leukemic cells immature mature Morphology:
Anemia Mild to severe Mild Typical myeloblast
Thrombocytopenia Mild to severe Mild - Large cell with very prominent nucleoli. There is abundant
White cell count Variable increased cytoplasm that is sometimes granular.
Organomegaly Mild Prominent
Auer rods
Note: There are congenital leukemia (born with the abnormality but - Inclusion bodies that is pathognomonic of myeloblast
the abnormality did not occur in the germline; will not be passed on to
the next generation; did not come from the sex chromosome) and Lymphoblast
inherited leukemia. Congenital leukemias are seen in patients with - Small cell compared to the myeloblast and they have
down syndrome (with risk for developing acute myeloid and lymphoid scanty cytoplasm. Indistinct nucleoli.
leukemia). In acute leukemia, if it is left untreated most patients will - Lymphoid blast has a rounded “regular” appearance
die because of the severe type of bone marrow failure that occurs in without cytoplasmic granules
acute leukemia. In comparison to aplastic anemia that also has bone
marrow failure but generally the patients are well except for the Cytochemical reactions useful in the diagnosis of acute
anemia. Because of the rapidity of the onset of the disease, the leukemia - The other way to differentiate a myelocytic from a
organomegaly is mild because there is no time for the leukemic cells lymphoid malignancy is by means of cytochemical stains:
to invade the organs. The white cell count is variable (not all acute - When +, it classifies the leukemia as belonging to the
leukemias have high white cell count; it could either be low count, myeloid series except for the PAS.
normal, or high). If t is chronic, white cell count is invariably or almost
always increased. You will not diagnose chronic leukemia in a patient Immunologic markers used in the classification of acute
with a low white cell count unless the patient is in the terminal stage leukemia
of the disease. Chronic leukemias are usually found n adults and are Lineage Antigen
seldom found in the pediatric age group. Clinical onset is indolent Lymphoid TdT
(slowly evolving disease) and some of them are diagnosed during B cells CD19, CD20, CD21, CD22,
routine or periodic examination. Because of the insidious nature of CD23, CD24
the disease, survival is quite long even in the absence of effective T cell CD1, CD2, CD3, CD4, CD5,
therapy. Live as long as 2-6 years because the leukemic cells are CD6, CD7, CD8
able to differentiate into mature cells so the marrow failure is Myeloid CD13, CD33, CD11b, CD15
generally mild (mild to absence of anemia, no thrombocytopenia). Monocytic
Because it is an indolent disease or evolving, by the time the patient
is diagnosed, there is organomegaly and is prominent. Symptoms of Note: Currently used. All the blood cells express certain surface
massive splenomegaly include early satiety. receptors designated by means of the so called cluster of
differentiation. At some point of the maturation of the cell, they
Acute Leukemia Diagnosis express unique surface markers that appear or disappear during
- The presence of >20% blast cells in the blood different stages of development. Some are called as Pan-B or Pan-T
- Acute leukemia could be diagnosed even if the blast is marker which means that they are expressed all throughout the
<20% if you could identify a specific leukemia associated development of the lymphocytes. Example: CD7 for T cell. TdT is a
marker for lympoih progenitor cell. TdT(+) means that you have a
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primitive type of leukemia. These are used to classify the different
types of leukemias either as myeloid, lymphoid, B cell, or T cell. This
is important because the treatment for T cell is different from the
treatment of AML. Treatment for lymphoid is different as compared to
the myeloid. There is a different prognosis for the myeloid as
compared to the lymphoid.

WHO Classification of AML (Harrison’s)

- AML with recurrent genetic abnormalities
o AML with t(8:21) (q22:q22) RUX1/RUX1T1
o AML with abnormal bone marrow eosinophils
 Inv(16)(p13q22) or t(16:!6) (p13:q22)
- AML with myelodysplastic related changes
- Therapy related myeloid neoplasms
- AML not otherwise categorized/classified
o no cytogenetic abnormality
o AML minimally differentiated
- Myeloid sarcoma
o Acute leukemia that presents initially as a solid
tumor
- Myeloid proliferation
o Associated with Down’s syndrome

Note: When you diagnose leukemia it is recommended that you do

genetic studies (PCR). Unfortunately, this increases the cost of the
diagnostic work-up of the patient.

Revised criteria for the classification of AML (FAB)

- M3 – Acute promyelocytic leukemia
o Variant: Granular and microgranular
o Types of cells where you find abundant Auer
rods
o It is important to identify the M3 because among
the AML, the treatment regimen for M3 or acute
promyelocytic leukemia is different. They are
given all-transretinoic acid.
o it has the highest incidence of spontaneous
remissions
o With good prognosis >50% cure rate as
compared to <30% in chemotherapy alone
o Presents with disseminated intravascular
coagulation (Acute leukemia + DIC)
- AML with monocytic component:
o M4 - Myelomonocytic
o M5 - Purely monocytic
o Monocytic – invades the gums; it is associated
with gingival hyperplasia. Because of this, this
group of patients initially consults a dentist.
Monocytic leukemias are one of the causes of
medico-legal problems among dentists
- Erythroleukemia
o Mimics megaloblastic anemia
o Also known as Di Guglielmo disease
- Megakaryocytic leukemia
o Least common; acute
o Characterized by fibrosis of the bone marrow;
hard to perform bone marrow aspiration

------to be continued-----

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