Anemia of Other Causes and

Hemoglobinopathies
 Anemias of Systemic Disorders

• REMEMBER:
• Hormones play a BIG ROLE in hematopoiesis!
Mas marami Hgb or Blood content ng MALES, kasi,

Testosterone is a form of androgen,

Testosterone stimulates the production of EPO (erythropoietin)
Kidneys produce erythropoietin
Kidneys filter blood

ANEMIA OF CHRONIC RENAL FAILURE

this give you from normocytic
normochromic, to microcytic hypochromic
anemia

• A hypoproliferative anemia that can be severe, almost invariably occurs in

patients with chronic renal failure (CRF)
• Related to the etiology of renal disease:
• Failure of renal excretory function with resultatnt accumulation of waste
products
• Failure of renal production and release of erythropoietin
• Uremia is always often present
Uremia - production of urea in blood

If there is chronic kidney failure, cell involve is echinocytes (burr cells)

If liver - acanthocytes (spur cells)
 Endocrine - plays a big part in hormones

ANEMIA OF ENDOCRINE DISORDERS

• HYPOTHYROIDISM - low oxygenation happening nagkakaroon ng tissue hypoxia

• Related to the body’s low oxygenation

• HYPOPITUITARISM Pituitary Gland - aka MASTER GLAND

• Anemia occurs because the pituitary gland influences the

functions of the thyroid (through TSH), gonads Through
FSH and LH), and adrenals (through ACTH)
• The anemia is caused by reduced metabolic demands and
a resultant decrease in stimulation of erythropoietin
production
• Anemia is mild to moderate, with N/N red cell morphology
• Vasopressin stimulates the release of erythropoietin as
well as growth hormone and prolactin
ANEMIA OF ENDOCRINE DISORDERS
• ADRENAL ABNORMALITIES
• Anemia occurs due to deranged cortisol secretion that
have multiple effects on blood cells, most markedly with
circulating eosinophils and lymphocytes
• Addison’s disease – hypocortisolism
• Cushing’s disease – hypercortisolism
• HYPOGONADISM - secondary sexual development
- involves sex organs

• Is characterized by retarded growth and secondary sexual

development
• REMEMBER: Testosterone is an androgen!
 Anemia of Pregnancy - nagkakaroon, because of increase demand sa vitamins, iron, folate
- decrease folate & decrease iron

• Most often related to iron deficiency or folate deficiency

Folate - important for brain development

VB12 - important for production of DNA/ DNA synthesis
 Haemoglobinopathies
• Inherited disorders of Hb Structure and/or function
• Thalassaemias
• Sickle cell disorders
• Unstable haemoglobins
Hemoglobinopathies - If there is involvement in the structure of Hgb
(QUALITATIVE)
Thalassemia - If there is a problem in the number of Hgb or Globin chain
Homozygous - same gene (x & x) (QUANTITATIVE)
Heterozygous - there's difference (x & y) Sickle Cell Disorder - If there is a problem or presence of Hgb SE
Unstable Hemoglobin - unstable hemoglobin

Trait - there is heterozygous in gene,

-- kahit di okay yung isa or may problem (yung gene), pwede icompensate nung isa
Disease - homozygous (pag homozygous, already considered as a disease)
-- kasi walang nag ccompensate, kasi same gene
Epidemiology Hemoglobinopathies - is asymptomatic (as trait?), unless it becomes a disease

• Worldwide occurrence
▪ 5% of world population harbor alleles for hemoglobinopathies
▪ 300,000 children born each year with hemoglobinopathy
▪ 200,000 children born yearly in Africa with Sickle Cell Disease

▪ Areas of Prevalence
▪ Sub-Saharan Africa
▪ S.C. trait frequency 10-40%
▪ S.C. disease freq </= 2%
▪ Highest rates in Ghana,
▪ Nigeria, Uganda

http://www.nslc.wustl.edu/sicklecell/part3/biogeography.html
 What is Sickle Cell Anemia?
they clump up in blood vessels, causing thrombosis,
serious infection, damage

⚫A serious condition in which red blood

cells can become sickle-shaped
⚫Normal red blood cells are smooth and
round. They move easily through blood
vessels to carry oxygen to all parts of the
body.
⚫Sickle-shaped cells don’t move easily
through blood vessels. They’re stiff and
sticky and tend to form clumps and get
stuck in blood vessels.
⚫The clumps of sickle cell block blood flow
in the blood vessels that lead to the limbs
and organs. Blocked blood vessel can cause
pain, serious infection, and organ damage.
Normal Haemoglobin

Normal Adult Blood

α2β2 = Hgb A (97%)
α2δ2 = Hgb A2 (2%)
α2γ2 = Hgb F (<1%)
Fetal Hgb

If there's increase in Hgb F, it has problem

To test it check with - Kleihauer Betke Test

http://sickle.bwh.harvard.edu/hbsynthesis.html
Pathophysiology
• Inheritance of mutated hemoglobin β-globin chain
• Mutation of GAG 🡪 GTG at 6th codon at chromosome 11
• Glutamic acid 🡪 Valine at 6th AA
• α1α2, β1β2 = normal hemoglobin
• α1α2, β1βS = heterozygote = Sickle trait
• α1α2, βSβS = homozygous recessive = Sickle cell
disease
 Pathophysiology A) Haemoglobin
bindings
A. Valine give non-
polarity (hydrophobic)
to haemoglobins. Val6
of B2 chain of 1st HbS
chain forms
hydrophobic bond
with Phe85 and Leu88
of a 2nd HbS B1 chain
B. Negative charge and
size of Glutamic acid
prevent haemoglobin
to aggregate B) Charge and size
prevent
6β Glu from
binding.
Normal and Sickled Red Blood Cells
in Blood Vessels
Figure B shows abnormal, sickled red blood cells clumping and
blocking the blood flow in a blood vessel. The inset image shows a
cross-section of a sickled red blood cell with abnormal strands of
hemoglobin.

Figure A shows normal red blood cells flowing freely in a

blood vessel. The inset image shows a cross-section of a
normal red blood cell with normal hemoglobin.
 If one parent has sickle cell
If one has trait, but
one doesn't have
trait (HbAS) and the other
anything/unaffected=
0% trait or disease
does not carry the sickle
hemoglobin at all (HbAA)
then none of the children
will have sickle cell anemia.
50% chance will get
the trait
50% chance unaffected
There is a one in two (50%)
chance that any given child
will get one copy of the
HbAS gene and therefore
have the sickle cell trait.
It is equally likely that any
given child will get two
HbAA genes and be
completely unaffected.

Inheritance of Sickle Cell Anemia

 If both parents have
If both have the trait =
25% chance that child
sickle cell trait (HbAS)
have scikle cell anemia there is a one in four
(25%) chance that any
given child could be born
25% chance unaffected with sickle cell anemia.
50% chance trait only
There is also a one in four
chance that any given
child could be completely
unaffected.
There is a one in two
(50%) chance that any
given child will get the
sickle cell trait.

Inheritance of Sickle Cell Anemia

 If one parent has
sickle cell trait (HbAS)
If one has the trait, and
one has the disease = and the other has
50% chance getting
trait only, 50% chance sickle cell anaemia
gets the disease itself
(HbSS) there is a one
in two (50%) chance
None unaffected that any given child
50/50 chance of
either trait or disease will get sickle cell trait
and a one in two
(50%) chance that any
given child will get
sickle cell anemia.
No children will be
completely
unaffected.

Inheritance of Sickle Cell Anemia

 If one parent has sickle
If one has the cell anaemia (HbSS) and
disease, one has
nothing/unaffected = the other is completely
100% child will have
the trait, but none will unaffected (HbAA) then all
have the disease
the children will have
sickle cell trait.
The parent with the
disease would just
pass the gene of None will have sickle cell
the disease ,
causing them to anemia.
have the trait
The parent who has sickle
cell anemia (HbSS) can
only pass the sickle
hemoglobin gene to each
of their children.

Inheritance of Sickle Cell Anemia

Sickle cell disease: clinical problems

• Anaemia (Hb 7-9g/dl in Hb SS)

• Infections
• Painful crises
• Stroke
• Leg ulcers
• Visual loss
• Chronic organ damage
• Kidneys, lungs, joints, heart
Clinical problems by age
Children:
Infection
Splenic sequestration
Pain
Stroke

Adults
Pain
Infection
Chest syndrome
Chronic organ damage
Painful crisis
• Commonest problem for patients
• Pain is variable in severity and site and may be
excruciating
• Unpredictable throughout life
• Often precipitated by infection, physical
environment, stress, menstrual cycle
• Associated with fear and anxiety
• Majority of patients manage at home and only
require admission for severe pain or other
complications
• Appropriate management in the early stages
will reduce length and severity of crisis
Management of acute sickle crisis
• Analgesia
• stepladder approach
• Treat associated infection
• Fluids
• Monitor for acute complications
Infections in SCD sickle cell disease

• Most common cause of death in children but a

major problem at all ages
• Due to splenic dysfunction from sickle damage
• occurs from a few months of age
• especially with certain bacteria eg pneumococcal sepsis
: 400 x ↑ risk
• Infection may be rapidly overwhelming
Infection in SCD
• prevention:
Hib - Haemophilus influenzae type B vaccine
• education
• Penicillin from 3/12 age
• Pneumococcal, Hib, Meningococcal vaccines
• travel prophylaxis : malaria
• aggressive treatment of infections
Acute sequestration crisis
• Splenic
• mostly < 2yrs
• acute massive splenic enlargement, ↓ Hb, shock
• often associated with infection
• significant mortality
• requires emergency transfusion
TREATMENT FOR SCD
1 Folic acid and penicillen administration
2 analgesics
3 transfusion therapy
4 bone marrow transplant
Summary of hemoglobin types
• There are hundreds of hemoglobin variants that involve involve genes
both from the alpha and beta gene clusters. The list that follows
touches on some of the more common normal and abnormal
hemoglobin variants.
• Normal Hemoglobins
• Hemoglobin A. This is the designation for the normal hemoglobin that exists after birth.
Hemoglobin A is a tetramer with two alpha chains and two beta chains (α2β2).
• Hemoglobin A2. This is a minor component of the hemoglobin found in red cells after
birth and consists of two alpha chains and two delta chains (α2δ2). Hemoglobin A2
generally comprises less than 3% of the total red cell hemoglobin.
• Hemoglobin F. Hemoglobin F is the predominant hemoglobin during fetal development.
The molecule is a tetramer of two alpha chains and two gamma chains (α2γ2).
present until 5th month of baby
• Hemoglobin A1 (Hb A1 or Hb A): makes up about 95%-98% of hemoglobin found in adults; it contains two alpha (α) chains and two beta (β)
protein chains.
• Hemoglobin A2 (Hb A2 ): makes up about 2%-3% of hemoglobin found in adults; it has two alpha (α) and two delta (δ) protein chains.
• Hemoglobin F (Hb F, fetal hemoglobin): makes up to 1%-2% of hemoglobin found in adults; it has two alpha (α) and two gamma (γ) protein
chains. It is the primary hemoglobin produced by the fetus during pregnancy; its production usually falls shortly after birth and reaches adult level
within 1-2 years.
Genetic changes (mutations) in the globin genes cause alterations in the globin protein, resulting in structurally altered hemoglobin, such as
hemoglobin S, which causes sickle cell, or a decrease in globin chain production (thalassemia). In thalassemia, the reduced production of one of
the globin chains upsets the balance of alpha to beta chains and causes abnormal hemoglobin to form (alpha thalassemia) or causes an increase
of minor hemoglobin components, such as Hb A2 or Hb F (beta thalassemia).
Four genes code for the alpha globin chains, and two genes (each) code for the beta, delta, and gamma globin chains. Mutations may occur in
either the alpha or beta globin genes. The most common alpha-chain-related condition is alpha thalassemia. The severity of this condition depends
on the number of genes affected.
Mutations in the beta gene are mostly inherited in an autosomal recessive fashion. This means that the person must have two altered gene copies,
one from each parent, to have a hemoglobin variant-related disease. If one normal beta gene and one abnormal beta gene are inherited, the person
is heterozygous for the abnormal hemoglobin, known as a carrier. The abnormal gene can be passed on to any children, but it generally does not
cause symptoms or significant health concerns in the carrier.
If two abnormal beta genes of the same type are inherited, the person is homozygous. The person would produce the associated hemoglobin
variant and may have some associated symptoms and potential for complications. The severity of the condition depends on the genetic mutation
and varies from person to person. A copy of the abnormal beta gene would be passed on to any children.
If two abnormal beta genes of different types are inherited, the person is “doubly heterozygous” or “compound heterozygous”. The affected person
would typically have symptoms related to one or both of the hemoglobin variants that he or she produces. One of the abnormal beta genes would
be passed on to children.
Red blood cells containing abnormal hemoglobin may not carry oxygen efficiently and may be broken down by the body sooner than usual (a
shortened survival), resulting in hemolytic anemia. Several hundred hemoglobin variants have been documented, but only a few are common and
clinically significant. Some of the most common hemoglobin variants include hemoglobin S, the primary hemoglobin in people with sickle cell
disease that causes the red blood cell to become misshapen (sickle), decreasing the cell’s survival; hemoglobin C, which can cause a minor
amount of hemolytic anemia; and hemoglobin E, which may cause no symptoms or generally mild symptoms.

Read more: https://askhematologist.com/abnormal-hemoglobins/#ixzz6TyslLWod

Some clinically significant variant
hemoglobins
• Hemoglobin S (α2βS2, severe). This the predominant hemoglobin in people with sickle cell
disease. The molecule structure is.
• Hemoglobin C (α2βC2, relatively benign). This results from a mutation in the beta globin gene
and is the predominant hemoglobin found in people with hemoglobin C disease.
• Hemoglobin E (α2βE2 , benign). This variant results from a mutation in the hemoglobin beta
chain. People with hemoglobin E disease have a mild hemolytic anemia and mild
splenomegaly. Hemoglobin E is common in S.E. Asia.
• Hemoglobin Constant Spring (named after isolation in a Chinese family from the Constant
Spring district of Jamaica). (severe). In this variant, a mutation in the alpha globin gene
produces an alpha globin chain that is abnormally long. Both the mRNA and the alpha chain
protein are unstable.
• Hemoglobin H. (β4, mild). This is a tetramer composed of four beta globin chains: it occurs
only with extreme limitation of alpha chain availability. Hemoglobin H forms in people with
three-gene alpha thalassemia as well as in people with the combination of two-gene deletion
alpha thalassemia and hemoglobin Constant Spring.
• Hemoglobin Barts (γ4, lethal). With four-gene deletion alpha thalassemia no alpha chain is
produced. The gamma chains produced during fetal development combine to form gamma
chain tetramers. Individuals with four-gene deletion thalassemia and consequent hemoglobin
Barts die in utero (hydrops fetalis).
• Hemoglobin S: this is the primary hemoglobin in people with sickle cell disease (also known as sickle cell anemia). Approximately 1 in 375 African
American babies are born with sickle cell disease, and about 100,000 Americans live with the disorder, according to the Centers for Disease Control and
Prevention. Those with Hb S disease have two abnormal beta chains and two normal alpha chains. The presence of hemoglobin S causes the red blood
cell to deform and assume a sickle shape when exposed to decreased amounts of oxygen (such as might happen when someone exercises or has an
infection in the lungs). Sickled red blood cells are rigid and can block small blood vessels, causing pain, impaired circulation, and decreased oxygen
delivery, as well as shortened red cell survival. A single beta (βS) copy (known as sickle cell trait, which is present in approximately 8% of African
Americans) typically does not cause significant symptoms unless it is combined with another hemoglobin mutation, such as that causing Hb C or beta-
thalassemia.
• Hemoglobin C: about 2-3% of African Americans in the United States are heterozygotes for hemoglobin C (have one copy, known as hemoglobin C
trait) and are often asymptomatic. Hemoglobin C disease (seen in homozygotes, those with two copies) is rare (0.02% of African Americans) and
relatively mild. It usually causes a minor amount of hemolytic anemia and a mild to moderate enlargement of the spleen.
• Hemoglobin E: Hemoglobin E is one of the most common beta chain hemoglobin variants in the world. It is very prevalent in Southeast Asia, especially
in Cambodia, Laos, and Thailand, and in individuals of Southeast Asian descent. People who are homozygous for Hb E (have two copies of βE) generally
have mild hemolytic anemia, microcytic red blood cells, and mild enlargement of the spleen. A single copy of the hemoglobin E gene does not cause
symptoms unless it is combined with another mutation, such as the one for beta-thalassemia trait.
There are many other variants. Some are silent – causing no signs or symptoms – while others affect the functionality and/or stability of the hemoglobin
molecule. Examples of other variants include Hemoglobin D, Hemoglobin G, Hemoglobin J, Hemoglobin M, and Hemoglobin Constant Spring caused by
a mutation in the alpha globin gene that results in an abnormally long alpha (α) chain and an unstable hemoglobin molecule. Additional examples
include:
• Hemoglobin F: Hb F is the primary hemoglobin produced by the fetus, and its role is to transport oxygen efficiently in a low oxygen
environment. Production of Hb F decreases sharply after birth and reaches adult levels by 1-2 years of age. Hb F may be elevated in several congenital
disorders. Levels can be normal to significantly increased in beta-thalassemia and are frequently increased in individuals with sickle cell anemia and
in sickle cell-beta thalassemia. Individuals with sickle cell disease and increased Hb F often have a milder disease, as the F hemoglobin inhibits sickling
of the red cells. Hb F levels are also increased in a rare condition called hereditary persistence of fetal hemoglobin (HPFH). This is a group of inherited
disorders in which Hb F levels are increased without the signs or clinical features of thalassemia. Different ethnic groups have different mutations causing
HPFH. Hb F can also be increased in some acquired conditions involving impaired red blood cell production. Some leukemias and
other myeloproliferative neoplasms are also associated with mild elevation in Hb F.
• Hemoglobin H: Hb H is an abnormal hemoglobin that occurs in some cases of alpha thalassemia. It is composed of four beta (β) globin chains and is
produced due to a severe shortage of alpha (α) chains. Although each of the beta (β) globin chains is normal, the tetramer of 4 beta chains does not
function normally. It has an increased affinity for oxygen, holding onto it instead of releasing it to the tissues and cells. Hemoglobin H is also associated
with a significant breakdown of red blood cells (hemolysis) as it is unstable and tends to form solid structures within red blood cells. Serious medical
problems are not common in people with hemoglobin H disease, though they often have anemia.
• Hemoglobin Barts: Hb Barts develops in fetuses with alpha thalassemia. It is formed of four gamma (γ) protein chains when there is a shortage of
alpha chains, in a manner similar to the formation of Hemoglobin H. If a small amount of Hb Barts is detected, it usually disappears shortly after birth due
to dwindling gamma chain production. These children have one or two alpha gene deletions and are silent carriers or have the alpha thalassemia trait. If
a child has a large amount of Hb Barts, he or she usually has hemoglobin H disease and a three-gene deletion. Fetuses with four-gene deletions have
hydrops fetalis and usually do not survive without blood transfusions and bone marrow transplants.
• Hemoglobin SC disease: inheritance of one beta S gene and one beta C gene results in Hemoglobin SC disease. These individuals have a mild
hemolytic anemia and moderate enlargement of the spleen. Persons with Hb SC disease may develop the same vaso-occlusive (blood vessel-blocking)
complications as seen in sickle cell anemia, but most cases are less severe.
• Sickle Cell – Hemoglobin D disease: individuals with sickle cell – Hb D disease have inherited one copy of hemoglobin S and one of hemoglobin D-
Los Angeles (or D-Punjab) genes. These people may have occasional sickle crises and moderate hemolytic anemia.
• Hemoglobin E – beta thalassemia: individuals who are doubly heterozygous for hemoglobin E and beta thalassemia have an anemia that can vary in
severity, from mild (or asymptomatic) to severe, dependent on the beta thalassemia mutation(s) present.
• Hemoglobin S – beta thalassemia: sickle cell – beta thalassemia varies in severity, depending on the beta thalassemia mutation inherited. Some
mutations result in decreased beta globin production (beta+) while others completely eliminate it (beta0). Sickle cell – beta+ thalassemia tends to be less
severe than sickle cell – beta0 thalassemia. People with sickle cell – beta0 thalassemia tend to have more irreversibly sickled cells, more frequent vaso-
occlusive problems, and more severe anemia than those with sickle cell – beta+ thalassemia. It is often difficult to distinguish between sickle cell disease
and sickle cell – beta0 thalassemia.

Read more: https://askhematologist.com/abnormal-hemoglobins/#ixzz6TytO1jxE

Hgb C crystals
Hgb H- golf ball pattern