Blood and Genetics

Zulkefley Othman
 Blood Components
• Plasma:
– The liquid part of blood.
– Contains dissolved salts (electrolytes) and proteins
• Albumin helps in keeping blood vessels from
leaking and carry hormones and drugs to different
parts of the body.
• Antibodies (immunoglobulins) that defend the body
against viruses, fungi, and cancer cells
– Serves as a reservoir that can absorb replenish or
absorb water from tissues when necessary.
– Prevents blood vessels from collapsing and clotting by
keeping them filled and circulating
– Plays a role in warming and cooling the body
 Blood Components

Red Blood Cells

– Erthrocytes: Make up 40% of the blood’s volume
– Produced in the bone marrow
– Contain hemoglobin, a protein that gives blood its red color
and enables it to carry oxygen.
• White Blood Cells
– Leukocytes: Fewer in number than RBCs (1:660)
– Primary responsibility: Defend the body against infection
• Platelets
– Thrombocytes: cell-like particles smaller than RBCs and WBCs.
– Helps with clotting process by gathering at bleeding site and
clumping together to form a plug that helps seal the blood
vessel.
Blood cells
 ANEMIA

• Iron-Deficiency Anemia (most common)

• Aplastic Anemia – bone marrow does not
produce enough RBC
• Hemorrhagic anemia – due to extreme
blood loss
• Pernicious anemia – B12 deficiency
• Sickle Cell Anemia (genetic)
 SICKLE CELL ANEMIA

• Genetic Disorder
• Abnormally
shaped blood
cells
• Parents can be
carriers
(asymptomatic)
 SICKLE CELL ANEMIA

• Hereditary type of chronic hemolytic anemia transmitted as

AUTOSOMAL RECESSIVE, nongender linked characteristic.
• Exclusively in blacks and in whites of Mediterranean origin.

HbA (normal) is genetically altered to produce HbS (Sickle cell),

Substitution of glutamic acid to valine at the sixth position of the

β globin chain (single base mutation at codon 6)
Location = (11p15.5)
 Sickle Cell Anemia
• Sickle cell disease causes
the red cell to assume a
nonpliable sickle shape
• The resultant cellular defect
leads to the main
manifestations of the
disease, which include:
– premature death of the
cells (hemolytic anemia)
– vascular occlusion of
vessels and subsequent
tissue infarction
– increased susceptibility
to infection
 Sickle Cell Anemia
• Erythrocytes have their normal
biconcave discoid shape
distorted, generally presenting a
sickle-like shape.
• Reduces both their plasticity and
lifetime from the normal 120 days
average down to 14 days.
• This results in the underlying
anemia and hypertrophic bone
marrow.
• In heterozygote- 40% of
hemoglobin is HbS
• In homozygote- nearly all
hemoglobin is HbS
If both parents are
carriers, child has a ¼
chance of having the
disease
Functional Presentation of
Sickle Cell Disease
• People with sickle cell
disease usually present in
the first decade of life with
complications of the three
main characteristics of the
disorder
– Anemia
– Vascular occlusion
(resulting in necrosis)
– Increase susceptability to
infections, particularly
pneumococcal pneumonia

Humeral head infarction and osteonecrosis

in a 50 year old female with sickle cell
disease
 Complications of Sickle Cell
Disease
• pain episodes • kidney damage and loss of
• strokes body water in urine
• increased infections • painful erections in men
(priapism)
• leg ulcers
• blood blockage in the spleen
• bone damage (osteo- or liver (sequestration)
necrosis)
• eye damage
• yellow eyes or jaundice
• anemia
• early gallstones
• delayed growth
• lung blockage
 Treatment of Sickle Cell
Disease
• There is no specific treatment for sickle cell disease,
therefore, most therapy is supportive in treatment of the
complications.

• Early recognition of infection, administration of

prophylactic antibiotics, and vaccination may forestall or
prevent other complications.

• If a painful crisis persists or there is infection of a major

organ (brain, lung, or heart), exchange transfusion is
performed to remove some of the sickle red cells - the
effect is temporary.
 Treatment of Sickle Cell
Disease
• General guidelines

– Taking the vitamin folic acid (folate) daily to help make new
red cells
– Daily penicillin until age six to prevent serious infection
– Drinking plenty of water daily (8-10 glasses for adults)
– Avoiding too hot or too cold temperatures
– Avoiding over exertion and stress
– Getting plenty of rest
– Getting regular check-ups from knowledgeable health care
providers
 HEMOPHILIA

• Hemophilia is a X-LINKED RECESSIVE hereditary blood disease

characterized by greatly prolonged coagulation time (bleeding
disorder).
• Inherited from one's parents through an X chromosome with a
nonfunctional gene.
– Hemophilia A is due to a deficiency of blood coagulation factor
VIII
• Mutation in factor 8 (F8) gene (missense mutation)
• Located in X chromosome (Xq28)
• Unable to produce coagulation factor VIII
• Accounts for 75% of hemophilia
• Incidence is 1 in 10,000 male births
– Hemophilia B is due to a deficiency of blood coagulation
Factor IX
• Mutation in factor 9 (F9) gene (missense mutation)
• Located in X chromosome (Xq27.1 – q27.2)
• Incidence is 1 in 75,000 male births
• Is clinically indistinguishable from hemophilia A
 Functional Presentation of
Hemophilia
• The person can present with mild, moderate, or severe
hemorrhagic disease, depending on the amount of active
protein produced.
– People with mild hemophilia rarely bleed spontaneously and
usually are discovered after excessive bleeding secondary
to trauma or surgery.
– People with moderate hemophilia have rare episodes of
spontaneous bleeding, but can hemorrhage with any trauma
– People with severe hemophilia have frequent spontaneous
hemorrhage from early childhood.
 Functional Presentation of
Hemophilia
• People with hemophilia can
bleed anywhere, but bleeding
into joints (hemarthrosis), soft
tissue (such as muscle), urine
(hematuria), and the brain are
common.
• Chronic bleeding into joints or
an acute bleed into the brain or
spinal canal can lead to chronic
disabilities, both functional and
psychological.
 Treatment and Prognosis
of Hemophilia
• The general principle of treatment of hemophilia is, first,
to avoid drugs than can interfere with clotting,
particularly aspirin and other NSAIDS that inhibit platelet
function.
• Second, early recognition of bleeding episodes or
potential trauma and treatment with replacement Factor
VIII or IX is imperative (crucial).
• Prognosis has improved with the advent of factor
concentrate treatment in the 1960s, with fewer severe
bleeds, less crippling arthritis from hemarthrosis, and
less intracranial bleeding.
Hemophilia is carried on the X chromosome

Female:
X H X H normal
X H X h carrier
X h X h hemophiliac

Male:
X H Y normal
X h Y hemophiliac
Pedigree of Hemophilia
 Thalassemia

• Thalassemia is a group of genetic disorders of hemoglobin

synthesis characterized by a disturbance of either alpha (α) or
beta (β) hemoglobin chain production (alpha thalassemia and
beta thalassemia).
• Causes a shortage of red blood cells and low levels of oxygen
in the bloodstream.
• HBA1 and HBA2 genes provide instructions for making alpha
globin.
• HBB gene provides instructions for making beta globin.
• An estimated 900,000 births are expected to occur in the next
20 years with clinically significant thalassemia disorders.
 Thalassemia

• First described by Thomas B Cooley in 1925.

• Thalassa means ‘sea’in Greek.
• 1 in 20 Malaysians are carrier.
• Highest number in Malay and Kadazan Dusun.
• Etiology
– AUTOSOMAL RECESSIVE genetic disorder of inadequate
production of normal hemoglobin.
• Clinical Manifestations
– Asymptomatic  major retardation  life threatening.
– Splenomegaly, hepatomegaly.

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 Alpha-thalassemia

• Results from deletions involving the HBA1 and HBA2 genes

(chromosome 16p).
• Shortage of alpha globin, leading to alpha thalassemia.
• People have two copies of the HBA1 gene and two copies of
the HBA2 gene in each cell.
• There are 4 alleles that produce alpha-globin.
• Each person inherits 2 alleles from each parent.
• Different types of alpha-thalassemia result from the loss of
some or all of these alleles.
• The precise risk depends on how many alleles are missing
and which combination of the HBA1 and HBA2 genes is
affected.
 Alpha-thalassemia
• Two types:
1. Hb Bart syndrome (more severe)
 characterized by hydrops fetalis;
severe anemia;
hepatosplenomegaly; heart
defects; and abnormalities of the
urinary system or genitalia.
2. HbH disease (milder)
 cause mild to moderate anemia;
hepatosplenomegaly; jaundice; or
bone changes.
 Alpha-thalassemia

 a person with 1 mutated allele is a carrier and has no

signs or symptoms.
 a person with 2 mutated alleles may have mild signs or
symptoms of alpha-thalassemia (called alpha-
thalassemia minor, or alpha-thalassemia trait).
 a person with 3 mutated alleles has moderate to severe
symptoms (HbH disease).
 a person with 4 mutated alleles, the condition is called
alpha-thalassemia major or hydrops fetalis (Hb Bart
syndrome).
 Beta-thalassemia
• Changes (mutations) in the HBB gene (chromosome 11) lead to
reduced levels of beta globin.
• Two main forms:
 Thalassemia major (Cooley's anemia) - homozygous
 the more severe form, causing severe anemia and enlarged liver and spleen
(hepatosplenomegaly).
 Becomes apparent before 2 years of age.
 Treatment - regular transfusions and chelation therapy to reduce iron overload.
- bone marrow transplantation or cord blood transplantation.
 Thalassemia intermedia
 the less severe form, becoming apparent later and causing milder anemia.
 does not require regular blood transfusion.
• Carrier (only one HBB gene mutation) known as thalassemia minor
(trait). May have some symptoms of anemia.
 Beta-thalassemia

• Clinical Manifestations of Thalassemia major:

• Occurs within the first 2 years of life.
• Siblings are commonly affected.
• Yellowish pallor of the skin
• Fever, chills, malaise,
• Generalized weakness
• Splenomegaly and hepatomegaly
• RODENT FACIES- develops mongoloid features due to
prominence of the cheeks, protrusion of the maxillary
anterior teeth, depression of the bridge of the nose.
 von Willebrand’s Disease
• vWD, a unique disorder that was described originally by Erik
von Willebrand in 1926.
• a bleeding disorder that slows the blood clotting process.
• caused by mutations in the VWF gene (12p13.2) that reduce the
amount of vW factor or cause the protein to function
abnormally.
• can result from inherited defects in the concentration,
structure, or function of von Willebrand’s factor (vWF).
• It promotes its function in two ways:
(1) by supporting platelet adhesion to the injured vessel
wall under conditions of high shear forces and
(2) by its carrier function for factor VIIIc in plasma.
• Transmitted as an AUTOSOMAL DOMINANT trait (mostly).
• vWD is classified into four primary categories.
1. Type 1 (85% of all vWD) includes partial quantitative
deficiency,
2. Type 2 (10–15% of all vWD) includes qualitative defects,
3. Type 3 (rare) includes virtually complete deficiency of vWF
4. pseudo- or platelet-type vWD, and it is a primary platelet
disorder that mimics vWD.
• Clinical features
• Usually mild and include mucosal bleeding,
• soft tissue hemorrhage, menorrhagia in women, and
hemarthrosis.
• TREATMENT - Transfusion of plasma, Antihemophilic factor and local
control of hemostasis.
 Diagnosis

• Blood plasma.
• Quantitative and qualitative deficiencies of vWF.
• Measuring the amount of vWF in a vWF antigen assay and
the functionality of vWF with a glycoprotein (GP)Ib binding
assay.
Thank you