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(ANEMIA)
INTRO TO PHYSIOLOGY
ALL SAINTS UNIVERSITY SCHOOL OF MEDICINE
GROUP 2 (HEMOLYTIC ANEMIA)
Objectives
● Definition of Anemia
● Types of Anemia
● Definition of Normocytic Anemia
● Types of Normocytic Anemia
● Definition of Hemolytic Anemia
● Types of Hemolytic Anemia
● Definition of intrinsic Hemolytic Anemia
● Types of intrinsic Hemolytic Anemia and sign &symptoms
● Causes, common population, Lab Value, Diagnosis and treatment of
each type of intrinsic Hemolytic Anemia
● Definition of extrinsic Hemolytic Anemia
● Types of extrinsic Hemolytic Anemia and signs & symptoms
● Causes, common population, lab values, Diagnosis and treatment of each
Types of extrinsic Hemolytic Anemia
Introduction
Blood diseases are disorders which primarily affect
the blood & blood-forming organs. Hematologic
diseases include rare genetic disorders, anemia, HIV,
sickle cell disease & complications from
chemotherapy or transfusions.
ANEMIA
•Definition:
Anemia is a red blood cell disorder in which
the blood has a reduced ability to carry
oxygen due to a lower than normal number of
red blood cells, or a reduction in the amount
of hemoglobin.
•Causes:
Lack of enough healthy red blood cells leads
to anemia. This could be due to lack of
production of RBCs or excessive bleeding.
•Symptoms:
Commonly observed symptoms are fatigue,
weakness, pale skin, and shortness of breath.
MAJOR TYPES OF ANEMIA
There are three major types of Anemia.
1. Microcytic Anemia
2. Normocytic Anemia
3. Macrocytic Anemia
Normocytic Anemia
Normocytic Anemia is a blood problem which means the red blood cell have normal size
but have a low number of them.
Normocytic Anemia is defined when the Mean Corpuscular Volume (MCV) is between
80 and 100(fL) which is within the normal and expected range. However, the hematocrit
and hemoglobin are decreased.
CLASSIFICATION OF NORMOCYTIC ANEMIA
HEMOLYTIC ANEMIA
Hemolytic Anemia is a form of anemia due to hemolysis, the abnormal
breakdown of red blood cells (RBCs) either in the blood vessels (Intravascular
Hemolysis) or elsewhere in the human body (Extravascular Hemolysis).
Hemolytic Anemia is further classified into Intrinsic Anemia and Extrinsic
Anemia.
Intrinsic Hemolytic Anemia
Definition:
Intrinsic hemolytic anemia is the destruction of the red blood cells due to a defect
within the red blood cells themselves. Intrinsic hemolytic anemias are often
inherited, such as sickle cell anemia and thalassemia.
Types of Intrinsic Hemolytic Anemia
Mechanism Examples
Enzyme deficiency Pyruvate kinase deficiency
G6PD (Glucose 6 phosphate
dehydrogenase)
Hemoglobinopathy Sickle cell
Thalassemia
Membrane defect Hereditary spherocytosis
Paroxysmal nocturnal
hemoglobinuria
Pyruvate kinase deficiency: Second most common cause of
enzyme-deficiency hemolytic anemia, following G6PD deficiency. Among the
symptoms of pyruvate kinase deficiency are:
● Cholecystolithiasis
● Tachycardia
● Hemochromatosis
● Splenomegaly
● Leg ulcers
● Jaundice
● Fatigue, shortness of breath
Pyruvate Kinase Deficiency
Causes:
Pyruvate kinase deficiency is due to a mutation in the PKLR gene. Two
pyruvate kinase isoenzymes are encoded by the PKLR gene, isoenzymes L and
R, which are used in the liver and red blood cells, respectively. Mutations in
the PKLR gene therefore cause a deficiency in the pyruvate kinase enzyme.
G6PD (Glucose 6 phosphate Dehydrogenase) : The most
common enzyme deficiency worldwide, an inborn error of metabolism that
predisposes to red blood cell breakdown. Most of the time, those who are
affected have no symptoms. Following a specific trigger, symptoms may
develop. Symptoms such as:
● Yellowish skin
● Dark urine
● Shortness of breath
● Feeling tired
G6PD
CAUSES
G6PD is caused by the inheritance of a defective gene from a parent. This is
linked to X-chromosome. The deficiency leads to break down of red blood
cells prematurely resulting in hemolytic anemia. The condition is triggered by:
This condition is inherited from both parents. Both parents must pass on the
defective form of the gene for the child to get affected.
Thalassemia: Symptoms can range from silent to severe, depending on
the degree of genetic mutation. If only one alpha gene is mutated, the person
will be a silent carrier of a disease. Three mutated genes result in moderate to
severe symptoms and four mutated genes result in stillbirth.
Patients may experience:
● Abdominal swelling
● Pale or yellowish skin
● Slow growth
● Dark urine
● Facial bone deformities
Thalassemia
CAUSES
Hemoglobin molecules are made of chains called alpha and beta chains that can be
affected by mutations. In thalassemia, the production of either the alpha or beta chains
are reduced, resulting in either alpha-thalassemia or beta-thalassemia.
● Anemia
● Jaundice
● Splenomegaly
● Fatigue
anemia
Splenomegaly in spherocytosis
Hereditary Spherocytosis
CAUSES
Hereditary spherocytosis is caused by a variety of molecular defects in the genes
that code for the red blood cell proteins spectrin(alpha and beta), ankyrin, band 3
protein, and other red blood cell membrane proteins. People of any race can have
hereditary spherocytosis, but it’s common in people of Northern European
descent.
Paroxysmal Nocturnal Hemoglobinuria
PNH, or Paroxysmal nocturnal hemoglobinuria, is a rare blood disease that causes red blood
cells to break apart. Doctors call this breaking apart "hemolysis." It happens because the
surface of a person’s blood cells are missing a protein that protects them from the body's
immune system.
When red blood cells break apart, the hemoglobin inside is released. Hemoglobin is the red
part of red blood cells that carries oxygen around the body. The release of hemoglobin causes
many of the PNH symptoms.
Symptoms :
● Shortness of breath(dyspnea)
● Back pain
● Difficulty swallowing(dysphagia)
● Erectile dysfunction
● Esophageal spasms
● Stomach pain
Paroxysmal Nocturnal Hemoglobinuria
CAUSES:
PNH happens when a genetic flaw affects how your red blood cells and platelets
work. The flaw launches a cascade of events that create serious and potentially
life-threatening medical issues. The cascade starts in the bone marrow, where
the body makes stem cells that eventually become mature red blood cells, white
blood cells and platelets. In PNH, a gene called PIG-A (Phosphatidylinositol
glycan, class A) in one stem cell mutates or changes into an abnormal stem
cell. This cell divides and makes additional abnormal stem cells that become
abnormal red blood cells and platelets.
LAB VALUE, COMMON POPULATION, DIAGNOSIS, AND TREATMENT
OF THE VARIOUS TYPES OF INTRINSIC HEMOLYTIC ANEMIA.
1. PYRUVATE KINASE DEFICIENCY: A normal value for the pyruvate kinase test is
typically 179 plus or minus 16 units of pyruvate kinase per 100 milliliters of
RBCs. Low levels of pyruvate kinase indicate the presence of pyruvate kinase
deficiency. There is no cure for pyruvate kinase deficiency.This deficiency can be
diagnosed by Doctors asking about symptoms, and whether family members have
similar symptoms, and do an exam. They also do tests that check for:
● problems in the red blood cells
● pyruvate kinase levels in the blood
● the gene changes that cause the condition
Doctors might do tests before birth if:
● A prenatal ultrasound shows fluid buildup in the baby's body, which can be a sign
of the condition.
● Pyruvate kinase deficiency runs in the family.
The prenatal tests used are amniocentesis and chorionic villus sampling.
Affected Populations
Pyruvate kinase deficiency is a rare disorder that affects both men and women. The frequency of the
disorder is unknown, although one estimate suggests that approximately 1 in 20,000 Caucasian people
develop the disorder. In clinical practice, the frequency is closer to 1 in 1,000,000 people. PKD has been
identified most commonly in Europe. However, rare disorders like PKD often go misdiagnosed or
undiagnosed making it difficult to determine their true frequency in the general population.
Children who have mild symptoms usually don't need treatment. Kids with moderate to severe symptoms will need
treatment. They're usually cared for by a pediatric hematologist (a doctor who treats children's blood problems).
● for jaundice: ultraviolet (UV) light (phototherapy) or replacing the baby's blood with donated blood.
● for anemia: blood transfusions, folic acid, and B vitamins.
● for iron buildup: iron chelation (key-LAY-shun), in which medicines send the extra iron out of the body in pee.
● to help prevent red blood cell breakdown: removing part of or the entire spleen (splenectomy).
● to help prevent gallstones: removing the gallbladder.
2. G6PD (Glucose 6 Phosphate Dehydrogenase): The normal range of G6PD test is
8.8-13.4U/g Hb.G6PD deficiency is one of the most common forms of enzyme deficiency and is
believed to affect more than 400 million people worldwide.
Treatment:The main treatment for G6PD deficiency is avoidance of oxidative stressors. Rarely, anemia
may be severe enough to warrant a blood transfusion and certain antibiotics, antimalarials and other
medications known to trigger hemolysis in G6PD-deficient individuals.Most affected individuals do not
require treatment. G6PD deficiency is often best managed by preventative measures. They are as follow;
● Avoiding certain medicines, foods, and environmental exposures
● Telling your providers that you have G6PD deficiency
● Checking with your provider before taking any medicine
3.SICKLE CELL: A normal hemoglobin level is around 12 to 15 g/dL. People with SCD have
hemoglobin levels of 6 to 11 g/dL.The exact number of people living with SCD in the U.S. is
unknown.It is estimated that:
SCD occurs more often among people from parts of the world where malaria is or was common. It
is believed that people who carry the sickle cell trait are less likely to have severe forms of malaria.
Diagnosis:A blood test can check for the form of hemoglobin that underlies sickle cell anemia. In
the United States, this blood test is part of routine newborn screening. But older children and
adults can be tested, too.In adults, a blood sample is drawn from a vein in the arm. In young
children and babies, the blood sample is usually collected from a finger or heel. The sample is then
sent to a laboratory, where it's screened for the sickle cell form of hemoglobin.A special ultrasound
machine can reveal which children have a higher risk of stroke.
This painless test, which uses sound waves to measure blood flow in the brain, can be used in children as
young as 2 years. Regular blood transfusions can decrease stroke risk.Sickle cell disease can be diagnosed
in an unborn baby by sampling some of the fluid surrounding the baby in the mother's womb (amniotic
fluid). If you or your partner has sickle cell anemia or the sickle cell trait, ask your doctor about this
screening.
Treatment:Management of sickle cell anemia is usually aimed at avoiding pain episodes, relieving
symptoms and preventing complications. Treatments might include medications and blood transfusions.
For some children and teenagers, a stem cell transplant might cure the disease.
Medications:
Surgical and other procedures: Blood transfusions AND Stem cell transplant.
4. THALASSEMIA: The most widely used cutoff values of MCV and MCH for indicating
thalassemia are 79 fl and 27 pg, respectively Thalassemia affects approximately 4.4 out of every 10,000
live births throughout the world. This condition causes both males and females to inherit the relevant gene
mutations equally because it follows an autosomal pattern of inheritance with no preference for gender.
Diagnosis:Most children with moderate to severe thalassemia show signs and symptoms within their first
two years of life. If your doctor suspects your child has thalassemia, he or she can confirm a diagnosis with
blood tests.Blood tests can reveal the number of red blood cells and abnormalities in size, shape or color.
Blood tests can also be used for DNA analysis to look for mutated genes.
Prenatal testing:Testing can be done before a baby is born to find out if he or she has thalassemia and
determine how severe it might be. Tests used to diagnose thalassemia in fetuses include:
Chorionic villus sampling. Usually done around the 11th week of pregnancy, this test involves
removing a tiny piece of the placenta for evaluation.
Amniocentesis. Usually done around the 16th week of pregnancy, this test involves examining
a sample of the fluid that surrounds the fetus.
Treatment:Mild forms of thalassemia trait don't need treatment.For moderate to severe
thalassemia, treatments might include:
● Frequent blood transfusions. More severe forms of thalassemia often require frequent
blood transfusions, possibly every few weeks. Over time, blood transfusions cause a buildup of
iron in your blood, which can damage your heart, liver and other organs.
● Chelation therapy. This is treatment to remove excess iron from your blood. Iron can build
up as a result of regular transfusions. Some people with thalassemia who don't have regular
transfusions can also develop excess iron. Removing the excess iron is vital for your health.
To help rid your body of the extra iron, you might need to take an oral medication, such as
deferasirox (Exjade, Jadenu) or deferiprone (Ferriprox). Another drug, deferoxamine
(Desferal), is given by needle.
● Stem cell transplant. Also called a bone marrow transplant, a stem cell transplant might be
an option in some cases. For children with severe thalassemia, it can eliminate the need for
lifelong blood transfusions and drugs to control iron overload.
This procedure involves receiving infusions of stem cells from a compatible donor, usually a
sibling.
5.Hereditary spherocytosis:HS affects 1 in 2,000 people in North America. It also occurs in
other regions of the world, although not as well studied. No genetic changes that are more common in
certain groups of people (founder mutations) have been reported. HS affects males and females equally.
Age at diagnosis of HS is often between 3 – 7 years but can occur in infancy with severe disease or into
adulthood with mild disease.
How is spherocytosis diagnosed?After the doctor takes a history and does a physical exam, the diagnosis of
spherocytosis is based upon identifying the abnormal red blood cells under a microscope. Blood tests that often are ordered
include:
● Reticulocyte count
Surgery: In moderate or severe disease, removing the spleen can prevent common complications that
result from hereditary spherocytosis.
Vitamins: Folic acid, a B vitamin, is usually recommended for everyone with HS. It helps you make new
red blood cells.
Transfusion: You may need red blood cell transfusions if you have severe anemia.
Light therapy: The doctor might use light therapy, also called phototherapy, for severe jaundice in infants.
Vaccination: Getting routine and recommended vaccinations are also important to prevent complications
from infections. Infections can trigger the destruction of red blood cells in people with HS.
6. Paroxysmal Nocturnal Hemoglobinuria:PNH is believed to affect males and
females in equal numbers, although some studies show a slight female preponderance.
The prevalence is estimated to be between 0.5-1.5 per million people in the general
population. The disorder has been described in many racial groups and has been
identified in all areas of the world. The disorder may occur with greater frequency in
individuals of Southeast Asia or the Far East who experience greater rates of aplastic
anemia. The disorder can affect any age group.
Diagnosis
A diagnosis of PNH may be suspected in individuals who have symptoms of
intravascular hemolysis (e.g., hemoglobinuria, abnormally high serum LDH
concentration) with no known cause. A diagnosis may be made based upon a
thorough clinical evaluation, a detailed patient history, and a variety of
specialized tests. The main diagnostic test for individuals with suspected PNH
is flow cytometry, a blood test that can identify PNH cells (blood cells that are
missing GPI-anchored proteins).
Treatment Options: Medical Therapy;
The most widely used drug to treat PNH is Eculizumab (Soliris). The drug binds to proteins in the blood
that can destroy red blood cells. It reduces the risk of blood clotting and can improve quality of life in PNH
patients. A newer drug called Ravulizumab (Ultomiris) works in a similar way to eculizumab.
While some of the secondary triggers to a TPP event are avoidable (i.e.
prescription of anti-platelet drugs in a patient with a past history of TPP),
there are not clear preventions for acquiring the deficiency in
ADAMTS13.
We will discuss warm and cold hemolytic anemias under the category
of auto-immune hemolytic anemias (AIHA).Both AIHAs have some
similar symptoms:
Jaundice.Splenomegaly.Pallor, fatigue, dyspnea
Warm AIHA
Warm AIHA is caused by IgG autoantibody that binds to the RBC membrane
for destruction in temperatures around 37°C. The primary cause may be
idiopathic (unknown), but other secondary factors like medication,
malignancies, autoimmune conditions, and viral infections can cause warm
AIHA.
Apart from the typical symptoms listed above, many people with cold hemolytic
anemia experience pain and a blue tinge to the limbs from poor circulation in the
extremities.
Population Affected
CAD most commonly affects people between the ages of 40 and 80. The
median age at symptom onset is around 65 years, meaning that half of
affected individuals develop symptoms before this age, and the other half after
this age. The disease is present in about 16 people per million (prevalence),
and develops in one person per million every year (incidence). The disease is
almost twice as common in women compared to men. Those living with
conditions associated with CAD (see “causes” section above) are more likely to
develop the disease. CAD is also potentially more common, or at least more
recognized, in colder climates.
Diagnosis
Warm antibody hemolytic anemia can often be differentiated from cold
agglutinin disease by the temperature at which the direct antiglobulin test is
positive; a test that is positive at temperatures ≥ 37° C indicates warm
antibody hemolytic anemia, whereas a test that is positive at lower
temperatures indicates CAIHA
Treatment of Cold AIHA