Hemoglobin Final Presentation

7/29/2019 Hemoglobin Final Presentation

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Hemoglobinopathies andCarbon Monoxide Poisoning

GROUP 9

Saliba Samonte Samoy Segubre Sese

Solana Sta. Ana Tan Gana Tee


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Major transport molecule for oxygen

carries carbon dioxide from the tissues to the lungsfor excretion

Protein with two major components:

a. Four nonprotein heme groups each containing iron in

the reduced ferrous form, which is the site of oxygenbinding

b. Globin portion consisting of four polypeptide chains

HEMOGLOBIN


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Hemoglobin Structure

Each of the 4 globin chains isrepresented in a different color.

Porphorin ring with iron atom ligandbound inside


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Alternative View of Hemoglobin


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In the normal subject these chains can be of four types:

- Alpha- Beta

- Delta

- Gamma

In normal and abnormal hemoglobins (with the exception ofhemoglobin H and Barts), two sets of identicalpolypeptide chains make up the globin. The structureof the globin chain, like all proteins, is genetically

controlled.


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among the most commonly performed blood tests, usually as part

of a complete blood countNormal results vary, but in general are:

Men: 13.8 to 18.0 g/dL (138 to 182 g/L, or 8.56 to 11.3 mmol/L)

Women: 12.1 to 15.1 g/dL (121 to 151 g/L, or 7.51 to 9.37 mmol/L)

Children: 11 to 16 g/dL (111 to 160 g/L, or 6.83 to 9.93 mmol/L) Pregnant: 11 to 12 g/dL (110 to 120 g/L, or 6.83 to 7.45 mmol/L)

(Dehydration or hyperhydration can greatly influence measuredhemoglobin levels. Albumin can indicate hydration status.)

Hemoglobin concentration

measurement


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Hemoglobin F (fetal hemoglobin)

This type is normally found in fetuses andnewborn babies.

is replaced by hemoglobin A (adult hemoglobin) shortly afterbirth

only very small amounts of hemoglobin F are made afterbirth.

Some diseases, such as sickle cell disease, aplastic anemia,and leukemia, have abnormal types of hemoglobin andhigher amounts of hemoglobin F.

Most Common Types of Normal

Hemoglobin


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Hemoglobin A

This is the most common type of hemoglobin found

normally in adults some diseases, such as severe forms of thalassemia, may

cause hemoglobin A levels to be low and hemoglobin Flevels to be high.

Hemoglobin A2

This is a normal type of hemoglobin found in small amountsin adults.


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Screen for, diagnose, and measure the severityof anemia (low RBCs, hemoglobin and hematocrit)or polycythemia (high RBCs, hemoglobin and hematocrit)

Monitor the response to treatment of anemia

Help make decisions about blood transfusions or othertreatments if the anemia is severe

Hemoglobin Test


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is a blood test done to check the different types of hemoglobin in the

blood. takes advantage of the fact that hemoglobin types have different

electrical charges.

an electrical current is passed through the hemoglobin in someone'sblood sample, which causes the hemoglobin types to separate at

different rates and form bands by comparing the pattern formed with that of a normal blood

sample, doctors can see the types and quantities of hemoglobinpresent in the blood sample.

Hemoglobin S and hemoglobin C are the most common types of

abnormal hemoglobins that may be found by an electrophoresis test.

Electrophoresis Process


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Hemoglobin electrophoresis

Hemoglobin A1: 96.5%-98.5% of total

hemoglobin or 0.96-0.985 mass

fractionHemoglobin A2: 1.5%-3.5% of total hemoglobin

or 0.015-0.035 mass fraction

Hemoglobin F: 0%-1% of total hemoglobin or

0-0.01 mass fraction

Abnormal hemoglobin types:None


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More than 400 different types of abnormal hemoglobin have been found,

but the most common are: Hemoglobin S - This type of hemoglobin is present in sickle cell disease.

Hemoglobin C - This type of hemoglobin does not carry oxygen well.

Hemoglobin E - This type of hemoglobin is found in people of Southeast

Asian descent. Hemoglobin D - This type of hemoglobin is present in a sickle cell

disorder.

Hemoglobin H (heavy hemoglobin) - This type of hemoglobin may bepresent in certain types of thalassemia.


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Structural defects in the hemoglobin molecule. Alterations in the

gene for one of the two hemoglobin subunit chains, alpha (a) or beta(b), are called mutations. Sickle hemoglobin exemplifies thisphenomenon.

Diminished production of one of the two subunits of the hemoglobinmolecule. Mutations that produce this condition are termed

"thalassemias."

Abnormal associations of otherwise normal subunits. A singlesubunit of the alpha chain (from the a-globin locus) and a singlesubunit from the b-globin locus combine to produce a normal

hemoglobin dimer.

Abnormalities in Hemoglobin


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sickle or crescent-shaped RBCs with decreased affinity to oxygen

clogs capillaries and prevents blood flow, causing poor circulationand leading to higher risks for stroke, organ damage, and bacterialinfections

Normal red blood cells live about 120 days in the bloodstream andthen die.

Sickle cells usually die after only about 10 to 20 days.

Sickle Cell Anemia


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Adult hemoglobin consists of two -globin chains and two -

globin chains there is a single substitution of valine for glutamate in position

6 of the -chain of hemoglobin that results in this disorder.

The mutated hemoglobin is called S-hemoglobin, for sickle cellanemia.

The tertiary configuration of low affinity, deoxygenatedhemoglobin (Hb) is known as the taut (T) state.

The quaternary structure of the fully oxygenated high affinityform of hemoglobin (HbO2) is known as the relaxed (R) state.

Biochemical Basis of Sickle-CellPathology


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in its T-state, the additional valine residues bind to a

hydrophobic area on other S-hemoglobin molecules

forming long, rod-like structures that cause red blood cells tobecome stiff and assume a sickle shape

This dangerous effect only occurs on hemoglobin in itsdeoxygenated state because oxygenated hemoglobin has theR conformation, which covers the hydrophobic patch that theextra valine binds to.


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autosomal recessive condition: gene can be passedon from a parent carrying it to male and femalechildren

must be inherited from both the mother and thefather, so that the child has two sickle cell genes

Inheritance


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inheritance of just one sickle gene: sickle cell trait orthe "carrier" state

does not cause sickle cell anemia

do not have many symptoms of the disease and have

normal hospitalization rates and life expectancies have one of the genes that cause sickle cell anemia

can pass the sickle hemoglobin gene on to their children


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conditions associated with low oxygen levels, increased acidity,

or low volume or dehydration of the blood conditions that occur as a result of injury to the body's tissues,

dehydrating states, or anesthesia

certain organs are predisposed to lower oxygen levels or

acidity, such as when blood moves slowly through the spleen,liver, or kidney

organs with particularly high metabolic rates (such as the brain,muscles, and the placenta in a pregnant woman with sickle cellanemia) promote sickling by extracting more oxygen from the

blood

Conditions that promote sicklingof RBCs in sickle cell anemia


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Some patients have mild symptoms and some have very severe

symptoms

basic problem: the sickle-shaped red blood cells tend to getstuck in narrow blood vessels, blocking the flow of blood

Hand-foot syndrome

small blood vessels in hands or feet are blocked

pain, swelling, fever, ulcerations may occur

may be the first symptom of sickle cell anemia in infants.

Signs and Symptoms


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Pain that occurs unpredictably in any body organ or joint

due to blocked oxygen flow to tissues

some have painful episodes or crises once a year

some have as many as 15 or more episodes in a year

pain can last a few hours to several weeks

may be hospitalized and treated with painkillers and IV fluids

principal symptom of sickle cell anemia in children and adults


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Fatigue, paleness, rapid heart rate, and shortness of breath

symptoms of anemia or a shortage of red blood cells

Yellowing of skin and eyes

signs of jaundice from the accumulation of bilirubin

results from the rapid breakdown of red blood cells


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Splenic Crisis

spleen becomes to large, scarred, or damaged due to anoverload of sickle cells flowing into it

cells clog the spleen and disrupts it usual function, which is to

fight infections by filtering out abnormal red blood cells leads to the shrinkage of the spleen

blood transfusion

Complications


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Acute chest syndrome

caused by infection or trapped sickled cells in the lung with symptomssuch as fever and chest pains.

can lead to pulmonary arterial hypertension

symptoms include irregular breathing patterns and high blood pressure

Stroke can happen when sickle cells flow into the brain and block blood vessels

can result from bursting blood vessels.

if death isnt the result of this complication, then a person mayexperience learning disabilities or paralysis.


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Vision blood vessels have to have the ability to transport oxygen into the eyes

small blood vessels become blocked by sickle cells

thin layers of the retina become damaged Can lead to blindness

Gallstone result of the release of hemoglobin from a dead red blood cell.

may form in the gallbladder due to the overload of bilirubin. nausea, vomiting, sweating, and chills can also occur

Multiple organ failure most serious complications of sickle cell anemia

occurs when three major organs fail


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Converts a single base paie from Glutamate to Valine-In the sixth position of Beta Globin

Converts CCT-GAG-GAG to CCT-GVG-GAG

MstII restriction enzyme recognizes CCT-GAG and not GVG

Prenatal Diagnosis


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Southern Blot Technique-DNA Recognition-Applicable for Sickle-Cell Anemia Diagnosis

Digestion of Fetal DNA with MstII using beta Globin as theradioactive probe whether the restriction site present in bothcopies.

Absent

Homozygous for the sickle trait-Missing in one copy

Heterozygous for the sickle trait-Missing in both copies

Prenatal Diagnosis


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Bone Marrow Transplantation

-Decreases the concentration of the Sickle-Cell RBC

Pain Management-Treated with Non-Steroidal Anti-Inflammatory Drugs,

Ketorolax tromethamine or Analgesics

Treatment


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colourless, odourless poisonous gas and is a common yetpreventable cause of death from poisoning worldwide

binds to the heme group of hemoglobin molecule at the samesite as oxygen and forms carboxyhemoglobin

binding of carbon monoxide to haemoglobin is over 200 timesas strong as the binding of O2 to haemoglobin.

sometimes called the "Silent Killer"

Carbon Monoxide


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Thus, at a concentration as small as 0.1%(Pco=0.5mmhg), CO will

combine with half the available hemoglobin molecules and reducethe oxygen carrying capacity of the blood by 50%.

Elevated blood levels of CO causes carbon monoxide poisoning, onesign of which Is a bright, cherry-red color of the lips and oralmucosa.

Administering pure oxygen, which speeds up the separation ofcarbon monoxide from the hemoglobin, may rescue the person.


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Produced by the incomplete burning of various fuels,

including coal, wood, charcoal, oil, kerosene, propane,and natural gas.

Products and equipment powered by internal combustion

engines such as portable generators, cars, lawn mowers,and power washers also produce CO


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Acute Lung Injury

Many of the initial studies done to characterize the location and functionof HO-1 in the lung used rodent

models of acute lung injury such as hyperoxia. In rodents, high

concentrations of inhaled oxygen result in lung edema and death withinseveral days. This oxidant injury results in increased expression of HO-1 inthe lung, and overexpression of HO-1 in the bronchiolar epithelium byadenoviral gene transfer results in enhanced protection from the lethaleffects of hyperoxia. Inhaled CO confers similar protection againsthyperoxic lung injury.

Abnormalities fromCarbon Monoxide


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Pulmonary Fibrosis

Immunohistochemical analysis of lung tissue from patients with variousforms of interstitial lung disease reveals increased expression of HO-1,

primarily in alveolar macrophages. Increased expression of HO-1 byadenoviral transfer has been shown to suppress lung fibrosis in a murinebleomycin model, and

Inhaled CO has similar effects.

Pulmonary Vascular Disease

CO has also been strongly implicated in the development ofhepatopulmonary syndrome in experimental models, and patients withhepatopulmonary syndrome have been shown to have highercarboxyhemoglobin levels than control subjects. CO production underconditions of physiological stress results in a wide range of adaptive

responses that are relevant to pulmonary disease.


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Obstructive Lung Disease

Asthma is a disease characterized by inflammation, and so it is not surprising that

exhaled CO levels have been shown to increase during asthma exacerbations.Exogenously administered CO has also been shown to decrease airwayhyperresponsiveness in mice, and as previously noted, CO may modulate the lungremodeling in asthma due to its inhibitory effect on airway smooth muscle cellproliferation. Exposure to reactive oxygen species and an imbalance inoxidant/antioxidant status are also thought to be major contributors to thepathogenesis of COPD.

Carbon Monoxide Poisoning

A potentially deadly condition caused by breathing carbon monoxide gas, whichprevents oxygenation of the blood. Common causes of carbon monoxide poisoninginclude malfunctioning furnaces and the use of kerosene heaters or similar devices inunventilated indoor spaces.


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CO reacts with the hemoglobin in red blood cells and forms

carboxyhemoglobin (COHb)

bond between carbon monoxide and hemoglobin is twohundred times stronger than that of oxygen and hemoglobin

CO displaces the oxygen levels in the blood with ease lack of oxygen results in organs starving of oxygen and suffering

serious or even permanent damage

damage depends upon the levels of CO inhaled.

Biochemical Basis ofCarbon Monoxide Poisoning


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Inhalation of CO can cause severe symptoms and poisoning

Signs and symptoms can be very difficult to diagnose dueto their non-specific nature that can be mistaken for flu orfood poisoning

Percentage of COHb in the body can determine the type ofsymptoms or levels of damage that may be experienced

Signs and Symptoms


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10-30%: headaches dizziness, fatigue and flu-type symptoms

around 30-50%: nausea, vomiting, headaches and breathingdifficulties

over 50%, loss of consciousness, seizures, and convulsions, and atthese levels the sufferer can quickly die

If breathed in at large enough levels, it can kill in just a few minutes. If breathed in at smaller levels but over a longer period of time, it

can lead to death or permanent damage.


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Combines with the reduced Heme Iron of cytochrome oxidase,

inhibiting mitochondrial electron transport, impairing normalenergy regeneration resulting death of the organism

Presents with Flu-like Viral Syndromes, depression, fatigue,chest pain and migraine

Other conditions respiratory distress syndrome, altitude sickness, lactic acidosis,

diabetic ketoacidosis, mengitis methemoglobinemia or opioid or

toxic alcohol poisoning

Diagnosis


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Hyperbaric Oxygen Therapy

It elevates the amount of oxygen in the body significantly

Treatment


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Sickle Cell Anemia

Carbon Monoxide Poisoning

Pathophysiology

1Viral or Bacterial infections 1Dehydration


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Hemostasis promotes a cycle of local hypoxia,

deoxygenation of more erythrocytes and

more sickling.

Spleen hemolyze sickle cells in the circulation Irreversible effects from recurrent sickling

1Viral or Bacterial infections

2High altitude

3Emotional or Physical Stress

4Surgery

5Blood Loss

Sickling episode

1Dehydration

2Increased hydrogen ion concentration

(acidosis)

3Increased plasma osmolality

4Decreased Plasma volume

5Low body Tempreature

Hypoxia

RBCs take on elongated, crescent shape.

Cannot easily pass through capillaries or

other small vessels and causes vascular

occlusion

Acute or Chronic tissue Injury


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Clinical Hallmarks:

1Vasoocclusive

phenomena

2Hemolysis

3Increased COHb Levels

Point mutation in the Beta-globin chain of

hemoglobin

Amino acid glutamic acid replaced with

hydrophobic amino acid valine at the sixthposition

Association of two wild type alpha-globin subunits with

two mutant beta-globin subunits forms hemoglobin S(Hbs)

Low oxygen concentrations promotes non covalent

polymerisation (aggregation) of hemoglobin

Distorts RBCs into sickle shape and decreases their

elasticitySickle Cell Anemia

Hemolyzed RBCs release

Hemoglobin into surrounding fluids

Increased Levels of COHb

CO Poisoning

Documents

Hemoglobin Final Presentation