Transcript
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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
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