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Hemoglobinopathies and Carbon Monoxide Poisoning

GROUP 9 Saliba Samonte Samoy Segubre Sese Solana Sta. Ana Tan Gana Tee

HEMOGLOBIN
Major transport molecule for oxygen carries carbon dioxide from the tissues to the lungs for excretion Protein with two major components:
a. Four nonprotein heme groups each containing iron in the reduced ferrous form, which is the site of oxygen binding Globin portion consisting of four polypeptide chains

b.

Hemoglobin Structure

Each of the 4 globin chains is represented in a different color.

Porphorin ring with iron atom ligand bound inside

Alternative View of Hemoglobin

In the normal subject these chains can be of four types: - Alpha - Beta - Delta - Gamma In normal and abnormal hemoglobins (with the exception of hemoglobin H and Barts), two sets of identical polypeptide chains make up the globin. The structure of the globin chain, like all proteins, is genetically controlled.

Hemoglobin concentration measurement


among the most commonly performed blood tests, usually as part of a complete blood count Normal 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 measured hemoglobin levels. Albumin can indicate hydration status.)

Most Common Types of Normal Hemoglobin


Hemoglobin F (fetal hemoglobin) This type is normally found in fetuses andnewborn babies. is replaced by hemoglobin A (adult hemoglobin) shortly after birth only very small amounts of hemoglobin F are made after birth. Some diseases, such as sickle cell disease, aplastic anemia, and leukemia, have abnormal types of hemoglobin and higher amounts of hemoglobin F.

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 F levels to be high.

Hemoglobin A2 This is a normal type of hemoglobin found in small amounts in adults.

Hemoglobin Test

Screen for, diagnose, and measure the severity of 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 other treatments if the anemia is severe

Electrophoresis Process
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's blood 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 hemoglobin present 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.

Hemoglobin electrophoresis Hemoglobin A1: 96.5%-98.5% of total hemoglobin or 0.96-0.985 mass fraction

Hemoglobin A2:

1.5%-3.5% of total hemoglobin or 0.015-0.035 mass fraction


0%-1% of total hemoglobin or 0-0.01 mass fraction

Hemoglobin F:

Abnormal hemoglobin types: None

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 be present in certain types of thalassemia.

Abnormalities in Hemoglobin
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 this phenomenon. Diminished production of one of the two subunits of the hemoglobin molecule. Mutations that produce this condition are termed "thalassemias." Abnormal associations of otherwise normal subunits. A single subunit of the alpha chain (from the a-globin locus) and a single subunit from the b-globin locus combine to produce a normal hemoglobin dimer.

Sickle Cell Anemia


sickle or crescent-shaped RBCs with decreased affinity to oxygen

clogs capillaries and prevents blood flow, causing poor circulation and leading to higher risks for stroke, organ damage, and bacterial infections Normal red blood cells live about 120 days in the bloodstream and then die.
Sickle cells usually die after only about 10 to 20 days.

Biochemical Basis of Sickle-Cell Pathology


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 cell anemia. The tertiary configuration of low affinity, deoxygenated hemoglobin (Hb) is known as the taut (T) state. The quaternary structure of the fully oxygenated high affinity form of hemoglobin (HbO2) is known as the relaxed (R) state.

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 to become stiff and assume a sickle shape
This dangerous effect only occurs on hemoglobin in its deoxygenated state because oxygenated hemoglobin has the R conformation, which covers the hydrophobic patch that the extra valine binds to.

Inheritance

autosomal recessive condition: gene can be passed on from a parent carrying it to male and female children must be inherited from both the mother and the father, so that the child has two sickle cell genes

inheritance of just one sickle gene: sickle cell trait or the "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

Conditions that promote sickling of RBCs in sickle cell anemia


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 cell anemia) promote sickling by extracting more oxygen from the blood

Signs and Symptoms


Some patients have mild symptoms and some have very severe symptoms

basic problem: the sickle-shaped red blood cells tend to get stuck 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.

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

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

Complications
Splenic Crisis
spleen becomes to large, scarred, or damaged due to an overload 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

Acute chest syndrome


caused by infection or trapped sickled cells in the lung with symptoms such 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 may experience learning disabilities or paralysis.

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

Prenatal Diagnosis

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
Southern Blot Technique -DNA Recognition -Applicable for Sickle-Cell Anemia Diagnosis
Digestion of Fetal DNA with MstII using beta Globin as the radioactive probe whether the restriction site present in both copies.
Absent
Homozygous for the sickle trait -Missing in one copy Heterozygous for the sickle trait -Missing in both copies

Treatment
Bone Marrow Transplantation -Decreases the concentration of the Sickle-Cell RBC Pain Management -Treated with Non-Steroidal Anti-Inflammatory Drugs, Ketorolax tromethamine or Analgesics

Carbon Monoxide

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

binds to the heme group of hemoglobin molecule at the same site as oxygen and forms carboxyhemoglobin
binding of carbon monoxide to haemoglobin is over 200 times as strong as the binding of O2 to haemoglobin. sometimes called the "Silent Killer"

Thus, at a concentration as small as 0.1%(Pco=0.5mmhg), CO will combine with half the available hemoglobin molecules and reduce the oxygen carrying capacity of the blood by 50%. Elevated blood levels of CO causes carbon monoxide poisoning, one sign of which Is a bright, cherry-red color of the lips and oral mucosa. Administering pure oxygen, which speeds up the separation of carbon monoxide from the hemoglobin, may rescue the person.

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

Abnormalities from Carbon Monoxide


Acute Lung Injury
Many of the initial studies done to characterize the location and function of 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 within several days. This oxidant injury results in increased expression of HO-1 in the lung, and overexpression of HO-1 in the bronchiolar epithelium by adenoviral gene transfer results in enhanced protection from the lethal effects of hyperoxia. Inhaled CO confers similar protection against hyperoxic lung injury.

Pulmonary Fibrosis
Immunohistochemical analysis of lung tissue from patients with various forms of interstitial lung disease reveals increased expression of HO-1, primarily in alveolar macrophages. Increased expression of HO-1 by adenoviral transfer has been shown to suppress lung fibrosis in a murine bleomycin model, and Inhaled CO has similar effects.

Pulmonary Vascular Disease


CO has also been strongly implicated in the development of hepatopulmonary syndrome in experimental models, and patients with hepatopulmonary syndrome have been shown to have higher carboxyhemoglobin levels than control subjects. CO production under conditions of physiological stress results in a wide range of adaptive responses that are relevant to pulmonary disease.

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 airway hyperresponsiveness in mice, and as previously noted, CO may modulate the lung remodeling in asthma due to its inhibitory effect on airway smooth muscle cell proliferation. Exposure to reactive oxygen species and an imbalance in oxidant/antioxidant status are also thought to be major contributors to the pathogenesis of COPD.

Carbon Monoxide Poisoning


A potentially deadly condition caused by breathing carbon monoxide gas, which prevents oxygenation of the blood. Common causes of carbon monoxide poisoning include malfunctioning furnaces and the use of kerosene heaters or similar devices in unventilated indoor spaces.

Biochemical Basis of Carbon Monoxide Poisoning


CO reacts with the hemoglobin in red blood cells and forms carboxyhemoglobin (COHb) bond between carbon monoxide and hemoglobin is two hundred 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.

Signs and Symptoms


Inhalation of CO can cause severe symptoms and poisoning Signs and symptoms can be very difficult to diagnose due to their non-specific nature that can be mistaken for flu or food poisoning

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

10-30%: headaches dizziness, fatigue and flu-type symptoms around 30-50%: nausea, vomiting, headaches and breathing difficulties over 50%, loss of consciousness, seizures, and convulsions, and at these 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.

Diagnosis
Combines with the reduced Heme Iron of cytochrome oxidase, inhibiting mitochondrial electron transport, impairing normal energy 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

Treatment
Hyperbaric Oxygen Therapy

It elevates the amount of oxygen in the body significantly

Pathophysiology

Sickle Cell Anemia Carbon Monoxide Poisoning

1Viral or Bacterial infections 2High altitude 3Emotional or Physical Stress 4Surgery 5Blood Loss

1Dehydration 2Increased hydrogen ion concentration (acidosis) 3Increased plasma osmolality 4Decreased Plasma volume 5Low body Tempreature

Hypoxia

Sickling episode

RBCs take on elongated, crescent shape.

Cannot easily pass through capillaries or other small vessels and causes vascular occlusion

Acute or Chronic tissue Injury

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

Point mutation in the Beta-globin chain of hemoglobin

Hemolyzed RBCs release Hemoglobin into surrounding fluids

Amino acid glutamic acid replaced with hydrophobic amino acid valine at the sixth position

Increased Levels of COHb

Clinical Hallmarks: 1Vasoocclusive phenomena 2Hemolysis 3Increased COHb Levels

Association of two wild type alpha-globin subunits with two mutant beta-globin subunits forms hemoglobin S (Hbs)

CO Poisoning

Low oxygen concentrations promotes non covalent polymerisation (aggregation) of hemoglobin

Distorts RBCs into sickle shape and decreases their elasticity

Sickle Cell Anemia

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