HEMOGLOBINOPATHIES prt.1 Flashcards
Chromosome 16
→ Alpha and Zeta Globin genes
→ Referred as: Alpha-like genes
Chromosome 11
→ Beta, gamma, delta and epsilon globin genes
→ Referred as: Beta-like genes
is a tetramer of four globin chains with a heme attached to each globin chain.
Hemoglobin
Heme biosynthesis starts with
Glucine
Succinyl CoA
What converts protoporphyrinogen IX to protoporphyrin IX
Protoporphyrinogen oxidase
Protoporphyrin IX to HEME
Ferrochelatase
Coproporphyrin III to Protoporphyrin IX
Coproporphyrinogen oxidase
symptoms of the disease have been traced in one Ghanaian family
1670
Sickle cell anemia was 1st reported by a Chicago cardiologist, Herrick, in a West Indiana Student with severe anemia
1910
Emmel recorded that sickling occurred in non-anemic patients and in patients who were severely anemic.
1917
_________described the pathologic basis of the disorder and its relationship to the hemoglobin molecule.
• Sickling occurred deficient in oxygen and the shape of the RBCs was reversible when oxygenated again.
1927
Hahn and Gillespie
_____reported that malarial parasites were present less often in blood films from patients with SCD that in individuals without SCD
1946
Beet
_______showed that when Hb S is subjected to electrophoresis, it migrates differently than does Hb A
1949
Pauling
More severe disease
Homozygotes (Hb SS)
Less severe disease
Heterozygotes Hb S (Hb SC
or Hb S-B-thal)
May dovelop when subjected to
extreme exertion
Asymptomatic but may have mild symptoms
Military boot camp and High level athlectics
Heteroyzgotes (Hb AS)
On the Beta chain at_____
_____ is replaced by____
Mutation occurs in______
____ replaces ______, resulting in A change in codon____ and the substitution of GTG for GAG
Position 6
Glutamic acid (GAG) is replaced
by Valine(GTG)
nucleotide 17
Thymine replaces adenine
6
Amino acid substitution produces a change in charge of (____) - affects electrophoretic mobility
• Also affects the way how molecules interact with one another within the erythrocyte cytosol
+1
Quaternary structure of the molecule does not produce a hydrophobic pocket for valine
• Remain soluble like Hb A and with normal RBC shape
(HbS)- fully oxygenated
Creates a hydrophobic pocket Phe 85 & Leu 88
Allows the valines from adjacent Hb
S molecules to BIND
Hb S - deoxygenated
Creates a hydrophobic pocket Phe 85 & Leu 88
Allows the valines from adjacent Hb
S molecules to BIND
Hb S - deoxygenated
Homozygotes
Sickling begins - oxygen saturation decreases to______
Heterozygotes
Sickling begins - Oxygen saturation is reduced to______
less than 85%
less than 40%
Hb S-containing RBCs that change shape in response to oxygen tension
-Circulate as normal biconcave discs when fully oxygenated, but undergo hemoglobin polymerization, show increased viscosity, and change shape on deoxygenation
Reversible sickle cell
DO NOT CHANGE their shape REGARDLESS OF CHANGE in oxygen tension or degree of hemoglobin polymerization.
Seen on peripheral blood film as elongated sickle cells with a point on each end
-RECOGNIZED ABNORMAL by the spleen and REMOVED FROM CIRCULATION, preventing them to enter the microcirculation and causing vasoocclusion
IRREVERSIBLE SICKLE-CELL
Other Reasons Affecting Sickling Process
Cellular dust
More than____ hemoglobin variants are known;
1200
8 genotypes cause
SEVERE DISEASES
- Hb SS,
- Hb S-BO-thal,
- severe Hb S-B1-thal,
- Hb SD-Punjab,
- Hb SO-Arab,
- Hb SC-Harlem,
- Hb CS-Antilles, and
- Hb S-Quebec-CHORI.
3 genotypes cause
MODERATE DISEASES:
- Hb SC
- moderate Hb S-B1-thal, and
- Hb AS-Oman.
3 genotypes cause mild disease
- Mild Hb S-bsilent-thal
- Hb SE
- Hb SA -Jamaica plain
2 produce very mild disease:
- Hb S-HPFH
- Hb S with a variety of mild variants
Clinical Features of Sickle Cell Disease
Vasocclusion
Bacterial infections
Hematologic defects
Cardiac defects
Others
Stunted growth
High-risk pregnancy
• Hallmark of SCD :
Accounts for most hospital and emergency department visits
Vasoocclusive Crisis
Frequency of painful episodes varies from none to six per year
Average: episodes persists for 4-5 days or may last for weeks
Vasoocclusive Crisis
Characterized by a sudden trapping of blood in the spleen
Leads to rapid decline in hemoglobin(<6 g/dL)
• Occurs most often in infants young children whose spleens are chronically enlarged.
SPLENIC SEQUESTRATION AND INFARCTS
Autosplenectomy
Gradual loss of splenic function
PBS- Evidence of______ and_____ in RBCs
Increases risk of bacterial infection
SPLENIC SEQUESTRATION AND INFARCTS
Howell-Jolly and Pappenheimer Bodies
Acute illness with fever and/or other symptoms that displays pulmonary infiltrates on chest radiograph.
• 2nd most common cause of hospitalization
• 3rd most common cause of death among adults with
SCD
Acute Chest Syndrome (ACS)
• Resulting in a decreased alveolar oxygen tension that induces Hb S polymerization and Sickle cell formation.
• Treatment and continuous
monitoring must be
promptly initiated to reduce morbidity and mortality.
• Oxygen is administered to maintain saturation at greater than or equal to 95% and intravenous fluids to prevent dehydration
Acute Chest Syndrome (ACS)
is a rare but often fatal sequalae of SCD
• It occurs more often in often in Hb SC (43%) and at similar frequency in Hb S-b1-thal (17%) and Hb SS (19%).
Fat Embolism Syndrome (FES) and Bone Marrow Necrosis (BMN)
Is a serious and potentially fatal sequelae of SCD
• nserious ton ote then ata sequed between the development of PHT and the nitrous oxide (NO) pathway,
• Patients with SCD have decrease in NO, and leads to vasoconstriction and hypertension.
Pulmonary Hypertension (PHT)
: Preased supeeptibity to lie threatening infecions from Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae.
• Common cause of death, especially in the first 3 years of life Septicemia are exacerbated by the autosplenectomy effect
Bacterial Infections
Shortened RBC survival (between 16-20 days)
Continuous screening and removal of sickle cells by the spleen perpetuate the chronic hemolytic anemia and autosplenectomy effect
Chronic Hemolysis
• Result from the sudden arrest of erythropoiesis caused by folate depletion
• Folic acid deficiency as a cause of exaggerated anemia in SCD
Prescribe prophylactic folic acid for patients with SCD
Megaloblastic Episodes
• Most common life-threatening
hematologic complications and usually associated with infection
• Are short lived, Require no therapy
• Sickle cell patients usually can compensate for the decrease in RBC survival by increasing bone marrow output.
Aplastic Episode (Bone Marrow Failure)
In patients with severe anemia, cardiomegaly can develop as the heart works harder to maintain
adequate blood flow and tissue oxygenation.
Cardiac Abnormalities
• Impaired blood supply to the head of the femur and humerus results in a condition called______
• 50% of patients with SCD developed AVN by age 35 years
Bone and skin abnormalities
avascular necrosis (AVN)
Hemorrhagic or ischemic stroke occurs in approximately 11% of children with SCD before age 20 years.
Stroke
occurs at a rate of 45% in patients with Hb SC, 11% with Hb SS, and 17% with Hb S-B-thal by early adulthood.
Retinopathy
occurs at a rate of 45% in patients with Hb SC, 11% with Hb SS, and 17% with Hb S-B-thal by early adulthood.
Retinopathy
