Test 3: Hemoglobinopathies Flashcards
-disease state involving the hemoglobin molecule
-due to a genetic mutation in one or more genes that affect hemoglobin synthesis
-mutation effects either the quality or quantity of hemoglobin synthesis
Hemoglobinopathy 
Hemoglobinopathy Effects either the quality or quantity of hemoglobin synthesis
____________ =  qualitative
____________ = Quantitative
Structural defects
Thalassemias
There are ____ functional human globin genes located on ____ different chromosomes
6, 2
________ and _______ are located on chromosome ___, and I referred to as alpha-like genes. 
Alpha, zeta
-chromosome 16
(Two alpha and one zeta globin genes per chromosome)
________, __________, ________ and _________ are located on chromosome 11 and are referred to as beta-like genes. 
Beta, gamma, delta, epsilon
(two Gamma and one beta, Delta, and alpha globin per chromosome) 
There are more than 1000 structural hemoglobin variants currently they are divided into what five categories? 
-Point mutation (most common, 90%)
-Deletion
-Insertions
-chain extensions (Stop codon is mutated, produces abnormally long globin chains affecting structure and function)
-Gene fusions- Produces abnormal folding of chains and effects hemoglobin function
What are the lab tests done for hemoglobinopathys? 
• traditional hematology (CBC and microscopic)
• Hemoglobin electrophoresis testing
• HPLC (High performance liquid Chromatography)
•PCR
What is the easiest and cheapest test done for hemoglobinopathies?
Hemoglobin electrophoresis
-Cellulose acetate (pH 8.4)
-Citrate agar gel (pH 6.2)
Both beta genes are mutated resulting in absence of hemoglobin A. What are the two types? 
Homozygous Beta-Hemoglobinopathies
-Sickle cell (Hb SS)
-Hgb C disease (CC) 
When only one gene is mutated and the other is normal.
Attempt to minimize the impact of abnormal hemoglobin, presents variant hemoglobin in lesser amount then hemoglobin A 
Heterozygous beta-Hemoglobinopathies 
Hgb S trait (HB AS) and Hgb C disease (Hb AC)
The most frequently occurring and the most severe of the abnormal hemoglobins
Symptomatic Hemoglobinopathy in which patients Expresses either hemoglobin SS or S in combination with another hemoglobin beta chain mutation
Sickle cell disease (SCD) 
SCD is caused by point mutation at the _______ amino acid in beta chain.
What type of mutation is it? 
6th *
Point mutation*
In SCD, what amino acid is substituted in the 6th amino acid position?
VALINE substitutes for glutamic acid**
Presence of just one sickle cell gene confers resistance to cerebral infection by…
Plasmodium falciparum
-When a malaria infected RBC sickles, the parasite dies 
How common is sickle cell disease in the African-American population? 
8 to 9% carry the trade. One in 300-600 are affected by SCD
-severe, moderate, and mild forms all exist. Unknown etiology as to variance in severity
Pathophysiology of SCD
When hemoglobin switches from relax to tense forms as it offloads O2 in capillaries, Hemoglobin a structural changes shape in such a way to bring it hydrophobic, sticky, mutated Valine into contact with each other, resulting in…
-Polymerization of the hemoglobin
-”locking up” of spectrins flexibility
-Bizarre deformation of the RBC
(Usually reversible, but depends on time, temperature, PH, and oxygen tension) 
SCD damages _____ channels of cell.
Potassium
RBC loses potassium and dehydration results leading to formation of intracellular crystals and further deformation. Hemoglobin molecule stack up “like firewood”
-RBCs are much more fragile and lyse easier
Sickle cell leads to __________ Blood viscosity and _________ Blood flow. 
Increased, slow
(This can prolong exposure to hypoxic environment, and lower tissue pH decreasing the oxygen affinity that further promotes sickling)
What is responsible for vaso-occlusion complications in SCD? 
Irreversible sickle cells are removed by the spleen, but reversible cells are responsible for the vaso-occlusion complications
Chronic injury response Means “ Sickle cell ________” Patients have increased numbers circulating endothelial cells which trigger the extrinsic coagulation pathway and promote formation of microthrombi, which cause Further necrosis that promotes a vicious cycle. 
Crisis
What is the reason SCD patients usually get hospitalized? 
Vaso-occlusion
Polychromasia and __________ Are typically found with sickle cell. 
Codecytes
What ends up happening to hemoglobin S RBCs? 
Permanently destroyed by the spleen (Extravascular hemolysis) 
In SCD, Bone marrow responds with increased erythropoiesis. And severe anemia marrow space is widen, bone cortex thins out, and extra medullary sites for hematopoiesis are recruited. Where are these sites?
 liver, spleen, and thymus
Overtime the spleen quits effectiveness
SDC causes a chronic, low level,  intravascular hemolytic anemia.
RBCs only have a lifespan of ______ days.
10-20
Enlarged spleen and sometimes spleen is removed
Seen in patients with SCD that is caused by any situation that produces excessive deoxygenation of RBCs Like hyper or hypo thermia, dehydration, infection, intense exercise, labor and delivery, and high altitude transitions
Sickle cell crisis
-About 80% of patients only have a rare crisis
 what are the five types of sickle cell crises? 
• Vaso-occlusion or pain crisis
• infectious crisis
• Bone and joint crisis
• Splenic sequestration crisis
• aplastic crisis
Type of SCD crisis that is characterized by rigid, sickle cells that increase blood viscosity and cause vascular occlusion and micro thrombi (strokes), Resulting in tissue necrosis. Number one cause of death in adult sickle cell patients
Vaso-occlusion or a chest crisis
(Called a cute chess syndrome, ACS, when it predominantly effects lungs)
What is the number one cause of death in sickle cell adult patients?
Vado-occlusion or pain crisis 
(or acute chest syndrome when in lungs) 
Type of sickle cell crisis that is precipitated by infection and is the primary cause of death in SCD children
Infectious crisis
(S. aureus, S. pneumonia, and H. flu) 
What is the number one cause for death and hospitalization in SCD patients?
Vaso-occlusion
Type of a sickle cell crisis where pain occurs in bones and joints (“Sympathy response”) as sickle cells accumulate in bone shafts. Bone marrow actually infarcts. 
Bone and joint crisis
Type of sickle cell crisis that occurs when enough sickle cells are trapped in the hypoxic, convoluted, splenic microcirculation. Becomes a vicious cycle as a spleen in larges and then traps even more cells. Hypovolumetric shock can happen due to extreme drop in blood volume.
Splenic sequestration crisis
How is splenic sequestration crisis monitored?
By a “pit count”, The number of pits in RBC membrane
Increased number of pits = worsening splenic function
What is usually the first clinical finding in infants with severe SCD? 
Dactylitis
-Due to painful extramedullary hematopoiesis
Type of sickle cell crisis where there is a decreased bone marrow hematopoiesis thought to be triggered by infection/fever.
Aplastic crisis (Common with parvovirus B19)
- Result in temporary decrease in RBC count, Hgb, Hct, and RPI 
Lab findings for SCD
-normo-, normo- anemia
-modified to marked Aniso (sickled cells, target cells) Polychromasia due to reticulocytosis, and basophilic stippling
-Increased RDW
-Howell-jolly and Pappenheimer bodies
Why are Howell-jolly and Pappenheimer bodies present in SCD patients?
If spleen worked, most would have been removed already
What is the most common screening test for SCD that is not diagnostic?
Hemoglobin solubility test*
How is hemoglobin solubility test done?
-blood is added to a reducing agent Sodium dithionate and a lysing agent that releases the Hemoglobin from the RBCs
-deoxygenated hemoglobin S is insoluble and precipitates in solution to give a turbid result
What can get a false positive result and what can give a false negative result on the hemoglobin solubility test?
-False positive with hyperlipidemia
-false negative results with low hematocrit or low RBC counts
All hemoglobins with the amino acid substitution found in hemoglobin _____ Will give a positive hemoglobin solubility test result even if there is a second substitution. 
S
Lab test that shows 80 to 90% hemoglobin S
Remainder is usually F and A2
Alkaline electrophoresis
