Sickle Cell Anemia - SIG 1

Sickle Cell Anemia, the First Molecular Disease
SIG 1 Notes
Section 1 (pp1295-1299)
Abstract and Introduction

-hemoglobin mutation is responsible for the formation of HbS polymerization
Pathophysiology is trigger by RBC injury (which is induced by sickling)
Disease is actually a group of related disorders each has varying degree of severity
Nosology of Sickle Cell Disease

Heterozygous carrier of HbS (has one normal Hb coding gene and one HbS coding) has
sickle cell trait Not considered sickle cell disease
o Sickle cell trait individuals only have 30-40% HbS, and HbS polymer is not
formed under most conditions
o Formation of polymer is seen in renal medulla, or occurs with vigorous exercise
o Carriers have few complications, have normal life span
Phenotype of sickle cell disease results from many genotypes

o Sickle cell anemia results from homozygous state for HbS mutation
o Many other compound heterozygous conditions all included under the umbrella
of sickle cell disease
Pathophysiology The Sickle Hemoglobin Mutation

Proximate cause of sickle cell disease is A-to-T transversion on the HBB gene, leading to
Glu to Val amino acid mutation
HbS heterozygote has a survival advantage given the selective pressure of mosquito
transmitted Plasmodium falciparum (malaria) infection
Critical accumulation of HbS in the cell causes cellular injury, recognized by hemolytic
anemia and vasoocclusion
Other Hb variants such as HbE and HbC are recognized and can be found in compound
heterozygotes with HbS
Thalassemias are found in conjunction with HbS or in individuals with sickle cell disease
A (brief) explanation of this table

In the left most column, different genotypes of sickle cell disease are listed (sickle
cell anemia among them).
PCV refers to packed cell volume (%), which is measured in a hematocrit.
Essentially, what this measures is RBC content in the blood. People with sickle cell
anemia have low PCV compared to those of normal phenotype
Retic refers to reticulocyte count. Reticulocytes are immature RBCs, and this count is
used to determine whether enough RBCs are being produced in the bone marrow
MCV refers to mean corpuscular volume. MCV is the average volume of RBCs: the
higher the number, the larger the cell.
HbF and HbA2 refer to the content of fetal and alpha 2 hemoglobin in the cell. These
amounts can be predictive of the severity of the disease
% variant refers to the different compositions of an affected individuals hemoglobin
HbS Polymer
Extent of HbS polymerization determines severity of hemolytic anemia and
vasoocclusion
Deoxy HbS grows rapidly into structured polymers with 7 pairs of elementary fibers
Cycles of polymerization and depolymerization cause irreversible damage to sickle RBC
cytoskeleton
Sickle Vasoocclusion
This is the process by which normal tissue perfusion is interrupted by sickle RBCs
Occlusion can happen in large arteries as well as capillaries, facilitated by many elements
(RBCs, WBCs, reticulocytesetc)
Causes of sickle vasoocclusion likely differ between patients
Hemolytic Anemia
Hemolytic anemia most severe in homozygote for HbS, less severe in those with
thalassemia
Even between individuals with same genotype, RBC survival may vary
Hemolysis mostly occurs extravascularly (outside vascular system), but can occur
intravascularly leads to saturation of hemoglobin binding proteins, allowing free Hb to
circulate
o Free circulating Hb reduces NO bioavailability
Section 2 (pp1301-1303)
Anemia
Patients with HbSC and HbS- + thalassemias are usually less anemic than those with
sickle cell anemia
Advancing renal disease common cause of increasing chronic anemia
Patients with most severe hemolysis can be categorized by LDH level surrogate
measure for intravascular hemolysis
Chronic hyperhemolysis defined by top quartile LDH level and compared to lowest LDH
quartile
o Hyperhemolysis subjects: higher systolic BP, higher prevalence of leg
ulcersetc. Higher risk factor for early death, increased presence of gallstones
o Painful episodes fewer in hyperhemolysis patients
o Hyperhemolysis influenced by HbF level and presence of thalassemia
Acute Anemic Episodes

Severe anemia can develop when blood cell production is interrupted by viral infection
Interruptions often require blood transfusion until spontaneous recovery
Inadequate folic acid can also cause anemia nutrient is necessary due to increased
erythropoiesis (blood cell production)
The Early Years

Most common complications are painful episodes
The Painful Episodes

Management of sickle cell disease requires dealing with acute and chronic pain
Acute painful episodes are most common vascooclusive events usually starts in hand or
foot (swelling)
o May lead to infection or tissue damage
Episodes last hours to days no useful laboratory tests can detect
Individuals with HbSC or other less sever genotypes have few painful episodes
>3 painful episode hospitalizations is associated with increased mortality in patients >=20
HbF levels inversely related to pain while concurrent thalassemia may increase pain
Brief explanation of figure:
The clinical manifestations (i.e. symptoms like leg ulcers, pain, stroke) and their
association with hyperhemolysis in sickle cell anemia (see the actual paper for more
details
https://openi.nlm.nih.gov/detailedresult.php?img=PMC2330070_pone.0002095.g004&re
q=4)
Odds-ratio = the odds that an outcome will occur given a particular exposure
o In our case, the outcomes are the clinical manifestations (y-axis) and the exposure
is the condition of hyperhemolysis
We can see that having hyperhemolysis is more likely to be associated with leg ulcers,
but less likely to be associated with pain
Section 3 (pp1308-1310)
General
Patient care best developed with a team consisting of hematologists, orthopedic surgeons,
nephrologists, and pain management experts
Must pay attention to immunizations and nutrition. Work and exercise encouraged as
tolerated
Neonatal screening to detect newborns with disease early administration of
prophylactic penicillin to prevent pneumonia
High concentrations of inhaled O2 cannot prevent HbS formation though it can reduce
abnormalities in HbS that accompany surgery
4 types of treatments
o Increase HbF and retard HbS polymerization
o Agents that affect inflammation
o Agents that preserve NO bioactivity
o Agents that affect sickle RBC density
Increasing HbF Concentration

HbF inhibits HbS polymerization because neither HbF (22) nor hybrid 2S can be
incorporated into the polymer phase
Inducing high HbF levels of at least 20% can inhibit HbS polymerization
o These levels are currently unrealistic, but some therapies approach them
HbF inducers include hydroxyurea, decitibine, arginine butyrate, deacetylase inhibitors
Hydroxyurea
A ribonucleotide reductase inhibitor has high ability to induce higher HbF levels in
most patients
Decreased morbidity associated with reduced mortality
HbF levels >= 0.5 g/dL associated with fewer painful episodes
Mechanism of action may rely on bone marrow to withstand moderate doses of
hydroxyurea
o Allows preferential synthesis of HbF over other blood cells
o Also may reduce the presence of neutrophils, monocytes, and reticulocytes

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Sickle Cell Anemia, the First Molecular Disease

Abstract and Introduction

Nosology of Sickle Cell Disease

Phenotype of sickle cell disease results from many genotypes

Pathophysiology The Sickle Hemoglobin Mutation

A (brief) explanation of this table

Acute Anemic Episodes

The Early Years

The Painful Episodes

Increasing HbF Concentration

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