Sickle Cell Disease | Pathophysiology, Symptoms and Treatment

Summary

This video provides an in-depth explanation of sickle cell disease, a hereditary blood disorder characterized by sickle-shaped red blood cells. It covers the genetic basis, where the disease is inherited in an incomplete autosomal dominant fashion, and explains how a point mutation in the hemoglobin beta globin chain leads to the abnormal shape. The pathophysiology, including RBC sickling, hemolysis, and vaso-occlusion, as well as acute and chronic complications such as pain, anemia, and organ damage, are discussed. Diagnosis and treatment options, including hydroxyurea and bone marrow transplants, are also highlighted.

Takeaways

• 🧬 Sickle cell disease is a hereditary blood disorder characterized by sickle-shaped red blood cells.
• 🧬 It is inherited in an incomplete autosomal dominant fashion, where individuals with two copies of the affected allele are fully affected.
• 🧬 People with one affected allele have sickle trait, which offers some protection against malaria but causes less severe symptoms.
• 🧬 The disease is caused by a single point mutation in the hemoglobin beta-globin chain, substituting glutamic acid with valine at position six.
• 🔬 Sickle-shaped red blood cells can clog small blood vessels, leading to painful vaso-occlusion and increased risk of organ damage.
• 🔬 Red blood cells in sickle cell disease have a shorter lifespan (around 17 days) compared to normal red blood cells (120 days).
• 💉 Acute complications include severe anemia, infections, and pain caused by the sickling of red blood cells during stress conditions like hypoxia and dehydration.
• 🩺 Chronic complications include hemolytic anemia, chronic pain, delayed growth, and neurological, renal, and cardiovascular issues.
• 🧪 Sickle cell disease can be diagnosed through prenatal testing, newborn screening, and hemoglobin electrophoresis.
• 💊 Hydroxyurea is a common treatment that reduces pain episodes and prolongs survival, while bone marrow transplants offer a potential cure for patients under 16.

Q & A

What is sickle cell disease?

Sickle cell disease is a group of hereditary blood disorders characterized by sickle-shaped red blood cells.

How is sickle cell disease inherited?

Sickle cell disease is inherited in an incomplete autosomal dominant fashion. Individuals with two copies of the affected allele (homozygous) are fully affected, while those with one copy (heterozygous) are carriers and can be slightly affected.

What is the difference between individuals with sickle cell disease and those with sickle cell trait?

Individuals with sickle cell disease are homozygous for the hemoglobin S allele, while those with sickle cell trait are heterozygous and experience milder or no symptoms.

Why does the sickle cell mutation persist in certain populations?

The sickle cell mutation provides protection against malaria, which is why it persists in populations where malaria is prevalent.

What causes the abnormal shape of red blood cells in sickle cell disease?

A single point mutation on the hemoglobin beta globin chain changes glutamic acid to valine at position six, causing hemoglobin S. When deoxygenated, hemoglobin S is less soluble and aggregates, leading to red blood cell sickling.

What complications arise from sickle-shaped red blood cells?

Sickle-shaped red blood cells can get trapped in small blood vessels, leading to vascular occlusion, hemolysis, and inflammatory responses, which cause pain, anemia, and other complications.

How long do sickle-shaped red blood cells live compared to normal red blood cells?

Sickle-shaped red blood cells have a significantly reduced lifespan, living about 10 to 20 days compared to normal red blood cells, which live around 120 days.

What are some of the acute complications of sickle cell disease?

Acute complications include an increased risk of infections, severe anemia, and vaso-occlusive pain due to sickled red blood cells blocking blood vessels.

What are some chronic complications of sickle cell disease?

Chronic complications include chronic hemolytic anemia, pain, neurologic deficits, pulmonary issues, renal problems, osteoporosis, cardiomyopathy, delayed growth, and chronic leg ulcers.

What treatments are available for sickle cell disease?

Treatment options include hydroxyurea, which reduces pain episodes and hospitalizations, blood transfusions for severe anemia, and hematopoietic cell transplantation, which is considered a potential cure for individuals under 16 years old.

Outlines

00:00

🔬 Understanding Sickle Cell Disease

Sickle cell disease is a hereditary blood disorder characterized by the presence of sickle-shaped red blood cells. The condition is inherited in an incomplete autosomal dominant pattern. Individuals with two copies of the affected gene are homozygous and fully affected, while those with one copy are heterozygous carriers (sickle cell trait) with milder symptoms. The mutation has been linked to protection against malaria, which is why it persists in populations where malaria is common.

05:02

🩸 Pathophysiology and Hemoglobin Mutation

The root cause of sickle cell disease lies in a mutation of the beta-globin chain of hemoglobin, where glutamic acid is replaced by valine at position six. This single-point mutation results in the formation of hemoglobin S, which tends to aggregate when deoxygenated, leading to the sickling of red blood cells. These misshapen cells get trapped in the microvasculature, leading to occlusion, hemolysis, and a dramatically shortened lifespan of sickle red blood cells (around 17 days compared to 120 days for normal cells).

10:03

⚠️ Acute and Chronic Complications of Sickle Cell Disease

Patients with sickle cell disease face increased risks of infections and severe anemia due to the sickling of red blood cells. Conditions like fever, dehydration, hypoxia, and acidosis exacerbate the problem. The sickling causes vaso-occlusion, leading to painful episodes, stroke, acute chest syndrome, renal infarction, myocardial infarction, and other complications. Over time, the disease leads to chronic hemolytic anemia, where the body tries to compensate by producing more immature red blood cells (reticulocytes). Blood smears show features like polychromasia and Howell-Jolly bodies.

🩺 Long-term Effects and Diagnostic Approaches

Chronic complications include pain from vaso-occlusion, neurological deficits, pulmonary conditions, renal hypertension, osteoporosis, and more. Diagnosing sickle cell disease involves prenatal testing, newborn screenings, high-performance liquid chromatography, and hemoglobin electrophoresis. A diagnosis is confirmed if more than 30% of hemoglobin is found to be hemoglobin S.

💉 Treatment and Management of Sickle Cell Disease

The main treatments for sickle cell disease include hydroxyurea, which reduces pain episodes, hospitalizations, and improves survival, and bone marrow transplantation, which is considered the only cure and typically performed in patients under 16. Blood transfusions are also used, especially in severe anemia cases. Pain management is crucial to improve the quality of life for affected individuals.

Keywords

💡Sickle-cell disease

Sickle-cell disease is a hereditary blood disorder characterized by the presence of abnormal, sickle-shaped red blood cells. These misshapen cells can cause blockages in blood vessels, leading to complications such as pain, anemia, and increased risk of infection. The disease is discussed throughout the video as a central theme, emphasizing its genetic nature and clinical consequences.

💡Hemoglobin S

Hemoglobin S is a variant form of hemoglobin that causes red blood cells to become misshapen or 'sickled' when deoxygenated. It is the result of a mutation in the beta-globin gene, where glutamic acid is replaced by valine. In individuals with sickle-cell disease, hemoglobin S leads to cell sickling and is less soluble, causing complications such as microvascular blockages.

💡Autosomal incomplete dominance

This refers to the genetic inheritance pattern of sickle-cell disease. Although individuals with two copies of the mutated allele are fully affected, even carriers with one mutated allele (heterozygous) can show mild symptoms, indicating incomplete dominance. This is highlighted to explain why some individuals with only one allele (sickle trait) experience minor effects.

💡Vaso-occlusion

Vaso-occlusion refers to the blockage of small blood vessels by sickled red blood cells. This leads to painful crises and other complications such as stroke and organ damage. The video describes this as one of the major symptoms of sickle-cell disease, particularly during stressful conditions like infection or dehydration.

💡Hemolysis

Hemolysis is the destruction of red blood cells, which occurs in sickle-cell disease due to the abnormal shape of the cells. This leads to anemia, as sickled red blood cells have a significantly reduced lifespan (around 17 days compared to the normal 120 days). Hemolysis is a core issue in the pathophysiology of sickle-cell disease, leading to chronic anemia and other complications.

💡Hydroxyurea

Hydroxyurea is a medication used to reduce the frequency of pain episodes, hospitalizations, and prolong the lifespan of individuals with sickle-cell disease. It is mentioned as a standard treatment option in the video and helps by increasing the production of fetal hemoglobin, which prevents sickling.

💡Bone marrow transplantation

Bone marrow transplantation, also known as hematopoietic stem cell transplantation, is a potential cure for sickle-cell disease. However, it is usually only performed on individuals under 16 years old. This is described in the video as one of the few curative treatments available for sickle-cell disease.

💡Sickle-cell trait

Sickle-cell trait refers to individuals who carry only one copy of the mutated gene (hemoglobin S). While they are usually asymptomatic, they can have mild symptoms under certain conditions. The video explains that about 7-8% of African Americans have this trait, which also provides partial protection against malaria.

💡Microvascular trapping

Microvascular trapping occurs when sickled red blood cells become stuck in small blood vessels, leading to blockages that cause pain, organ damage, and other complications. The video emphasizes this as a key reason for many symptoms of sickle-cell disease, such as pain crises and increased risk of infection.

💡Reticulocytes

Reticulocytes are immature red blood cells that increase in number as the body attempts to compensate for the destruction of sickled red blood cells. The video mentions that patients with sickle-cell disease often have elevated levels of reticulocytes as the bone marrow works to produce more red blood cells to replace the ones being destroyed prematurely.

Highlights

Sickle-cell disease is a group of hereditary blood disorders characterized by sickle-shaped red blood cells.

Sickle-cell disease is inherited in an incomplete autosomal dominant fashion, meaning even carriers with one allele can show mild symptoms.

Individuals homozygous for hemoglobin SS are fully affected by sickle-cell disease, with an estimated prevalence of 1 in 400 to 1 in 600 African Americans.

Carriers with one sickle-cell allele (heterozygous) are referred to as having sickle trait, which affects about 7-8% of African Americans.

The sickle-cell mutation appears to provide protection against malaria, explaining its persistence in populations where malaria is prevalent.

The disease is caused by a single point mutation at position 6 on the beta globin chain of hemoglobin, substituting glutamic acid with valine.

Deoxygenated hemoglobin S is less soluble than normal hemoglobin A, leading to red blood cell sickling during stress, hypoxia, or dehydration.

Sickled red blood cells can occlude small blood vessels, causing microvascular trapping and leading to severe complications like hemolysis and vaso-occlusion.

Sickled red blood cells have a dramatically shortened lifespan, living about 17 days compared to 120 days for normal red blood cells.

Patients with sickle-cell disease are at increased risk of infections, severe anemia, and complications from vaso-occlusion, such as stroke and acute chest syndrome.

Acute complications include infections, anemia, and vaso-occlusive crises, which can lead to severe pain, stroke, and other organ damage.

Chronic complications include hemolytic anemia, pain, neurologic deficits, renal hypertension, osteoporosis, and retinopathy.

Diagnostic methods include prenatal tests, newborn screenings, high-performance liquid chromatography, and hemoglobin electrophoresis.

Hydroxyurea is a common treatment that reduces pain episodes, hospitalizations, and prolongs survival in patients with sickle-cell disease.

Bone marrow or stem cell transplantation is the only potential cure for sickle-cell disease, typically performed in patients under 16 years old.

Transcripts

hey everyone and this is we're talking

about sickle-cell disease so what is

sickle-cell disease well is a group of

hereditary blood disorders with

characteristic sickle shaped red blood

cells so you can see here the cell on

the right is a sickle shaped red blood

cell and the one on the left is a normal

red blood cell now sickle cell disease

is inherited and is actually inherited

an incomplete autosomal dominant fashion

so on the right here in the schematic

you can see that an individual an

affected individual has two copies

they're homozygous so they have two

copies of the affected allele so they're

considered affected so in individuals

with only one allele are considered

unaffected carrier so it appears to be

recessive condition but in fact even

individuals with one of the affected

alleles can be can be affected to a very

slight degree so that's why we

considered incomplete autosomal dominant

so as I mentioned again an individual

with two copies of hemoglobin s s just

standing for the sickle cell disease

allele so he below man s s or homozygous

these are the affected these are the

individuals that are fully affected by

sickle cell disease and these homozygous

individuals make up about one one in

four hundred to one in six hundred

african-americans have or are homozygous

for sickle-cell disease and the other

portion of individuals the individuals

with only one affected allele are

considered heterozygous and they are

considered to have sickle trait so again

they're very slightly affected but not

as much to the degree as someone that

has homozygous hemoglobin s s and

individuals with the sick of trade over

heterozygous individuals about seven to

eight percent of African Americans have

sickle trade now the sickle cell

mutation appears to be protective

against malaria so that's the reason why

it seems to be pro our persistent

some of the populations where malaria is

prevalent so individuals with one allele

seems to be the best way to be able to

protected against malaria so what is

some of the pathophysiology of sickle

cell disease well it all has to do with

the hemoglobin beta globin chain so the

beta globin chain of hemoglobin is

affected and this beta globin chain is

encoded on chromosome 11 and in sickle

cell disease it's actually all due to an

amino acid substitution at position six

on the bladed globin chain and all it is

is a substitution from glutamic acid to

valine so there is only a single point

mutation changing glutamic acid to

valine at position six on the globe beta

globin chain and this is what causes the

deformed red blood cell shape the

problems in sickle cell disease are all

just due to a single point mutation and

what happens is when this beta globin

chain is mutated we considered

hemoglobin s and deoxygenated hemoglobin

s is less soluble than deoxygenated

hemoglobin a the normal hemoglobin so

that means that whenever Kim globin is

the option in Aidid for some reason it

can lead to increased polymerization so

that means that hemoglobin s can start

to aggregate in accumulate together it

leads to RBC sickling so deoxygenated

hemoglobin s can lead to RBC sickling

and the RBC sickling occurs during

conditions of stress and when red blood

cells do undergo sickling they can lead

to hemolysis and they can lead to

occlusion of the vasculature in these

individuals and you can think about it

if the red blood cells are traveling

through different

vasculature like capillaries for

instance if the cells are misshapen in

particular in a sickle shell shape they

may get clogged and they may get stuck

in certain areas in the vasculature this

is what leads to a lot of this occlusion

and a lot of symptoms related to sickle

cell disease and this is something we

call micro vascular trapping and all of

this leads to hemo phagocytosis so a lot

of times we'll get white blood cells

coming in and they will be essentially

cleaning up a lot of these red blood

cells a lot of these sickle red blood

cells and this leads to a dramatically

reduced lifespan of sick old red blood

cells and in fact it's about 17 days so

on average and normal red blood cell

lives for about 120 days but a sick old

red blood cell can live from anywhere

from 10 to 20 days usually about 17 days

so again it's because these red blood

cells become sickle they get clogged in

certain areas specifically in micro

vascular areas this can lead to an

inflammatory reaction white blood cells

can come in and start to phagocytize

these red blood cells and that's why you

see a dramatically reduced lifespan of

cycled red blood cells so what are some

of the signs and symptoms of sickle cell

disease well some of the acute

complications of sickle cell disease are

that individuals with sickle cell

disease are at an increased risk of

infections furthermore because of the

sickling of red blood cells these

patients can experience severe anemia

and again it's because of the sickling

of red blood cells and again signaling

of the red blood cells occurs during

conditions of stress so what are some of

those conditions of stress well they can

include fever they can include infection

they can include dehydration hypoxia and

acidosis

so anything that leads to a deoxidation

or further the oxygenation of hemoglobin

s Kenley

to sickling of the red blood cells which

can lead to complications so again these

individuals are at an increased risk of

infections and in fact affections can

lead to sickling so it's a vicious cycle

of sickling and symptoms of the red

blood cell cycling when the red blood

cells do undergo a sickling they can

lead to basal occlusion and a lot of

symptoms of sickle cell disease are due

to basal occlusion some of them include

acute basal occlusive pain so when a lot

of these sickle red blood cells get get

essentially trapped or occluded within

the vasculature it can cause pain it can

lead to stroke in some patients there

can be acute chest syndrome there can be

renal infarction myocardial infarction

priapism in venous thromboembolism so

anything that can lead to clogging up of

vasculature can lead to formation of

thrombi mbola emboli can lead to

infarction so essentially cutting off

the blood supply to certain areas like

the kidneys in the heart can all be due

to red blood cells being sickle and

essentially clogging up those arteries

or clogging up those vascular areas so

what are some of the chronic

complications of sickle cell disease

well essentially the biggest

complication is chronic compensated

hemolytic anemia so chronic compensated

chronic it's a long term process

compensated the body attempts to

compensate because of the chronicity of

the anemia and hemolytic anemia

hemolytic essentially means the body is

destroying the red blood cells and this

leads to these individuals essentially

having chronically low levels of

hemoglobin essentially it's a it's

usually these patients can have

hemoglobin levels from anywhere from 60

to 90 grams per liter the hematocrit is

usually low as well at about 20 to 30%

these patients when you look at a blood

smear the cells can have or the cells

can be polychromatic or have

polychromasia so when you look at them

they can be different colors so on a

blood smear you can see here's some

normal cells and you can see these other

cells that are different colors so

that's essentially what polychromasia

means these individuals can have

reticulocyte ptosis it's about 3 to 15%

of blood cells can be reticulocytes

reticulocytes are just immature red

blood cells so what happens it what is

when the body is destroying through that

hemophagocytic process you're destroying

those sick old red blood cells the body

compensates it starts to try to produce

more red blood cells and releases more

immature red blood cells that's why we

see increased levels of reticulocytes

and another thing you can see in a blood

smear is something called Howell Jolly

bodies and how jolly bodies are these

basal philic nuclear remnants inside a

red blood cell so you can see those as

well when you look at a blood smear in

other chronic complications include pain

usually from the basal occlusion there

can be neurologic deficits in some

patients pulmonary conditions due to

increased risk of infections there can

be renal hypertension osteoporosis

cardiomyopathy due to diastolic

dysfunction hepatic toxicity delayed

puberty reduced growth chronic leg

ulcers and proliferative retinopathy so

not all of these can occur in every

patient but some patients can have some

of these other complications some of

them are due to the basal occlusive

properties of sickle red blood cells so

pain again due to vaso occlusion due

because of pain individuals may not be

as active as other individuals so they

can have decreased bone mineral density

leading to an increased risk of

osteoporosis there can be again chronic

leg ulcers due to some of these basal

occlusive properties as well so how do

you diagnose sickle cell disease well

there's prenatal tests to deter

if a fetus carries sickle-cell alleles

there are newborn screenings to do the

same thing to see if a newborn infant is

carrying a mutated allele for

sickle-cell disease high performance

liquid chromatography can be performed

to assess and also haemoglobin

electrophoresis can be used to diagnose

sickle cell disease and usually it's

either with a cellulose acetate or

citrate agar gel and if you see more

than 30% hemoglobin s in these patients

then you can say okay these patients

most likely have sickle cell disease so

once we diagnose sickle cell disease how

do we treat it well one of the main

State treatments of sickle cell disease

is hydroxyurea hydroxyurea can reduce

episodes of acute pain it can reduce

hospitalization rates and can prolong

survival of patients with sickle cell

disease another possible treatment is

matoke we dick cell transplantation this

is thought to be usually thought to be

the only cure for sickle cell disease

and it's usually performed only in

individuals less than 16 years old and

blood transfusion can be performed in

patients with sickle cell disease

because especially in patients with

severe anemia if they have very low

hemoglobin and because of many of the

symptoms I've mentioned before due to

vaso occlusion and pain management is

very important in patients with sickle

cell disease as well anyways guys that

was a lesson on sickle cell disease I

hope you found this video helpful if you

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videos like this one and as always thank

you so much for watching and I'll see

you next time