Sickle Cell Disease
Under stress, tissues require more oxygen
This causes more hemoglobin to release its oxygen, leading to increased numbers of deoxygenated and polymerized cells.
Sickle cell disease occurs when:
Two sickle cell genes are inherited (one from each parent) One sickle cell gene and another abnormal hemoglobin is inherited, so that almost all of the hemoglobin is abnormal
Acute clinical manifestations of sickling are called crises or episodes, and usually fall into one of four categories:
Vaso-occlusive or thrombotic Aplastic (bone marrow suddenly stops producing RBCs, which result in sudden and severe anemia) Sequestration (happens when a lot of sickled red blood cells become trapped in the spleen) Hyperhemolytic (rare)
. Hyperhemolysis
develops in some patients as a consequence of the formation of alloimmune responses to erythrocyte antigens. Results in a delayed transfusion reaction with significant acute hemolysis of erythrocytes.
Occlusion of the microcirculation
increases hypoxia, which causes more erythrocytes to sickle, and a vicious cycle is perpetuated
Deoxygenation of sickle cells
induces potassium efflux (followed by water) from the erythrocyte. This increases cell density and the tendency of hemoglobin S to polymerize
Decreased postnatal hemoglobin F
inhibits sickling
Hemolysis of RBC (Chronic intravascular damage)
inhibits the production of nitric oxide, thus blocking the beneficial effects of nitric oxide, resulting in vasoconstriction
Heterozygous hemoglobin SC
is a result of inheriting one sickle cell gene and one gene for another abnormal type of hemoglobin called C.
Accumulation of sickled erythrocytes obstructing blood vessels
produces acute and chronic tissue injury.
Infarcts can also occur
in the microvascular
Average sickle cell life
10 - 20 days (normal is 120 days). Erythrocytes cannot be replaced fast enough, and anemia is the result.
Stroke occurs in
11 percent of sickle cell disease patients younger than 20 years old, causing death or severe disability. Large vessels can become stenosed through chronic injury to the endothelium
Sickle cell disease
Autosomal recessive disorder characterized by the presence of an abnormal form of hemoglobin, called hemoglobin S within the erythrocytes.
The most severe complication of sickle cell disease
Cerebral infarct, which occurs in the large blood vessels, where blood moves rapidly and the vessel diameter is wide.
Two primary pathophysiologic features of sickle cell disorders are:
Chronic hemolytic anemia resulting in ischemic injury Vasoconstriction resulting in ischemic injury
Hemoglobinopathies
Diseases resulting from an abnormality in the formation of hemoglobin. Since hemoglobin is essential for life, anomalies in the shape, size, content or oxygen-carrying capacity can lead to severe problems.
Heterozygous hemoglobin SC people
Exhibit more ophthalmological and orthopedic complications, because of their increased blood viscosity.
Presents with low-grade fever and symmetric, painful, diffuse, non-pitting edema in the hands and feet, extending to the fingers and toes
Fairly common phenomenon seen almost exclusively in the young infant and child
the faster the polymerization occurs
Higher the concentration of deoxygenated sickled hemoglobin molecules and the lower the blood pH
Symptoms are similar to that of strokes in patients without sickle cell disease
Includes paralysis, weakness, speech difficulties, seizures, and tingling/numbness of extremities.
In sickle cell disease, not only are the hemoglobin cells abnormal but so are the blood vessel walls
Likely due to sickled cells adhering to and damaging endothelium, which leads to an inflammatory response of the leukocytes, cytokines, chemoattractants, and procoagulants. Over time, smooth muscle cells migrate into the vessel wall, where they proliferate and narrow the lumen of the vessel.
Many cognitive effects from these microvascular strokes result in learning problems. Children demonstrate problems with:
Memory, attention, visual motor performance, and academic or social skills Neural motor delays Mild hearing loss, and auditory processing disorders Failed speech and language screening
Autosplenectomy
Over time, the spleen is severely damaged and becomes completely fibrotic
complications for ppl with sickle cell disease can be decreased by protective measures such as:
Prophylactic penicillin in children (until about age 5 years) Maintaining current vaccinations (pneumococcus, meningococcus, Haemophilus influenzae type b, hepatitis B virus, annual vaccination against influenza virus) Avoidance of excessive heat or cold and dehydration Early contact with a specialist center. Precautions are most effective if susceptible infants are identified at birth.
Acute chest syndrome:
Results from the inability of sickled cells to become reoxygenated in the lungs. Sickle cells adhere to the lung endothelium cells, cause more inflammation, occlude vessels, and result in infarction. Symptoms include chest pain, shortness of breath, fever, wheezing, and cough. Chest radiographs typically demonstrate infiltrate, sometimes days after the symptoms began. Prognosis is poor and is one of the most common causes of death. Most common precipitants are infection, fat emboli (from infarcted bone marrow), and infarction.
Organs at greatest risk are those with:
Sluggish circulation, low pH, and a high level of oxygen extraction (spleen, bone marrow) Limited terminal arterial supply (eye, head of the femur). No tissue or organ is spared from this injury
Risk factors that cause physiologic stress, resulting in sickling of the erythrocytes
Stress from viral or bacterial infection Hypoxia Dehydration Extreme temperatures hot or cold Alcohol consumption Fatigue may precipitate an episode.
Rods cause the normally smooth, donut shaped erythrocytes to:
Take on a sickle or curved shape Lose their ability to deform and squeeze through tiny blood vessels
Irregular form of hemoglobin
a single mutation in the beta hemoglobin chain where the amino acid, glutamate acid at position 6, is substituted with valine.
Life threatening thrombotic complications associated with sickle cell disease
are acute chest syndrome and stroke
Children with sickle cell disease
are at increased risk for severe morbidity and mortality, especially during the first three years of life
Sickle cell disease and thalassemia
are the hemoglobinopathies with the most potential for serious complications.
For a limited amount of time, this sickling is reversible
because the cells are re-oxygenated in the lungs
Sickled cells
become stiff and sticky, clog small blood vessels and deprive tissue from receiving an adequate blood supply
Since sickle cell disease is inherited as an autosomal recessive trait
both parents of an offspring must have the hemoglobin S gene for the child to have the disease.
Sequestration can occur in the liver
but less frequently than splenic sequestration.
Pulmonary hypertension (that more than 1/3 of people with sickle cell disease develop pulmonary hypertension)
can be a severe consequence of repeated microthrombotic events in the lung, even without a history of acute chest syndrome.
Significantly narrowed or stenotic arteries
can collect sickled cells, thereby occluding the lumen and resulting in stroke
Hypovolemic shock
can occur, particularly in children, accompanied by a tender spleen and splenomegaly. Sequestration episodes are precipitated by infection and can be fatal in children.
Presence of hemoglobin S
causes RBCs to change shape from concave to a crescent (sickle) shape when oxygen is released (deoxygenated) from hemoglobin.
Jaundice
common manifestation of sickle cell disease. Since sickled cells do not live as long as normal cells, they die more rapidly than the liver can filter them. Bilirubin from these broken down cells builds up in the system, causing jaundice.
In the process of sickling and unsickling
erythrocyte membrane becomes damaged and the cells are removed (hemolyzed)
Affected persons with intravascular damage from sickled cells
exhibit symptoms of right heart failure (edema, renal insufficiency).
Older clients with sickle cell disease often report
extremity and back pain during vascular episodes
Hemoglobin F or fetal hemoglobin
found in infants
Beta thalassemias
genetic mutations that destroy production of the beta-globin subunit of hemoglobin.
DNA recombinant technology
has identified the genetic locus for the beta-globulin on chromosome 11
When both parents have sickle cell trait
have a 25 percent chance with each pregnancy of having a child with sickle cell anemia.
People with heterozygous hemoglobin SC
have fewer complications than people with homozygous hemoglobin S.
Children with severe manifestations of sickle cell anemia
have low bone mineral density and possess significant deficits in dietary calcium and circulating vitamin D, which complicates growth.
Spleen
is very susceptible to thrombotic occlusion (low blood flow, low oxygen tension, low pH). In sequestration episodes, large numbers of cells undergo sickling in this organ, leading to ischemia, acute hemolysis, and necrosis of this organ. this organ is destroyed in most children with sickle cell disease
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Acute obstruction and resulting inflammation
lead to further hypoxia and acidosis, and a vicious cycle of continued sickling.
Increased production of hemoglobin S
leading to the increased concentration of hemoglobin S
Intravascular sickling and hemolysis
may begin at 6-8 weeks of age. Clinical manifestations do not usually appear until the infant is at least 6 months old.
Normally, when hypoxia is present
nitric oxide is produced to cause local vasodilation, inhibit endothelial damage, and prevent proliferation of vascular smooth muscle.
Narrowing arteries cause
occluding of the vessel (by a clot made of sickle and normal cells, leukocytes, platelets, thrombin) causing a cerebral infarct.
Sickle cell defect
occurs in hemoglobin (oxygen-carrying component of erythrocytes). Hemoglobin contains four chains of amino acids Two of the amino acid chains are alpha-globin chains, and two are beta-globin chains.
Ischemic reperfusion injury
occurs including endothelial cell damage, platelet clumping, releases cytokines, and the attraction of granulocytes, macrophages, T cells, and NK T cells to the site.
Homozygous hemoglobin SS
occurs when an individual inherits two sickle cell genes.
Most common symptom of sickle cell disease
pain caused by sickled erythrocytes (thrombosis) blocking blood flow
Sickle cell trait
people who carry only one hemoglobin S gene.
After hemoglobin electrophoresis and other measurement are done on both prospective parents
people with sickle cell trait can receive nondirective genetic counseling
Priapism
prolonged erection of the penis --> thrombotic complication that requires immediate medical attention. Repeated and prolonged episodes can lead to impotence. Kidneys exhibit thrombotic complications and slowly lose function, end-stage renal disease can occur.
Heterozygous hemoglobin S beta thalassemia
results from inheriting one sickle cell gene and one gene for a type of thalassemia
Single point mutation of valine for glutamic acid
results in a loss of two negative charges that then cause RBC abnormalities
Stroke or cerebral infarction
serious thrombotic complication of sickle cell disease. By the age of 45, 24% of people with sickle cell disease will have experienced a ___.
Although most infants switch to making alpha and beta hemoglobin
some continue to make hemoglobin F (called hereditary persistence of hemoglobin F.
Sickle cell disease causes
stroke, hypertension, and a decrease in nitric oxide production by the endothelial cells.
After repeated cycles of sickling and unsickling
the RBCs are permanently damaged and hemolyzed (destroyed) . -hemolysis is responsible for the anemia that is characteristic of sickle cell disease.
In normal hemoglobin
the amino acid in the sixth position on the beta-globin chains is glutamic acid
In people with sickle cell disease
the amino acid in the sixth position on the beta-globin chains is valine
When sickled cells reoxygenate
the cell resumes its normal shape
If one parent has sickle cell trait and the other has hemoglobin C trait
the chance of having a child with hemoglobin SC disease is 25 percent with each pregnancy.
Sickled hemoglobin transports oxygen normally. After releasing oxygen
the hemoglobin molecules that contain the beta-globin chain defect stick to one another (instead of remaining separate) Hemoglobin then polymerizes (changes molecular arrangement), forming long, rigid rods or tubules inside the erythrocytes.
If one parent has sickle cell disease and the other has sickle cell trait
the risk of having a child with sickle cell disease is 50 percent.
Despite radiographic changes and swelling
the syndrome is almost always self-limiting, and the bones usually heal without permanent deformity.
If one parent has sickle cell trait and the other has beta thalassemia disorder
they have a 25 percent chance of having a child with the sickle beta thalassemia syndrome.
If a person inherits one sickle gene and the hereditary persistence of hemoglobin F
they make alpha2 gamma2 hemoglobin, and do not develop severe symptoms of sickle cell disease.
Eventually, small vessels become thickened and blocked by
thrombin and fibrous tissue with the loss of the vascular bed.
Sick cell disease occurs
unpredictably in any organ, bone, or joint of the body, wherever and whenever a blood clot develops
Some of the complications associated with sickle cell disease are treated with transfusions
which can result in iron overload
Vasoocclusive episodes
which cause ischemic tissue damage may last 5-6 days, require hospitalization, and subside gradually
Thrombotic complications include hand and foot syndrome (dactylitis)
which occurs when microinfarction (clot) involves the blood vessels that supply the metacarpal and metatarsal bones, causing ischemia. This may be an infant's first problem caused by sickle cell disease.
