Sickle cell disease


Autosomal recessive disorder.

According to the NIH , approximately 100,000 people in the United States have sickle cell disease.

A single gene disorder in which 1 DNA base-pair alteration in the gene coding for hemoglobin produces sickle hemoglobin (HbS) when inherited in an autosomal recessive fashion with the second HbS or when combined with the hemoglobin variants, such as HbC or beta thalassemia.

Clinical severity varies among individuals with SCD, although patients with heterozygote genotype tend to have complications, such as splenic infarction or acute pain episodes later in life, than people who have a homozygous genotype, who often experience complications as young children.

The disease occurs most often in African-Americans, Latinos and other minority groups.

The average life expectancy for patients with sickle cell disease in the United States is approximately 40 to 60 years, or 20 years less than the general population.

Affects one of every 396 black newborns.

About 2000 new cases annually in US.

It is estimated 400,000, affected births, worldwide each year.

Life expectancy in the US is about 54 years.

Young sickle cell patients have increased mortality rates.

The incidence of sickle hemoglobinopathies is greatest in sub-Saharan Africa with more than 300,000 babies with sickle cell disease born annually, representing approximately 1% of births.

Approximately one in for individuals with SCD have no acute care encounters per year and approximately one in  five have three or more per year.

A to T transversion in the sixth codon of the human ß-globin gene.

The sickle mutation occurs when glutamate is replaced by valine and the 6th amino acid position of the beta-globe and chain of the hemoglobin molecule.

Hemoglobin S is a variant of normal adult hemoglobin A that is produced when the beta globin gene contains a single E6V missense mutation.

Transversion changes a polar glutamic acid residue to a nonpolar valine in the ß-globin chain on the surface of HbS (α2 ßS2) tetramers.

Homozygous individuals for ß-hemoglobin (HBB) mutations have HbS and compound heterozygotes for HBB glu6val and glu6lys (HbC) mutations have sickle cell HbC disease.

Valine substitution creates a hydrophobic projection that fits a natural hydrophobic pocket formed on hemoglobin tetramers after blood is deoxygenized.

Results from a single nucleotide substitution in which valine replaces glutamic acid at the six position of the beta-globin chain of hemoglobin A.

Dehydrated red blood cells with high hemoglobin concentration have short lives as they are selectively trapped in the microcirculation during vasoocclusive episodes.

When sickled cells cluster to occlude blood vessels and impair oxygenization veno-occluive disease results and is characterized by pain.

Venoocclusive pain is considered to be more severe than labor pains and has an impact on morbidity and mortality.

On deoxygenation hemoglobin S polymerizes, leading to abnormally shaped red cells and downstream clinical sequelae including painful vaso-occlusive crises, chronic hemolytic anemia, progressive and irreversible organ damage, decreased quality-of-life and early death.

Red blood cell dehydration results from hemoglobin S polymerization and cation transport.

Polymerization of hemoglobin when deoxygenated within capillary beds, distorts the red blood cell into the sickle shape.

Sickled cells different from normal red blood cells with increased adhesion molecules that facilitate binding to endothelial walls, and hemolyze rapidly leading to increases in reticulocyte production and causes local endothelial dysfunction.

Precipitation of HbS causes oxidant damage to irreversibly sickled cells but also in normal appearing cells.

Sickling and the hemolytic characteristics of sickle RBCs incite an inflammatory cascade with interactions of the endothelium, white blood cells and platelets.

Recurrent sickling and hemolysis with endovascular inflammation cause acute and chronic organ damage associated with complications.

The most common complications is vaso-occlusive crisis, in which the occlusion of blood vessels by the sickle cells leads to severe pain.

Vaso-occlusive crisis is the hallmark of sickle cell disease.

Another common complication is acute chest syndrome, which is the leading cause of mortality in sickle cell disease.

Less common complications, include a vascular necrosis, leg, ulcers, stroke, priapism, splenic sequestration crisis, and multiple system organ failure.

The potassium-chloride cotransporter (KCC) system that normally regulates the volume of hemoglobin in the reticulocyte pathologically increases the target hemoglobin concentration and promotes the sickling of reticulocytes.

With hemoglobin S polymerization and deoxygenation a nonselective cation leak activation occurs in a number of sickle cells.

Results in membrane injury with increased red blood cell calcium, which is normally excluded.

Calcium ions in red blood cells activate potassium ion channel causing the efflux of potassium and water, resulting in intracellular dehydration and increased mean cell hemoglobin concentration.

With deoxygenation HbS red blood cell cytosol converts from a freely flowing liquid to a viscous gel and with continued lack of oxygenation aggregated HbS molecules assemble into long needle like fibers within red blood cells, producing sickle shaped cells.

Sickling of red blood cells is initially a reversible process, but with repeated episodes membrane damage occurs and the process becomes irreversible.

Repeated episodes of deoxygenating caused sickled cells to be abnormally sticky.

The interaction of tetramers forms HbS polymers/fibers that cause red blood cells to become rigid, nondeformable and able to occlude small capillaries.

A phenotypically diverse process, with a range of symptoms from none to debilitating.

Vascular occlusive events can cause strokes, splenic infarction, renal failure, liver and lung disorders and pain crises.

The vaso-occlusion with associated ischemia is primarily responsible for acute pain, acute chest pain, and avascular crisis.

Hemolysis related endothelial dysfunction underlies stroke, pulmonary hypertension, priapism, and leg ulcers.

In children with sickle cell anemia, abnormally high flow velocity in cerebral arteries is associated with ischemic stroke, stenoses, and silent cerebral infarcts.

SCD is the leading cause of stroke in children and it occurs in approximately 10% of children with hemoglobin S and hemoglobin S beta thalassemia.

Vasogenic-occlusive crises result in tissue ischemia and infarction with end organ damage.

Acute ischemic stroke in children is usually do to sickle cell related vasculopathy seen on imaging as stenosis or  complete occlusion of major cerebral arteries with the without the development of collateral vessels: treated with emergency RBC each exchange transfusion in which HgbS is reduced to less than 30% or hemoglobin A greater than 70%.

Adults with acute ischemic stroke should be treated with standard therapy.

The risk of ischemic stroke recurrences are decreased by  monthly chronic RBC transfusions for children with Hgb S less than 30%.

Clinical severity varies among individuals with SCD: people who have a heterozygous genotype such as hemoglobin SC disease have complications, such as splenic infarct and acute pain episodes later in life, than people who have a homozygote genotype, who often experience these complications as young children.

Patients often will require hospitalization, high doses of chronic opioids and risk of tolerance and addiction.

Children and adolescents experience 5 to 7 crises per year.

Cycles of red blood sickling cause increased cellular fragility and produces chronic hemolytic anemia.

Leading cause of death and hospitalization is acute chest syndrome.

Half of individuals with sickle cell anemia develop acute chest syndrome at least once.

Leucocytosis, high hemoglobin concentrations and low hemoglobin F levels predispose patients to acute chest syndrome.

Acute chest syndrome is defined as a new infiltrate on chest imaging plus any two of the following: pleuritic chest pain, hypoxemia, tachypnea, or fever.

Acute chest syndrome is managed with attempts to decrease the proportion of hemoglobin S in the circulation by transfusion plus anticoagulants in patients with coincidental thromboembolism, and usually antibiotic.

Most common single gene disorder in black Americans, one in 375 persons.

More than 100,000 Americans the majority of whom are of African, Medit2241anean, Middle Eastern , or East Indian descent are affected.

Hemoglobin SS patients account for 65% of sickle cell disease patients.

More than 300,000 individuals worldwide suffer with the disease.

The 4 most common types of sickle cell disease in the U.S. are SS, SC disease, S-ß+ thalassemia, S-ß ° thalassemia.

Homozygous sickle cell anemia (SS) is the most severe form of disease, but is phenotypically variable.

Some patients have frequent vaso-occlusive complications with premature death, while others have few medical problems and a normal life span.

Vaso-occlusive crisis occurs at a rate of approximately 2 per person year in the absence of treatment.

Vaso-occlusive disease associated with the mean length of hospitalization of 4.5 days for children age 10-14 years.

As many as 20% of patients hospitalized with vaso-occlusive disease develop acute chest syndrome, and that life-threatening lung injury prolongs length of stay to a mean of 14 days. But

About 1 in 4000 babies born in the U.S. have a form of sickle cell disease.

Approximately 8% of American blacks are heterozygous for HbS.

In heterozygous disease only about 40% of hemoglobin is HbS, the remainder being normal hemoglobins.

Diagnosis by hemoglobin electrophoresis, isoelectric focusing or DNA analysis.

Children born in countries with newborn screening programs, may be diagnosed shortly after birth.

Solubility testing methods with Sickledex and sickle cell preparations are inappropriate diagnostic techniques.

In 50 states and the District of Columbia newborns are screened for sickle cell disorders.

Common in Mediterranean countries, Turkey, Arabian Peninsula and the Indian subcontinent.

Sickle cell disease-in children dactylitis, hemoglobin < and leucocytosis predict adverse outcomes later in childhood.

Children who experience dactylitis in their first year of life are more likely to have adverse outcomes in later childhood with more frequent pains, recurrent chest syndrome, stroke and death.

The Cooperative Study of Sickle Cell Disease report that the rate of pain measures clinical disease severity and is correlated with early mortality in adults.

Low hemoglobin associated with increased risk of death in childhood, adulthood and stroke.

acute anemia, in children is most frequently associated with splenic sequestration.

Common problems include acute chest syndrome, pulmonary hypertension, splenic sequestration, gallstones, priapism, leg ulcers, stroke, neuropsychological dysfunction, avascular necrosis of the hip and retinopathy.

Leg ulcers are due to vaso-occlusion of the skin and occur over bony prominences.

The presence of leg ulcers is approximately 8 to 10% in the US.

Sickle retinopathy occurs in nearly all adults with SCD secondary to retinal ischemia, neovascularization and hemorrhage.

Patients may have retinal detachment and central retinal artery infarction.

Hyposthenuria, loss of renal concentrating ability, occurs early in life, and microalbuminuria is common.

RBC, sickling in the renal medulla, and a hypoxemic and acidotic environment may lead to glomerular and tubular damage.

Gallstone disease secondary to RBC hemolysis seen in approximately 12% of young children and 43% at age 15 to 19 years, and the prevalence is high at 75% among adults.

Priapism, defined as a painful erection of more than four hours, affects approximately 40% of males with SCD starting in childhood.

Incidence of leg ulcers in sickle cell disease varies from 8-75% depending upon the geographic location of the patient, genotype of hemoglobin abnormality, age, contribution of trauma to the ulceration, hemoglobin concentration, and accompanying hypercoagulable state, or the presence of a lupus anticoagulant.

In the past the leading cause of mortality was pneumococcal sepsis due to loss of spleen function.

Patients with SCD, have functional asplenia that predisposes them to infection, especially with encapsulated  or atypical bacteria, such as Sreptococcus pneumonia, Neisseria meningitidis, and Haemophilus influenza.

Adherence to childhood and adult vaccination schedules for asplenic patience is a necessity for health maintenance.

Renal disease in sickle disease includes impaired urinary concentrating abilities, hematuria, chronic kidney disease, albuminuria, and end-stage renal disease.

Acute dactylitis is frequently the first evidence of sickle cell disease in an infant.

Dactylitis is associated with painful, usually symmetric, swelling of the hands and feet.

Dactylitis is not seen beyond the age of five, as red bone marrow is not persistent in the hands and feet in later childhood.

Acute bone infarction is associated with acute localized pain, swelling, and fever.

In young children pain most frequently involves the extremities, while in older patients pain in the chest, abdomen, and back are more common.

The most frequent bone and joint manifestations in children are bone and joint pain, osteomyelitis, joint effusion, and septic arthritis with a frequency of 81%, 61%, 14%, and 3.5%.

Osteomyelitis occurs predominately in patients younger than 10 years, whereas avascular bone process is more common in adolescents with sickle cell anemia.

Avascular necrosis occurs due to bone ischemia and affects approximately 11 to 22% of individuals with SCD, and typically involves the hips, shoulders, and spine.

Avascular necrosis may be associated with bone collapse, and join arthroplasty may be necessary in approximately 5% of patients.

The most frequently involved bones with osteomyelitis are the femur and tibia, followed by the humerus.

Osteomyelitis occurs in 18% of patients with sickle cell disease,

Septic arthritis occurs in 7% of patients with sickle cell disease.

Osteomyelitis and septic arthritis occur at a higher incidence in patients with sickle cell anemia related to abnormal blood cells reduce flow in the smallest blood vessels resulting in relative ischemic zones.

Osteomyelitis is most common in the diaphyses of long bones in patients with sickle cell anemia.

There is an increased incidence of salmonella osteomyelitis in sickle cell patients.

The long bones and joints of the lower extremities are more commonly affected, especially in children younger than 10 years of age.

The childhood mortality has been reduced to approximately 6% for HbSS/HbSB-thalassemia and 2% for other types of sickle cell disease.

Mortality is now infrequent until the late teens and early adulthood.

Musculoskeletal manifestations the For up to 80% of hospitalizations.

Orthopedic manifestations account for much of the morbidity associated with sickle cell disease and include pain, osteoporosis, arthritis, and sepsis.

Pain may be acute due to skeletal or soft tissue infarction or chronic as relates to vascular necrosis of bone.

Abnormal erythrocytes can block capillaries resulting in bone infarction in the diaphysis, causing medullary infarcts and in the epiphyses causing the appearance of avascular necrosis.

Bone changes occur due to bone marrow hyperplasia, tissue ischemia, and infarction from the vasoocclusion.

Bone infarction can present as classic painful bone crises.

Higher hemoglobin levels correlate with increased risks of acute chest syndrome and painful crisis.

Between 5 and 30% of adult patients develop pulmonary hypertension.

About 12% of adult patients have EKG evidence of pulmonary hypertension.

The mortality rate is higher in patients with pulmonary hypertension and sickle cell disease, than those without pulmonary hypertension.

In the presence of pulmonary hypertension lower pulse oximetry and severely shortened survival exists.

Endothelial damage from sickling, smooth muscle hypertrophy, and thromboembolic disease contribute to the increased prevalence of pulmonary hypertension.

Cardiac enlargement is frequently part of the clinical spectrum.

The left atrium have left ventricle are significantly increased in more than 60% of children, and especially those older than two years (Ebong WW et al).

Left ventricle ventricular wall thickness is increased in 20% of older children with sickle cell disease.

Median survival for patients with pulmonary hypertension is only 25-26 months after diagnosis is confirmed by cardiac catheterization (Castro).

Approximately 3% of death due to pulmonary hypertension.

Mortality due to pulmonary hypertension independent of the degree and severity of pulmonary hypertension.

A tricuspid regurgitant jet velocity of at least 2.5 m per second, confrming pulmonary hypertension, is independently predictive of an increased risk of death.

In a prospective study of 398 SS patients the prevalence of tricuspid jet velocity of a least 2.5 m per second was 27%, but pulmonary hypertension was confirmed on right heart catheterization was 6% (Parent F et al).

Cardiac disease in sickle cell disease is related to volume overload effects of chronic anemia.

15% of children with the lowest hemoglobin levels have ischemic EKG changes on exercise testing.

Among children with sickle cell anemia silent cerebral infarct are the most common neurologic injury.

Children with sickle cell anemia and a silent cerebral infarct have an increased risk for stroke, new or enlarged silent cerebral infarct, poor academic achievements, lower IQ performance than children with sickle cell anemia who have normal brain MRI or with siblings without sickle cell anemia.

Most common cause of childhood stroke with and incidence of 0.28-0.61%.

By age 18 years 11% will have had an apparent stroke while 15-22% will have had a silent cerebral infarct.

Incidence of stroke in children is 0.61-0.76 events for 100 patient-years and a

cumulative of childhood incidence of 7-11%.

After first stroke, the rate of recurrence or progression is high, even with chronic transfusion therapy.

In children having a stroke, and subsequently receiving transfusions and median of

5.5 years of follow up, had 17.5% incidence of stroke and an additional 27 1/2% had

silent cerebral infarcts (Hulbert M et al).

Children with sickle cell disease with silent cerebral infarcts seen on MRI have lower intelligence quotients than those with a normal MRI.

In the Stroke Prevention Trial in Sickle Cell Anemia (STOP) utilizing prophylactic red blood cell transfusions in children found to have high risk disease for stroke based on transcranial Doppler ultrasonograms reduced incidence of stroke from 10% per year to 1% per year.

Transcranial Doppler ultrasound is associated with a 40% stroke risk within three years in patients with time-averaged mean of a maximum velocity of 200 cm/s or greater, a 7% stroke risk with those with intermediate time-averaged mean of maximum velocity at 170+199 cm/s and a 2% stroke risk with those with time-averaged mean of maximum velocity is less than 170 cm/s.

In the TWITCH trial for primary stroke prevention in children with sickle cell anemia high transcranial Doppler flow velocity of 200 cm/s, the incidence of strokes per year is less than 1% with regular blood transfusion therapy and approximately 10-13% without.

Before screening techniques were available, 11% of children with homozygous sickle cell anemia had ischemic stroke by the 20th birthday.

Most children with sickle cell anemia will have neurological recovery after stroke, but approximately 1/3 will have long-term neurologic sequelae including motor impairment.

Children with sickle cell anemia who have had a stroke often have neurocognitive impairment and difficulties with academic performance.

In the above study transfusion therapy was associated with a 92% relative risk reduction and a 14.8% absolute risk reduction for stroke.

The above study suggests that seven patients needed to be treated for every child with elevated transcranial Doppler measurements with blood transfusions for one stroke to be prevented.

For high risk children with sickle cell anemia and abnormal transcranial Doppler flow velocities who have received at least one year of transfusions and have no MRA defined severe vasculitis, hydroxyurea treatment can substitute for chronic transfusions to maintain transcranial Doppler flow velocities and help prevent primary stroke(Ware RE et al).

Blood transfusion therapy reduces the incidence of infarct recurrence among children with sickle cell anemia who had silent cerebral infarcts (DeBaun MR et al).

Chronic transfusions utilized in patients with eighth history of stroke can reduce stroke by 80-85%.

Chronic transfusions may be required repeatedly to prevent new or recurrent strokes, chronic pain, pulmonary hypertension, acute chest syndrome, cardiac or renal failure.

Chronic pain affects approximately 40% of adults with SCD, and includes nociceptive, neuropathic, and central components.

Opioid use disorder needs to be prevented.

Possible complications of transfusions include hyperviscosity and iron overload.

25% and 10% of patients with SS and SC disease respectively, have had a stroke by age 45 years.

Stroke, particularly in adults, may result in life threatening brain hemorrhage.

The distal internal carotid and proximal middle and anterior cerebral arteries are stenotic or occluded in such patients who have experienced a stroke.

Cerebral flow is markedly increased in such patients associated a response to chronic anemia and chronic hypoxemia.

The most common sites of ischemic stroke are the areas supplied by the anterior and middle cerebral arteries and the border areas between their distal circulations.

When an episode of increased hypoxic stress occurs the cerebrovasculature is unable to undergo further dilation and ischemia occurs in the brain leading to stroke.

In sickle cell centers, the most common indication for chronic transfusion is the prevention of primary stroke in the child at risk based on transcranial Doppler ultrasound with the finding of increased blood flow velocity in the major cerebral arteries.

In severe forms of the disease red blood cell lifespan shortens to 10-16 days from 120 days in the normal person.

Most common reason for acute severe anemia is an infection.

The most common infectious cause of acute severe anemia is the parvovirus B19.

In areas where malaria is endemic in Africa up to 30% of the population are heterozygous for hemoglobin S, and hemoglobin S protects against falciparum malaria.

Patients are deficient in L-arginine the substrate for nitric oxide.

Oral supplementation with arginine results in faster reduction of pain associated with vaso-occlusive episodes among young patients with sickle cell disease.

Increased arginase activity, dysregulated l-arginine metabolism and association with pulmonary hypertension.

Pain may be related to neurogenic inflammation from neuropeptides released from mast cells

When associated with pulmonary hypertension has a high mortality rate.

Pulmonary hypertension associated with anemia, high hemolysis rate, iron excess and systemic vasculopathy.

Elevation of plasma arginine secondary to erythrocyte arginase release during intravascular hemolysis.

Inflammatory changes, hemolysis and end-organ damage are sources of increased arginase activity.

Greater than 90% of patients have elevated arginase levels and two-thirds have increased plasma and red blood cell lysate arginase activity.

Characterized by a state of nitric oxide resistance.

Inhaled nitric oxide has been shown to decrease pain, opioid usage and a reduction in length of hospitalization and sickle cell disease (Wiener DL et al).

In a prospective, double-blind, randomized, placebo controlled clinical trial with 72 hours of inhaled nitric oxide gas versus inhaled nitrogen placebo in 150 participants with vaso-occlusive crisis with sickle cell disease: nitric oxide compared with placebo did not improve time to crisis resolution (DeNOVO Investigators).

Pulmonary hypertension common in children and adults and is n important predictor of increased mortality.

30-60% of pediatric patients with sickle cell disease have reactive airways disease.

All types of disease have extremely variable phenotypes with some individuals having a mild process which can be clinically inapparent, while others have severe processes with pulmonary hypertension, priapism, strokes, painful crises, leg ulcerations, acute chest syndrome, and avascular necrosis of the bone.

Intensity of hemolysis associated with pulmonary hypertension, priapism, leg ulceration, and stroke.

Increased systolic blood pressure increases the odds of death by 3.4 and is a marker of early death in this disease.

Pregnancy is associated with increased maternal and neonatal complications: preeclampsia, UTI, low, birthweight, acute chest syndrome, acute pain episodes, high rates of DVT and pulmonary embolism.

Hydroxyurea is typically discontinued during pregnancy and breast-feeding.

Because SCD has hypercoagulability, estrogen containing contraceptives are avoided and barrier methods and progestin only contraceptive are preferred.

Hypogonadism is common in males at about 24% with low testosterone, infertility, erectile dysfunction and poor libido.

Sperm abnormalities may occur in his many is 90% of men with S CD, secondary to testicular infarction or hypogonadism.

Prophylactic RBC transfusions during pregnancy, is associated with lower rates of maternal and perinatal mortality.

Hydroxyurea is used to increase fetal hemoglobin levels.

Hydroxyurea is a ribonucleotide reductase inhibitor that induces fetal hemoglobin production, which is normally suppressed shortly after birth.

Hemoglobin F inhibits hemoglobin S polymerization, reducing red blood cell rigidity and hemolysis, thereby improving anemia.

Hydroxyurea also increases nitric oxide of potent vasodilator, decreasing rate, cell adhesion, and decreases leukocytes which contribute to vaso-occlusion.

Short-term hydroxyurea therapy can result in a substantial reduction in the frequency of painful episodes and acute chest syndrome.

Long-term therapy with hydroxyurea can result in reduced mortality.

Hydroxyurea therapy be offered in children beginning at 9 months of age, including those who are asymptomatic.

Fetal hemoglobin inhibits sickle hemoglobin polymerization, reducing erythrocyte injury, increasing red cell lifespan, and reduces reticulocytosis.

Sickle cell anemia patients have greater risk of death compared with sickle cell anemia and concurrent α-thalassemia and with HbSC disease.

Presently, allogeneic hematopoietic stem cell transplantation is the only curative procedure.

Hematopoietic stem cell transplantation can be curative and is recommended:

For patients who have overt stroke or abnormal transcranial Doppler examinations

For patients with frequent pain and inadequate response to standard therapies

Suggested for patients with recurrent acute chest syndrome

Suggested for patients who are younger rather than older.

Survival of children given hematopoietic stem cell transplant results in a disease free survival rate of 95%(Bernaudin F).

Transplantation with allogeneic hematopoietic stem cells result in the donors cells completely replacing those of the recipients, however in some cases, both recipient and donor cells persist, a mixed chimerism, and this mixture is sufficient to reverse the sickle cell disease phenotype (Walters MC).

In a study of 10 adults treated with a non-myeloablative transplantation with CD34 positive peripheral blood stem cells from HLA matched siblings treated with 300 cGy of total body irradiation plus alemtuzumab before transplantation, and sirolimus afterword; results. All 10 patients alive at a median follow-up of 30 months after transplantation and nine patients had long-term stable, donor lymphohematopoietic engraftment sufficient to reverse sickle cell disease(Hsieh M).

Successful engraftment in stem cell hematopoietic transplants in children with sickle cell disease ranges from 91.5 to 95.5%.

Young patients with symptomatic SCD who have an HLA-matched sibling donor should be transplanted as early as possible, preferably before school age, as thee importance of early transplantation has long been well recognized.

Limitations of allogeneic hematopoietic stem cell transplantation is higher risk of complications in older the patients, a risk of severe graft versus host disease, and lack of available matched sibling in approximately 80% of cases.
Gene therapy with LentiGlobin for sickle cell disease (lovotibeglogene autotemcel consists of autologous transportation transplantation of the patient’s ownhemopoietic stem cells introduced with the BB305 lentiviral vector encoding thebeta globin gene which is designed to produce antisickling hemoglobin A.
Gene therapy with LentiGlobin for sickle cell disease leads to reduced hemolysis and complete resolution of severe vaso-occlusive events.
Lentviral vector (LentiGlobin) infused engineered cells modifying them so they can produce more fetal  hemoglobin or express  fetal  like hemoglobin changes containing a glutamine residue in place of threonine at position 87 creating hemoglobin A t87q.
The production of high levels of polymerization blocking hemoglobin by engineered autologous hematopoietic stem and progenitor cells can reverse the common complications of sickle cell disease.
It is suggested that if the hemoglobin of each erythrocyte consisted of approximately 30% fetal hemoglobin, the complications of sickle cell disease would be prevented or reversed: cell based gene therapy can achieve this goal.

Goal of chronic transfusions is to keep hemoglobin SS at 30-50% from as high as nearly 100% to prevent spontaneous sickling and thrombosis.

Associated with a high prevalence of thrombotic complictions, making it a hypercoaguable state.

Thromboprophylaxis should be considered for hospitalized children and adults.

Associated with chronic activation of coagulation with increased plasma levels of markers of thrombin and fibrin generation, including thrombin-antithrombin, complexes, prothrombin fragment, fibrinopeptide A,D dimers and plasmin-antiplasmin complexes.

Estimated 90% of patients with sickle cell anemia require red blood cell transfusions to prevent complications.

For acute pain crisis the American Pain Society guidelines recommend parenteral analgesics should begin within 30 minutes of arrival at a emergency center.

Acute pain episodes, also known as pain crises, are the most common complications of sickle cell disease.

Acute pain crises consist of severe, unrelenting, bone pain.

Severe pain episodes, often require care in the ED department for analgesia with parenteral opioids, with or without nonsteroidal anti-inflammatory agents.

Faster administration of analgesics result in lower hospitalizations.

Prasugrel an adenosine diphosphate antiplatelet agent had no significant reduction in pain in the vasoocclusive crises in patients with sickle cell anemia.

Treatment with etavopivat, a small molecule activator of erythrocyte pyruvate kinase (PKR), improved anemia and decreased intravascular hemolysis in patients with sickle cell disease (SCD) treated for up to 12 weeks. 

Studies have demonstrated that etavopivat resulted in decreased levels of 2,3-disphosphoglyceric acid (2,3-DPG) and increased levels of adenosine triphosphate (ATP) in red blood cells (RBCs) of healthy volunteers and patients with SCD. 

In the present analysis, researchers evaluated the effects of etavopivat in two-week multiple ascending dose (MD) cohorts and a 12-week open-label study.

20 patients were randomized 8:2 to receive etavopivat 300 mg then 600 mg or placebo once daily for two weeks. 

Among patients treated, 73% achieved a hemoglobin (Hb) increase of ≥1 g/dL from baseline, with an average increase of 1.1 g/dL. 

In addition, decreases in absolute reticulocyte count (ARC), indirect bilirubin, and lactate dehydrogenase (LDH) were observed.

Etavopivat enhanced survival of sickle RBCs and significantly improved the severe anemia associated with SCD.

Of the patients in the open-label cohort who had completed 12 weeks of treatment, five (83%) achieved an Hb increase of ≥1 g/dL from baseline. 

The etavopivat-treated RBCs  had improved functional health, including point of sickling and deformability.

These long-living red blood cells have improved membrane health that may further reduce the risk of vaso-occlusive crises [VOC] and end-organ damage.

Etavopivat was well-tolerated.

L-glutamine is an oral amino acid supplement with properties that decrease reactive oxygen species in red blood cells, thereby reducing sickling and RBC adhesity.

In patients five years and older L-glutamine reduces acute pain crises by 25%, hospitalizations by 33%, and mean length of hospital stay from 11 to 7 days.

L-glutamine should be prescribed in patients with at least two pain crises pre-year, despite hydroxyurea, and those unable to take hydroxyurea.

L-glutamine by oral administration reduces hospitalizations and has fewer associated acute chest syndromes but has a high discontinuation rate.

Crizanlizumab is an intravenous human mono clonal antibody that binds to P-selectin and  binds with its ligand.

P-selectin, and adhesion molecule found on the surface of the endothelium and is involved in the adhesion of sickle erythrocytes to the vessel surface.

Crizanlizumab reduces venous occlusive episodes.

High doses of Crizanlizumab reduce pain crises, and it should be appropriately prescribed in patients who have more than two pain crises despite hydroxyurea or for individuals unable to take hydroxyurea.

Voxelotor is an oral small molecule that binds to alpha globulin chains of hemoglobin, increasing hemoglobin oxygen affinity and inhibits the polymerization of sickle hemoglobin.

Voxelotor stabilizes the oxygenated state of hemoglobin in SCD, by promoting hemoglobin S binding to oxygen, decreasing sickle hemoglobin, polymerization and related hemolysis.

In sickle cell anemia it provides a modest increase in hemoglobin from within 50% of patients.

Voxelotor use is appropriate for use in patients with low, hemoglobin level and more than one pain crisis per year, despite hydroxyurea.

CRISPR-Cas9 CD34 cell targeting of the BC11A transcription factor increases fetal hemoglobin.

Casgevy-CRISPR Cas9 Gene editing treatment increases fetal hemoglobin levels, helps fetal hemoglobin stop red blood cells from sickling, improves blood flow and prevents painful vasal, occlusive crisis.

Lyfegenia CRISPR Cas9 Gene modifies blood stem cells to produce a form, hemoglobin similar to hemoglobin a but, like fetal hemoglobin, is less prone to sickling.

Xagamglogene autotemcel cell (exa-cel)is a non-viral cell therapy designed to reactivate fetal hemoglobin synthesis by means of ex vivo clustered, regularlyinterspersed, short palindrome repeats (CRISPR)-CAS9 gene editing of autologous CD34 positive in hematopoietic stem and progenitor cells at the erythroid specific enhancer region of BCL11A.

Treatment with exa-cel eliminated vaso-occlusive crisis in 97% of patients with sickle cell disease for a period of 12 months or more.




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