Sickle cell Anemia
Sickle cell anemia is one of a group of disorders known as “Sickle cell disease”. This anemia is due to an inherited red blood cell disorder in which the red blood cells are inefficiently carrying the oxygen throughout the body. They lose their shape and “sickle” resembling to a crescent moon. They become unable to circulate freely into the lumen of the small blood vessels to carry the oxygen and get entrapped. There is no cure although recently many studies have shown progresses with bone marrow transfusions and treatments has relieved pain and prevent more complications.
Sickle cell Disease (SCD) is inherited from a parent suffering from the disease. The hemoglobin in the red cell become defective and unable to carry the oxygen. Then the red blood cells lose their flexibility and sickle. This phenomenon is first seen around the age of six months, manifested by pain and swelling to the hands and feet (Hands and Feet syndrome) and such painful episodes are called a Sickle cell crisis. Bacterial infections, anemia and even a stroke may complicate the picture while the patient get older. The life expectancy is in the 50’s.
When a person inherits one deficient copy of the Beta Hemoglobin gene from a parent he/she will have the “Sickle cell disease”. These genes are closely bounded to the chromosome 11. There may be several subtypes depending on the mutation. The one having the disease can manifest symptoms under stress, dehydration and high altitude. When a person benefits of one deficient copy of the Beta Hemoglobin gene from only one parent, he/she may generally lack the symptoms of pain or occasionally have mild discomfort. They are called “carriers” and said to have the “sickle cell trait”. A diagnostic blood test can determine easily the difference. There are countries where all babies are tested at birth.
The best way in treating patients suffering from sickle cell disease is to prevent infection with proper vaccination, antibiotics, folic acid, high fluid intake and occasionally pain medication. In time of crisis, blood transfusions and hydroxyurea may be needed. As discussed earlier, a small amount of people suffering from the disease can see a cure when they benefit from a transplantation of bone marrow. A little more than 4 millions of people in the USA are known to have the disease while more than 40 million carry the trait. It was determined in 2015 that around 4.4 million of people may have the disease and up to 45 million may have the trait. India, the sub-Saharan Africa, India and other of African descent have contributed to 115,000 deaths. This is in 1910 that an American physician James B Herrick described the disease. Later in 1954, the genetic transmission was demonstrated by J. Neel and E Beet.
The clinical symptoms of Sickle Cell Disease (SCD) manifests early in childhood. Although in the early six months, infants are protected largely by their elevated levels of Hb F. Soon thereafter, the condition becomes evident. The most common clinical manifestation appears in vaso-occlusive crisis due to an obstruction of the microcirculation by the sickled red blood cells creating an ischemic injury to any organ and resulting in pain. These crises which represent the most distinguishing feature of sickle cell disease, lead to emergency room visits and hospital admissions. About half of the individuals with homozygous Hb S will develop 5 or 6 vaso-occlusive crisis a year generally starting with sudden pain involving bilaterally the hands and the feet, lasting hours or days. The pain can affect any body part like the abdomen, the bones and joints or the soft tissues. Typically, in the early childhood, it will involve the hands and feet creating a “Dactylitis” (Hands and Feet syndrome) in the first 18 months to the first three months of life. The severity can vary from person to person. As the child grows older, the pain may involve later the longer bone of the extremities. The metacarpal and the metatarsal bones can present cortical thinning and even bone destruction almost a month after the swelling began, forcing a differential diagnosis of osteomyelitis. Dactylitis is not seen after the age of 5 because the hematopoiesis in the small bones of the hands and feet has ceased. The disease will manifest by a multitude of acute or chronic episodes of pain. The more crisis, the more complications leading to a high mortality rate among the one suffering from the disease.
The one suffering from Sickle Cell Disease appears to have a protective effect against the plasmodium of the Malaria. Repeated painful crisis will result in an anemia due to a vaso-occlusive phenomenon varying between a crisis vaso-occlusive, anaplastic or hemolytic. Most crisis last around a week and often dehydration, acidosis or infection can be the predisposing factors. A vaso-occlusive crisis is manifested when the red blood cells lose their shape and get trapped in the capillaries obstructing the flow of blood to a specific organ. Pain due to necrosis and ischemia to a specific organ will result. The spleen will repeatedly be subject to infarct and individuals will develop an ‘auto splenectomy” predisposing the one suffering from the disease to life-threatening infections. Splenic sequestrations occur in the first 5 years of life in the patients suffering from sickle cell disease but can be seen at any age in the other sickle syndromes. A life-threatening anemia with an enlargement of the spleen at high reticulocyte count. This is a medical emergency in which an early recognition with aggressive blood transfusion will save life. The parents should be familiar to the syndrome because it tends to recur. Many may also advocate long-term transfusions or early splenectomy in older children. The liver may infarct and progress to failure. The Kidney may develop also a papillary necrosis leading to an inability to concentrate urine (Isothenuria} and resulting in a large loss of water contributing to dehydration. Renal failure may also be a complicating factor initiated by a massive proteinuria in a nephrotic syndrome coupled with deep long bone pain. Bone pain is generally due to bone marrow infarction. A precipitating cause is not always discovered but Hypoxemia with respiratory complications, Dehydration, Fever and Hemo-concentration can all trigger a common mechanism creating a shift of the oxygen dissociation curve (Bohr effect). Many individuals may have a relief in their chronic pain, mainly involving the bones and joints.
Anemia is universally present under the form of a chronic and hemolytic anemia generally well tolerated. Many patients with a Hb level of 7 g/dl are able to participate in their daily life activities and their tolerance for exercises tend to be limited. Anemia can bring megaloblastic changes secondary to a folate deficiency resulting in an increase in the red cell turnover precipitating occasional hyper-hemolysis. Children in playground may have an increase in the heart rate and the stroke volume which can be noted while they are participating on the playground or during gym activities. A more serious complication is caused by a Parvovirus B-19 (B19V) infection, responsible of the “Aplastic Anemia”. This infection infects the RBC progenitors in the bone marrow itself, impairing the cell division and causing a drop in the hematocrit by creating a short life span to the normal erythrocytes and a rapid drop in the hemoglobin. This is a self-limited condition with fever, malaise and a mild rash with the bone marrow recovering in around ten days to produce more reticulocytes.
The more the HbS replaces the HbF, the more the sickling phenomenon start damaging the red cell membrane and other organ like the spleen is attacked (asplenia). rendering the individual to be prone to bacterial infections. like Streptococcus Pneumoniae with a 25% mortality rate. Dactylitis have been found to be complicated by Osteomyelitis after vaso-occlusive pain. Salmonella infections was also found to be dominant but one of our clinical papers at Howard University Hospital has clearly demonstrated that the Staphylococcus was more predominant. (Reference # 6 Epps, D’Orsay, Coles, Castro in the JBJS).
During childhood and adolescence, the disease is associated with growth retardation, delayed sexual maturity and a tendency for patients to being underweight. Some have demonstrated a relation between the growth rate independently associated to a decrease in the Hb concentration and an increase in total energy expenditure. Males were shorter than their counterpart. The Central Nervous System involvement in Sickle cell disease has a devastating effect on the life of the one suffering from Sickle Cell. It is manifested by strokes and different levels of neurological defects in 30% of children. It can be ischemic among children while it is more commonly hemorrhagic in the adult. They will manifest with a hemiparesis or may have additional convulsions depending on the location of the infarct. Convulsions can be isolated or associated with the stroke, pain crisis, aplastic crisis and even priapism. Any rapid transfusion aiming at restoring a hemoglobin level to 12 g/dl may contribute to more stroke because of an increase in the blood viscosity. Some children may have silent infarcts associated with a deterioration of the cognitive function bearing negative effects on their ability to act with possible changes in behavior. Finally, a hemorrhagic stroke can be seen with rupture of aneurysm resulting in a vascular injury or a cerebral hemorrhage reaching at time a 30% rate of death.
In young children, a “syndrome” called “Acute chest syndrome “is described, consisting in Chest Pain, Fever, Cough, Tachycardia, Leukocytosis with pulmonary infiltrates involving the upper lobes. Adults are generally afebrile but dyspneic with intense chest pain. This is also a medical emergency which need prompt medical treatment or an acute respiratory distress syndrome will impose more complications. It is believed that the syndrome starts with an infarction of the ribs leading to an atelectasis although it may be difficult to recognize it immediately. Infections in children, Fat emboli from bone marrow infarction or Pulmonary Infarction can precipitate the syndrome. Chronic anemia and micro-infarcts will enlarge the heart especially when hemolysis and blood transfusion lead to hemosiderin deposition into the myocardium, dilating both ventricles. Researchers have found that coronary artery dilatation in often seen as well as coronary artery ectasia (17%). Finally, a systolic murmur is generally present with wide radiation to the pericardium.
The blood in the pulmonary circulation is deoxygenated and the lungs develop many islands of micro-infarction and micro-thrombi resulting in a lack of oxygenation of the pulmonary tissue which aggravate the sickling process. A pulmonary hypertension sets up partly because of the depletion of nitric oxide. Shortness of breath with decrease in exercise tolerance and even episodes of syncope can result. This hypertension worsens with age in more than 30% of the patients. Even familial clustering of the condition has been recognized with subsequent Hypoxia, coupled with Asthma, recurrent chest syndrome, obstructive sleep apnea being contributing factors. On echocardiography it is recognized that one can predict a tricuspid “regurgitant” jet velocity in almost 25% of the cases bearing a high mortality rate in the adulthood. Children suffering from the pathology appears to enjoy a lesser mortality rate although both children and adults may show evidence of pulmonary hypertension even if one is walking a short distance.
A common finding in children with Sickle Cell Disease is their ability to form common bile stones following a chronic hemolysis with hyperbilirubinemia. Often asymptomatic, they may manifest in an acute cholecystitis requiring surgical intervention. The common bile duct can become obstructed and the liver itself can be involved in the process with right upper quadrant pain and jaundice. We remember well as a surgical resident the way a referred right shoulder pain was a pointer to a biliary colic through the irritation of the diaphragm. A well-known fact in those patients is that often they will not produce any biliary stone but a “sludge” will be present able to create an obstruction of the common bile duct. Just in a parenthesis, people with sickle cell disease are not the only one developing this sludge. Sludge can be also seen in Native American Indians, in diabetics more commonly in women than men. It can be found also in people who had benefited from an organ transplant.
Patients can develop a peri-orbital infarction resulting in a ptosis but also retinal changes can be observed. A proliferative retinitis may lead to a loss of vision. I will have one of our ophthalmologist in the AMHE find time to elaborate on the subject. Leg ulcers can represent a chronic but painful problem originating from minor injuries around the malleolae or the leg and because of the poor circulation, micro-infarcts with the sickling phenomenon will delay the healing process and set up the wound for possible infections.
Sickle cell patients are known to have a well-recognized but poorly understood complication in Priapism. This is an unwanted, and persistent but painful penile erection which if prolonged can lead to impotence. It can appear as early in a young 12-year-old gentleman but is more frequently encountered around the age of 20. It is believed that almost 90% of male with sickle cell disease will have experienced by this age at least one episode or more of priapism. Such erection is considered as “prolonged: if it last more than 3 hours or as “stuttering” if it only lasts few minutes.to an hour. Priapism is considered as an emergency requiring a urologic consultation. Recurrent episodes can lead to fibrosis of the cavernosal tissue and impotence when adequate treatment is not administered on time. Although current technologies to prevent progression are poor because of a lack of fundamental understanding in the molecular mechanism observed in the penile fibrosis, a novel causative factor “Adenosine” is believed to be related to the fibrosis. This has been demonstrated experimentally in mice by the action of the “Adenosine” on the tissue.
30% of patients with the disease will develop hip pathology around the age of 30. Avascular Necrosis involving the femoral head or the humeral head is a striking consequence of complications due to a vascular occlusion of the nutrient artery. Infarction will follow impending on the ability to ambulate. The head will collapse. In the upper extremity, because the humerus is not a weight bearing joint unless the patient is a lower extremity amputee, the disability may be overlooked. The avascular necrosis can be seen in younger patients as well and conservative treatment can be offered with analgesics like Aspirin or anti-inflammatory medication, protected weight bearing with crutches or walker to allow a remodeling process of the femoral head. A similar vascular disease is seen with Legg Calve Perthes disease but often these patients will develop further angular deformities like Coxa Vara or Coxa Valga, progressive deformity of the head and further collapse which may result in degenerative arthritis. We have experienced the failure of a metallic Hemi-arthroplasty in combining metal with newer prosthetic devices like Titanium or combined with Ceramic component to bring relief to the suffering of such patients.
Hydration, pain medication or blood transfusion is the best way in resolving the crises. An opioid drug may be chosen as well to help in pain control. Non-steroidal anti-inflammatory medications like Naproxen, Diclofenac can be sufficient to ease the discomfort but more severe intravenous opioids may be required. In patients with frequent and painful crisis, an admission to the hospital for a controlled analgesia device, is often necessary. The lungs especially are prone also to the vaso-occlusive crisis necessitating red blood cell transfusion. Breathing exercises are encouraged with Incentive spirometry to fight the atelectasis.
We have seen already the way the spleen become defective for trying to clear the body from the damaged red blood cells during childhood and become infarcted bringing a higher risk of infection. It is the reason that preventive antibiotics and vaccinations are recommended among people suffering from sickle cell disease. The spleen enlarges while the red blood cells are being trapped and the hemoglobin level may drop to a point that a hypovolemic shock will follow. It becomes then urgent to admit such patients for circulatory failure or death may follow shortly in hours. This crisis can last twenty-four hours. Chest pain, fever, pulmonary infiltrate and respiratory symptoms with hypoxemia are also common and are responsible for a quarter of the deaths among patients suffering from the disease. This phenomenon is called “Acute chest syndrome”.
The anemia may worsen suddenly with a patient with tachycardia and a profound fatigue. This crisis is generally triggered by a virus (papovirus B19) affecting directly the production of the blood cells by invading and destroying the immature forms during two or three days. This phenomenon can arrive without any adverse reactions in healthy individuals but can be of devastating effect and life-threatening for the one with the disease. Reticulocytes drops abruptly affecting the level of Hemoglobin, requiring often blood transfusion. The red blood cell can also be destroyed faster in a hemolytic crisis especially if there is an associated G6PD deficiency. There again, blood transfusion may be needed.
One of the earlier manifestation in sickle cell disease was seen with the “hands and feet syndrome” which represent a dactylitis in the first 6 months of age among patient suffering from the disease and also the one carrying the cell trait. The episode lasts less than a month generally but the older the patients become the more they may develop signs of pneumonia with the phenomenon of sickling in the lung creating an acute chest syndrome or vice versa a pulmonary infection which can trigger the painful crisis with bone marrow embolization. Atelectasis is frequently encountered necessitating opiate administration. Rarely at this age, surgical treatment is required. Occasionally, hematopoietic ulcers may complicate the picture. I have seen during my stay at Howard University Hospital cases of dactylitis changing into Osteomylitis in 2 kids with recurrent hand and foot syndrome. I will refer you to the paper published in the JBJS.
Humans carry a Hemoglobin A which consists of two Alpha and two Beta chains, a Hemoglobin A2 which also consists in two Alpha and two Delta chains and finally a Hemoglobin F which consists also in two Alpha chains and 2 Gammas chains in their bodies. at birth and until the age of 6 weeks, Hemoglobin F dominates until the Hemoglobin A become the dominant one during the remaining life. To be diagnosed with sickle cell disease, you will need to have at least one of the Beta-sub-unit of the Hemoglobin A, replaced by an abnormal Hemoglobin S. Sickle cell has an “autosomal recessive” pattern of inheritance from one or both parents. When only one parent transmits the gene to their descendants, the child will have 50% chance in having the trait but if both parents transmits the gene, a child will have 25% chance to develop sickle cell disease, 25% chance to be free of the trait and 50% of chance to carry the trait.
The sickle cell trait is a gene defect found in different geographic areas alone or associated to other hemoglobinopaties in African countries like Cameroun, Benin, Senegal, Mali and in Saudi-Asia. A higher level of Hemoglobin F is encountered in Saudi- Asia. The gene defect is due to a single nucleotide mutation of the Beta-globin gene which result in a substitution of glutamic acid by valine at the position “6” (E6Vsubstitution) on the Hemoglobin chain. The same substitution can be noted for the Hemoglobin S. This is a benign mutation until the normal oxygen concentration level changes in the system. The presence of a long chain polymers of HgS distort the shape of the red blood cell from a smooth doughnut-like shape to a spike obstructing the capillaries. A current nomenclature likes to count the methionine as the first amino-acid placing the glutamic acid to a position 7.
The allele for sickle cell anemia is in the short arm of the chromosome 11. Any children receiving the defective gene through both parents (homozygote) will develop the disease while a child receiving only one defective gene (allele) will become a carrier (heterozygote) but can transmit the gene without being sick. The homozygotes are protected against Malaria but the heterozygote may contract the disease in a less severe form. A theory that the red blood cells die prior to the multiplication of the parasite in the cell, avoiding the development of the disease, explains well the resistance of such patients. Malaria was endemic in the southern Europe and was declared eradicated in the mid-20th century but it continues to show a strong presence in the countries of Africa, India, the Mediterranean and the Middle East.
The malaria parasite is a plasmodium which needs to reproduce itself. It passes a part of their life cycle in the red blood cells. In a heterozygote or a carrier, the parasite causes the red blood cells with their defective hemoglobin to rupture prematurely and become unable to reproduce. This is the reason why in the areas where malaria is endemic and epidemic, chances of survival increase in the sickle cell trait population. In the United States, African American enjoy the fact that they are living in a non-endemic malaria zone with a low prevalence (0.25%) for the disease compared to a 4% among people living in West Africa. Our black population is composed of a mixture of African and non-African ethnic groups descendants of survivors from slavery, but we have seen a sickle cell incidence declining because of genetic dilution via crossbreeding.
The loss of the red blood cell elasticity represents the pathophysiologic hallmark of Sickle Cell Disease. A normal red blood cell is disc shaped, in a biconcavity allowing them to deform while passing through the capillaries. A low level of oxygen promotes sickling and the more this phenomenon repeats itself, the more the red blood cells lose their elasticity. Once these cells fail to return to a normal shape, they become more rigid and unable to deform while passing through the narrow capillaries. Vessel occlusion and ischemia follow. A destruction of the red blood cell become imminent with a subsequent Hemolysis inducing an Anemia. A healthy red blood cell lasts generally 120 days while in the sicklers they may last less than 20 days.
The hemoglobin level ranges to a 6-8 g/dl with a high reticulocyte count as a way for the bone marrow to compensate for the loss of the red blood cells. Target cell and Howell-Jilly bodies may also be seen because of the hyposplenism. A solubility test can demonstrate the sickling of the red blood cells just by adding sodium metabisulfite but if you add sodium dithionite to the HbS you will appreciate a turbid appearance while the addition of the same product to a normal Hb will give a clear solution. An electrophoresis of the hemoglobin can detect any abnormality. HgS and HgC or HgSC or in combination with other hemoglobinopaties like thalassemia, are the abnormal types to look for. The diagnosis is then confirmed with high performance liquid chromatography. Any infection or a state of dehydration can precipitate an acute sickle cell crisis. A chest X-Rays may reveal a pneumonia or other pulmonary infections. A Urine analysis can also detect a urinary tract infection. Those tests should be ordered on a routine basis upon admission of a symptomatic sickler.
Rarely genetic testing can be ordered especially in carrier (sickle cell trait) prior to have kids or in counselling prior to a wedding. For the unborn, the amniotic fluid can be also analyzed genetically to search for the sickle cell trait or a blood sample can be taken from the fetus to reach the same conclusion. Taking the blood from the umbilical cord carry a higher risk. Neonatal screening is generally used as a method of detection for the one carrying the sickle trait.
Let us review briefly the treatment of this complexed disease to terminate our presentation. Many of the projections will be based on my training first at Howard University Hospital and my personal experience in taking care of patients with sickle cell disease with my mentors, O Castro MD and Charles Epps MD and I different countries I visited in medical missions. I may take the opportunity to refer the lectors to one of our published articles:
It is generally recommended to avoid any form of dehydration. In the past, exercises were prohibited but nowadays, we believe that daily living exercises may be beneficial. A diet rich in calcium and vitamin D is strongly recommended. The FDA has supported the use of L-glutamine in the pediatric population. The use of Folic acid and Penicillin at birth to 5 years of age has been encouraged to boost the immune system and enforced by the WHO, but it remains unclear about the effect on the disease itself. We have already discussed the protective effect of the “sickle cell trait” against the proliferation of the plasmodium of Malaria while the one presenting with the disease is living in an endemic area. It is the recommended lifelong medications to prevent a crisis.
The hallmark of sickle cell disease in developing painful vaso-occlusive crisis can vary in frequency, intensity and duration. These crises are generally treated symptomatically with pain medication with anti-inflammatory medication (Naproxen, Diclofenac) in mild cases, rehydration. In more severe cases. pain-controlled analgesia and intravenous opioids are most useful. Diphenhydramine is often used to control itching. Rehydration orally or via intravenous route remain essential. A monoclonal antibody targeting p-selectin was introduced in 2019 and has helped in reducing the frequency of vaso-occlusive crisis in adolescents and adults.
The one suffering from sickle cell disease may develop respiratory problems like an acute chest syndrome which can be managed the same way than any vaso-occlusive crisis but with the addition an antibiotic like a quinolone or a macrolide, Oxygen supplementation for hypoxia during their admission will be necessary to treat any hypoxia. Such patients may require also blood transfusion or an exchange transfusion to replace a significant red cell mass by normal red cells, in the hope of decreasing the level of hemoglobin S but benefits or the possibility of acute chest syndrome will have to be weighted. Drugs have been used to reduce the frequency of painful episodes. There is insufficient evidence that Hydroxyurea can reduce the risk of life-threatening illness and death but it has been combined to phlebotomy to reduce pain and to decrease the risks of life-threatening illness and death. Voxelor has been approved by the FDA to encourage an increase in the hemoglobin, in patients suffering of SS or SC disease.
Blood transfusion has been used in the management of sickle cell disease. In children preventive RBC transfusion therapy has shown to reduce the risk of silent stroke when a transcranial Doppler ultrasonography is used appropriately to demonstrate an abnormal cerebral blood flow. Bone marrow transplant has proven to be an important tool in the treatment of children with sickle cell disease but can be difficult to obtain because of the specific HLA typing. Generally, a close relative, allogenic is the best donor.
Sickle cell disease patient are prone to avascular necrosis generally involving the femoral head or the humeral head creating pain and discomfort often requiring core decompression, bone grafting, joint arthroplasty or joint replacement when conservative treatment like pain management or rehabilitation with protective weight bearing or physical therapy have failed to relieve pain. Patient education as well as cognitive and behavioral therapies have played an important role in delaying any surgical treatment. This is a complementary to the medical treatment. It is interesting to observe how over the years, a” sickler” has learned how to adapt to the daily life. Advances in medical and surgical treatments have improved their ambulation. If in the 70’s their life expectancy was found to be in the mid 20’s, nowadays their mean survival reaches the mid 50’s. It seems that women have out lived men especially when we are talking about homozygous individuals with SC or SS disease. It was definitively the way we saw it at Howard University sickle cell center as a world referral center during the time of my residency.
The individuals suffering from sickle cell disease are at risk for severe infections because of the loss of their functioning spleen (auto-splenectomy). Like for an individual undergoing a surgical splenectomy, they become prone to bacterial infections like Hemophilus influenzae, and Streptococcus pneumoniae. Patients will present a decrease in the efficacy of their immune system due to the hyposplenism. It is always recommended to provide a prophylaxis with daily penicillin dosage to growing children by some and others suggest to continue for lifelong this regimen. A routine vaccination is also recommended for Streptococcus pneumonia. There is also a narrowing of the blood vessels especially in the brain facilitating the entrapment of the deformed hemoglobin unable to carry the oxygen. A silent stroke or a full stroke can easily be seen among such adult patients. Damage to the brain due to an infarction with brain damage can be seen. Around 15% of younger children with sickle cell disease will suffer from strokes.
Sickle cell patients who have experienced pain to the right upper quadrant of the abdomen because of gallstones formation and cholecystitis with jaundice. and hemolysis. The penis can be involved also in the disease and a thrombosis of the corpus cavernosus of the penis can produce priapism, a form of painful erection. Patients become prone to infection. The species Salmonella (Salmonella enteritis’s, Salmonella cholera suis, Salmonella typhimurium and Salmonella paratyphi, followed by the staphylococcus aureus and Gram negative) may invade the infarcted bowel. The kidneys are often involved with an acute papillary necrosis and often will develop a chronic kidney failure manifesting itself in a sickle cell nephropathy with Hypertension, Hematuria and proteinuria may progress to an end-stage renal failure. They may require dialysis but a poor diagnosis. Often, they will develop vascular leg ulcers.
During pregnancy, the fetus may be subject to intrauterine growth retardation, pre-eclampsia and even spontaneous abortion. Chronic pain also can be reported in absence of acute vaso-occlusive pain. Regular annual eye examination is recommended for all in sickle cell disease: One is at risk for reactive retinopathy with retinal detachments and vitreous hemorrhages. More than three quarter of sickle cell cases occur in Africa where 2% of newborns in Nigeria were found affected by the disease and 150,000 babies are believed to be affected yearly. There is a significant decrease in infant mortality rate (2-16 months) in the sickle cell trait population especially in predominant malarial zones. In Uganda, 20,000 babies are born each year with the disease. 13% of the population carries the trait and 0.7% has the disease. In United States one in 5,000 people of African descent are affected. One out of 365 African American children and one out of 16,000 Hispanic American children will have the disease. There are 2 million carriers with the trait. Routine neonatal screening is done in all the United State to identify the gene generally with a heel-prick. You may have it done at 2 or 4 weeks of age. This is certainly the most common genetic disorder among African Americans. 8% are carriers while one baby in 375 is born with the disease. Some believe that not much money is allocated to research like it is done with cystic fibrosis or hemophilia presenting a blatant case of discrimination. Sickle cell gene is also found in any country where slaves were imported to work on the colonial plantations. The inheritance remains through an autosomal recessive pattern with each of the parents carrying a copy of the mutated gene.
Sickle cell disease has become a problem in France because of the migration of African Caribbean and African from North and South African.SCD, the Mediterranean, the Arabic peninsula, the Indians are is the most common genetic disease of the country with an overall birth prevalence of one in 2,400 in the metropolitan area ahead of phenylketonuria (one in 11,000), congenital hypothyroidism (one in 3,000), adrenal hyperplasia (one in 19,000) and cystic fibrosis (one in 5,000). For the last twenty years the screening for sickle cell disease has been performed on a national level on all newborns at risk.
In the United Kingdom 15,000 people are believed to have sickle cell disease and 250,000 were found to have the trait. All new born babies will undergo a routine blood screening and the parents as well. Blood donors in the high risk group are screened the same way and if they are found to be carriers, their blood can be used for the same ethnic group but not for the group with sickle cell disease. Sickle cell disease is common in some ethnic group in Central India with a prevalence ranging from 9 t0 22% in area of Chhattisgarh or Rajasthan. It is also endemic among the Tharu people in Nepal and while they live in an endemic area for Malaria, they have a seven-fold lower rate in catching the disease. In Jamaica, 10% of the population carry the sickle cell gene making it the most prevalent genetic disorder in the country. In Saudi Arabia, 4% of the population carry the sickle cell gene and a .25 % (1/4) have the disease. The eastern provinces have the highest prevalence with 17% carrying the gene and 1.2% with the disease. In 2005, Saudi Arabia introduced a mandatory pre-marital test for Hb electrophoresis, and thalassemia. In Bahrain in 2005, they found out that 2% of the newborns have sickle cell disease, and 18% of the population surveyed has the trait while 24% were carriers of the gene mutation causing the disease. Pregnant women and babies were mandatorily tested and further a law was passed in 2004 offering free pre-marital counseling and testing.
We believe that the first reported case of sickle cell disease may have been in 1847 because of the findings of an autopsy on an executed runaway slave, a “maroon”. In the medical report, it was clearly mention of the absence of a functional spleen as a striking finding. It was well known in the United States that African slaves exhibited resistance to malaria but were prone to develop leg ulcers. In 1910, Ernest E Irons, a student of Professor James Herrick (1861-1954) discovered a peculiar elongated and sickle-shape red blood cell while analyzing a smear of blood taken from Walter Clement Noel, a first year dental student from Grenada. He was recently admitted with a diagnosis of Anemia at the Chicago Presbyterian Hospital. Final diagnoses of “muscular rheumatism” and “bilious attacks” were given for his repeated admissions to the hospital. He returned to Grenada (St George’s) after completing his studies in Dentistry, to practice. He died of pneumonia in 1916. Another similar case was reported by the Virginia Medical discussing a” peculiar elongated and sickle-shaped red blood in a case of anemia” on a patient treated at the University of Virginia on November 15,1930. The name of Sickle Cell was the first time used by Verne Mason in 1922. The term” Drepanocytosis” may have been already used in the past.
A researcher in Memphis, Lemuel Diggs was the first to make a difference between sickle cell disease and sickle cell trait in 1933 but this is really in 1949 that Linus Pauling described the unusual chemical behavior of the Hb S until the molecular changes were noted by Vernon Ingram during the late 1950’s. Soon after, the introduction of Hemoglobin electrophoresis allowed the distinction in subtype like Hg-SC, Hg-SS, HgS-Thalassemia etc. The 1970’s and the 1980’s have seen a widespread intervention to encourage the use of antibiotics for pneumococcal infections. Bill Cosby’s Emmy Award winner1972 movie, depicted the story of the parents of a kid with sickle cell disease. The 1990’s have seen the development of new drugs like Hydroxycarbamide and later in the late 2007 procedures like bone marrow transplantation. The Social Security Administration started providing background information on the disease and how you were able to apply for disabilities. Many African Americans experienced the impact of the stigmas on a social and a psychological point of view. They started feeling discrimination in the workplace and among their peers. The government supported the screening for this genetic disease, a way to ease the discriminatory impact on the disease and on their ability to obtain work. In fact, the screening was discriminatory and allowed employers to place restrictions on the workers with the trait or the disease. Medical care was also affected especially among the children between adolescence and adulthood often requiring more hospitalizations. The NIH was suggesting screening for the disease through their genetic counselors in a way to discourage black women for having children. The government, because of the risks, and also many saw in the fact, an attempt to limit black fertility. and encourage pregnant women to abort.
There is light at the end of the tunnel when researchers have predicted cure if a suitable donor can be found for a procedure which carries a 7% death-rate. Gene therapy was also found in 2001 bringing a successful way to treat the disease in the mice, in producing an HbF, similarly obtained with the use of Hydroxyurea at birth to stimulate the production of that fetal hemoglobin and relieving temporary the symptoms of the disease. Many clinical trials are on the way for the last 5 years like the gene editing platform CRISPR, to edit bone marrow into fetal hemoglobin. Recently, another cancer medication trial has used the medication” Mozobil” to overproduce stem cells. Hope is on the way for the one suffering from this disease.
Maxime Coles MD
Nov 28, 2020
Boca Raton FL 33496
PS: The AMHE is planning to build a materno-infantile clinic near Leogane, in Darbonne, Haiti, with the capability to handle the one suffering from the disease. We are actively collecting donations for this project through our AMHE Foundation and we would appreciate your generosity. You can easily go on the AMHE Foundation Webpage to visit and pledge… AMHE Foundation.org
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