What are the typical baseline blood study abnormalities in patients with sickle cell disease. How does sickle cell anemia affect hematocrit levels. What other blood markers are impacted by sickle cell disease.

Understanding Sickle Cell Disease and Its Impact on Blood Studies

Sickle cell disease (SCD) is a group of inherited red blood cell disorders characterized by abnormal hemoglobin, known as hemoglobin S. This abnormality causes red blood cells to become crescent or sickle-shaped, leading to various complications and affecting multiple blood parameters. To better understand the disease’s impact on blood studies, it’s crucial to examine the typical baseline abnormalities observed in SCD patients.

What is the primary cause of blood abnormalities in sickle cell disease?

The root cause of blood abnormalities in SCD is the presence of hemoglobin S. This abnormal hemoglobin polymerizes under low-oxygen conditions, causing red blood cells to become rigid and sickle-shaped. These sickled cells are prone to hemolysis (premature breakdown) and can obstruct small blood vessels, leading to various complications and alterations in blood parameters.

Hematocrit Levels in Sickle Cell Anemia: A Key Indicator

Hematocrit, the volume percentage of red blood cells in blood, is a critical parameter in assessing the severity of anemia in SCD patients. Understanding how SCD affects hematocrit levels is essential for proper disease management and treatment.

How does sickle cell anemia affect hematocrit levels?

Sickle cell anemia typically results in decreased hematocrit levels. The normal hematocrit range for adults is approximately 36-46% for women and 41-53% for men. However, in SCD patients, hematocrit levels are often significantly lower, ranging from 18-30%. This reduction is primarily due to the shortened lifespan of sickled red blood cells and chronic hemolysis.

Are hematocrit levels consistent in all SCD patients?

Hematocrit levels can vary among SCD patients depending on factors such as the specific type of SCD, overall health status, and concurrent treatments. For instance, patients with sickle cell trait (carriers of one sickle cell gene) may have near-normal hematocrit levels, while those with more severe forms of SCD, like HbSS, typically have lower hematocrit values.

Hemoglobin Abnormalities: The Hallmark of Sickle Cell Disease

Hemoglobin, the oxygen-carrying protein in red blood cells, is fundamentally altered in SCD. This alteration is at the core of the disease and influences various blood parameters.

What are the typical hemoglobin levels in SCD patients?

SCD patients generally have lower hemoglobin levels compared to healthy individuals. While normal hemoglobin ranges are approximately 12-15 g/dL for women and 13-17 g/dL for men, SCD patients often have hemoglobin levels between 6-9 g/dL. In severe cases, levels may drop even lower, necessitating blood transfusions.

How does hemoglobin electrophoresis help in diagnosing SCD?

Hemoglobin electrophoresis is a crucial diagnostic tool for SCD. It separates different types of hemoglobin based on their electrical charge. In SCD patients, this test typically reveals an abundance of hemoglobin S, often comprising more than 50% of total hemoglobin. The presence and proportion of other hemoglobin types, such as hemoglobin F (fetal hemoglobin), can also provide valuable information about disease severity and potential treatment approaches.

Red Blood Cell Indices: Beyond Hematocrit and Hemoglobin

While hematocrit and hemoglobin are primary indicators, other red blood cell indices provide additional insights into the nature and severity of SCD.

Which red blood cell indices are typically affected in SCD?

Several red blood cell indices are often abnormal in SCD patients:

• Mean Corpuscular Volume (MCV): Often elevated due to the presence of reticulocytes (immature red blood cells).
• Red Cell Distribution Width (RDW): Typically increased, reflecting the variation in red blood cell size.
• Reticulocyte Count: Usually elevated as the bone marrow tries to compensate for rapid red blood cell destruction.

These indices help paint a comprehensive picture of the red blood cell dynamics in SCD patients.

White Blood Cell and Platelet Abnormalities in Sickle Cell Disease

SCD doesn’t only affect red blood cells; it can also lead to changes in white blood cell and platelet counts, further complicating the blood profile of patients.

How are white blood cell counts affected in SCD?

SCD patients often exhibit leukocytosis, or an elevated white blood cell count. This increase is typically in the range of 12,000-20,000 cells/μL, compared to the normal range of 4,500-11,000 cells/μL. The persistent elevation of white blood cells is thought to contribute to the increased risk of vaso-occlusive crises and other complications in SCD patients.

What platelet abnormalities are common in SCD?

Platelet counts in SCD can be variable. Some patients may have normal platelet counts, while others might experience thrombocytosis (elevated platelet count) or, less commonly, thrombocytopenia (low platelet count). The increased platelet activation and aggregation observed in SCD contribute to the hypercoagulable state often seen in these patients.

Biochemical Markers: Assessing Organ Function and Disease Severity

Beyond hematological parameters, various biochemical markers provide crucial information about organ function and disease severity in SCD patients.

Which liver function tests are typically abnormal in SCD?

Liver function tests often show abnormalities in SCD patients due to chronic hemolysis and potential liver damage. Common findings include:

• Elevated bilirubin levels, particularly unconjugated bilirubin
• Increased lactate dehydrogenase (LDH) levels
• Mildly elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT)

These abnormalities reflect ongoing hemolysis and potential liver involvement in SCD.

How do renal function markers change in SCD?

Renal function can be affected in SCD, leading to changes in various markers:

• Creatinine levels may be lower than normal due to increased glomerular filtration rate in early stages
• Urine concentration ability may be impaired, leading to isosthenuria
• Microalbuminuria or proteinuria may be present, indicating early kidney damage

Regular monitoring of these parameters is crucial for early detection and management of renal complications in SCD.

Inflammatory Markers and Acute Phase Reactants in SCD

SCD is characterized by chronic inflammation, which is reflected in various inflammatory markers and acute phase reactants.

Which inflammatory markers are typically elevated in SCD?

Several inflammatory markers are often elevated in SCD patients, even in the absence of acute complications:

• C-reactive protein (CRP): Often chronically elevated
• Erythrocyte sedimentation rate (ESR): Usually increased
• Ferritin: May be elevated due to inflammation and increased iron turnover

These markers can help assess the overall inflammatory state and may correlate with disease severity and complications.

How do acute phase reactants change during vaso-occlusive crises?

During vaso-occlusive crises, acute phase reactants typically show more pronounced elevations:

• CRP levels may spike significantly
• Fibrinogen levels often increase
• Serum amyloid A protein may rise dramatically

Monitoring these changes can help in assessing the severity of acute crises and guiding treatment decisions.

Specialized Tests for SCD Complications and Severity Assessment

Beyond routine blood tests, several specialized assessments provide valuable information about disease complications and severity in SCD patients.

What specialized tests are used to assess hemolysis in SCD?

To evaluate the extent of hemolysis in SCD, several specialized tests are employed:

• Haptoglobin levels: Often very low or undetectable due to increased hemoglobin binding
• Plasma free hemoglobin: Elevated in cases of intravascular hemolysis
• Hemopexin levels: May be decreased due to increased heme binding

These tests help quantify the degree of hemolysis and can guide treatment decisions, particularly regarding transfusion therapy.

How is iron overload assessed in SCD patients?

Iron overload is a common complication in SCD patients, especially those receiving regular blood transfusions. Assessment of iron status typically includes:

• Serum ferritin: Often elevated, but can be influenced by inflammation
• Transferrin saturation: May be increased in iron overload
• Liver iron concentration: Measured by MRI or liver biopsy in severe cases

Regular monitoring of iron status is crucial for preventing complications associated with iron overload in SCD patients.

Genetic and Molecular Testing in Sickle Cell Disease

Genetic and molecular testing plays a crucial role in diagnosing SCD, determining its specific type, and identifying potential modifying factors.

What genetic tests are used to confirm SCD diagnosis?

Several genetic tests are employed to confirm SCD diagnosis and determine its specific type:

• DNA analysis: Detects specific mutations in the beta-globin gene
• Polymerase chain reaction (PCR): Amplifies and identifies the sickle cell mutation
• Restriction fragment length polymorphism (RFLP) analysis: Can differentiate between homozygous and heterozygous states

These tests provide definitive diagnosis and help in genetic counseling for families affected by SCD.

How do genetic modifiers influence blood study results in SCD?

Genetic modifiers can significantly impact the severity of SCD and, consequently, blood study results. Some key modifiers include:

• Alpha-thalassemia traits: Can lead to lower MCV and potentially milder anemia
• Hereditary persistence of fetal hemoglobin (HPFH): Associated with higher hemoglobin F levels and often milder disease course
• G6PD deficiency: Can exacerbate hemolysis in certain conditions

Understanding these genetic modifiers helps in interpreting blood study results and predicting disease severity in individual patients.

In conclusion, the baseline blood study abnormalities in sickle cell disease are diverse and complex, reflecting the multisystemic nature of the disorder. From altered hematocrit and hemoglobin levels to changes in white blood cell counts, platelets, and various biochemical markers, these abnormalities provide crucial insights into disease severity, complications, and overall patient health. Regular monitoring of these parameters, along with specialized and genetic tests, is essential for effective management of SCD patients and early detection of potential complications. As research in this field continues to advance, our understanding of these blood abnormalities and their clinical implications will undoubtedly deepen, leading to improved care and outcomes for individuals living with sickle cell disease.

What are the typical baseline blood study abnormalities in patients with sickle cell disease (SCD)?

Author

Joseph E Maakaron, MD Research Fellow, Department of Internal Medicine, Division of Hematology/Oncology, American University of Beirut Medical Center, Lebanon

Disclosure: Nothing to disclose.

Coauthor(s)

Ali T Taher, MD, PhD, FRCP Professor of Medicine, Associate Chair of Research, Department of Internal Medicine, Division of Hematology/Oncology, Director of Research, NK Basile Cancer Center, American University of Beirut Medical Center, Lebanon

Disclosure: Nothing to disclose.

Specialty Editor Board

Jeanne Yu, PharmD 

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Acknowledgements

Roy Alson, MD, PhD, FACEP, FAAEM Associate Professor, Department of Emergency Medicine, Wake Forest University School of Medicine; Medical Director, Forsyth County EMS; Deputy Medical Advisor, North Carolina Office of EMS; Associate Medical Director, North Carolina Baptist AirCare

Roy Alson, MD, PhD, FACEP, FAAEM is a member of the following medical societies: Air Medical Physician Association, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, National Association of EMS Physicians, North Carolina Medical Society, Society for Academic Emergency Medicine, and World Association for Disaster and Emergency Medicine

Disclosure: Nothing to disclose.

Jeffrey L Arnold, MD, FACEP Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center

Jeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physicians

Disclosure: Nothing to disclose.

Robert J Arceci, MD, PhD King Fahd Professor of Pediatric Oncology, Professor of Pediatrics, Oncology and the Cellular and Molecular Medicine Graduate Program, Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine

Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, and American Society of Pediatric Hematology/Oncology

Disclosure: Nothing to disclose.

Wadie F Bahou, MD Chief, Division of Hematology, Hematology/Oncology Fellowship Director, Professor, Department of Internal Medicine, State University of New York at Stony Brook

Wadie F Bahou, MD is a member of the following medical societies: American Society of Hematology

Disclosure: Nothing to disclose.

Dvorah Balsam, MD Chief, Division of Pediatric Radiology, Nassau University Medical Center; Professor, Department of Clinical Radiology, State University of New York at Stony Brook

Disclosure: Nothing to disclose.

Salvatore Bertolone, MD Director, Division of Pediatric Hematology/Oncology, Department of Pediatrics, Kosair Children’s Hospital; Professor, University of Louisville School of Medicine

Salvatore Bertolone, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Education, American Association of Blood Banks, American Cancer Society, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Kentucky Medical Association

Disclosure: Nothing to disclose.

Barry E Brenner, MD, PhD, FACEP Professor of Emergency Medicine, Professor of Internal Medicine, Program Director, Emergency Medicine, Case Medical Center, University Hospitals, Case Western Reserve University School of Medicine

Barry E Brenner, MD, PhD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Chest Physicians, American College of Emergency Physicians, American College of Physicians, American Heart Association, American Thoracic Society, Arkansas Medical Society, New York Academy of Medicine, New York Academy of Sciences,and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group

Disclosure: No financial interests None None

Nedra R Dodds, MD Medical Director, Opulence Aesthetic Medicine

Nedra R Dodds, MD is a member of the following medical societies: American Academy of Anti-Aging Medicine, American Academy of Cosmetic Surgery, American College of Emergency Physicians, American Medical Association, National Medical Association, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

James L Harper, MD Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University School of Medicine; Director, Continuing Medical Education, Children’s Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center

James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society

Disclosure: Nothing to disclose.

Adlette Inati, MD Head, Division of Pediatric Hematology-Oncology, Medical Director, Children’s Center for Cancer and Blood Diseases, Rafik Hariri University Hospital; Research Associate, Balamand University; Head of Post Bone Marrow Transplant Clinic and Consultant Hematologist, Chronic Care Center; Founding Faculty, Lebanese American University School of Medicine, Lebanon

Adlette Inati, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Hematology, European Hematology Association, and International Society of Hematology

Disclosure: Nothing to disclose.

Ziad N Kazzi, MD Assistant Professor, Department of Emergency Medicine, Emory University; Medical Toxicologist, Georgia Poison Center

Ziad N Kazzi, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Emergency Physicians, and American College of Medical Toxicology

Disclosure: Nothing to disclose.

Richard S Krause, MD Senior Clinical Faculty/Clinical Assistant Professor, Department of Emergency Medicine, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

Richard S Krause, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Ashok B Raj, MD Associate Professor, Section of Pediatric Hematology and Oncology, Department of Pediatrics, Kosair Children’s Hospital, University of Louisville School of Medicine

Ashok B Raj, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, Children’s Oncology Group, and Kentucky Medical Association

Disclosure: Nothing to disclose.

Sharada A Sarnaik, MBBS Professor of Pediatrics, Wayne State University School of Medicine; Director, Sickle Cell Center, Attending Hematologist/Oncologist, Children’s Hospital of Michigan

Sharada A Sarnaik, MBBS is a member of the following medical societies: American Association of Blood Banks, American Association of University Professors, American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Hosseinali Shahidi, MD, MPH Assistant Professor, Departments of Emergency Medicine and Pediatrics, State University of New York and Health Science Center at Brooklyn

Hosseinali Shahidi, MD, MPH is a member of the following medical societies: American Academy of Pediatrics, American College of Emergency Physicians, and American Public Health Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Garry Wilkes MBBS, FACEM, Director of Emergency Medicine, Calvary Hospital, Canberra, ACT; Adjunct Associate Professor, Edith Cowan University; Clinical Associate Professor, Rural Clinical School, University of Western Australia

Disclosure: Nothing to disclose.

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Ulrich Josef Woermann, MD Consulting Staff, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland

Disclosure: Nothing to disclose.

Grace M Young, MD Associate Professor, Department of Pediatrics, University of Maryland Medical Center

Grace M Young, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Emergency Physicians

Disclosure: Nothing to disclose.

Blood counts and sickle cell disease

What are blood counts?

Blood is made up of cells in a liquid called plasma. Blood cells are made in the bone marrow (the soft center of the bones). Then they are released into the body to do their jobs. The body has 3 main types of blood cells: red blood cells, white blood cells, and platelets. Sickle cell disease mainly affects the red blood cells, but can sometimes affect other blood cells. Medicines for sickle cell disease can also affect blood cells.  

If your child has sickle cell disease, counting and studying blood cells can tell the St. Jude staff about your child’s disease and how to treat it. A complete blood count (CBC) is a test that tells your child’s doctor about all 3 types of blood cells: red blood cells, platelets, and white blood cells.

Red blood cells

The main purpose of red blood cells is to deliver oxygen to the body. The part of the blood that carries oxygen is called hemoglobin. People with sickle cell disease have abnormal hemoglobin, called sickle hemoglobin or hemoglobin S. If your child has sickle cell disease, her red blood cells do not last as long because the sickle hemoglobin damages them. This means your child has fewer red blood cells than normal, a condition called anemia. People with normal hemoglobin usually have a hemoglobin level around 12 g/dL. People with sickle cell disease have lower hemoglobin levels, usually between 6–11 g/dL. The exact level may be different depending on the type of sickle cell disease and the person. It is important to know your child’s usual hemoglobin level. Blood tests done over a period of time will tell the doctor what is normal for your child. 

Reticulocyte count

A reticulocyte is a young red blood cell that is forming in the bone marrow. Normally, reticulocytes stay in the bone marrow until they develop into red blood cells and enter the blood. The reticulocyte count is a test that measures the number of reticulocytes in the blood. For most people, the number is very low because most reticulocytes stay in the bone marrow. If your child has sickle cell disease, she may have a higher reticulocyte count. This is because your child’s body has to make more red blood cells due to anemia. A normal amount of reticulocytes in the blood is between 0.45–1.8 percent. If your child has sickle cell disease, she may have a reticulocyte count of 2–3 percent or more.  The number of reticulocytes is different for each person with sickle cell disease.  If your child’s reticulocyte count drops very much, it might mean her body is making fewer red blood cells. This could be dangerous. The St. Jude staff will test your child’s reticulocyte count at each clinic visit.

White blood cells

White blood cells help the body fight infection. A normal white blood cell count is 5,000–10,000/mm3. When the white blood cell count is low, it is easier to get an infection and harder to get over it. If your child has sickle cell disease, her white blood cell count will usually be normal or higher than normal. However, illness and some medicines can make the white blood cell count go up or down for a short time.  

Neutropenia

A neutrophil is a type of white blood cell that kills bacteria. Neutrophils help prevent infection.  If your child does not have enough neutrophils, this is called neutropenia.  Children taking hydroxyurea for sickle cell disease often have mild neutropenia. If your child is taking hydroxyurea, the St. Jude staff will keep track of your child’s neutrophil count.

The doctor will use a measurement called the Absolute Neutrophil Count (ANC) to keep track of your child’s neutrophils. The ANC shows how well the body can fight infections, especially bacterial infections.

Platelets

Platelets are blood cells that help stop bleeding by making the blood clot. A normal platelet count is 150,000 to 400,000/mm3. If your child has a low platelet count, she may bruise or bleed more easily. Normally, sickle cell disease does not cause low platelet levels.

Keeping track of your child’s blood counts

If your child has sickle cell disease, the St. Jude staff will keep track of her blood counts. Your child will usually have a complete blood count (CBC) and reticulocyte count at each clinic visit. The doctor will tell you if your child needs more blood tests. Keeping track of your child’s blood counts is an important part of treatment. The St. Jude staff will review the test results with you and give you a copy each time your child sees the doctor. You should keep these results with your child’s medical records.

Questions?

If you have questions about your child’s blood counts or what they mean, ask the doctor or nurse. If you are outside the hospital, refer to your Important Phone Number Card. You may also call the St. Jude operator at (901) 595-3300 or toll-free 1-866-2STJUDE (1-866-278-5833) and ask for your child’s nurse case manager.

Sickle Cell Disease | Johns Hopkins Medicine

What is sickle cell disease?

Sickle cell disease is an inherited blood disorder. It is marked by flawed hemoglobin. That’s the protein in red blood cells that carries oxygen to the tissues of the body. So, sickle cell disease interferes with the delivery of oxygen to the tissues.

Red blood cells with normal hemoglobin are smooth, disk-shaped, and flexible, like doughnuts without holes. They can move through the blood vessels easily. Cells with sickle cell hemoglobin are stiff and sticky. When they lose their oxygen, they form into the shape of a sickle or crescent, like the letter C. These cells stick together and can’t easily move through the blood vessels. This can block small blood vessels and the movement of healthy, normal oxygen-carrying blood. The blockage can cause pain.

Normal red blood cells can live up to 120 days. But, sickle cells only live for about 10 to 20 days. Also, sickle cells may be destroyed by the spleen because of their shape and stiffness. The spleen helps filter the blood of infections. Sickled cells get stuck in this filter and die. With less healthy red blood cells circulating in the body, you can become chronically anemic. The sickled cells also damage the spleen. This puts you are at greater at risk for infections.

What causes sickle cell disease?

Sickle cell is an inherited disease caused by a defect in a gene.

• A person will be born with sickle cell disease only if two genes are inherited—one from the mother and one from the father.
• A person who inherits just one gene is healthy and said to be a “carrier” of the disease. A carrier has an increased chance of having a child with sickle cell disease if he or she has a child with another carrier. 

For parents who are each carriers of a sickle cell gene, there is a 1 in 4, or a 25 % chance of having a child with sickle cell disease.

What are the risk factors for sickle cell disease?

Having a family history of sickle cell disease increases your risk for the disease. In the United States, it mainly affects African Americans.

What are the symptoms of sickle cell disease?

The following is a list of symptoms and complications associated with sickle cell disease. However, each person may experience symptoms differently. Symptoms and complications may include:

• Anemia. Because sickled cells are short-lived or destroyed, there are less red blood cells available in the body. This results in anemia. Severe anemia can make you feel dizzy, short of breath, and tired.
• Pain crisis, or sickle crisis. This occurs when the flow of blood is blocked to an area because the sickled cells have become stuck in the blood vessel. The pain can occur anywhere, but most often occurs in the chest, arms, and legs. Infants and young children may have painful swelling of the fingers and toes. Interruption in blood flow may also cause tissue death.
• Acute chest syndrome. This occurs when sickling occurs in the chest. This can be life-threatening. It often occurs suddenly, when the body is under stress from infection, fever, or dehydration. The sickled cells stick together and block the flow of oxygen in the tiny vessels in the lungs. It resembles pneumonia and can include fever, pain, and a violent cough.
• Splenic sequestration (pooling). Crises are a result of sickle cells pooling in the spleen. This can cause a sudden drop in hemoglobin and can be life-threatening if not treated promptly. The spleen can also become enlarged and painful from the increase in blood volume. After repeated episodes,  the spleen becomes scarred, and permanently damaged. Most children, by age 8, do not have a working spleen either from surgical removal, or from repeated episodes of splenic sequestration. The risk of infection is a major concern of children without a working spleen. Infection is the major cause of death in children younger than age 5 in this population.
• Stroke. This is another sudden and severe complication of people with sickle cell disease. The misshapen cells can block the major blood vessels that supply the brain with oxygen. Any interruption in the flow of blood and oxygen to the brain can result in severe brain damage. If you have one stroke from sickle cell anemia, you are more likely to have a second and third stroke.
• Jaundice, or yellowing of the skin, eyes, and mouth. Jaundice is a common sign and symptom of sickle disease. Sickle cells do not live as long as normal red blood cells and, therefore, they are dying faster than the liver can filter them out. Bilirubin (which causes the yellow color) from these broken down cells builds up in the system causing jaundice.
• Priapism.  This is a painful obstruction of the blood vessels in the penis by sickle cells. If not promptly treated, it can result in impotence.

The symptoms of sickle cell disease may look like other blood disorders or medical problems. Always consult your health care provider for a diagnosis.

How is sickle cell disease diagnosed?

Along with a complete medical history and physical exam, you may have blood and other tests.

Many states routinely screen newborns for sickle cell so that treatment can begin as soon as possible. Early diagnosis and treatment can reduce the risk of complications.

Hemoglobin electrophoresis is a blood test that can determine if a person is a carrier of sickle cell, or has any of the diseases associated with the sickle cell gene.

How is sickle cell disease treated?

Your doctor will consider your age, overall health and other factors when determining the best treatment for you.

Early diagnosis and prevention of complications is critical in sickle cell disease treatment. Treatment aims to prevent organ damage including strokes, prevent infection, and treat symptoms. Treatment may include:

• Pain medications. This is for sickle cell crises.
• Drinking plenty of water daily (8 to 10 glasses). This is to prevent and treat pain crises. In some situations, intravenous fluids may be required.  
• Blood transfusions. These may help treat anemia and prevent stroke. They are also used to dilute the sickled hemoglobin with normal hemoglobin to treat chronic pain, acute chest syndrome, splenic sequestration, and other emergencies.
• Vaccinations and antibiotics. These are used to prevent infections.
• Folic acid. Folic acid will help prevent severe anemia.
• Hydroxyurea. This medication helps reduce the frequency of pain crises and acute chest syndrome. It may also help decrease the need for blood transfusions. The long-term effects of the medication are unknown.
• Regular eye exams. These are done to screen for retinopathy.  
• Bone marrow transplant. Bone marrow transplants can cure some people with sickle cell disease. The decision to have this procedure is based on the severity of the disease and ability to find a suitable bone marrow donor. These decisions need to be discussed with your doctor and are only done at specialized medical centers.

What are the complications of sickle cell disease?

Any and all major organs are affected by sickle cell disease. The liver, heart, kidneys, gallbladder, eyes, bones, and joints can suffer damage from the abnormal function of the sickle cells and their inability to flow through the small blood vessels correctly. Problems may include the following:

• Increased infections
• Leg ulcers
• Bone damage
• Early gallstones
• Kidney damage and loss of body water in the urine
• Eye damage
• Multiple organ failure

Living with sickle cell disease

Sickle cell disease is a life-long condition. Although the complications of sickle cell disease may not be able to be prevented entirely, living a healthy life-style can reduce some of the complications.

It is important to eat a healthy diet with lots of fruits, vegetables, whole grains, and protein, and drink lots of fluids.

Do not take decongestants because they cause constriction of blood vessels and could trigger a crisis.

Other factors that may trigger a crisis include high altitudes, cold weather, swimming in cold water, and heavy physical labor.

Avoid infections by getting an annual flu shot, washing your hands frequently, avoiding those who are sick, and getting regular dental exams.

Key points

• Sickle cell disease is an inherited blood disorder marked by defective hemoglobin.
• It inhibits the ability of hemoglobin in red blood cells to carry oxygen.
• Sickle cells tend to stick together, blocking small blood vessels causing painful and damaging complications.
• Sickle cell disease is treated with pain medications as needed, drinking 8 to 10 glasses of water each day, blood transfusions, and medications.

Next steps

Tips to help you get the most from a visit to your health care provider:

• Before your visit, write down questions you want answered.
• Bring someone with you to help you ask questions and remember what your provider tells you.
• At the visit, write down the names of new medicines, treatments, or tests, and any new instructions your provider gives you.
• If you have a follow-up appointment, write down the date, time, and purpose for that visit.
• Know how you can contact your provider if you have questions.

Sickle Cell Anemia: Symptoms, Causes, Treatments

Overview

What is sickle cell anemia?

Sickle cell anemia is a blood disease that affects red blood cells. Normal red blood cells are round. In people with sickle cell anemia, hemoglobin – a substance in red blood cells – becomes defective and causes the red blood cells to change shape. The faulty hemoglobin is called hemoglobin S (HgbS), and it replaces normal hemoglobin which is called hemoglobin A (HgbA). Over time, the red blood cells become rigid and shaped like crescent moons or sickles.

The sickle-shaped red blood cells:

• Clog blood vessels, causing episodes of pain and cutting off oxygen to tissues and organs.
• Get trapped in the spleen (an organ that gets rid of old cells) where they are destroyed. The body cannot replace the lost cells fast enough. As a result, the body has too few red blood cells, a condition known as anemia.

Sickle cell anemia is a serious disease that can require frequent hospital stays. Children and young adults can die from the disease.

Who gets sickle cell anemia?

In the United States, the disease occurs most often among African Americans (in about 1 of every 400 African American births) and among Hispanics of Caribbean ancestry (1 in every 1,000 to 1,400 Hispanic American children). Throughout the world, the disease is also found among people of Arabian, Greek, Italian, Sardinian, Turkish, Maltese, and southern Asian ancestry.

Is there a difference between sickle cell anemia and sickle cell trait?

Yes. A person can have a mixture of normal and faulty hemoglobin in their red blood cells without having sickle cell disease. This condition is called “sickle cell trait.” People with sickle cell trait have enough normal hemoglobin in their red blood cells to prevent the cells from sickling. One in 12 African Americans in the United States has sickle cell trait.

It’s important to remember that people with sickle cell trait do not have sickle cell disease. They also usually do not develop sickle cell disease, except in unusual circumstances. However, people with sickle cell trait can genetically pass the trait to their children. If two people with sickle cell trait have children together, there is a 1 in 4 chance that their children will have sickle cell anemia.

What are the chances that my child will be born with sickle cell anemia or sickle cell trait?

If you and your partner both have sickle cell trait, your child has a 25% chance of being born with sickle cell anemia. If only one of you has sickle cell trait, your child cannot be born with sickle cell anemia, but there is a 50% chance that your child will be born with sickle cell trait.

If one parent has sickle cell disease and one parent has sickle cell trait, there is a 50% chance that their children will be born with sickle cell disease.

Symptoms and Causes

How does a person get sickle cell anemia?

People with sickle cell anemia inherit the disease, which means that the disease is passed on to them by their parents as part of their genetic makeup. Parents cannot give sickle cell anemia to their children unless they both have the faulty hemoglobin in their red blood cells.

What are the symptoms and complications of sickle cell anemia?

• Periods of pain that can last a few hours to a few days.
• Blood clots.
• Swelling in hands and feet.
• Joint pain that resembles arthritis.
• Chronic neuropathic pain (nerve pain).
• Life-threatening infections.
• Anemia (decrease in red blood cells).

Diagnosis and Tests

How can I know if I have sickle cell trait?

Your healthcare provider can perform a special blood test to tell if you have sickle cell anemia or sickle cell trait. You may decide to have this test before you plan to have children.

In many states, the law requires newborn babies to be tested for sickle cell disease, regardless of their ethnic background. The testing is done right away so that children born with sickle cell disease can receive treatment to protect them against life-threatening infections. These children need to be followed very closely by a healthcare provider.

Management and Treatment

Can sickle cell anemia be cured?

No. As of today, there’s no cure for sickle cell anemia. However, there are treatments that have reduced the death rate among children and the levels of pain caused by the disease.

If your baby has sickle cell anemia, your healthcare provider will explain what you can do to help your child live a normal life. Your baby may need to take medicine by the mouth for up to 10 years to prevent life-threatening infections. Later in life, care focuses more on managing pain.

Living With

How can I manage my pain if I have sickle cell anemia?

Acute pain can occur during a vaso-occlusive crisis (VOC). This happens when the sickle-shaped blood cells block the flow of blood in small vessels. The VOC can lead to tissue damage and pain. This type of pain should be treated as a medical emergency.

Some patients develop chronic pain, which is pain that lasts for more than 3 to 6 months. The exact mechanism that causes chronic pain in some patients and not others is not known. The treatment of the chronic pain should be tailored to the specific type of pain that is being experienced. Wokring with a pain management doctor can help you manage your pain by applying different methods. The goal is to use the least of amount of medication and gain the greatest amount of function.

How Does Sickle Cell Cause Disease?

How Does Sickle Cell Cause Disease?
last revised April 11, 2002

How Does Sickle Cell Cause Disease?

The Mutation in Hemoglobin

Sickle
cell disease is a blood condition seen most commonly in people of African
ancestry and in the tribal peoples of India.
Clinically significant sickle cell syndromes also occur in people of Mediterranean
and Middle Eastern background. Here, the most common problem is a combination
sickle cell and beta thalassemia genes. The sickle cell mutation reflects
a single change in the amino acid building blocks of the oxygen-transport
protein, hemoglobin. This protein, which is the component that gives red
cells their color, has two subunits. The alpha subunit is normal in people
with sickle cell disease. The beta subunit has the amino acid valine at
position 6 instead of the glutamic acid that is normally present. The alteration
is the basis of all the problems that occur in people with sickle cell
disease. The schematic diagram shows the first eight of the 146 amino acids
in the beta globin subunit of the hemoglobin molecule. The amino acids
of the hemoglobin protein are represented as a series of linked, colored
boxes. The lavender box represents the normal glutamic acid at position
6. The dark green box represents the valine in sickle cell hemoglobin.
The other amino acids in sickle and normal hemoglobin are identical.

 The molecule, DNA (deoxyribonucleic acid), is the fundamental
genetic material that determines the arrangement of the amino acid building
blocks in all proteins. Segments of DNA that code for particular proteins
are called genes. The gene that controls the production of the beta globin
subunit of hemoglobin is located on one of the 46 human chromosomes (chromosome
#11). People have twenty-two identical chromosome pairs (the twenty-third
pair is the unlike X and Y chromosomes that determine a person’s sex).
One of each pair is inherited from the father, and one from the mother.
Occasionally, a gene is altered in the exchange between parent and offspring.
This event, called mutation, occurs extremely rarely. Therefore, the inheritance
of sickle cell disease depends totally on the genes of the parents.

  If only one of the beta globin genes is the “sickle” gene and
the other is normal, the person is a carrier for sickle cell disease. The
condition is called sickle
cell trait. With a few rare exceptions, people with sickle cell trait
are completely normal. If both beta globin genes code for the sickle protein,
the person has sickle cell disease. Sickle cell disease is determined at
conception, when a person acquires his/her genes from the parents. Sickle
cell disease cannot be caught, acquired, or otherwise transmitted.
Also, sickle cell trait does not develop into sickle cell disease. Sickle cell trait
partially protects people from the deadly consequences of malaria. The frequency
of the sickle cell gene reached high levels in Africa and India due to the protection
against malaria that occurred for people with sickle cell trait.

  The hemoglobin molecule (made of alpha and beta globin subunits)
picks up oxygen in the lungs and releases it when the red cells reach peripheral
tissues, such as the muscles. Ordinarily, the hemoglobin molecules exist
as single, isolated units in the red cell, whether they have oxygen bound
or not. Normal red cells maintain a basic disc shape, whether they are
transporting oxygen or not.

The
picture is different with sickle hemoglobin (Figure 2). Sickle hemoglobin exists as
isolated units in the red cells when they have oxygen bound. When sickle
hemoglobin releases oxygen in the peripheral tissues, however, the molecules
tend to stick together and form long chains or polymers. These rigid polymers
distort the cell and cause it to bend out of shape. While most distorted
cells are simply shaped irregularly, a few have a cresent-like appearence
under the microscope. These cresent-like or “sickle shaped” red cells gave
the disorder its name. When the red cells return to the lungs and pick
up oxygen again, the hemoglobin molecules resume their solitary existence
(the left of the diagram).

   A single red cell may traverse the circulation four times
in one minute. Sickle hemoglobin undergoes repeated episodes of polymerization
and depolymerization. This cyclic alteration in the state of the molecules
damages the hemoglobin and ultimately the red cell itself.

 Polymerized sickle hemoglobin does not form single strands. Instead,
the molecules group in long bundles of 14 strands each that twist in a
regular fashion, much like a braid (Figure 3).

These bundles self-associate into even larger structures that stretch and
distort the cell. An analogy would be a water balloon which was stretched
and deformed by icicles. The stretching of the balloon’s rubber is
similar to what happens to the membrane of the red cell. Polymers tend
to grow from a single start site (called a nucleation site) and often grow
in multiple directions. Star-shaped clusters of hemoglobin S polmers develop
commonly.

  Despite their imposing appearance, the sickle hemoglobin polymers
are held together by very weak forces. The abnormal valine amino acid at
position 6 in the beta globin chain interacts weakly with the beta globin
chain in an adjacent sickle hemoglobin molecule. The complex twisting,
14-strand structure of the bundles produces multiple interactions and cross-interactions
between molecules. The weak nature of the interaction opens one strategy
to treat sickle cell disease.

   Some types of hemoglobin molecules, such as that found
before birth (fetal hemoglobin),
block the interactions between the deoxygenated hemoglobin S molecules.
All people have fetal hemoglobin in their circulation before birth. Fetal
hemoglobin protects the unborn child and newborns from the effects of sickle
cell hemoglobin. Unfortunately, this hemoglobin disappears within the first
year after birth. One approach to treating sickle cell disease is to rekindle
production of fetal hemoglobin. The drug, hydroxyurea
induces fetal hemoglobin production in some patients with sickle cell disease
and improves the clinical condition
of some people.

The Sickle Red Cell

Figure 4 shows the changes that occur as sickle or normal red
cells release oxygen in the microcirculation. The upper panel shows that
normal red cells retain their biconcave shape and move through the smallest
vessels (capillaries) without problem. In contrast, the hemoglobin polymerizes
in sickle red cells when they release oxygen, as shown in the lower panel.
The polymerization of hemoglobin deforms the red cells. The problem, however,
is not simply one of abnormal shape. The membranes of the cells are rigid
due in part to repeated episodes of hemoglobin polymerization/depolymerization
as the cells pick up and release oxygen in the circulation. These rigid
cells fail to move through the small blood vessels, blocking local blood
flow to a microscopic region of tissue. Amplified many times, these episodes
produce tissue hypoxia (low oxygen supply). The result is pain, and often
damage to organs.

 The damage to red cell membranes promotes many of the complications
of sickle cell disease. Robert Hebbel at the University of Minnesota and
colleagues were among the first workers to show that the heme
component of hemoglobin tends to be released from the protein with repeated
episodes of sickle hemoglobin polymerization. Some of this free heme lodges
in the red cell membrane. The iron in the center of the heme molecule promotes
formation of very dangerous compounds, called reactive oxygen species.
These molecules damage both the lipid and protein components of the red
cell membrane. Membrane stiffness is one of the consequences of this injury.
Also, the damaged proteins tend to clump together to form abnormal clusters
in the red cell membrane. Antibodies develop to these protein clusters,
leading to even more red cell destruction (hemolysis).

  The anemia in sickle cell disease is caused by red cell destruction,
or hemolysis. The production of red cells by the bone marrow increases
dramatically, but is unable to keep pace with the destruction. Red cell
production increases by five to ten-fold in most patients with sickle cell
disease. The average half-life of normal red cells is about 40 days. In
patients with sickle cell disease, this value can fall to as low as four
days. The volume of “active” bone marrow is much greater than normal in
patients with sickle cell disease due to the demand for greater red cell
production.

The degree of anemia varies widely between patients. In general,
patients with sickle cell disease have hematocrits that are roughly half
the normal value (e.g., about 25% compared to about 40-45% normally).
Patients with hemoglobin SC disease (where one of the beta globin genes
codes for hemoglobin S and the other for the variant, hemoglobin C) have
higher hematocrits than do those with homozygous Hb SS disease. The hematocrits
of patients with Hb SC disease run in low- to mid-thirties. The hematocrit
is normal for people with sickle cell trait.

 

 

New Views of Sickle Cell Disease Pathophysiology and Treatment | Hematology, ASH Education Program

^*

Life Sciences Division, Lawrence Berkeley Laboratory, 1 Cyclotron Road, Bldg. 74-157, Berkeley CA 94720

An important pathophysiologic feature of sickle cell disease is episodic occurrence of vasoocclusive events that precipitate acute painful episodes. Vasoocclusion of small and sometimes large vessels is the hallmark of sickle cell disease, accounting for much of its morbidity and mortality. Decades of research on sickle hemoglobin polymerization have culminated in elegant elucidations of the contributions of polymerization-dependent processes to various pathophysiologic manifestations of the sickle cell disease. However, it is reasonable to surmise that hemoglobin polymerization in and of itself is not sufficient to account for the episodic nature of vascular occlusion.

Based upon studies from a number of laboratories, there is emerging consensus that a key contributor to vasoocclusion may be the increased tendency of sickle red cells to adhere to vascular endothelium.^1,2  Vasoocclusion can occur when transit time of red cells through the capillaries is longer than the delay time for deoxygenation-induced hemoglobin polymerization of sickle hemoglobin. As adherence of sickle red cells to vascular endothelium will impede blood flow and thereby increase capillary transit time, it has been suggested that increased cell adherence can initiate and propagate vasoocclusion.

Factors such as inflammatory mediators that activate endothelial cells and thereby enhance endothelial adhesivity of sickle red cells thus have the potential to trigger vasoocclusive episodes. A partial list of agonists that may alter endothelium and play a role in sickle cell disease includes TNF-α, interferon-γ, IL-1β, vascular endothelial growth factor (VEGF), thrombin, and histamine, and the effects of hypoxia and reperfusion.

Seminal studies by Hebbel two decades ago demonstrated that sickle red cells exhibit increased adherence to endothelial cells in vitro and that the extent of in vitro sickle cell adhesivity correlated with vasoocclusive severity.³  Mohandas and Evans showed that both red cell membrane changes and plasma factors account for increased sickle cell adherence to endothelial cells in vitro.⁴  Subsequently, a number of studies have defined adhesion pathways involved in sickle cell adherence to cultured endothelial cells under static and flow conditions.^5,6,7,8,9,10  Adhesive ligands identified on sickle red cells include CD36, α₄β₁ integrin, sulfated glycolipid and the Lutheran blood group antigen. On the endothelial side, cytokine-induced VCAM-1, a ligand for α₄β₁, and α_vβ₃ integrin that binds von Willebrand factor (vWf) and thrombospondin (TSP) have been shown to mediate sickle cell adherence. Other potential adhesive receptors on endothelial cells include GPIb and CD36. The adhesive proteins in plasma, TSP released by platelets, and vWF released by endothelial cells mediate adhesion by serving as bridging molecules between adhesive receptors on red cells and endothelial cells. Sickle red cell interaction with the vessel wall may also involve interaction with subendothelial matrix components such as laminin, TSP, vWf or fibronectin exposed by vascular injury. The Lutheran blood group antigen has been shown to be a major laminin receptor on red cells, while a sulfated glycolipid has been shown to bind to laminin and to TSP. Based on data from these extensive series of in vitro studies it is reasonable to conclude that sickle red cells indeed exhibit an increased adhesive phenotype and that a large number of cell adhesion receptors, plasma proteins and subendothelial matrix components are involved in mediating adhesive interactions.

The critical question that has not yet been adequately addressed is the extent to which the in vitro documented adhesive phenotype of sickle red cells contributes to vasoocclusion in vivo. While there are no easy experimental strategies to address these problems, some progress is being made through physiological studies using animal models. Intravital microscopy has been employed to study sickle red cell interaction with vessel wall using rat mesocecum ex vivo perfused with human sickle cells and in transgenic mice that express high levels of human sickle hemoglobin.^11,12,13  The ex vivo rat studies showed that deformable low-density sickle red cells are more likely to adhere than undeformable dense sickle cells and that adhesion was limited to postcapillary venules. A recent study using the same ex vivo rat model has convincingly demonstrated that treatment with the α_vβ₃-blocking antibody largely abolished platelet-activating factor-stimulated sickle red cell adhesion to vessel wall.¹⁴  These types of in vivo studies are beginning to provide support to the thesis that increased sickle cell adherence could have significant effects on flow dynamics in the microvasculature and that anti-adhesive therapy may have clinical benefits.

There are, however, a number of significant issues regarding the in vivo role of sickle cell adherence that cannot be addressed using ex vivo animal models. A major hurdle for progress has been the lack of a suitable animal model for sickle cell disease. The recent development of transgenic/knockout sickle mice that express exclusively human sickle hemoglobin and exhibit many clinical features of human disease¹⁵  is likely to prove to be a valuable tool to begin to critically evaluate the role of cell adherence in vasoocclusion and the potential clinical benefit of anti-adhesive therapeutic strategies. While much work still remains to be done, with the recent exciting breakthroughs in our understanding of cell adhesion it is likely that anti-adhesion therapies may become viable treatment options for management of vasoocclusive crisis during the coming decade.

Hematocrit among Blacks with Sickle Cell Trait on JSTOR

Abstract

Hematocrit levels were studied in 8,581 male and 10,618 female Blacks aged 0-59 years, in Upstate New York. Persons with sickle-cell trait and with normal hemoglobin were compared. Differences in mean levels were small and not statistically significant, except for males aged 12-13 and females aged 8-9. Lower means for trait persons at these ages could be a chance finding, or could possibly reflect delayed physical maturation. Criteria of “low” and “high” hematocrit were selected somewhat arbitrarily, from previously reported standards based on population distributions. The frequency of “low” hematocrit did not differ between trait and normal groups in any age-sex category. Adult males (aged 17-59), but not females, with the trait were less likely to have a “high” hematocrit compared with normal males. These findings suggest the need for more detailed analysis on other large populations.

Journal Information

A worldwide forum for state-of-the-art ideas, methods, and techniques in the field, Human Biology focuses on genetics in its broadest sense. Included under this rubric are: human population genetics, evolutionary and genetic demography, quantitative genetics, evolutionary biology, ancient DNA studies, biological diversity interpreted in terms of adaptation (biometry, physical anthropology), and interdisciplinary research linking biological and cultural diversity (inferred from linguistic variability, ethnological diversity, archaeological evidence, etc.)

Publisher Information

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Gene therapy of sickle cell anemia in adolescents using lentiviral vector

In article New England Journal of Medicine dated March 2
2017 published a clinical case about the successful treatment of a patient with a severe form
sickle cell anemia (SCA) through gene therapy.

Sickle cell anemia is one of the most common hereditary monogenic
diseases.About 90,000 people in the United States have sickle cell disease and
worldwide, more than 275,000 babies are born with the disease every year.

SKA is a disease based on a change in the shape of erythrocytes, due to
the appearance of pathological hemoglobin S (HbS), as a result of a point mutation in the β-chain gene
hemoglobin

Clinical manifestations are vaso-occlusive crises in vital organs.What is the bottom line
leads to irreversible organ damage, poor quality of life, reduction
life expectancy and even death.

The main method of treatment is the use of a hydroxyurea preparation, the mechanism of action
which is to increase the level of fetal hemoglobin. Many patients use
hydroxyurea, is the only treatment that relieves the manifestations of the disease.

Allogeneic transplantation is currently the only therapy for patients with
severe form of SKA. However, less than 18% of patients have fully compatible
sibling donor.

The use of gene therapy in patients with SCD may provide long-term clinical
remission.

Previously, there were reports of effective treatment of SCA in mice, through gene therapy with
using a viral vector.In this article, the results of a successful
treating a patient who received gene therapy in clinical study HGB-205.

Clinical case :

Boy, 13 years old

Diagnosis: severe form of SCA, with the βS / βS genotype (point deletion of the gene 3.7 kb
α-globin)

Clinical manifestations: numerous vaso-occlusive crises, episodes of angina pectoris,
bilateral osteonecrosis of the hip joints.

Operations: cholecystectomy and splenectomy.

Treatment: from 2 to 9 years received hydroxyurea therapy, clinical symptoms remained
the old ones. Since 2010, the boy has been treated with chelated iron at a dose of 17 mg / kg in
day.

In October 2014, gene therapy was applied using a lentiviral vector.

Lentiviral vector encoding human βA-globin gene, similar to gamma globin,
subunit of fetal hemoglobin, quenches HbS polymerization.

The patient underwent myeloablative conditioning with busulfan.

After a 2-day break, reinfusion of autologous transduced CD34 + cells (5.6
× 106 / kg MT CD34 +).

Substitution blood transfusions were continued until the HbA content was 25 to 30% of
total hemoglobin.

Basic laboratory parameters before gene therapy (at screening) and at 3-month intervals
after transfusion of transduced autologous CD34 + cells

* replacement transfusions were performed prior to initiation of gene therapy, and maintenance transfusions were
erythrocytes were completely discontinued 88 days after transplantation.

At the moment, the patient is in complete clinical remission, with full compensation of hemolysis and
lack of clinical manifestations of the disease.

The advantage of this approach is the reduced risk of bone marrow rejection compared to
allogeneic transplantation, and there is no need to search for a donor.

“Complete clinical remission can be achieved with this treatment,” said
Steven J.Gray, PhD, from the Gene Therapy Center at the University of North Carolina, Chapel
Hill, for Medscape Medical News.

“Sickle cell anemia, one of the classic genetic diseases, about which
everyone learns in their freshman year of biology. For those who work in the field of gene therapy, everyone
day, this is a real chance to achieve a complete cure for sickle cell anemia. And it gives
hope that the next generation of students will read about this incurable disease
only in history books, ”added Steven J.Gray.

Sources :

1. http://www.nejm.org/doi/full/10.1056/NEJMoa1609677
2. Brousseau DC, Panepinto JA, Nimmer M, Hoffmann RG. The number of people with sickle-cell
   disease in the United States: national and state estimates. Am J Hematol 2010; 85: 77-8.
3. Modell B, Darlison M.Global epide- miology of haemoglobin disorders and derived service
   indicators. Bull World Health Organ 2008; 86: 480-7.
4. Ingram VM. A specific chemical dif- ference between the globins of normal human and
   sickle-cell anaemia haemo-globin. Nature 1956; 178: 792-4.
5. Strouse JJ, Lanzkron S, Beach MC, et al. Hydroxyurea for sickle cell disease: a systematic
   review for efficacy and toxicity in children.Pediatrics 2008; 122: 1332-42.
6. Bernaudin F, Socie G, Kuentz M, et al. Long-term results of related myeloabla- tive
   stem-cell transplantation to cure sickle cell disease. Blood 2007; 110: 2749-56.
7. Bhatia M, Walters MC. Hematopoietic cell transplantation for thalassemia and sickle cell
   disease: past, present and future. Bone Marrow Transplant 2008; 41: 109-17.
8. Krishnamurti L, Abel S, Maiers M, Flesch S. Availability of unrelated donors for
   hematopoietic stem cell transplantation for hemoglobinopathies. Bone Mar- row Transplant
   2003; 31: 547-50.
9. Mentzer WC, Heller S, Pearle PR, Hackney E, Vichinsky E. Availability of related donors for
   bone marrow trans- plantation in sickle cell anemia.Am J Pediatr Hematol Oncol
   1994; 16: 27-9.

Material prepared : Subora Anton Yurievich, hematologist of the Department of Oncology,
hematology and bone marrow transplantation with intensive care unit, and clinical resident Oleinik
Yu.A.

Sickle cell anemia “Lakhta Clinic” Lakhta Clinic

Terminology

For more details about the composition and biological role of blood, about the essence of anemia – see.material “Anemia. Blood and bloodlessness. ”

Sickle cell anemia is a severe hereditary disease, also known as drepanocytosis, meniscocytosis, S-hemoglobin disease, Herrick’s syndrome, African hemolytic anemia (hemolytic – Greek literal “dissolving, decomposing blood”). Modern history The study of this type of anemia began, as it is believed, in the middle of the 19th century , when the spleen was not found in the body of an African slave executed for escape during an autopsy.Then in 1910 a message appeared, sponsored by Professor of Cardiology James B. Herrick and his intern Ernest E. Irons . In a blood test of a 20-year-old student who, since 1904, had been treated for “anemia, muscular rheumatism and bile spillage” (he died of pneumonia in 1916) Ironz observed and for the first time described erythrocytes of a strange shape, which he defined as “elongated and sickle. ” The name “sickle cell anemia” was first used as a diagnosis by Verne Mason in 1922 . Since the 1930s, epidemiological studies of this disease have begun in samples of children of African descent.

It can be assumed that the genetic mutation leading to sickle cell anemia appeared on the African continent – and, oddly enough, was fixed in the population as a useful trait: carriers of the gene and patients with this form of anemia show relative resistance to malaria. Plasmodium malaria parasitizes and destroys red blood cells, but erythrocytes, genetically mutilated and carrying a completely different hemoglobin (see.below), for Plasmodium “inedible”. And although the anemia of malaria is not sweeter, the mortality rate of swamp fever is still higher: those who had at least some immunity survived.

In an actively migrating humanity, which is becoming more and more international and gradually interracial, sickle cell anemia is widespread. However, a certain endemicity persists today: in Equatorial Africa, the Mediterranean Basin, India, and the Middle East, the frequency of genetic carriage (not to be confused with clinical morbidity) reaches 40%.
According to a special study conducted in 2001 in Jamaica, the average life expectancy of patients with homozygous sickle cell disease is 53 years for men and 58 years for women. About 90% live to 20 years old, about half to 50 years.

In other words, the problem is very serious, it is characterized by high medical and social significance and needs effective solutions, which are currently being searched for by leading specialized research centers.The prevalence of hereditary hemoglobinopathies (including sickle cell anemia) in the world is estimated at 3-7%. In the early 2010s, WHO classified sickle cell anemia as a global health problem.

The epidemiological situation and mortality rates in third world countries are unknown or insufficiently reliable.

According to the literature data, due to migration processes, the incidence in Russia shows a significant and stable tendency to increase, especially in Moscow and St. Petersburg.

Reasons

S-hemoglobin (from the English “a sickle” – sickle), encoded by a faulty gene, is much more viscous and about a hundred times less soluble than normal A-hemoglobin; in addition, the ability to bind oxygen and transport it to tissues is many times lower, which is what causes the anemic symptomatology of hypoxia itself. Erythrocytes containing altered hemoglobin differ in the shape of an elongated deformed crescent or sickle from normal blood cells, which have the appearance of a relatively thick biconcave disc.The unnatural shape and stiffness of S-erythrocytes leads to a tendency for them to block capillary channels. Hemolysis is sharply accelerated, i.e. the lifespan of S ‑ erythrocytes is much shorter than that of normal red cells.

In the patient’s blood, both normal and abnormal erythrocytes, or only abnormal ones, may be present. Obviously, in the second case, the disease is much more severe and the prognosis is worse; the first option may be little or even asymptomatic.
The type of inheritance is autosomal recessive.This means that for two parents – carriers of the gene, the probability of having a child with the same gene is 50%, and with the clinical form of sickle cell anemia – 25%. If only one of the parents is the carrier, the probability of inheriting the gene remains fifty percent, but the disease itself does not manifest in the child.

Symptoms

Like most genetic diseases, sickle cell disease is characterized by an extraordinary variety of possible symptoms, syndromes and complications.Their variability is so great that no clinical picture and no individual case can be considered typical.

The debut in most cases occurs in early childhood, and then three periods can be traced in the development of the disease.

In the initial period , as a rule, the symptoms of microthrombosis, osteoarticular pains and pains of other localization, swelling of the joints, enlargement of the spleen, and yellowness (due to the accelerated breakdown of hemoglobin) dominate.Such children are highly prone to infections, including osteomyelitis. The course of the disease at this stage is often of a crisis nature and is easily aggravated under any unfavorable conditions. For example, a hemolytic-type crisis is often provoked by an infection and can be fatal; aplastic, sequestration, vascular (thrombotic) crises are also life-threatening syndromes.
In many cases, there is a characteristic deformation of the structures of the musculoskeletal system and the bones of the skull: kyphosis, lordosis, acrocephaly (“tower skull”), as well as serious delays in psychophysical development.

At the second stage , abnormally intense production of erythrocytes can be observed as compensation for their failure. Due to thrombosis, heart or renal failure, strokes, diabetes mellitus, cirrhosis of the liver, trophic ulcers of the legs often develop. Most patients with such a severe picture of the second period die within several years.

The third period, if it occurs at all, is characterized by moderate hemolytic symptoms.The absence of the spleen (see above) is due to the phenomenon of wrinkling and self-destruction (autosplenectomy) after repeated heart attacks. The liver remains enlarged, there is a high predisposition to the purulent-inflammatory course of any infectious diseases.

Optional (possible in different cases, but not mandatory) complications of sickle cell anemia are cholelithiasis, aseptic necrosis of bone tissue (avascular osteonecrosis), immunodeficiency, priapism in men, preeclampsia and miscarriages in pregnant women, intrauterine growth retardation, necrosis, retinopathy (retinal detachment can result in complete blindness), pulmonary hypertension, and many others.dr.

More or less prolonged attacks of acute pain in bones, joints and muscles are characteristic. The National Health Service of Great Britain has included sickle cell anemia in the list of the most painful conditions.

Diagnostics

The diagnosis is established by the characteristic combination of symptoms common for anemias and specific manifestations. A thorough multifactorial laboratory blood test is being performed .A medical genetic examination is prescribed.

Treatment

Today there are only palliative, symptomatic treatment , which in many cases requires the participation of several specialized specialists. Prevention of infectious diseases, good nutrition, control of adequate intake of vitamins (especially B9 and B12) are of great importance.

It should be noted that in March 2017 The New England Journal of Medicine published an article in which a large group of authors reported the first case of significant relief of sickle cell anemia by genetic engineering.A French teenager received this treatment at the Necker University Hospital (Paris), known since 1802 as the world’s first specialized medical facility for children.

However, the prognosis of the further development and course of the disease, as well as the prospects for introducing the method into clinical practice, are still unclear. Hopefully, this success is definitely outstanding! – will mark the long-awaited and much-needed revolution in the treatment of sickle cell anemia and, in general, chromosomal diseases.

90,000 Blood transfusion policy for sickle cell disease during pregnancy

What is the problem?

Sickle cell anemia is an inherited disorder of the structure of hemoglobin, a protein in red blood cells that carries oxygen. In this condition, abnormal hemoglobin S from one parent is combined with another abnormal hemoglobin from the other parent. Hemoglobin S inherited from both parents (HbSS genotype), characterized as sickle cell disease, is the most common form.

Why is it important?

When the partial pressure of oxygen is low, hemoglobin S crystallizes and the red blood cells become sickle-shaped. Sickle reduces the ability of red blood cells to move through small blood vessels, causing vascular blockage and early destruction of red blood cells. Breakdown of red blood cells and massive accumulation of damaged red blood cells in the liver and spleen cause anemia. Acute illnesses include painful crises, pulmonary embolism, acute chest syndrome, and congestive heart failure.Therefore, a pregnant woman with sickle cell disease should be closely monitored.

Depending on the policy of the healthcare organization, blood transfusions can be given to a pregnant woman with HbSS at regular intervals with relatively few or no symptoms to improve the ability of cells to carry oxygen by increasing the concentration of hemoglobin in the blood and decreasing the level of hemoglobin S; or only with the development of medical complications or complications of pregnancy.Frequent blood transfusion carries the risk of developing blood-borne infections and excess iron levels.

This review aims to determine if there is a difference between blood transfusion at regular intervals before serious complications and medically indicated blood transfusion, and whether these methods have different effects on maternal and child health.

What evidence have we found?

We searched for evidence as of May 30, 2016 and found one clinical trial with an unclear risk of bias in which 72 women with sickle cell disease (hemoglobin SS) before 28 weeks of gestation were randomized (randomly assigned) to one of two groups with different strategies of blood transfusion.The clinical trial found no differences in severe illness and mortality among mothers or newborns. There was also no difference in the risk of a delayed response to a blood transfusion. This clinical trial suggests that blood transfusion at frequent intervals reduces the risk of a painful crisis with a high degree of uncertainty about the size of the effect, compared to transfusion only when medically indicated. Blood transfusion was performed in a ratio of 4: 1 as prophylactic versus selective, respectively.Overall, the quality of the evidence for outcomes meaningful to women is very low.

What does this mean?

The available evidence is insufficient to support changes in clinical practice and policy. More research is needed.

How sickle blood cells adhere to blood vessels

One of the most common complications of sickle cell disease is that deformed red blood cells clump together, blocking tiny blood vessels and causing severe pain and swelling in the affected parts of the body.

A new study from the Massachusetts Institute of Technology sheds light on how “vaso-occlusive” pain occurs.

“These painful crises are very unpredictable. In a way, we understand why they happen, but we don’t have a reliable way to predict them, ”says Ming Dao, chief scientist in the Department of Materials Science and Engineering at MIT and one of the senior authors of the study.

Sickle cell anemia is an inherited blood disorder in which red blood cells (erythrocytes) are sickle-shaped instead of the usual discoid.This is due to a mutation in the hemoglobin gene, as a result of which the red blood cells acquire a sickle shape and poorly carry oxygen.

To understand how red blood cells interact with blood vessels and cause vaso-occlusive pain, the researchers modeled a specialized microfluidic system that mimics the post-capillary vessels carrying deoxygenated blood from the capillaries.

One of the conditions of the experiment was to control the oxygen level.

Studies have shown that when oxygen levels are very low (hypoxia) similar to those observed in post-capillary vessels, sickle cells are two to four times more likely to attach to the walls of blood vessels than when oxygen levels are normal. At the same time, in a state of hypoxia, hemoglobin inside the sickle cells forms rigid fibers that grow and displace the cell membrane outward. These fibers also help cells adhere more tightly to the blood vessel endothelium.

The researchers also found that in patients with sickle cell disease, immature red blood cells called reticulocytes are more likely to adhere to blood vessels due to the fact that they have a larger cell membrane surface area than mature red blood cells, which allows them to create more adhesion sites.

Expert opinion:

Cell adhesion is indeed a very complex process. This discovery will help not only to understand in detail the mechanism of the occurrence of vaso-occlusive pain, but also to develop methods for predicting these crises in patients.

SICKLE ANEMIA | Encyclopedia Around the World

Contents of the article

SICKLE-CELL ANEMIA, hereditary human disease, in which red blood cells (erythrocytes), donating their oxygen, take on a bizarre elongated shape resembling a crescent or sickle. Normally, erythrocytes, giving off oxygen, change only color – bright red to bluish, but retain their usual rounded shape. With this disease, cells change not only color, but also shape.The immediate reason for this is a slight change in the chemical structure of hemoglobin, the main component of red blood cells. However, this change (replacement of only one amino acid in the protein part of the molecule) leads to the fact that the hemoglobin (hemoglobin S) formed in patients, giving off attached oxygen, becomes less soluble than normal hemoglobin (hemoglobin A), and turns into dense, semi-solid gel, which causes deformation of red blood cells. The synthesis of abnormal hemoglobin is generally referred to as hemoglobinopathy.

Sickle cell anemia is inherited, i.e. affects certain families, passing through the genes of parents to children. Thus, it can only be contracted by being born with a corresponding genetic disorder. If one of the family members is sick, sickle cells should be present in other family members, especially in parents and children, often in brothers and sisters, and often in more distant relatives.

The disease can be quite easy or very difficult.In the first case, symptoms occur rarely or only in special conditions. A very severe form usually leads to complete disability, proceeding with frequent attacks (crises) and shortening the life of patients. There are also intermediate forms of the disease, in which there are rarely such severe consequences and a longer life expectancy is possible, but they are also accompanied by crises from time to time.

Inheritance.

Studies have shown that a mild form of the disease is usually found in heterozygotes for this trait – in other words, in those who inherited the defective gene from only one parent and will pass it on to only half of their possible offspring.These persons have the so-called. heterozygous sickle cell anemia (S – A, or A – S). Although they themselves are practically not sick and may never get sick, they are still carriers of the disease, and – before special testing – latent carriers.

The most severe form of the disease affects homozygotes for the defective gene, i.e. inherited it from both mother and father; they will pass this gene on to all their descendants. Their condition is called homozygous sickle cell anemia (S – S).

An intermediate form of the disease is usually found in double heterozygotes, i.e.That is, individuals who are heterozygous for both this and any other hemoglobinopathy (for example, they synthesize hemoglobin C). In such cases, one speaks of S – C disease or some similar condition.

Prevalence.

Most affected families are of the black race, but the disease occurs in the white population as well. It is widespread in some African countries, in particular in Ghana, but in other regions, for example in South Africa, it is extremely rare.Sick families were also found in the southern regions of India, Italy, Greece and Turkey. In the western hemisphere, sickle cell disease affects people from Africa, India and the Mediterranean countries, regardless of where they live. This disease occurs throughout the United States and South America, but most often in areas where African Americans live. According to rough estimates, in the United States, one in 10 African Americans is a carrier of the disease, and one in 375 has an overt form; overall, the number of patients with sickle cell disease in the United States is estimated to exceed 50,000.

The mechanism of the disease.

In persons with sickle cell anemia, the majority of red blood cells retain their normal discoid shape. However, in certain circumstances, namely with a lack of oxygen, their shape changes. They become elongated, pointed and rigid, which prevents their free movement along the vascular bed and leads to blockage of blood vessels, especially the smallest ones. Due to insufficient blood supply to the tissues, the processes of decay and inflammation begin in them, causing pain and functional disorders.Most often, pain occurs in the limbs, abdomen, lower back, or in the head. The most commonly affected organs are the lungs, bones, spleen, kidneys, heart, and brain.

In addition to their bizarre shape, sickle cells are less durable than normal cells and have a shorter lifespan. Therefore, in patients with sickle cell anemia, despite the increased rate of erythrocyte formation, the hemoglobin content is reduced. They appear anemic and often somewhat icteric (due to the rapid breakdown of red blood cells).Growth and maturation are slowed down in childhood and adolescence. Patients are extremely susceptible to any infection; they tolerate malnutrition and dehydration worse, since the kidneys lose their ability to retain water; surgery and childbirth are more dangerous. It should be emphasized that complications and crises occur only from time to time. Even the most severely ill have long periods when they feel relatively healthy and can lead a normal life.

Diagnostic tests.

The diagnosis of sickle cell anemia is based on the analysis of the physical properties of hemoglobin. The first and oldest method of such analysis is the study of the so-called. “Wet smear”. When a blood smear is moistened with sodium metabisulfite, erythrocytes give off oxygen and under a microscope you can see a characteristic change in their shape. For greater accuracy, the study is repeated after 24 hours. Another, more common method is based on the detection of sickle cell hemoglobin by its reduced solubility in some buffer solutions, which is determined by the turbidity of a solution containing such hemoglobin.The widespread use of this method is associated with the ability to quickly obtain results (within 10-15 minutes).

Unfortunately, these methods do not allow distinguishing a heterozygous state from a homozygous one. Currently, this can only be done using hemoglobin electrophoresis, i.e. analysis of its mobility in an electric field. Neither accurate diagnosis nor reliable counseling is possible without such an analysis, but for mass examinations it is too expensive and time-consuming.

Treatment.

Today sickle cell anemia is an incurable disease. However, its identification is extremely important for the correct treatment of other diseases in these patients, as well as for providing them with adequate surgical and obstetric care. Correct management of patients with chronic sickle cell disease helps to prevent severe exacerbations (crises) and prolong life.

In some cases, the development of a severe crisis can be prevented by the rapid introduction of antibiotics in its early stages (to stop the infection) and the infusion of fluid (hydration).Oxygen, pain relievers, intravenous fluids, and antibiotics are commonly used to treat an advanced crisis. Sometimes it is necessary to resort to transfusion of red blood cells, as well as to use many other drugs, such as anticonvulsants, to relieve certain symptoms. See also ANEMIA.

90,000 The story of the first patient to receive CRISPR therapy for sickle cell disease

When Victoria Gray was three months old, doctors diagnosed her with sickle cell disease.The cause of this dangerous hereditary disease is a mutation in the hemoglobin gene, due to which red blood cells acquire a characteristic curved shape and cannot carry oxygen normally. Worse, at times, the deformed cells block the blood flow, causing severe bouts of pain and heart attacks.

Due to illness, Victoria was unable to play with other children and spent a lot of time in hospitals. As the girl grew older, she managed to go to college, but in the end anemia took its toll, forcing her to drop out and give up her dream of becoming a nurse.She later had to leave her job as a cosmetics saleswoman.

By the age of 34, Victoria, who lives in Mississippi, had two children. However, the girl still felt inferior, because she could not spend enough time with them and often went to hospitals – sometimes right in the middle of the night.

The girl considered the possibility of a bone marrow transplant, which is sometimes used to treat her illness. However, she knew that this was a very risky procedure.Fortunately, doctors offered Victoria another way – to participate in the first clinical trials of gene therapy for sickle cell disease using CRISPR. Unsurprisingly, she agreed.

With the patient’s consent, doctors at the Sarah Cannon Research Institute in Nashville, Tennessee began their procedures. They removed her bone marrow cells and used CRISPR to turn them on to produce fetal hemoglobin, which normally stops synthesizing immediately after birth.According to the doctors’ idea, this was to compensate for the malfunctioning of the “adult” hemoglobin and return some of the red blood cells to normal. After editing the cells, they were multiplied and injected back into the girl’s body. In total, she received 2 billion edited cells.

The operation took a lot of forces from Victoria. The most difficult was chemotherapy, which was needed to make room for the edited cells in the bone marrow.

After several months of waiting, the doctors told Victoria the news she had been waiting for: the transplanted cells began to produce fetal hemoglobin.Analysis showed that this type of hemoglobin made up half of all hemoglobin in her body. This is enough to relieve the symptoms of sickle cell disease. No side effects were identified.

However, the girl herself felt an improvement. Since the operation, she has had no bouts of pain, although they usually recur on a regular basis. In addition, all this time she did not need blood transfusions.

Physicians and researchers are extremely encouraged by Victoria’s findings.Encouraging news came from a second CRISPR patient, a German woman with beta-thalassemia. However, experts urge caution. It will take years to evaluate the results and possible side effects of the treatment.

Researchers in the United States have found a simple way to increase the efficiency of CRISPR by modifying the ends of the inserted genes. This paves the way for its widespread use in medicine.

Blood (part 3 of 8)