Abstract - 2018 - Research and Practice in Thrombosis and Haemostasis

Researchers Say Deadly Twist Key To Sickle Cell Disease

Patients with sickle cell disease have mutant haemoglobin proteins that form deadly long, stiff fibres inside red blood cells. A research team led by University of Warwick researcher Dr Matthew Turner, propose a mathematical model in the 28 March online issue of PRL to explain the persistent stability of these deadly fibres. The theory suggests that an inherent "twistiness" in the strands that make up the fibres could be the key to their durability and possibly to new treatments.

Red blood cells supply oxygen to the body using their cargo of haemoglobin, a protein that can capture and release oxygen. Haemoglobin molecules normally float freely in the cell, but sickle cell patients have a mutated, "sticky," form of haemoglobin that tends to clump together into long fibres. The stiff fibres form a scaffolding that distorts the cells into their namesake "sickle" shape, so they jam up trying to pass through small blood vessels. The traffic jams deprive vital organs of oxygen, so patients end up with anaemia, jaundice, major organ damage, and many other maladies.

A sickle haemoglobin fibre can be made up of anywhere from 14 to more than 400 individual strands of haemoglobin molecules linked into long chains. Matthew Turner, of the University of Warwick in the UK, wondered why these strands tend to clump together into long, stiff, fibres rather than compact crystals, which would be less harmful. "A scaffolding made of the rigid fibres is much worse than a couple little sugar-cube-like crystals floating around," Turner says. So he and his colleagues constructed a mathematical model.

The team's equations start with the trade-offs that exist in any material as it tries to find the shape with the least overall stress. The forces at work include bending and stretching, and for haemoglobin strands, there is also a propensity to stick together. This stickiness would normally make a thick, compact crystal more stable than a thin fibre, Turner explains, because a crystal maximizes the contact area of the protein with itself. But for sickle haemoglobin, fibres are more stable. To favour fibres, the equations needed to include the fact that the individual strands of molecules are inherently "twisty." They behave like the coiled wire that attaches a telephone to its handset, apparently because the molecules link up in a way that favours twisting. The strands wrap around one another like threads of rope to form the fibres. In their paper, the team shows that their model's predictions for two of the mechanical properties of fibres agree with experiments.

Turner says that the model suggests a possible treatment for sickle cell disease. Gene therapy could introduce a haemoglobin mutant that formed less-twisty individual strands, and this "good mutant" might turn fibres into less harmful crystals. Simply introducing normal haemoglobin has been shown not to work, perhaps because the few normal haemoglobin molecules cannot eliminate the fibres.

What Is Sickle Cell? - De Montfort University

Sickle cell disorders (SCD) are inherited chronic illnesses that affect all ethnic groups. They occur more frequently in people of African, Caribbean, Middle Eastern, Indian and Mediterranean descent. Sickle-cell anaemia is the most common of these inherited conditions. SCD affects many parts of the body, and is associated with severe painful crises.

People with sickle-cell anaemia have a type of haemoglobin (called haemoglobin S (HbS) or sickle haemoglobin) which differs from usual haemoglobin (haemoglobin A or HbA). Haemoglobin is the substance in our red blood cells that gives blood its red appearance. The function of haemoglobin is to transport oxygen from the lungs to the rest of the body.

The transfer of oxygen takes place in the narrow blood vessels called capillaries. These may be no more than the width of a red blood cell. In people with usual haemoglobin A, the red blood cells remain round and flexible to enable them to squeeze through the capillaries. However in people with sickle haemoglobin, the haemoglobin forms into long rigid chains.

These chains distort the cell membrane into odd shapes - often like the shape of the old-fashioned farming implement called a sickle. Such sickle-shaped cells are not as flexible and easily become stuck in the narrow blood vessels. When this happens, that part of the body becomes deprived of oxygen. The result is mild, moderate or excruciating pain in the part of the body affected, with the possibility of permanent damage to the tissue.

The current treatments for sickle-cell anaemia are painkillers for the crises, and blood transfusions for particular types of crises where the bone marrow production of new blood cells collapses. The most recent promising treatment involves a drug called hydroxyurea, which has been shown to reduce the incidence of crises, though at the cost of some side effects.

The aim is therefore to try to prevent the complications that can arise with sickle-cell anaemia. Penicillin is given daily to try to ward off infections which, especially for the first seven years of life, could be life threatening for children.

A full and up-to-date set of vaccinations is also vital for people with sickle cell. Folic acid supplements are given to promote the production of red blood cells. Certain factors have been identified as more likely to precipitate a painful sickle cell crisis. These include infections, cold/damp conditions, dehydration, strenuous exertion, stress, sudden changes in temperature, alcohol, smoking and anaesthetics.

Advice to sufferers on preventing crises therefore includes keeping warm, eating healthily, taking moderate exercise, taking plenty of fluids, and keeping up to date with medications and vaccinations.

Sickle Cell Carriers

A sickle cell carrier is someone who carries a gene associated with sickle cell, but who, except in rare exceptional circumstances, is usually perfectly healthy themselves. There are about 250,000 sickle cell carriers (people with sickle cell trait) in the UK with around 15,000 people living with a sickle cell disorder.

If both biological parents are sickle cell carriers, then in each pregnancy there is a one in four chance that they will have a child with sickle-cell anaemia; a one in four chance they will have a child with usual haemoglobin; and a one in two chance that they will have a child who is a sickle cell carrier

The Pattern of Inheritance of Sickle Cell Disorders

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Simon DysonProfessor of Applied SociologyRoom 1.27 Hawthorn BuildingDe Montfort UniversityLeicester LE1 9BHT: +44 (0)116 257 7751E: sdyson@dmu.Ac.Uk

Sickle Cell Explained

Sickle Cell Disorders (SCD) are inherited chronic illnesses that affect all ethnic groups. They occur more frequently in people of African, Caribbean, Middle Eastern, Indian and Mediterranean descent. Sickle Cell anaemia is the most common of these inherited conditions. SCD affects many parts of the body and is associated with severe painful crises.

People with Sickle Cell anaemia have a type of haemoglobin (called haemoglobin S (HbS) or Sickle haemoglobin) which differs from usual haemoglobin (haemoglobin A or HbA). Haemoglobin is the substance in our red blood cells that gives blood its red appearance. The function of haemoglobin is to transport oxygen from the lungs to the rest of the body.

The transfer of oxygen takes place in the narrow blood vessels called capillaries. These may be no more than the width of a red blood cell. In people with usual haemoglobin A, the red blood cells remain round and flexible to enable them to squeeze through the capillaries. However in people with Sickle haemoglobin, the haemoglobin forms into long rigid chains.

These chains distort the cell membrane into odd shapes - often like the shape of the old-fashioned farming implement called a Sickle. Such Sickle-shaped cells are not as flexible and easily become stuck in the narrow blood vessels. When this happens, that part of the body becomes deprived of oxygen. The result is mild, moderate or excruciating pain in the part of the body affected, with the possibility of permanent damage to the tissue.

The current treatments for Sickle Cell anaemia are painkillers for the crises, and blood transfusions for particular types of crises where the bone marrow production of new blood cells collapses. The most recent promising treatment involves a drug called hydroxyurea, which has been shown to reduce the incidence of crises, though at the cost of some side effects.

The aim is therefore to try to prevent the complications that can arise with Sickle Cell anaemia. Penicillin is given daily to try to ward off infections which, especially for the first seven years of life, could be life threatening for children.

A full and up-to-date set of vaccinations is also vital for people with Sickle Cell. Folic acid supplements are given to promote the production of red blood cells. Certain factors have been identified as more likely to precipitate a painful sickle cell crisis. These include infections, cold/damp conditions, dehydration, strenuous exertion, stress, sudden changes in temperature, alcohol, smoking and anaesthetics.

Advice to sufferers on preventing crises therefore includes keeping warm, eating healthily, taking moderate exercise, taking plenty of fluids, and keeping up to date with medications and vaccinations.

Sickle Cell Carriers

A Sickle Cell carrier is someone who carries a gene associated with Sickle Cell, but who, except in rare exceptional circumstances, is usually perfectly healthy themselves. There are about 250,000 Sickle Cell carriers (people with Sickle Cell trait) in the UK with around 15,000 people living with a sickle cell disorder.

If both biological parents are Sickle Cell carriers, then in each pregnancy there is a one in four chance that they will have a child with Sickle Cell anaemia; a one in four chance they will have a child with usual haemoglobin; and a one in two chance that they will have a child who is a Sickle Cell carrier.

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