Sickle cell disease and pathophysiology


Sickle cell disease is an inherited condition that affects red blood cells. There are several different types of sickle cell disease with a range of symptoms and complications.   It can increase the risk of severe morbidity and mortality in sickle cell patients. Sickle cell disease is complex and incompletely understood, it is worth summarising the current understanding of the morbid anatomy of these diseases.  Due to the abnormal beta globin chain, red cell survival is curtailed and there is chronic anaemia. Even more important is polymerisation of haemoglobin S (HbS) within red cells, resulting in the irreversible sickling of red cells under certain physical conditions. The clinical manifestations of sickle cell are diverse.

The consequences are numerous and affect most of the organs in the body:

Haemolysis resulting in anaemia: Haemolytic anaemia is a disorder in which red blood cells are destroyed faster than they are made.  The destruction of red blood cells is called haemolysis.  Red blood cells are broken down more quickly than they can be replaced, resulting in anaemia.  Anaemia is the condition of having less haemoglobin (the substance on the red blood cells which carries oxygen) than normal.

Sickle cell obstruction of small vessels causing ischaemic damage

(A) In bones, this is the origin of the sickle bone pain and the source of fat and marrow embolism.  A fat embolism is a piece of intravascular fat that lodges within a blood vessel and causes a blockage of blood flow.  Fat embolism usually occurs after fractures to the long bones of the lower body, specifically the femur (thighbone), tibia (shinbone), and pelvis, resulting in avascular necrosis and local infection (osteomyelitis). Osteomyelitis can be an acute or a chronic inflammatory process of the bone caused by infection.

(B) In lungs, it may cause acute chest syndrome. Acute chest syndrome is a severe lung-related complication of sickle cell disease that affects both children and adults.  It creates pneumonia-like illness and is one of the leading causes of morbidity, hospitalisation and death in children and adults living with sickle cell.

(C) In kidneys, it causes medullary damage with impaired urinary concentrating ability. People with sickle cell can develop chronic kidney disease because of reduced blood flow to the common cause of death for people’s kidneys. Chronic kidney disease can lead to end-stage renal disease and is a common cause of death for people with SCD.

(D) In skin, it causes chronic leg ulcers. The cause is complex but is thought to be related to the sickled red cells causing obstruction to the small blood vessels, reducing oxygen to the skin and venous incompetence.  Pain within sickle crisis can also reduce mobility and may cause stiffening of the ankle, thereby reducing venous function further.  The combination of these factors can create the environment for an ulcer to develop followed by infection inflammation.

(E) Cumulatively, it can result in multi-organ failure. Acute multiorgan failure syndrome is a severe, life-threatening complication of pain episodes in patients with otherwise mild sickle cell.  Sickle cells that block blood flow to organs deprive the affected organs of blood and oxygen.  In sickle cell anaemia, blood is always low in oxygen. This lack of oxygen-rich blood can damage nerves and organs including kidneys, liver, and spleen and this can become fatal.

Sequestration of sickle cells in e.g., spleen and liver, causing sequestration crises. These occur when an excessive amount of blood becomes trapped in the spleen, causing a dangerous drop in the circulating blood volume.

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Sickle cell/endothelial cell interaction and cumulative vascular damage in:

(A) Lungs causing pulmonary hypertension. One possible reason sickle cell patients develop pulmonary hypertension is that increased breakdown of red blood cells within the blood vessels causes inflammation and a decrease of nitric oxide (a substance that causes relaxation of the blood vessels).  This causes constriction of the small arteries of the lungs which may lead to pulmonary hypertension.

(B) The brain, causing arterial abnormalities and stroke (ischaemic and haemorrhagic). An ischemic stroke occurs when a blood vessel supplying the brain becomes blocked and a hemorrhagic stroke occurs when a blood vessel bursts, leaking blood into the brain.

(C) Sickle cell diseases produce many structural and functional abnormalities in the kidney, including glomerular abnormalities, causing glomerular renal failure. Glomerular disease reduces the kidneys’ ability to maintain a balance of certain substances in the bloodstream.  Normally, the kidneys filter toxins out of the bloodstreams and excrete them in the urine but keep red blood cells and protein in the bloodstream. In people with glomerular renal failure, the red blood cells and protein may be excreted into the urine, while toxins may be retained.

(D)Skin-causing leg ulcers. The cause of leg ulcers is related to the sickled red blood cells causing obstruction to the small blood vessels, reducing oxygen to the skin and veins.  Pain within the sickle crisis can also reduce mobility and may cause stiffening of the ankle thereby reducing venous function. The combination of all these factors can create the environment for an ulcer to develop, followed by infection and inflammation

I will conclude the pathophysiology of sickle cell disease next week.

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