Hemolysis is the term given to when red blood cells break down. It’s an important underlying feature of sickle cell diseases.
To understand why hemolysis happens in people with sickle cell disease, it’s useful to understand the basic structure of hemoglobin molecules.
Hemoglobin molecules have four subunits, two beta-globin, and two alpha-globin molecules. In normal hemoglobin, these four subunits are finely balanced to allow oxygen to bind and unbind without causing the hemoglobin to change shape.
Sickle cell disease causes a mutation (SS) in the two beta-globin subunits. In instances of low oxygen, the abnormal hemoglobin clumps to form long chains This is called “polymerization.” This in turn changes the structure of the red blood cell membrane. Unlike normal red blood cells, which are flexible and disc-shaped, sickle cells become rigid and sticky, sticking to each other and the blood vessel walls. When there is enough oxygen, sickle cells can resume their normal shape.
Have you ever broken a wire by bending it back and forth repeatedly? This is essentially what happens when sickle cells repeatedly change their shape. In time, they fracture and break apart. This breakdown is known as hemolysis. The normal lifespan of a red blood cell is 120 days, the lifespan of a sickle cell is just 14 days.
Hemolysis is considered an important part of the pathophysiology of sickle cell anemia. (The term pathophysiology relates to the processes within the body that contribute to a disease). The breakdown of red blood cells releases hemoglobin into the bloodstream that can lead to many complications. The most obvious result of hemolysis is anemia, due to the fact that the production of red blood cells can not keep up with the hemolysis.
Hemolysis can lead to very low hemoglobin levels. Symptoms include:
More serious symptoms include anemia which can be a result of something called “splenic sequestration”. That’s when the spleen swells with blood. The blood count falls dramatically which can lead to death if not recognised and treated in time. The liver can also swell with blood, causing anaemia. For more information see Complications below.
The release of hemoglobin into the blood stream can cause many problems for people who have sickle cell disease. Hemolysis is associated with increased inflammation, pulmonary and systemic hypertension, leg ulcers, priapism, stroke, hyperbilirubinemia and gall stones. There is an increased risk of early death for people who have severe persistent hemolytic anemia.
Delayed Hemolytic Transfusion Reaction
There are two types of transfusion reactions that occur in people who have sickle cell disease. The most common is Delayed Hemolytic Transfusion Reaction (DHTR). This usually occurs with people who have rare blood types which are difficult to match with donor blood.
If the recipient’s blood type doesn’t match that of the donor, the recipient’s immune system reads the blood given for transfusion as foreign and destroys the transfused blood cells over time. This leads to decreased hemoglobin.
Hyperhemolytic Transfusion Reaction
A much less common reaction to a transfusion is called a hyperhemolytic transfusion reaction. This can be delayed, but frequently occurs soon after the transfusion. Sometimes it can be caused by a mismatch, but often the exact reason isn’t known.
The hemolysis is severe and not only are the transfused red cells destroyed, the patient’s own red cells are destroyed leading to severe anemia. Giving further blood transfusions sometimes leads to worse anemia and can be life-threatening. The treatment is to suppress the immune system.
HS usually happens when there is a higher rate of hemolysis, and red blood cells are destroyed by macrophages. Macrophages are cells of the immune system that usually destroy bacteria in the body. They are our body’s army against unwanted pathogens. However, in HS, these macrophages can become hyper-activated and start killing cells that they should not be, like red blood cells.
Increased hemolysis increases the demand for folate. This is because folate is an important component in building red blood cells. If red blood cells are constantly breaking down, then they continually need to be produced in the body. This can lead to folate deficiency, which can be dangerous because folate helps to maintain stable hemoglobin levels and effective red blood cell production as well as prevent blocked blood vessels. Of note, folic acid is frequently given to people who have sickle cell disease without knowing that the folate level is low and the vitamin B 12 level is normal. This blanket treatment has been discouraged by some experts.
Splenic sequestration happens when blood cells get trapped in the spleen. The spleen is responsible for filtering the blood for infection and filtering out old red blood cells. After hemolysis, these broken-down red blood cells go through the spleen. Sometimes, the sickle cells cause the spleen to enlarge and trap more sickle cells, leading to anaemia. This commonly occurs in children under three, but can occur in adults. t trapped. Splenic sequestration might present as pain in the left side of the belly.
Along with the serious complications above, studies have also shown that complications of sickle cell anemia due to hemolysis can include leg ulcers, priapism, and pulmonary hypertension. Leg ulcers are open sores or wounds, priapism is persistent and often painful erections, and pulmonary hypertension is high blood pressure in the blood vessels of the lungs.
Some diagnostic tests for hemolytic anemia include:
Since sickling often leads to damaged red blood cells, hemolysis, and sickle cell anemia, many of the treatments for hemolysis target sickling. However, the treatments listed below are specific to hemolysis.
Fetal hemoglobin (quite literally, the hemoglobin produced by fetuses and young babies) doesn’t contain beta-globins, instead it contains gamma-globin subunits. These are not affected by the sickle cell mutation. So fetal hemoglobin can keep red blood cells from sickling. Hydroxyurea is a Food and Drug Administration (FDA)-approved drug that has been proven to prevent pain in sickle cell disease by increasing fetal hemoglobin levels, which increase the amount of healthy red blood cells in the body.
Since the abnormal red blood cells are what cause sickling and hemolysis, blood transfusions in which healthy red blood cells replace unhealthy ones are a common way to treat hemolysis in sickle cell disease. In the case of spleen or liver sequestration, or parvoviral infections, blood transfusions are used in an emergency.
They cannot be used in cases of transfusion reaction unless the offending red cell membrane antigen is identified and the transfused red blood cells do not have this antigen.
The two kinds of transfusions are simple and exchange transfusions. Simple transfusions deliver healthy red blood cells but don’t take blood away from the patient. Exchange transfusions replace the patient’s sickle-shaped blood cells with healthy red blood cells.
Generally only simple transfusions are used for hemolytic anemia as automated red cell exchange is not as safe in a person with a very low hemoglobin. A simple transfusion is easier and just as effective.
Splenic sequestration is a common complication of hemolysis, and an enlarged spleen can actually malfunction and destroy even more red blood cells, making the sickle cell anemia even worse. A common surgery to treat hemolysis is to remove the spleen.
The spleen is necessary for the removal of some bacteria such as pneumococcus and H. influenza. Young children who have a splenectomy are at higher risk of infection and should be treated with antibiotics (amoxicillin or penicillin prophylaxis) following a splenectomy. In hemoglobin SS the spleen is not functional in most children by the age of five years.
Bone marrow stem cell transplant:
A bone marrow stem cell transplant can completely cure sickle cell anemia. This is because the bone marrow is where the faulty red blood cells with abnormal hemoglobin are made. With a bone marrow transplant, healthy stem cells from a donor replace the abnormal stem cells in the patient, meaning they will no longer produce red blood cells that can sickle and cause hemolysis.
To prepare for transplant, the recipient is given preparative chemotherapy for a week or so prior to the transplant to destroy their bone marrow. Some regimens include hydroxyurea given for a longer period of time.
The destroyed marrow is replaced by a matched donor’s marrow. Following infusion of the donor cells, there is now chemotherapy (cyclophosphamide) given to prevent the donated bone marrow from viewing the recipient’s body as foreign and attacking their cells.
Today, both children and adults with SCD can be treated with a stem cell transplant. However, it is not a perfect cure. Only 1 in 10 children with SCD have a family member without SCD that is a match. Additionally, older adults have a greater risk of rejecting the transplant.
Abdu A. et al. “The oxygen affinity of sickle hemoglobin.” Respir Physiol Neurobiol, 2008 Mar 20; 161(1): 92-4.
Ballas, Samir K. et al. “Folic acid supplementation and twin pregnancy in patients with sickle cell disease.” Blood. 2004. 104(11): 3744.
Banks, Mara, MD, PhD and Shikle, James, MD. “Hyperhemolysis Syndrome in Patients with Sickle Cell Disease.” Archives of Path & Lab Med. 2018 Nov; 142(11): do: https://doi.org/10.5858/arpa.2017-0251-RS.
“Blood Transfusion.” Sickle Cell Anemia News. https://sicklecellanemianews.com/blood-transfusion/ (accessed July 27, 2019).
Bykersma, Alexander. “Sickle Cell Disease and Hydroxyurea Treatment.” AMSJ, April 16, 2018, http://www.amsj.org/archives/6388 (accessed July 27, 2019).
Charache, S. “Mechanism of action of hydroxyurea in the management of sickle cell anemia in adults.” Semin Hematol, 1997 Jul; 24(3 Suppl 3): 15-21.
DeBaun, Michael. “A New Therapy for Sickle Cell Disease: FDA Approves Oral L-glutamine for Prevention of Acute Vaso-occlusive Events in Children and Adults.” American Society of Hematology, October 2, 2018.
“Hemolytic anemia.” AMBOSS, https://www.amboss.com/us/knowledge/Hemolytic_anemia# xid=rT0fH2&anker=Z958cf76990e9ccf502442ead34e224b0 (accessed July 25, 2019).
“Hemolytic Anemia.” NIH, https://www.nhlbi.nih.gov/health-topics/hemolytic-anemia (accessed July 27, 2019).
“How is Hemolytic Anemia Treated?” Centers for Cancer Care and Blood Disorders,
https://www.hoacny.com/patient-resources/blood-disorders/what-hemochromatosis/how-hemolytic-anemia-treated (accessed July 27, 2019).
Kahn, April, Nall, Rachel, Sampson, Stacy, DO. “Hemolytic Anemia: What It Is and How to
Treat It.” Healthline, Feb 5, 2019. https://www.healthline.com/health/hemolytic-anemia (accessed July 25, 2019).
Ikechukwu Okwerekwu and J. Andrew Skirvin. “Sickle Cell Disease Pain Management.” US Pharm. 2018 43(3): 12.
Kato, GJ, Steinberg, MH, and Gladwin, MT. “Intravascular hemolysis and the pathophysiology of sickle cell disease.” J Clin Invest 2017 Mar; 127(3): 750-760. doi: 10.1172/JCI89741. Epub 2017 Mar 1.
“The Lymph System.” The Sickle in Me, August 23, 2014. http://www.thesickleinme.org/the-lymph-system.html (accessed March 14, 2019).
Saldana, Jose Ignacio. “Macrophages.” British Society for Immunology, https://www.immunology.org/public-information/bitesized-immunology/c%C3%A9lulas macrophages (accessed July 27, 2019).
“Sickle cell disease.” NIH U.S. National Library of Medicine, August 2012.
https://ghr.nlm.nih.gov/condition/sickle-cell-disease#definition (accessed July 25, 2019).
“Stem Cell Transplant Reverses Sickle Cell Disease in Adults.” NIH. July 14, 2014, https://www.nih.gov/news-events/nih-research-matters/stem-cell-transplant-reverses-sickle-cell-disease-adults (accessed July 27, 2019).
Taylor, James G. IV et al. “Chronic Hyper-Hemolysis in Sickle Cell Anemia: Association of Vascular Complications and Mortality with Less Frequent Vasoocclusive Pain.” PLOS One, 2008 May; 3(5): e2095. https://doi.org/10.1371/journal.pone.0002095