This is the first part of our series about the condition based on our patient booklet “Fast Facts for Patients and Supporters: Pyruvate Kinase Deficiency”, which is freely available online. This article explains what pyruvate kinase deficiency is.
Pyruvate kinase (PK) deficiency is a rare genetic disease that affects red blood cells. Everyone who has PK deficiency is born with it, even if they are diagnosed later in life. To understand how PK deficiency affects you, you need an understanding of the role of healthy red blood cells and pyruvate kinase, and what happens to red blood cells in PK deficiency.
The Role of Red Blood Cells
Red blood cells have a flexible shape called a biconcave disc, which looks like a flattened sphere. This flexible shape allows the cells to squeeze through narrow blood vessels (capillaries) as they deliver oxygen to the body. Healthy red blood cells can squeeze through the smallest capillaries.
The Role of Pyruvate Kinase
Red blood cells make energy by converting glucose (a sugar) into pyruvate (an important molecule in metabolism) and a high-energy molecule called adenosine triphosphate (ATP) in a multistep process called glycolysis.
Pyruvate kinase is an enzyme that makes the last step in this process happen. It converts a protein called phosphoenolpyruvate into pyruvate and ATP. Less pyruvate kinase results in less ATP, so red blood cells have less energy.
The energy generated by glycolysis helps healthy red blood cells to keep their normal shape, stay flexible and protect themselves from injury (oxidative damage). In people with a normal amount of pyruvate kinase, red blood cells can generate enough ATP to last an average of 120 days.
The Breakdown of Red Blood Cells
The breakdown of red blood cells is called hemolysis. Normally, after 120 days, red blood cells break down and are removed from the circulation by the spleen.
Red blood cells that do not have enough pyruvate kinase cannot make enough energy to hold their shape, and they break apart more easily than healthy red blood cells. Instead of lasting 120 days, PK-deficient red blood cells only last a few days to weeks.
The breakdown of red blood cells (hemolysis) causes hemolytic anemia (a low red blood cell count or low hemoglobin level) and jaundice (yellowing of the skin), which is caused by bilirubin, a substance released from red blood cells as they break down.
Replacement of Red Blood Cells
In healthy individuals, the bone marrow makes enough young red blood cells (reticulocytes) to balance the old or damaged red blood cells that are removed from the circulation by the spleen. Reticulocytes usually make up 1–2% of all the circulating red blood cells. The bone marrow also makes more reticulocytes when PK-deficient red blood cells break down, but overall more red blood cells break apart than are made.
Reticulocytes require more energy in the form of ATP than older red blood cells but, unlike mature red blood cells, they can make energy through pathways other than glycolysis. Reticulocytes are therefore less reliant on normal levels of pyruvate kinase than mature red blood cells. However, these alternative pathways rely on the presence of oxygen. The capillaries in the spleen are low in oxygen, so when reticulocytes flow through the spleen the alternative energy pathways no longer function, and the reticulocytes become reliant on glycolysis for energy.
In this environment, PK-deficient reticulocytes cannot make enough ATP and become dehydrated. They are then quickly destroyed in the spleen and/or liver. If people with PK deficiency have their spleen removed surgically (splenectomy), the reticulocytes have enough oxygen to make energy through the alternative energy pathways and can last longer. This is why the reticulocyte count increases after splenectomy in patients with PK deficiency.
What Else Happens to Glycolysis in Pyruvate Kinase Deficiency?
Although the main problem in PK deficiency is the inadequate amount of ATP made at the end of glycolysis, without enough pyruvate kinase for glycolysis to work efficiently, products made earlier in the pathway build up.
2,3-DPG controls the release of oxygen from red blood cells to different parts of the body. As 2,3-DPG rises, more oxygen is released from hemoglobin into the tissues.
Normally, the amount of 2,3-DPG is tightly regulated so that the body receives the right amount of oxygen. In PK deficiency, the levels of 2,3-DPG rise and more oxygen is released from hemoglobin into the tissues. Because of this, people with PK deficiency may tolerate a lower hemoglobin level than people with other types of anemia in which 2,3-DPG is not elevated.
Information based on Fast Facts for Patients and Supporters: Pyruvate Kinase Deficiency (Karger, 2019).