Vaso-Occlusive Crisis in Sickle Cell Patients

Hemoglobin S (HbS) is an abnormal form of hemoglobin and is transmitted through genetically from parents to a child. Normal hemoglobin is mostly made up of 4 globin chains; 2 alpha chains and 2 beta chains. The underlying problem is a single mutation in the beta-chain of the hemoglobin where adenine nucleotide is replaced with a thymidine nucleotide resulting in a missense mutation and changing the amino acid glutamate at no. 6 position with valine. This change in amino acids from glutamate to valine results in changes in the 3-dimensional structure of the beta-chain of hemoglobin. These changes include 1) lower affinity for oxygen, 2) ability to join with other hemoglobin molecules and form polymers, 3) increase oxidation of the RBC cell membrane proteins.

Normal hemoglobin gets oxygenated in the lungs and carries oxygen to the tissues. Oxygen is released in the tissues and hemoglobin gets deoxygenated and returns back to the lungs for oxygenation. Normal hemoglobin remains soluble within the RBC throughout this process. On the other hand, deoxygenated HbS starts forming long filamentous through polymerization of hemoglobin molecules. Importantly, the process takes several seconds in fresh red blood cells (RBC) before polymerizations occurs and there is sufficient time for RBCs to return back to the lungs and get oxygenated.

However, some cells continue to get stuck in blood vessels resulting in completion of polymerization and breakdown of RBCs within the vessels (called intravascular hemolysis). This chronic, slow process of premature destruction of RBC in sickle cell patients is the reason for chronic anemia as well as other slowly developing manifestations of sickle cell disease.

In sickle cell vaso-occlusive crisis, large number of blood vessels are blocked resulting in marked pain and morbidity. Typically, the crisis is precipitated by some event, such as dehydration or an infection. The event stimulates the vascular endothelium making them sticky through expression of cell-binding receptors on the surface. These receptors then bind with other receptors on the surface of RBCs, white blood cells, and platelets resulting in blockage of the vessel lumen. The red blood cells with HbS are already primed to binding with other cells through expression of certain proteins as well as exposure of certain lipid products on the surface. Thus, the vaso-occlusive crisis results from the interaction of HbS containing RBC, endothelium, white blood cells, and platelets.