I saw this vignette in the New England Journal of Medicine (NEJM). What follows by way of intervention, I believe, is still relevant. An 18-year-old woman with sickle cell anemia has had increasing symptoms, with painful crises and episodes of the acute chest syndrome. She was hospitalized three times in the past year. She was started on hydroxyurea therapy.(Orah S. PlattHydroxyurea for the Treatment of Sickle Cell Anemia.N Engl J Med 2008;358:1362-9).
Sickle cell anaemia is primarily seen in persons of African heritage, about 1 in 14 of whom is an asymptomatic carrier. One in 700 newborns of African heritage is affected. Patients with sickle cell anaemia have a wide spectrum of clinical manifestations. Patients with this disorder have a chronic hemolytic anaemia, but the rates of the most common acute vaso-occlusive events (acute painful crises and the acute chest syndrome) vary considerably. Other common complications include stroke, chronic lung disease, avascular necrosis, and leg ulcers. Health-status surveys suggest that patients with sickle cell anaemia have a low quality of life, similar to that of patients with arthritis or myocardial infarction. Before the era of hydroxyurea, the average life expectancy was in the 40s.
Normal adult haemoglobin, designated haemoglobin A, consists of two α-globin chains and two β-globin chains. The cause of sickle cell anaemia is a point mutation in the β-globin gene. This genetic abnormality leads to the production of sickle haemoglobin, a protein that has the unique property of polymerizing into long fibers when deoxygenated, and damaging the cell membrane. Polymerization is highly dependent on the level of sickle haemoglobin in the cell and is dramatically reduced when other forms of haemoglobin, without the mutant sickle β-globin chains, are present.
Red blood cells (rbcs) containing high levels of sickle haemoglobin contribute to the pathophysiological development of sickle cell anaemia in three major ways. The rbcsbecome deformed when deoxygenated, leading to vascular obstruction and ischaemia. This is a critical factor underlying painful crises, the acute chest syndrome, functional asplenia, and acute stroke. Secondly, membrane damage shortens the life span of the red blood cell, causing chronic intravascular and extravascular haemolysis. Intravascular haemolysis contributes to decreased availability of nitric oxide, increased vascular tone, and pulmonary-artery hypertension.Third, damaged rbcs have abnormal surfaces that result in increased adherence to and damage of vascular endothelium, a process that enhances acute vaso-occlusion and also provokes a proliferative lesion involving white cells, platelets, smooth-muscle cells, cytokines, growth factors, and coagulation proteins. Such lesions underlie large-vessel stroke and possibly pulmonary-artery hypertension.
The rbcs of a normal adult generally contain almost 100% hemoglobin A and those of a person with sickle cell anaemia contain almost 100% sickle hemoglobin. A smaller population of rbcs comes directly from immature progenitors. These progenitors have unusually active γ-globin genes and produce rbcs with relatively high levels of haemoglobin containing two α-globin chains and two γ-globin chains. This form of haemoglobin is designated foetal haemoglobin, because it predominates in foetal red cells. The foetal haemoglobin mitigates the damage caused by sickle haemoglobin. RBCs containing high levels of sickle haemoglobin contribute to the pathophysiological development of sickle cell anaemia. Intravascular haemolysis contributes to decreased availability of nitric oxide, increased vascular tone, and pulmonary-artery hypertension. Damaged rbcs have abnormal surfaces that result in increased adherence to and damage of vascular endothelium, a process that enhances acute vaso-occlusion and also provokes a proliferative lesion involving white cells, platelets, smooth-muscle cells, cytokines, growth factors, and coagulation proteins. Such lesions underlie large-vessel stroke and possibly pulmonary-artery hypertension.
A major therapeutic approach to sickle cell anemia has been to try to shift haemoglobin production from sickle haemoglobin to foetal haemoglobin. The cytotoxic effect of hydroxyurea reduces the production of rbcs containing a high level of sickle haemoglobin, which tend to arise from rapidly dividing precursors, and favours the production of rbcs containing a high foetal haemoglobin level. Hydoxyurea also reduces the numbers of white blood cells (wbcs) and platelets, potentially reducing their roles in vascular injury. The metabolism of hydroxyurea results in the production of nitric oxide that results in the production of foetal haemoglobin.
Before initiating therapy, it is important to obtain a complete blood count and to establish the patient’s baseline foetal haemoglobin level, hepatic function, and renal function. Hydroxyurea is given daily in a single oral dose. At 2 weeks, the haemoglobin level and blood counts are reassessed.
At this point allow me to take a leaf from a statement from the National Institute of Health (NIH) on Hydroxyurea Treatment for Sickle Cell Disease (NIH Consensus and State-of-the-Science Statements Volume 25, Number 1 February 25–27, 2008). The burden of suffering is tremendous among many patients with sickle cell disease. These patients experience disease-related pain on many days of their lives and usually do not seek medical attention until their symptoms are overwhelming. They often attempt to treat themselves and thus do not always come to the attention of the health care system. Obtaining optimal care for patients with sickle cell disease is challenging. Hydroxyurea is an important major advance in the treatment of sickle cell disease. Strong evidence supports the efficacy of hydroxyurea in adults to decrease severe painful episodes, hospitalizations, number of blood transfusions, and the acute chest syndrome. Erythrocytes (red blood cells) in people with sickle cell disease become deoxygenated (depleted of oxygen), dehydrated, and crescent-shaped or “sickled.” The cells aggregate, or clump together, and stick to blood vessel walls. Aggregation blocks blood flow within limbs and organs. This can cause painful episodes and permanent damage to the eyes, brain, heart, lungs, kidneys, liver, bones, and spleen. Infections and lung disease are the leading causes of death in people with sickle cell disease.
Sickle cell disease is a major public health problem with over 200,000 babies born per year with SCD in Africa. Approximately 80% of all children born with SCD are in sub-Saharan Africa. In Ghana, 2% (about 15,000) of newborns have SCD (Asare E. Burden of Sickle Cell Disease in Ghana: The Korle-Bu Experience. Hindawi Advances in Hematology Volume 2018, Article ID 6161270).
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