Mortality trends in sickle cell patients.

Am J Blood Res 2020;10(5):190-197 www.AJBlood.us /ISSN:2160-1992/AJBR0112865 Original Article Mortality trends in sickle cell patients Juan Cintron-Garcia, Germame Ajebo, Vamsi Kota, Achuta K Guddati Division of Hematology/Oncology, Georgia Cancer Center, Augusta University, Augusta, GA 30909, USA Received April 19, 2020; Accepted September 1, 2020; Epub October 15, 2020; Published October 30, 2020 Abstract: Background: Sickle cell disease affects a significant portion of US patients with African descent. It continues to be one of the leading causes of frequent hospitalizations and high in-hospital morality risk. Until the approval of disease-modifying therapies in last two years, medical therapy has relied mostly on management of pain episodes and the use of hydroxyurea. We discuss the nationwide analysis of trends in in-hospital mortality in patients with Sickle Cell Disease from 2000 to 2014. Methods: Trends of in-hospital mortality in sickle cell patients were analyzed from a database provided by the Agency of Healthcare Research and Quality. From the data hospitalization rates and in-hospital mortality in categories by region in the US, hospital size, health insurance status, comorbidities and gender were examined. Patterns of in-hospital mortality were analyzed by logistic regression. Results: Ratio for hospitalization and mortality among the four regions described Northeast, Midwest, South, West with respective values of 0.63%, 0.65%, 0.76% and 0.89% with P = 0.008 and OR = 1.07. Odds ratio for sickle cell patients that died during hospitalization and health insurance status was OR = 0.08. Comorbidities considered in sickle cell patients; diabetes mellitus (DM), hypertension (HTN), hyperlipidemia (HLD), chronic kidney disease (CKD), smoking status. The odds ratio for comorbidities show A-fib with a value of OR = 4.47, followed by hypertension OR = 1.92, diabetes mellitus OR = 1.44 and chronic kidney disease OR = 1.29, smoking status OR = 0.60. Mortality-hospitalization ratio by gender was: males 0.77% and females 0.69% with OR = 0.87. Conclusions: In-hospital mortality by US regions, as well as health insurance status are important measurable elements that show the impact of the disease from a public health perspective. Further and more specific data of regions by states, comorbidities by states and sex, as well as health insurance status by states will provide further insight in local mortality trends. Keywords: Delay time, polymerization, social determinants of health, sickle cell, literacy Introduction Sickle cell disease (SCD) encompasses a group of genetic diseases that result from a single point mutation in the position 6 of the gene that encodes hemoglobin subunit ß [1]. It includes sickle cell anemia (SCA), sickle cell hemoglobin C (HbSC) and sickle ß-thalassemia. The molecular structure of hemoglobin consists of combined globin subunits which in association with the heme cofactor confers its oxygen carrying capacity. Adult hemoglobin is made up of two α subunits and two ß subunits [1]. The substitution of valine for glutamic acid within the molecular structure of the ß-globin subunit, is the mutation which drives in the production of hemoglobin S (HbS) [2]. It is an autosomal recessive disease, where the two copies of the ß subunits need to be mutated for evident clinical manifestation. Surface charge in hemoglobin S is characterized by a variation which under conditions of deoxygenation tends to polymerize and create fibers as a conse- quence of intracellular crystallization. The gradually increasing fibers through crystallization contributes to the rigidity of the red cell and progressively higher viscosity of blood. Of note, there is a latency period of time or “delay time” where hemoglobin is deoxygenated, however it does not become polymerized during the initial fraction of time [3]. If transit through microvasculature is beyond the delay time, hemoglobin will be at higher risk of aggregating and will favor “sickling” [3]. As hemoglobin S polymerizes, it weakens the erythrocyte membrane, promoting a dehydrated state with a higher tendency to hemolyze. Repeated episodes of deoxygenation over time causes an irreversible stiffness of the red cell - a “sickle” shape. Acquired sickle shape and stiffness of the red cells results in higher blood viscosity, red cell membrane fragmentation and as a consequence shortened red blood cell lifespan. This is a continuous process as the higher viscosity results in a slower transit through the microvasculature causing higher oxygen extraction Mortality in sickle cell patients [3]. The lower oxygen affinity of HgS and its deoxygenation worsens the sickling of the red cells. Progressively slower transit of red cells through the capillaries increases the delay time, worsens the deoxygenation and sickling as the process continues [3]. Over time sickle cell disease leads to a chronic inflammatory state through episodic vaso-occlusion causing ischemia, pain and important organ system complications. The process of intravascular hemolysis and release of cellfree hemoglobin creates reactive oxygen species which cause nitric oxide (NO) consumption and oxidative damage [4]. As a third pathophysiologic mechanism, the reduced bioavailability of NO is thought to trigger the expression of adhesion molecules and at the same time production of the vasoconstrictor endothelin-1 [1]. Endothelial cells in activated state are associated with increased vascular tone and production of inflammatory mediators responsible for vascular damage [1]. There is an overall increase in activation of the endothelium, coagulation proteins, leukocytes and platelets with increased adhesion to endothelium mediated to some extent by P-selectin [1, 5]. It is thus a predisposing factor to endothelial dysfunction and proliferative changes in the intima and smooth muscle of the vasculature, which results in eventual systemic, pulmonary hypertension and organ injury [4]. Microvascular phenomena also manifest with multiple organ damage. Beginning early in life complications that stem from microvascular changes predispose patients to vaso-occlusive pain episodes. This same mechanism can also manifest as cerebrovascular events, acute chest syndrome (due to vaso-occlusion of pulmonary vasculature). Acute chest syndrome is in fact the second most common cause of hospital admissions and most common cause of sickle cell mortality [6]. The cascade of consequences as a result of generalized vasculopathy translates into cardiopulmonary complications, in which heart failure with or without pulmonary hypertension is the primary cause of mortality [7]. Gradually there is more organ involvement in these patients, including progressive decrease in renal function [8]. Renal medulla is the most prominent site of injury as capillaries here are relatively hypoxic, acidic and hypertonic all of which favor sickling [9]. This results in greater adhesion of erythrocytes to the (...truncated)