Splenic infarction in sickle cell trait: A comprehensive systematic review of case studies

Abstract Sickle cell trait (SCT), a commonly asymptomatic condition, has many associated clinical complications that upon presentation, can be very difficult to attribute to SCT. The effects of SCT on the spleen, for example, are not completely understood, though there have been a number of case reports detailing related complications in diverse populations. Our objective was to perform the first comprehensive case report review of splenic infarction in SCT patients to highlight the relevance of this seemingly rare condition. We conducted an extensive literature search reviewing case reports and case series of acute splenic infarctions from 1970 to 2020. This comprehensive search resulted in 54 articles with a total of 85 individuals. The ages ranged from 7 to 65, 12% were female. Individuals were of African‐American (26%), European (16%), South Asian (13%), Middle Eastern (7%), Latin American (7%), North or East African (4%), Mediterranean (4%), West African (1%), and unknown (22%) origins. Although splenic infarct in SCT patients has been associated with high altitudes, 39% of cases reporting altitude occurred below 3000 m. Among cases where HbS values were recorded, 88% occurred in individuals with HbS levels higher than 35%, suggesting that high HbS values may be a risk factor for splenic infarction. Our findings indicate that splenic infarct occurs across a wide range of demographic populations and environmental settings. While our understanding of SCT evolves, the findings here suggest that future advances in research and healthcare could benefit more from real‐time surveillance and registry initiation for various SCT outcomes such as splenic infarct.


F I G U R E 1 Method of systematic review
the United States, individuals who may have had ancestry in these regions, such as African Americans and Hispanic or Latinx/a/os, are more likely to be affected by SCT. [5] Unlike as in sickle cell disease (SCD), the erythrocyte sickling does not generally occur in SCT carriers, and the carrier status has historically been described as benign. However, several high-profile cases involving SCT-associated clinical complications among athletes and military personnel continue to raise questions about the benignity of the heterozygous state. Research has suggested that some individuals living with SCT are at higher risk of certain conditions, including venous thromboembolism, chronic renal diseases, renal medullary cancer, hematuria, renal papillary necrosis, hyposthenuria, and splenic infarction. [6][7][8] This review focuses specifically on SCT and splenic infarction, one of the most widely reported but possibly least understood complications associated with SCT [9]. The underlying pathophysiology is thought to result from subacute erythrocyte sickling in the spleen in settings of low oxygen tension [10]. The aim of this study is to conduct a case study literature review of splenic infarction in individuals with SCT and comprehensively examine the risk factors for the development of this complication in children and adults with SCT.

METHODS
A comprehensive literature review of peer-reviewed journal articles published between January 1, 1970 and February 1, 2020 was conducted ( Figure 1). The literature search was conducted using bibliographic databases, including PubMed, Web of Science, Scopus, Google Scholar, Embase, and CINAHL. The following search terms were used: ("Splenic Infarction"[Mesh]) AND "Sickle Cell Trait" [Mesh]; "splenic infarction" AND "sickle cell trait"; "splenic infarction" AND "sickle cell trait"; sickle OR cell OR anemia OR trait "splenic infarction"; "sickle cell trait" AND "splenic infarction"; "sickle cell trait" AND "splenic infarction," respectively.
Five reviewers (JMJ, WS, and NU, KA, YJJB) screened articles based on predetermined criteria. Duplicate articles and publications not related to splenic infarction were excluded. Titles and abstracts were then assessed for eligibility to be included in the literature review. The following were excluded: (1) research articles that reported exclusively on patients with SCD or in vitro cells; (2) articles that were not case reports or case series, including meeting abstracts, prevalence studies and commentaries; and (3) case reports or case series not involving splenic infarction. The full texts of all remaining case reports and series were examined. After a systematic and comprehensive review of these full texts, case reports and series were excluded on the following parameters: (1) non-English publications; (2) case reports and series not exclusively on individuals with SCT (e.g., related to spherocytosis), and (3) case series without individual-level data.
After removing duplicates, we retrieved 161 articles. Each reviewer conducted two separate rounds of exclusions-the first round excluding publications based on titles and abstracts and the second excluding based on a full text review. From these exclusions, 54 articles (11 case series and 43 case reports) were identified and abstracted ( Figure 1). . It is therefore difficult to deduce an approximate altitude at which splenic infarction is likely to occur and is important to acknowledge the possibility of infarction in the absence of a high altitude or hypoxic environment.
There is controversy over whether those of non-African ancestry with SCT are more susceptible to splenic infarcts. Several prior reports have suggested that splenic infarction is more likely to occur in SCT individuals of European descent compared to those of African descent [18,38,66]. Genetic differences, such as frequency of α-thalassemia mutations, have been postulated to underlie this difference [47]. In our current review, though we found that 22/83 cases were African-American, this area is limited by the small number of studies and ambiguous definitions of population categorizations across studies. In our current review, we found that there may be an under-reporting in AAs overall [9, 15, 16, 18, 22, 28, 31, 34-38, 44, 45, 53]. Underreporting may be due to misdiagnosis as presenting symptoms that are similar to "mountain sickness." Nonetheless, our study demonstrates that SCTrelated splenic infarction appears across multiple geographic-descent populations ( Table 3).
As with ancestry, the association between sex, as a predisposing factor, and splenic infarction is unclear. Our review of the literature confirms that both men and women are at risk of splenic infarction. This contrasts with what was observed in Goodman et al. in which all the patients were male [66]. In our review, there were ten reported cases occurring in women, three of which occurred in high altitude environments (> 3000 m) [22,34,37]. Although there is more frequent reporting of males, the potential reasons underlying this phenomenon are manifold; for example, one cause among many may be related to more men than women historically engaging in mountain climbing and other strenuous activities at low oxygen levels [21].
The amount of circulating HbS may influence the prevalence of clinical complications in SCT. Co-inheritance of alpha-thalassemia, which lowers HbS levels, has been found to decrease urinary concentrating dysfunction among individuals with SCT [47]. In SCT carriers without alpha-thalassemia, the average HbS percent is between 35% and 45%.
In our review, we found that most of the reports with recorded HbS values (44/48 or 88%) occurred in individuals with HbS levels above 35%; therefore, high HbS values may predispose individuals to splenic infarction in SCT. Additionally, several case reports noted other potential risk factors such as drug use, sleep apnea, and infection, which may contribute to the pathophysiology of splenic infarction in SCT individuals [14,18,38,56].
The pathophysiology of splenic infarction in SCT is not clear. The risk of pulmonary embolism has been noted to be higher in individuals with SCT compared to those without [8], and a few of the case reports in our review did mention a history of pulmonary embolism or infarction in SCT carriers who also experienced splenic infarction [24,39,49]. While chronic hypercoagulability likely plays a role in venous thromboembolism, it is not known whether acute arterial complications such as splenic infarction also have a common underlying mech- There is a need for a more comprehensive reporting of splenic infarction and specifically, a better understanding of presenting symptoms and physical examination findings to reduce its misdiagnosis (e.g., mountain sickness) and improve clinical outcomes. We have not discussed clinical presentation of the cases. Future studies and more data collection, possibly through the initiation of patient registries, are needed to better characterize risk factors for this complication in people with SCT and to determine optimal clinical management.