Negative Health Implications Of Sickle Cell Trait in High Income Countries: From The Football Field To The Laboratory

Abstract

Worldwide, sickle cell trait is a highly prevalent gene carrier state. While generally a benign condition with a normal life expectancy, it is becoming increasingly clear that the sickle trait is associated with certain adverse outcomes. This article will focus on three of these outcomes, namely exertional rhabdomyolysis and sudden death, chronic renal dysfunction, and venous thromboembolism. In each case, the epidemiological evidence for the association is reviewed, together with the existing data on potential underlying mechanisms. Because newborn screening programmes for sickle cell anaemia also identify those with sickle cell trait, it is imperative that further studies determine what, if any, preventive measures can be taken to reduce the burden of these uncommon but potentially morbid complications in affected individuals.

Introduction

1.1 Epidemiology of sickle cell trait

It is estimated that 300 million people worldwide are heterozygous for the mutation in the HBB gene (HBB E6V, also termed HbS mutation or ’sickle gene’) that results in sickle cell anaemia (SCA), and are said to have sickle cell trait (SCT). In the overwhelming majority of cases, SCT is a benign entity associated with a normal life expectancy (Stark, et al 1980). However, the purpose of this article is to review the most contemporary data on potential adverse outcomes that can be associated with SCT.

The sickle cell mutation arose and remained evolutionarily conserved in those parts of the world where malaria is or was once highly endemic, including sub-Saharan Africa, parts of the Mediterranean, the Middle East and India. Within these regions, the prevalence of SCT may vary widely, with pockets of very high prevalence (30% or more) corresponding to high loco-regional malaria burdens. This striking association was first reported by Allison in a landmark study in Kenya 60 years ago (Allison 1954). The evolutionary advantage afforded by SCT is presumably related to the fact that, although carriers are not protected from parasitaemia when exposed to falciparum malaria, they are about 90% less likely to suffer the severe consequences of infection (May, et al 2007, Williams, et al 2005a). The precise mechanism(s) by which SCT confers this protective effect in red blood cells (RBCs) remains a topic of active research. Possibilities that have been invoked include; 1] blunting of intracellular parasite growth; 2] abnormal trafficking, expression and display of parasite virulence factors on host RBCs; 3] activation of the innate immune system and enhanced acquisition of adaptive immunity to malaria; and/or 4] enhanced clearance of parasitized RBCs (Gong, et al 2012, Taylor, et al 2013, Williams, et al 2005b).

The HbS concentration in SCT may demonstrate considerable variability. While typically in the range of 42%, it has been shown to have a trimodal distribution in the African-American population, caused by the interaction with α-thalassaemia. Up to 30% of this population possesses a deletion of one α-globin gene (-α/αα), ωηereas about 2% of the population is homozygous (-α/−α) for the deletion. The HbS levels in these individuals are more typically around 37% and 29%, respectively (Steinberg and Embury 1986). Interestingly, despite the fact that both SCT and α-thalassaemia are individually protective against severe falciparum malaria, the protection is lost when both conditions are inherited together (Williams, et al 2005b).

The slave trade trafficking and population migrations in recent centuries led to the dissemination of the sickle gene to other parts of the world. In the United States, for example, 6-9% of the African-American population and 0.01-0.05% of other racial/ethnic groups, equating to an estimated 3 million persons, are carriers of the sickle gene. In the French Caribbean Islands, such as Guadeloupe and Martinique, 6-7% of the population has SCT.

1.2. History of research in SCT

The history of research into adverse outcomes associated with SCT has a rather long and sometimes troubled history. In 1971, then President Richard Nixon declared a ‘war on sickle cell disease’. The following year, partly in response to the widely held opinion that subjects with SCT were suffering multiple adverse outcomes, the U.S. Congress passed the National Sickle Cell Anemia Control Act. This Act stated that “efforts to prevent sickle cell anemia must be directed toward increased research....and the education, screening and counseling of carriers of the sickle cell trait”. The majority of the allocated funds however were spent on mass screening of African-Americans (which was intended to be voluntary), rather than research. In addition, there were no provisions to facilitate counselling, and there was widespread misinformation about the distinction between SCA and SCT (Beutler, et al 1971, Sullivan 1987). This unfortunate episode had two major negative impacts: first, many additional studies appeared in the literature purporting to show an association between multiple co-morbidities and SCT (Johnson 1982). However, the conclusions were often flawed, due to a combination of inaccurate diagnostic approaches and/or erroneous statistical considerations (Gima and Bemis 1975, Heller 1973). The other major effect of this screening programme was to promote occupational discrimination, inflation of health and life insurance premiums, and even occasional reports of medically recommended sterilization for individuals with SCT. As a result of the confusion and inauspicious consequences of the screening programmes, there were calls to limit further research on SCT (Culliton 1972, Gima 1975).

1.3. Contemporary areas of research focus in SCT

With the advent of more sophisticated tools and clinical study designs, the opportunity to re-examine whether SCT is associated with adverse health outcomes has prompted a renewed interest in this topic. The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes for Health (NIH) recently convened a roundtable to review existing evidence and determine future research priorities in SCT (Goldsmith, et al 2012). A similar workshop also took place at the Centers for Disease Control (Grant, et al 2011). It was recommended that “a more methodologically sophisticated approach” to defining adverse outcomes was required, and that research into complications, such as those resulting in thrombosis and renal abnormalities, should be complemented by appropriate ethical, social and behavioral research (Goldsmith, et al 2012).

The remainder of this review will focus on three conditions in which the association with SCT is now increasingly well established, including exertional rhabdomyolysis and sudden death, renal disease and venous thromboembolism (VTE).

2. Exercise-related complications in SCT carriers

2.1. The military experience

Numerous case studies have reported exercise-related death in subjects with SCT over the past 5 decades. One of the earliest (Jones, et al 1970) described metabolic acidosis, hyperkalaemia and a kind of “sickle cell crisis” in a carrier that occurred abruptly after running 1 mile at mild altitude. Zimmerman et al (1974) described the case of an individual with SCT who developed rhadomyolysis and myoglobinuria after running 3 miles and died 65 hours later. Greater attention was focused on this association following the publication of a large epidemiological study that retrospectively evaluated the risk of exercise-related death in U.S. Armed Forces recruits over a 5-year period (1977-1981) (Kark, et al 1987). The relative risk of exercise-related death explained by pre-existing disease (largely silent heart disease) was 2.3 for SCT, which was not statistically significant. In contrast, the relative risk of exercise-related death unexplained by pre-existing disease was 28 for SCT subjects (95% confidence interval [CI], 9-100; p<0.001). The timing of exercise-related complications in SCT has generally been linked to the immediate stress of exercise. About 50% of the deaths resulted from heat illness from overexertion, while the remaining cases were classified as ‘idiopathic’. Poor physical conditioning of recruits and dehydration appeared to increase the risk for adverse events during exercise (Kark, et al 1987, Kark and Ward 1994, O'Connor, et al 2012).

2.2. The athlete experience

Exercise-related death has also been described in athletes with SCT (Dincer and Raza 2005, Eichner 2010, Harris, et al 2012, Kerle and Runkle 1996). Harmon et al (2011) reviewed the causes of all cases of sudden death in student-athletes from the National Collegiate Athletic Association (NCAA) in the U.S. between January 2004 and December 2008. 72 deaths occurred in (American) football players due to trauma unrelated to sports activities or medical causes. Of the 20 deaths due to medical causes, 13 occurred during exertion; these cases were in turn accounted for by cardiac disease (n=6; 46%), SCT (n=5; 39%) and heat stroke unrelated to SCT (n=2; 15%). All deaths associated with SCT occurred in African-American Division I football players. The overall risk of exertional death from any cause was 5.2 times higher in African-American players with or without SCT compared with that in non African-American football players. The calculated relative risk of exertional death in all Division I football players (i.e. all ethnicities) with SCT was 1:827, which represented a 37-fold higher relative risk than in athletes without SCT. The relative risk of exertional death in African-American Division I football players with SCT was 22 times greater than in those without SCT (Harmon, et al 2012). It has been suggested that the repetition of very intense exercise with incomplete recovery during football training sessions results in massive sickling and rhabdomyolysis leading to death in affected individuals (Eichner 2014).

2.3. Physiology and possible pathophysiological mechanisms in subjects with SCT

Although epidemiological studies suggest that SCT may be a risk factor for exercise-related death, it is very difficult to prove a cause-effect relationship. In patients with SCA, anaemia, haemolysis, impaired blood rheology, decreased nitric oxide bioavailability, impaired vascular function, activation of coagulation and inflammation, oxidative stress and vascular adhesive phenomena play a role in the occurrence of acute vaso-occlusive events and the development of vasculopathy and chronic organ damage (Kato, et al 2007). Indeed, several studies have measured biomarkers of these processes in exercising SCT carriers during various protocols lasting from 1 to 40 min. Briefly, exercise in SCT results in: 1) a slight decrease of RBC deformability, with or without evidence of sickled RBCs in the circulation (Martin, et al 1989, Tripette, et al 2010a); 2) a moderate to marked increase of whole blood viscosity (Diaw, et al 2013a, Tripette, et al 2010a); 3) oxidative stress (Faes, et al 2014); and 4) evidence of systemic inflammation (Monchanin, et al 2007, Tripette, et al 2010b). Although these biological responses can also be found in non-SCT subjects, they appear to be exaggerated in individuals with SCT. Whether these abnormalities are capable of triggering vaso-occlusive-like episodes is unknown. However, the magnitude of the biological responses induced by physical stress in SCT is far less than that observed on a chronic basis in patients with SCA, especially during painful vaso-occlusive crises. Nevertheless, a few of these biomarkers, such as blood viscosity, could be of potential clinical relevance. Depending on the underlying vascular function, increased blood viscosity could result in increased vascular resistance and impaired blood flow (Tripette, et al 2013, Vincent, et al 2010). Notably, increased blood viscosity has also been identified as a risk factor for vaso-occlusive crisis in patients with SCA (Lamarre, et al 2012, Nebor, et al 2011). Individuals with SCT usually manifest higher blood viscosity than those without the gene at rest (Tripette, et al 2009). In the general population, exercise causes a rise of blood viscosity as a consequence of the increase of haematocrit and plasma viscosity and the changes in RBC rheological properties (i.e., deformability and aggregation). Exercise also leads to a rise of blood viscosity in SCT with an increase that is more pronounced than in healthy individuals, particularly in subjects who are dehydrated (Diaw, et al 2013b, Tripette, et al 2010c). Theoretically, this amplified response could increase the risks for end organ perfusion disorders in SCT, but only when vascular reactivity is blunted. Vascular function has been poorly studied in SCT, but recent findings suggest that vascular reserve could be slightly decreased compared to non-carriers at rest (Tripette, et al 2013). However, no study has investigated vascular function in SCT during exercise. Further studies using appropriately sensitive techniques on large cohorts are needed to characterize vascular function in carriers during exercise.

2.4. Potential approaches to prevent SCT-associated sudden death

The participants in the NHLBI workshop noted that “the reported deaths in NCAA Division I athletes all occurred during conditioning, not during game play, either in sprinting or speed drills, and in one case with weight lifting” (Goldsmith, et al 2012). It was proposed that a sickling syndrome could be responsible for vaso-occlusion within exercising skeletal muscle, ultimately leading to rhabdomyolysis. However, it was noted that the proof of such a mechanism is still lacking, and alternative causes, such as the presence of other gene defects that could predispose SCT (or non-SCT) carriers to exercise-induced rhabdomyolysis, should be considered (Deuster, et al 2013, Goldsmith, et al 2012, O'Connor, et al 2012).

It has been proposed that universally applied precautions, such as longer breaks during practice, more frequent hydration, and shortening the intensity and duration of exercise -- particularly in hot weather or at high altitude -- should be sufficient to decrease the risks of adverse events in all situations involving intense exercise (Goldsmith, et al 2012). In applying such precautions to all participants, such a strategy would obviate the need for screening for SCT, a practice that could lead to negative discriminatory consequences. This position was endorsed by the Sickle Cell Disease Association of America (SCDAA) and the American Society of Hematology (http://www.sicklecelldisease.org/index.cfm?page=sickle-cell-trait-athletics; Eichner 2012; http://www.hematology.org/Advocacy/Statements/2650.aspx). In contrast, the NCAA proposed to implement systematic screening for SCT in student-athletes, with the expressed goal of targeting educational efforts on approaches to reduce the risk of serious complications to coaches and affected individuals (Tarini, et al 2012). The legislation requiring SCT screening in incoming Division I athletes was adopted in 2010, and has since been adopted also in Division II and III athletic programmes, albeit with some resultant controversy (Bonham, et al 2010, Jordan, et al 2011, O'Connor, et al 2012). Alternatively, athletes may show proof of prior testing or sign a waiver releasing an institution from liability (http://www.nata.org/sites/default/files/SickleCellTraitAndTheAthlete.pdf).

In fact, in the absence of a sound understanding of the mechanism(s) of the complications, the optimal strategy to reduce the risks for exercise-related death in SCT carriers is unknown. Promoting active hydration during exercise is likely to be beneficial (Kark and Ward 1994), as adequate hydration does normalize blood viscosity in SCT during exercise (Diaw, et al 2013a, Tripette, et al 2010a). Moreover, comparisons of sedentary with trained SCT subjects showed that the former group exhibited exaggerated inflammatory and oxidative stress responses during exercise, as well as higher blood viscosity (Aufradet, et al 2010, Chirico, et al 2012, Kark and Ward 1994). Indeed, achieving a high degree of physical fitness probably helps carriers to better tolerate unaccustomed strenuous exercise during training periods (O'Connor, et al 2012). In a subsequent roundtable organized by the American College of Sports Medicine (ACSM) and the Consortium for Health and Military Performance (CHAMP), it was emphasized that SCT military recruits at highest risk are those who have repeatedly had difficulty passing the Army Physical Fitness Tests (O'Connor, et al 2012). Here again, the consensus was that prior to fitness testing, military leaders should ensure that recruits are adequately hydrated and rested in a shaded or indoor cooled environment (O'Connor, et al 2012). In addition, a minimum of 48 h should elapse between strenuous field training and fitness testing.

3. Renal Complications of Sickle Cell Trait

3.1. Epidemiology of SCT and Chronic Kidney Disease

Renal abnormalities are among the best-recognized complications of SCT. It has been conclusively demonstrated that individuals with SCT have impaired urinary concentrating ability, albeit to a lesser degree than that seen in SCA (Gupta, et al 1991). In a large retrospective series of African-American males hospitalized in Veterans’ Administration facilities, haematuria was found to occur about twice as frequently (2.5% vs. 1.3%; p <0.001) among those with SCT than in those without (Heller, et al 1979). Numerous case reports and series have suggested that up to 50% of patients presenting for evaluation of haematuria may exhibit the more severe papillary necrosis (Li and Carroll 2014, Zadeii and Lohr 1997). Because of these associations, several studies have attempted to identify a relationship between SCT and kidney disease.

One of the first studies to evaluate SCT and its influence on renal disease was performed in a cohort of haemodialysis patients based in the Southeastern United States (Yium, et al 1994). Six of 12 patients with polycystic kidney disease (PKD) as the cause of their end-stage renal disease (ESRD) had concomitant SCT compared to 6 of 80 African-American patients with ESRD due to other causes. Furthermore, those with PKD and SCT initiated dialysis at a median age of 10 years younger than PKD patients without trait (p<0.003). These data suggest that sickle trait may accelerate the progression of PKD.

Other studies have evaluated surrogate markers of renal disease. A Brazilian study that compared SCA and SCT individuals with preserved renal function included 40 subjects with SCT. Microhaematuria was present in 30%, whereas microalbuminuria (which was felt to be more probably associated with evident renal disease) was present in 8% of individuals with SCT (Sesso, et al 1998). In another study assessing the presence of albuminuria, 181 Afro-Caribbean individuals (34 with SCT) were recruited sequentially and in an unselected fashion from patients with type 2 diabetes mellitus presenting to an outpatient clinic. Among these diabetic subjects, SCT was associated with a slightly greater likelihood of albuminuria (odds ratio 1.19) although this did not reach statistical significance (p=0.68) (Oli, et al 2004). In contradistinction, another study of 52 Nigerian type 2 diabetics demonstrated that proteinuria (defined as >0.5 g/24 h) was more likely among those men with SCT than those without SCT (75.0% v. 21.7%, p<0.02). Women with SCT and diabetes were also more likely to have proteinuria, although the difference was less profound and was not statistically significant (25% v. 15.4%) (Ajayi and Kolawole 2004). In another group of 376 African-Americans from a single centre, SCT was not associated with proteinuria, estimated glomerular filtration rate (eGFR) or a composite microvascular outcome that included end- stage kidney disease. SCT assessment in this group was derived from the same instrument used to perform Hb A1c testing. However, in this cohort proteinuria was missing in a large proportion of individuals, thereby limiting the analyses to some degree (Bleyer, et al 2010).

Recently, a number of studies have evaluated the prevalence of SCT in dialysis populations. In a single academic centre study of four dialysis units that included 188 African-American patients, SCT was identified in 14.9% compared to a prevalence of 7.1% in the background population as determined by newborn screening data (Derebail, et al 2010). A subsequent study of 1,085 African Americans with non-diabetic ESRD and 996 with type 2 diabetes-associated ESRD compared these individuals to 1,177 controls. The prevalence of SCT was similar in each of the groups (in the range of 7.1% to 8.7%) (Hicks, et al 2011). However, a more recent study utilized data from a large national dialysis company, and ascertained the prevalence of SCT in 5,319 African-American ESRD patients. Within this cohort, 542 SCT subjects were identified, giving a prevalence of 10.2%, which was higher than the rates reported among population studies of African-Americans (6.5%-8.6%, p<0.001) (Derebail, et al 2014). All three of these studies were limited by their cross-sectional design; their inconsistent results suggest that the evaluation of prevalence of SCT in ESRD may not be the best approach to determine a link between SCT and renal disease.

Other studies have suggested a clearer association between SCT and kidney disease. Bucknor et al (2014) conducted a study of 13,462 African Americans enrolled in the Kaiser Permanente Northern California health system. Among these individuals, 2,642 were identified as having SCT, with >98% of those having confirmed laboratory profiles. In multivariate analyses, SCT was found to be associated with chronic renal disease (risk ratio 1.13; 95% CI 1.03-1.23, p=0.008). However, outcomes in this study were limited by diagnostic determination that used International Classification of Diseases (ICD)-9 diagnostic codes (Bucknor, et al 2014).

The most compelling data linking SCT and renal disease come from a large pooled population cohort study of nearly 16,000 African-Americans, in which the associations between SCT and various renal outcomes were evaluated (Naik, et al 2014a). The study cohort was derived from five population-based cohorts – the Atherosclerosis Risk in Communities Study (ARIC), the Women's Health Initiative (WHI), the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA) and the Coronary Artery Risk Development in Young Adults (CARDIA). Each of the outcomes – CKD at any point in the studies, incident CKD, rapid eGFR decline (> 3ml/min/1.73 m²/year) and albuminuria - were assessed in each cohort individually and then pooled in a meta-analysis. These analyses were adjusted for age, sex, clinic or region, African genetic ancestry, diabetes and hypertension. For each outcome in each cohort, SCT demonstrated a consistent association, albeit with varying effect sizes. In the pooled analysis, for each cohort, SCT was statistically significant with each of the primary outcomes. Thus, for CKD, SCT demonstrated an odds ratio (OR) of 1.57 [95% CI, 1.34-1.84); for incident CKD, an OR of 1.79 (95% CI, 1.45-2.20); and for decline in eGFR, an OR of 1.32 (95% CI, 1.07-1.61). SCT was also associated with albuminuria with an OR of 1.86 (95% CI, 1.49-2.31) (Naik, et al 2014a). Alternative definitions for CKD and continuous measures of eGFR and albuminuria were assessed in sensitivity analyses and demonstrated a consistent association. When stratified by diabetes, the association between SCT and incident CKD maintained a similar effect size. Each of these analyses also demonstrated that the influence of SCT on outcomes were independent of the APOL1 genetic risk variants, which are known to be associated with renal disease in African-Americans (Parsa, et al 2013). The consistency of the analyses among the individual cohorts and in sensitivity analysis is persuasive of an association between SCT and kidney disease, with an estimated population-attributable risk for incident CKD of about 6% (Naik, et al 2014a).

3.2. Potential underlying mechanisms of renal injury in SCT

While the link between SCT and kidney disease has arguably now been reasonably well established, only indirect data exist to explain the underlying pathophysiology. Certainly, the common manifestations of haematuria and impaired urinary concentration suggest injury to the renal medulla. The renal medulla provides a favourable environment in which sickling of RBCs may occur due to its high osmolality, high acidity and very low partial pressure of oxygen (10-20 mmHg) (Noguchi, et al 1981). Ischaemic injury from clinically silent episodes of sickling may play a role in ongoing renal injury and, in rare cases, progression to renal medullary carcinoma (Statius van Eps, et al 1970, Tsaras, et al 2009). Indeed, microradioangiographic studies performed on renal autopsy specimens of individuals with SCT demonstrate evidence of disruption and obliteration of the vasa recta (Statius van Eps, et al 1970). While not as severe as that seen in SCA, these studies suggest an intermediate vascular phenotype that is probably produced by repetitive ischaemic events. The drop out in these vessels could increase renal hypoxia, which has been shown to mediate further tubulointerstitial damage, fibrosis and subsequent loss of kidney function. A similar process has been hypothesized to drive progression of CKD, irrespective of cause. Those individuals with established CKD and SCT could be particularly susceptible to this self-perpetuating process of CKD-induced hypoxia and hypoxia-induced CKD progression (Fine and Norman 2008, Nangaku 2006).

Just as in SCA, several potential modifiers may also play a role in the development of renal disease. The concomitant presence of α-thalassaemia has been shown to attenuate the severity of urinary concentration impairment (Gupta, et al 1991). Furthermore, a single report of a family of PKD patients with SCT and early onset of renal disease demonstrated these individuals to have the Central African Republic (CAR) haplotype of the HbS mutation (Kimberling, et al 1996). This haplotype has been previously demonstrated to lead to more severe outcomes in individuals with SCA, including kidney disease (Powars, et al 1994). Both haplotype and α-thalassaemia modulate the relative concentration of HbS, as well as the rheological properties of RBCs (Connes, et al 2014, Monchanin, et al 2005, Powars, et al 1994). Indeed, one may speculate that these genetic factors would influence sickling and ischaemic injury.

Studies on the mechanisms of renal disease in SCA have demonstrated that kidney injury is not simply driven by vaso-occlusion alone. Ischaemia-reperfusion injury, inflammation and oxidative stress from free haem, endothelial injury, nitric oxide deficiency and an underlying procoagulant state all play some role (Ataga, et al 2014, Nath 2012). Whether similar, albeit muted, processes of renal damage are in play in individuals with SCT remains unknown but certainly seem to be plausible avenues of future investigation. Additional information on whether co-inheritance of α-thalassaemia modulates the incidence and/or severity of renal disease (beyond hyposthenuria) would also be of interest.

3.3. Screening for SCT in the context of renal disease

Screening for SCT in individuals with kidney disease or determined to be at high risk for kidney disease is of unclear benefit (Cavanaugh and Lanzkron 2010). At present, no intervention exists to alter the course of progression of CKD specific to SCT. One could advocate that knowledge of SCT status and its increased risk may encourage adherence to non-specific CKD therapies, such as hypertension control, but presently, no data exist to guide screening. Certainly, if SCT status is known from prior screening (either neonatal, prenatal or as part of athletic screenings), this information could be helpful in outlining an overall risk profile for affected individuals. Similarly, whether screening for CKD, either by urinary albumin assessment or more frequent monitoring of renal function, is beneficial is unknown. With the recent data from Naik et al (2014a), an argument could be made for pursuing this course of action if the diagnosis of SCT is already established, but at what age and in which individuals this would be most helpful is also unknown.

In the setting of renal transplantation, screening for SCT has been the norm in some centres, although with a large degree of inconsistency between institutions. In a survey of US transplant centres, 83% of the 137 responding centres had no established policy for screening potential donors. In practice however, 34% did perform routine screening, and 37% of centres excluded donors known to have SCT or if found to have SCT during screening (Reese, et al 2008). A single survey study performed in 1980 identified 21 SCT patients who received a renal transplant; it was concluded they had similar outcomes to the overall population (Chatterjee 1980). However, at present, there are limited data to guide policy on donor evaluation. Future studies utilizing retrospective data from SCT donors may be helpful in both determining allograft outcomes and donor outcomes. These data then could be used to inform the overall risk assessment of renal transplant evaluation.

3.4 Renal Medullary Carcinoma

A very rare complication of SCT is renal medullary carcinoma. This very aggressive malignancy has been reported almost exclusively in individuals with SCT (Davis, et al 1995). In the original report of these malignancies, none were limited to the kidney at presentation and many were metastatic. Median survival after diagnosis was approximately 4 months. These tumours often present in young people, with a median age of 26 years, and appear to have a male predominance at younger ages (Davis, et al 1995). These tumours appear to have a predilection for the right kidney and are associated with necrosis within the tumour, caliectasis and regional adenopathy (Blitman, et al 2005, Davis, et al 1995, Liu, et al 2013). The pathogenesis of renal medullary carcinoma remains unknown but it was originally thought to arise from the calyceal epithelium (Davis, et al 1995). Loss of SMARCB1 expression, responsible for repressing cyclin D1 transcription, has been described in these tumours, as have ALK re-arrangements (Liu, et al 2013, Marino-Enriquez, et al 2011). Presently, therapy of these lesions includes nephrectomy in the absence of metastatic disease and various chemotherapeutic regimens that have had limited success, with median survival still only six months (Maroja Silvino et al 2013), although there have been rare case reports of successful treatment (Gangireddy, et al 2012, Walsh, et al 2010). Therefore, early detection of these lesions is paramount and cross-sectional imaging of individuals with SCT presenting with haematuria is important for identifying these and other urothelial malignancies (Gill, et al 2012).

4. Sickle Cell Trait and Venous Thromboembolism

4.1. Epidemiology of SCT and VTE

An association between SCT and pulmonary embolism (PE) was first noted by Heller et al (1979) in their study of African-American Veterans’ Hospital discharges (2.2% incidence of PE vs. 1.5% in controls with normal haemoglobin profile; p<0.001). In another large case-control study of African-Americans with VTE in Atlanta (the ‘GATE study’), SCT was shown to be a risk factor for VTE (OR = 1.8 (95% CI: 1.2-2.9)). This risk was particularly marked when considering PE (OR = 3.9 (95% CI: 2.2-6.9)) as opposed to DVT (Austin, et al 2007). Although a relatively modest risk factor overall, based on a population prevalence of SCT of 7-8%, the attributable risk of SCT in VTE among African-Americans was calculated to be higher than the attributable risk of the F2 (prothrombin gene) G20210A mutation in white Americans (≈7% vs. ≈3%, respectively) (Austin, et al 2007). In the previously mentioned study of more than 13,000 African-Americans enrolled in the Kaiser Permanente Northern California health system, an association of SCT with PE, but not DVT, was also noted (Bucknor, et al 2014). Finally, this association was confirmed in the ARIC prospective cohort study, where the hazard ratio (HR) for PE was 2.05 (95% CI, 1.12-3.76), while the HR for DVT without PE was not significant at 1.15 (95% CI, 0.58-2.27) (Folsom, et al 2014). Overall, therefore, the data consistently demonstrate that SCT is a modest risk factor for VTE, and in particular, PE. Whether or not co-inheritance of α-thalassaemia modulates the incidence of VTE is unknown.

4.2. Potential underlying mechanisms of VTE in SCT

The association between SCA and VTE has also only been recently documented. In parallel with SCT, the risk appears to be particularly elevated for PE rather than isolated DVT (Lim, et al 2013, Naik, et al 2014b, Novelli, et al 2012, Stein, et al 2006). Mechanistically, many more studies have evaluated the laboratory manifestations of activation of coagulation and platelets in SCA (Ataga and Key 2007, Lim, et al 2013) compared to SCT (Lawrie, et al 2012, Westerman, et al 2002). Although it is premature to assume a common mechanism, the proximal event is presumably related to the abnormal sickle haemoglobin. Therefore, it is tempting to speculate that, as with hypoxic exercising skeletal muscle or hypoxic acidotic renal medulla, the extremely low partial pressure of oxygen in the venous valve sinuses of the lower extremities (Hamer, et al 1981, Sevitt 1974), where DVT originates, may be sufficient to cause erythrocyte sickling and endothelial adhesion that initiates intravascular thrombosis (Brooks, et al 2009). In addition, the high blood viscosity frequently found in SCT may also promote thrombosis (Tripette, et al 2013). However, why PE is over-represented compared to DVT in sickle haemoglobinopathies is not easily explained by these hypotheses. Possibilities include an increased risk of embolization, or possibly the formation of in-situ pulmonary artery thrombosis (Adedeji, et al 2001, van Langevelde, et al 2012). Further mechanistic studies addressing this paradox are therefore needed.

4.3. Screening for SCT in the context of VTE

At present, no firm recommendation can be made for routine screening for SCT as part of a thrombophilia evaluation. Further studies are required to define whether SCT is a risk for recurrent VTE as it is for a first event, and whether there is any interaction with other risk factors, including pregnancy (Noubouossie and Key 2015, Pintova, et al 2013, Porter, et al 2014) and hormonal contraceptive therapy use (Austin, et al 2009). Until these data are available, it seems prudent to view SCT as a weak risk factor for VTE, with recommendations that mirror those of other similar penetrance mutations, such as the F2 G20210A mutation.

5. Implications of Defining Medical Complications of SCT

Given that newborn screening programmes for sickle haemoglobinopathies are now routine in many developed and developing countries, a greater appreciation of not only the scope, but also the underlying mechanisms of SCT-related complications will continue to be a prerequisite for accurate and appropriate counselling of affected individuals. At present, at least in the United States, counselling for subjects with SCT is purely focused on reproductive implications and choices. However, a consensus on any medical conditions for which carriers are at risk is an important public health priority, so that appropriate evidence-based interventions (when available) can be enacted.