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J.Z. Xu et al.
Figure 2. Aids to unraveling the molecular basis of sickle complications in individuals with purported sickle cell “trait”. Individuals with purported sickle cell trait suffering complications of sickle cell disease may have an unrecognized rare genetic alteration or co-inherited red cell disorder and present a diagnostic challenge. The first step is to obtain a detailed clinical and family history, and to perform family studies if family members are available. Detailed hematologic evaluation, includ- ing hemoglobin electrophoresis, high-performance liquid chromatography (HPLC), examination of the peripheral blood smear, and qualitative sickle solubility assay, are essential. The hematologic data should always be interpreted in conjunction with genetic data. HbA in excess of HbS validates heterozygosity for the bS allele and, if found, should prompt investigation into whether the bS allele could be dominantly inherited with a double mutation. The patient could also have co-inherited other genetic variants [e.g. pyruvate kinase (PK) deficiency] that increase the likelihood of HbS polymerization. If HbS is in excess of HbA, and the inheritance pattern from parents is consistent with HbAS, somatic mosaicism should be considered. If hemoglobin electrophoresis or HPLC shows only HbS, genetic testing shows het- erozygosity for HbS, and only one parent has HbAS, one should consider the possibility of a “functional homozygote” with the trans b gene structurally intact but functionally inactivated, such as can be seen in deletion of the trans upstream b locus control region.
logical confirmation.19 Subsequent large cohort studies have identified SCT as a risk factor for venous throm- boembolism36 as well as pulmonary embolism, but not deep vein thrombosis.36-38 One study suggested that the risk of venous thromboembolism attributable to SCT among blacks is higher than the risk attributable to the pro- thrombin G20210A mutation among whites.36 However, the reason that HbS might predispose a subject to pul- monary embolism over deep vein thrombosis is unknown and merits further investigation.
A number of other reported associations – e.g. splenic infarction, pregnancy complications, acute chest syn- drome, retinopathy and traumatic hyphema – are backed by at times significant anecdotal evidence and have been reviewed in recent publications.1,2,4 This perspective arti- cle is limited in its ability to explore all reported associa- tions in depth, but it is important to note that interpreta- tion of these associations may not be straightforward. For example, the occurrence of splenic infarction in individu- als with SCT has been documented in a number of case reports, often but not always in men exposed to high alti- tudes.39-41 However, as discussed in the next section, detailed genetic testing was not performed in these cases, so it is not possible to draw the conclusion that the splenic infarction was a complication of SCT alone.
SCT has also been reported to be associated with a variety of maternal and fetal complications during preg-
nancy or the puerperium, but the existing evidence is con- flicting.1,4 Some of these associations are concerning, such as potentially higher rates of pre-eclampsia, maternal infections, and fetal loss.42,43 However, in a prospective Nigerian cohort, pregnant women with SCT did not experience more morbidity than women with HbAA, and in fact, had fewer attacks of malaria during pregnancy.44 In yet another study the observed risk of venous throm- boembolism was higher in pregnant subjects with SCT (relative risk, 1.6; 95% CI: 0.5-5.5),45 but the magnitude of the difference did not suggest that the risk of venous thromboembolism was increased above that associated with SCT alone.
A recent analysis found moderate-quality evidence for a null association between SCT and low pediatric height and weight, as well as between SCT and heart failure/car- diomyopathy and stroke.2 In a field in which many ques- tions remain unanswered, it is crucial to recognize and promote such null findings in order to prevent unneces- sary concern, unfounded stigmatization, and psychologi- cal harm to carriers of HbS.
Molecular factors worsening the HbAS phenotype
The key event in the pathophysiology of SCD is poly- merization of the deoxygenated HbS, which under cer-
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haematologica | 2019; 104(6)