The cell surface protein of EPCR was originally cloned in 1994 . Multiple ligands of EPCR have been found, including PfEMP1, protein C (PC)/activated protein C (APC), factor VIIa, tissue factor, and a specific variant of the T-cell receptor. Under physiological conditions, Protein C is activated by the thrombin-thrombomodulin complex, and activated protein C (APC) then cleaves the protease-activated receptor (PAR1) at Arg46, which triggers an anti-apoptotic and anti-inflammatory reaction to inhibit thrombin production and stabilizes endothelial barrier function [21, 28, 29]. In SM, PfEMP1 binding to EPCR, which subsequently blocks APC binding to EPCR. Once eliminating the APC/EPCR binding, thrombin upregulates of NFĸB, tumor necrosis factor (TNF) and interleukin (IL)-6, downregulates Angiopoietin 1 (Ang1). Consequently, APC induces apoptosis, inflammation, and disrupts endothelial barrier integrity [11, 13, 22].
Each Plasmodium falciparum genome holds about 60 PfEMP1 encoding var genes. DC13-containing PfEMP1 variants can bind to both ICAM-1 and EPCR . Both ICAM-1 [30-32] and EPCR [9, 33-36] are involved in the pathogenesis of CM, for instance, ICAM-1: PfEMP1 binding and resetting have been identified as one of the virulence factors , while EPCR: PfEMP1 binding enables parasites dominate host infections with limited anti-malaria immunity [9, 33-36]. sEPCR is released from surface EPCR on the endothelial cells, so two of them share the same binding affinity; therefore, the recombinant sEPCR’ binding to PfEMP1-DC13 and -DC8 variants could displace cellular EPCR on the surface of endothelial cells , which probably increases the risk of venous thrombosis by way of increased activation of APC [19, 38]. Thus, if individual who is less likely to develop SM due to expressed EPCR would show a higher risk for thrombotic disease [19, 38].
To assess the effect of rs867186-GG polymorphism for the risk of SM, we analyzed genotyped patients with mild malaria and SM on rs867186-GG of previous publications. We found that the rs867186-GG genotype appears significantly more frequent in patients with mild malaria than those with SM (P=0.03 in Fig. 3). However, when we compared genotypes rs867186-GG versus rs867186-AA in malaria patients and healthy individuals, the frequency of rs867186-GG in malaria patients and healthy controls is very similar (p=0.90 in Fig. 2). This was not caused by studies bias, as the heterogeneity is calculated as I2=0 (Fig. 2), and this implies that we can take a fixed-effect model to pool the ORs rather than a random effect model. The genotype difference of the GG and AA alleles of rs867186 is likely due to the pressure exerted by parasites of the genus Plasmodium that cause malaria. Thus, comparing healthy controls that lack these pressure with any disease status is unnecessary. This is a possible reason that these genotypes distinguish between mild and SM but not between healthy controls and malaria patients. The studies from Hansson et al.  and Schuldt et al.  reported that the genotype rs867186-GG does not have a protective role in malaria patients compared to healthy controls. However, they did not compare the difference in rs867186-GG genotype between SM and MM.
The metalloprotease cleaves the surface cellular EPCR, which releases a soluble EPCR (sEPCR) that circulates in the plasma . The relationship between the polymorphisms in EPCR and plasma sEPCR levels has been conducted in patients with thrombosis to evaluate the risk of venous thrombosis by Medina et al. . Their data indicate that individuals carrying some specific genotypes have high sEPCR and APC levels, thus having a lower risk of venous thromboembolism . However, no systemic analysis has been made in malaria patients regarding the EPCR genotype and plasma EPCR levels. When we examined the relationship between rs867186 polymorphisms and plasma sEPCR evaluating risk of SM, we found that the carriers of the rs867186-GG genotype have significantly higher sEPCR levels than those with the AG and AA genotypes in SM; carriers of the rs867186-AG genotype have significantly higher sEPCR levels than those with AA genotype in uncomplicated malaria, and carriers of the rs867186-GG genotype have significantly higher sEPCR levels than those with AG genotype in healthy individuals (Table 3). These results support that the rs867186 GG genotype is associated with elevated sEPCR levels in SM (Table 3). The loss of endothelial protein C receptor link coagulation and inflammation to parasite sequestration in CM [26, 40], and rs867186-GG is associated with increased soluble EPCR and can potentially mediate protection against SM.
Two studies involving adult malaria patients [2, 12] revealed that the EPCR rs867186-G allele could mediate protection against SM, while the other three studies involving child malaria patients showed that EPCR gene variants are not associated with SM [1, 25] or increased mortality among children with CM . Although they utilized similar criteria for SM, adult and child malaria may have different pathophysiology. If more studies in this field are available in the future, the EPCR polymorphism study should be conducted on adult and child malaria separately.