Table 2.

Clinical Hpx and SCD Research.

Reference	Age, Sample, Sex, Duration, Location	Study Design	Outcomes
Yalamanoglu, et al., 2018 [28] Depletion of haptoglobin and hemopexin promote hemoglobin-mediated lipoprotein oxidation in sickle cell disease	≥18 year n = 19 (SCD) & n = 11 (controls) 50% M Aurora, CO, USA	Prospective Case-control study	In SCD patients, HDL and LDL plasma levels were lower compared to controls (25 ± 16 and 82 ± 26 mg/dl vs control 53 ± 18 and 128 ± 21 mg/dl). SCD patients had an increase in heme bound to Hb (9.5 ± 4 μM) and total plasma heme levels (60 ± 23 μM) compared to plasma obtained from control patients (4.6 ± 4.2 μM and 19 ± 11 μM).
Camus, et al., 2015 [31] Circulating cell membrane microparticles transfer heme to endothelial cells and trigger vasoocclusions in sickle cell disease	≥18 year n = 47 (SCD), n = 22 (AA) Paris, France	Retrospective Case-control	In patients with SCD, annexin-a5+ MPs were increased 5-fold and plasma Hb were increased 3-fold compared to controls (p < 0.001 and p = 0.007, respectively). SCD erythrocytes released MPs that contained 2X the concentration of heme compared to control MPs (p = 0.038).
Roumenina, et al., 2020 [32] Complement activation in sickle cell disease: Dependence on cell density, hemolysis and modulation by hydroxyurea therapy	≥18 year n = 106 (SCD) & n = 176 (AA) Paris, France	Retrospective	sC5b-9, a marker of complement activation, was increased in 42% of SCD patient plasma (p < 0.001) and was higher in SCD patients treated with hydroxyurea compared to the nontreatment SCD group (p < 0.005). In nontreated-SCD patients, sC5b-9 levels were higher after incubation of SCD RBCs with normal human serum compared hydroxyurea-treated SCD and control RBCs (p = 0.038 and p = 0.006, respectively). Endothelial cells incubated with SCD serum led to the C3 deposits on the surface of cells and were decreased after the addition of Hpx (p = 0.0117).
Santiago, et al., 2018 [33] Serum haptoglobin and hemopexin levels are depleted in pediatric sickle cell disease patients	<18 year n = 179 (SS), n = 93 (SC), n = 28 (AA) University of Bahia, Brazil	Cross-sectional study	SS and SC patient groups showed lower Hp and Hpx levels (SS < SC < AA) and increased reticulocyte counts and serum LDH (SS > SC > AA). SCD patient (SS and SC) serum analysis showed a negative correlation between Hpx and LDH (r = −0.509, p < 0.001) and heme (r = −0.592, p < 0.001).
Whyte-Stewart, et al., 2017 [34] The association between hemopexin and silent cerebral infarcts in pediatric sickle cell disease	5–15 year n = 340 Baltimore, Maryland	Prospective Cross-sectional study	In patients who experienced silent cerebral infarcts, Hpx levels were lower than controls (p = 0.0082). Hpx was shown to be associated with an increased risk of silent cerebral infarct (p = 0.03).
Vendrame, et al., 2018 [35] Differences in heme and hemopexin content in lipoproteins from patients with sickle cell disease	35 year (AA; n = 37; 32% F), 45 year (SC; n = 39; 62% F), 37 year (SS; n = 40; 48% F) Campinas, Brazil & Seattle, WA, USA	Prospective Case-control study	In SCD groups (SC and SS) compared to controls (AA), erythrocytes and Hb concentrations were lower while reticulocyte, bilirubin, and serum LDH levels were increased (p = 0.0001). In SS group alone, heme was reported at higher levels compared to AA or SC groups (p = 0.0001). In SC and SS patient groups, soluble VCAM-1 levels were increased compared to controls (p = 0.0001) and were shown to be higher in SS patients over SC patients (p = 0.02). Additionally, in SS and SC groups, total cholesterol and LDL levels were decreased compared to controls (p = 0.001).
Detterich, et al., 2019 [36] Erythrocyte and plasma oxidative stress appears to be compensated in patients with sickle cell disease during a period of relative health, despite the presence of known oxidative agents	23 ± 8.8 year (SCD; n = 55) 27 ± 8.9 year (AA; n = 44) 28 day Los Angeles, California	Retrospective Case-control	Measured at the time of phlebotomy, SCD patients demonstrated higher % metHb (p = 0.004). In the plasma, free Hb and heme, were elevated in SCD patients compared to controls and increased rapidly at Hpx levels less than 200 μg/mL SCD patients.
Santaterra, et al., 2020 [37] Endothelial barrier integrity is disrupted in vitro by heme and by serum from sickle cell disease patients	>18 year n = 20 (SCD), n = 10 (AA) Campinas, Brazil	Retrospective Case-control In vitro study	In SCD patients, Hpx levels were lower than comparative healthy volunteers (0.33 ± 0.32 vs 1.29 ± 0.23; p < 0.001). Heme-induced endothelial barrier disruption was correlated with Hpx levels, most significantly at 12 min (Rs = 0.68; p < 0.0001).