Hemoglobin-based oxygen carriers, oxidative stress and myocardial infarction

Abstract

Introduction: Development of hemoglobin-based oxygen carriers (HBOCs) for use as temporary blood replacement solutions and treatment of hemorrhagic shock has been hindered because of evidence HBOC infusion increases the risk of myocardial infarction (MI).

Methods: To gain insight into potential toxicity mechanisms, MI incidence from later stage clinical testing of five HBOCs was compared to pharmacokinetic and biochemical parameters to identify correlations suggestive of cause-and-effect hypotheses.

Results: There are positive correlations between MI incidence and HBOC dose, size, intravascular half-life and area under the plasma concentration versus time curve (AUC). Furthermore, MI incidence is positively correlated with initial rates of HBOC autoxidation, oxidation by nitric oxide, and AUCs estimated for these HBOC oxidation products.

Conclusions: These observations imply that increased MI risk after HBOC infusion is due to intravascular reactions which exacerbate oxidative stress.

Keywords: AUC; HBOC; hemoglobin autoxidation; hemoglobin-based oxygen carriers; myocardial infarction; nitric oxide; oxidative stress; pharmacokinetics.

FIGURE 1

Example of best linear fit of HBOC plasma half-life versus dose using data for Hemolink. Data taken from (Carmichael et al., 2000). Linear best fit was determined using the Excel data analysis package.

FIGURE 2

Comparison of MI ratios to average HBOC dose (A), size (B), circulatory half-life (C), estimated AUC (D), initial rate of autoxidation (E), and initial rate of oxidation by NO (F), for crosslinked and polymerized (CP) HBOCs (squares) and Hemospan, a PEG modified HBOC (PEG, circle). The equations of best fit (Table 4) are for the CP HBOCs (n = 4) except for the comparison with average molecular size (n = 5). Data are derived from clinical trials enrolling a total of 206–592 patients in each treated or control group for each HBOC.

FIGURE 3

Comparison of AUC values predicted from a mathematical model of HBOC pharmacokinetics for crosslinked and polymerized (CP) HBOCs (squares) and Hemospan, a PEG modified HBOC (PEG, circle). Calculations assumed autoxidation rate constants 0.3 that reported by (Meng et al., 2018) and a zero NO secretion rate. Specific AUCs are for total (A), reduced (B), autoxidized (C), and total oxidized (D) HBOCs. The adjusted coefficients of determination, p values, and y intercepts for equations of best fit for the CP HBOCs are given in Table 7. Data are derived from clinical trials enrolling a total of 206–592 patients in each treated or control group for each HBOC.