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When hemoglobin (Hb) bursts from RBCs because of hemolysis, the naked Hb, devoid of its antioxidant sentries that are normally available within the RBC, can wreak oxidative havoc in the vasculature and in exposed tissues.1 To neutralize Hb and its reactive ferric protoporphyrin-IX group (hemin), specialized plasma scavenger proteins sequester the toxic moieties and transit them to compartments where heme-oxygenases can break down hemin into less toxic metabolites. Other molecules and reducing substances contribute to this protective physiology. However, when these clearance and detoxifying systems are overwhelmed by intravascular hemolysis, such as during sickle cell disease, blood transfusion, malaria, or sepsis, Hb and hemin trigger vascular and organ dysfunction that leads to adverse clinical effects (Figure 1). This perspective reviews the mechanisms of Hb toxicity in different disease states, updates how haptoglobin (Hp) and hemopexin (Hpx) efficiently handle free Hb and hemin, and explores why the time has come to consider these proteins as therapeutics in patients with excessive intravascular hemolysis.

Adverse clinical effects associated with excessive free Hb can be attributed to several specific structural and biochemical properties of the Hb molecule and are caused by the following 4 mutually interacting mechanisms: (1) extravascular translocation of Hb, which is a principal requirement that Hb and hemin can unleash their adverse reactivity in tissues; (2) nitric oxide and oxidative reactions; (3) release of free hemin; and (4) molecular-signaling effects of hemin. These mechanisms are outlined in the subsequent sections and are summarized in Figure 2.

The current understanding of the biochemistry and pathophysiology of these reactions have largely been derived from the study of Hb-based oxygen carriers (HBOCs) and their well-documented adverse effects on hemodynamics.4 Targeted mutagenesis of Hb aimed at limiting interactions with NO or chemical modifications to limit access to sites of NO bioavailability within the vascular wall (eg, by chemical cross-linking of Hb into large polymers or surface-decorated conjugates) attenuate vasoconstriction and hypertension.5,6 Therefore, NO depletion by extracellular Hb is now a widely accepted hypothesis to explain the acute hypertensive response that occurs during massive hemolysis (reaching moderate to high plasma levels of free Hb) or during HBOC infusion.6,7 In addition to vasodilator depletion, another result of Hb-NO reactions might be the generation of Hb-Fe3+ within tissue parenchyma. Accumulation of Hb-Fe3+ within tissues may promote hemin release and/or transfer of hemin to other proteins/lipids with secondary toxicity driven by the free hemin.

The biochemistry of the Hb reaction with peroxides has been scrutinized over the past 40 years,8 but the significance of these reactions for Hb- and hemin-driven pathophysiology is still poorly defined. The assumption that oxidative Hb side reactions could be an important determinant of Hb toxicity was based on observations that peroxides are formed and released into the extracellular space in relatively large quantities during inflammation and ischemia-reperfusion. Under in vitro conditions, the Hb reaction with peroxide results in the formation of Hb-Fe3+, higher oxidation iron species such as ferryl Hb (Hb-Fe4+), and associated radicals (Figure 2 mechanism II). It has been suggested that globin-chain free radicals are available for localized amino acid oxidations (eg, within Hb) or radical transfer to non-Hb molecules (eg, lipoproteins).9,10 The proposed final outcome of these reactions is Hb self-destruction, hemin loss, and globin chain cross-linking/precipitation, which can ultimately lead to tissue damage.11 It should be noted that the putative impact of these reactions on disease conditions is based on limited and indirect experimental evidence, so it remains uncertain whether significant quantities of Hb-Fe4+ and radicals are generated during in vivo hemolysis and if they contribute to disease. The only oxidized Hb species that can be consistently quantified in vivo are Hb-Fe3+ and hemichrome, a structurally distorted form of Hb-Fe3+. The disparity between in vitro biochemical observations and in vivo findings may be because of the shifted balance between oxidation and reduction reactions in in vivo conditions.12 The availability of large quantities of small-molecule and enzymatic reductants may reduce the stability of higher-oxidation-state Hb species and Hb-derived radicals to undetectable levels. Intramolecular Hb cross-links, porphyrin-globin covalent adducts, and globin chain amino acid oxidations have been defined as surrogate markers for Hb-Fe4+ formation. Such modifications have been found in Hb recovered from the spinal fluid after subarachnoid hemorrhage and from the urine, suggesting that peroxidative reactions may contribute to Hb toxicity in vivo.13,14

A third mechanism of Hb toxicity is through release of hemin from Hb-Fe3+, which is the main product of the oxidative reactions described in the previous section. Hemin release allows for transfer of the reactive porphyrin to cell membranes or soluble plasma proteins and lipids and provides free hemin as a ligand for molecular signaling interactions. As a hydrophobic molecule, it is unlikely that significant quantities of free, monomeric hemin can be present in the plasma. Therefore, transferred hemin in the form of low-affinity hemin protein (eg, hemin-albumin) or hemin-lipid complexes are the most likely physiologic end products of hemin release. Depending on the protein or lipid environment, free iron-protoporphyrin can function as an intermediate and transform the recipient molecule into a reactive end product. The most identifiable toxic end product of hemin release is oxidized low-density lipoprotein (oxLDL).15 LDL oxidation and the associated inflammatory and cytotoxic activities represents a critical example of the ability of Hb to induce vascular injury.16,17

Hemin can selectively bind to several receptors, transcription factors, and enzymes and thereby alter cell activation state, gene transcription, and metabolism. The most well-defined interaction is the binding of hemin to the transcriptional repressor Bach-1, which regulates transcription of heme-oxygenase 1 (HO-1) and other antioxidant enzymes essential for the adaptive response to enhanced intracellular hemin levels.18 Hemin is also a ligand of the nuclear hormone receptor REV-ERB, which regulates circadian rhythm, glucose metabolism, and adipogenesis.19 Inhibition of the proteasome by hemin and by some designed hydrophilic porphyrins has thus far been documented in biochemical assays only.20,21 However, if confirmed in biologic systems, this activity may help explain aspects of hemin toxicity. In addition, activation of TLRs and downstream inflammatory signaling, particularly of the TLR-4 pathway, can be triggered by free hemin in some models.22-24

In summary, the definitive pathophysiology of extracellular Hb is dependent on timing, quantity, and tissue localization of Hb/hemin exposure in a specific clinical condition and may result from cumulative effects largely described by the 4 mechanisms discussed in the sections above. For example, systemic and, to some extent, pulmonary hypertension is the most apparent and readily measurable effect of free Hb after intravascular hemolysis. The mechanisms driving acute elevations in blood pressure are Hb translocation into subendothelial spaces, local NO depletion within the vessel wall, and subsequent vasoconstriction. Vascular complications of chronic and/or intermittent Hb exposure are likely to be more complicated, involving inflammation, localized oxidative reactions, thrombosis, vascular remodeling, and renal impairment.25-28 As outlined in the following sections, all 4 mechanisms of Hb and hemin toxicity are specifically attenuated by the natural scavenger proteins Hp and Hpx, explaining the extraordinary protective function of these molecules.

Hp fundamentally changes the biochemical and physiologic profile of free Hb.29 When bound within the large molecular size Hb:Hp complex (> 150 kDa), Hb remains sequestered within the intravascular space and its translocation into the kidney and across the endothelial layer appears to be prevented. This simple mechanism keeps potentially adverse biochemical reactions of the free Hb with NO and/or peroxides away from the most susceptible anatomic sites such as the vascular wall. Intravascular sequestration appears to be the most effective way by which Hp prevents Hb-induced hypertension and renal damage (Figure 3). In addition, Hb remains contained within the reducing (ie, antioxidant-rich) environment of the blood plasma until monocyte and macrophage clearance is complete.

Recent in vitro experiments suggest that Hp may also alter Hb's oxidative reactions. Hp decreases the redox potential of bound Hb-Fe3+, stabilizes the higher oxidation state of Hb-Fe4+, and prevents radical transfer to non-Hb molecules in the presence of oxidants.30,31 The recently resolved crystal structure of the porcine Hb:Hp complex provided some structural basis for the protection of critical amino acids that are primary targets of globin oxidation.32 As a result of this protection, globin oxidation with subsequent protein degradation does not occur when Hb is sequestered in the Hb:Hp complex.33 The structural stability of the complex may prevent accumulation of proinflammatory Hb-degradation products that can evade clearance by scavenger receptors.14,34 In addition, hemin resides firmly in the Hb:Hp complex, it cannot transfer to hemin acceptors such as Hpx, lipoproteins, and albumin.35 Therefore, the prevention of hemin transfer is another essential mechanism by which Hp protects against Hb-driven oxidation of membrane lipids and plasma lipoproteins, preventing the accumulation of free hemin.

Hemolysis and vasoocclusion are the hallmarks of sickle cell disease. Intravascular hemolysis accounts for one-third of RBC destruction leading to increases in plasma free Hb and hemin. In the 1960s, it was recognized that plasma levels of free Hb can be as high as 25μM during sickle cell crisis, with basal plasma Hb levels at 5-10μM in sickle cell patients. Hp and Hpx levels were found to be depleted.45 Low Hp and increased plasma free Hb levels were associated with increased protein carbonyl and nitrotyrosine levels in sickle cell anemia.54 Clinically, uncomplicated pain episodes were found to be associated with increases in plasma hemoglobin levels,55,56 and low levels of Hp were correlated with pulmonary hypertension in sickle cell anemia.57 Although the reported plasma Hb levels in sickle cell patients are much lower than the plasma Hb levels that have been explored in hemodynamic studies of HBOC administration and some animal models of severe hemolysis, these data suggest that free Hb could be a strong pathophysiologic component of the vascular complications of sickle cell disease. 2b1af7f3a8

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