p(HGNC:HBB)
We found that hemoglobin contents in hematoma were significantly higher in the DFX treated group compare to the vehicle-treated group (15.9 ± 1.8 vs. 11.8 ± 0.8 mg/g, p<0.05, Fig. 5A). PubMed:27125525
Analysis of Hb release from ex vivo vessel chamber experiments revealed a significant (p 0.05; n 4) increase in Hb levels following FeCl3 treatment of isolated aorta in the presence of flowing blood (157 45 g/ml), whereas FeCl3 pretreatment of vessels prior to blood perfusion caused no hemolysis (Fig. 2A). PubMed:19276082
Analysis of the time course of hemolysis in whole blood revealed a rapid linear increase in Hb levels, peaking 10 min after FeCl3 addition (Fig. 2B), a time course consistent with the rapid hemolysis and vascular injury observed in the ex vivo aortic thrombosis model. PubMed:19276082
Plasma hemoglobin scavenges nitric oxide and causes vasoconstriction, platelet aggregation and inflammation9,22–24. PubMed:27515135
Children undergoing open heart surgery experience a progressively increasing risk of postoperative infection and thrombosis, increasing need for mechanical ventilation and inotropes, increasing Day 1 through Day 2 peak blood lactate, and decreased nadir mean arterial pressure as the levels of free Hb increase and the levels of haptoglobin decrease. PubMed:29603246
In animal experiments, the administration of lipopolysaccharide (LPS) to induce systemic inflammation leads to a significant increase in plasma concentration of cell-free hemoglobin as well [5–8]. PubMed:29956069
The results reported here indicate that, once exposed to oxidized plaque material, erythrocytes are lysed, the liberated hemoglobin is oxidized and heme dissociates from the resultant ferrihemoglobin. PubMed:20378845
The second biochemical process relates to the ability of Hb to facilitate oxidative reactions outside of the reducing environment of the RBC, leading to the accumulation of ferric metHb(Fe3+) in tissue.24 PubMed:29610666
In the current observational study in patients undergoing multilevel spinal fusion surgery, we tested the hypothesis that moderate doses of stored RBC transfusions increase intravascular cell-free Hb and decrease NO availability in surgical patients. PubMed:27308950
Old blood transfusion resulted in systemic free Hb total exposure (AUC0–∞) of 4600 μmol heme-h/l, which was primarily cleared by the kidney within 24 h. PubMed:26794659
In old blood-transfused animals, strong Hb and iron deposition was observed in the tubule lumen and epithelial cells, respectively. PubMed:26794659
In mice resuscitated with SRBCs, plasma hemoglobin levels were greater than in mice resuscitated with FRBCs or in sham-treated mice at two, four, and 24 hours after transfusion (Figure 1C). PubMed:27515135
There is a clear need for, and medical benefit from, blood transfusions; nonetheless, administration of red blood cells (RBCs) does result in exposure to toxicants specific to hemoglobin (Hb) and its degradation components, hemin and iron. PubMed:30281034
When RBCs are damaged by high shear in continuous flow ventricular assist devices, free hemoglobin induces platelet aggregation, contributing to high risk of thrombotic complications [33]. PubMed:28458720
Because of its large molecular size, this complex is maintained in the intravascular space, preventing the association of otherwise free Hb with nitric oxide (NO; Reiter et al., 2002) and inhibiting the release of free heme (Melamed-Frank et al., 2001). PubMed:24904418
Macrophages and liver cells capture large HP-Hb complexes clearing the plasma from free hemoglobin. PubMed:28088643
During DIC, fibrin strands within the fibrin mesh formed could cut red blood cells, resulting in the formation of schistocytes (strongly deformed red blood cells or fragments of red blood cells) and the release of hemoglobin. PubMed:29956069
Old blood transfusion resulted in systemic free Hb total exposure (AUC0–∞) of 4600 μmol heme-h/l, which was primarily cleared by the kidney within 24 h. PubMed:26794659
Nevertheless, the crosstalk between glucose and heme metabolism in sepsis is bidirectional since an excessive accumulation of cell-free heme following hemolysis influences the glucose metabolism by iron-driven oxidative inhibition of the glucose-6-phosphatase (a liver enzymes being important for endogenous glucose production via gluconeogenesis and glycogenolysis) [14]. PubMed:29956069
Plasma hemoglobin scavenges nitric oxide and causes vasoconstriction, platelet aggregation and inflammation9,22–24. PubMed:27515135
An increase in plasma cell-free Hb and vascular dysfunction also has been shown after transfusion of autologous RBCs with long storage duration to healthy human subjects.19,20,37 PubMed:27308950
Sickle cell disease (SCD) and malaria are paradigmatic hemolytic disorders, in which alteration in the structure of red blood cells (RBCs) leads to the release of Hb and heme into the circulation. PubMed:26675351
During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. PubMed:29694434
In addition to inflammation, cell-free hemoglobin (Hb) released via hemolysis is a potent inducer of oxidative stress. PubMed:30505280
There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246
Our findings in the complex setting of critically ill pediatric cardiac surgery patients demonstrate that higher levels of free Hb and lower levels of haptoglobin are associated with serious postoperative clinical complications (infection, thrombosis, death), immunomodulation, and inflammation. PubMed:29603246
The first process links the nitric oxide (NO) reactivity of oxyHb to a cascade of cell-free Hb extravasation, hemolysis-associated NO-depletion, and vasoconstriction.21–23 PubMed:29610666
Spontaneous decomposition of Hb via auto-oxidation leads to the formation of ROS, free heme groups and free iron, which are highly reactive and have the ability to damage lipids, proteins, and DNA (Olsson et al., 2012). PubMed:30505280
Release of hemoglobin (and ultimately heme), and arginase-1 into the plasma results in binding of nitric oxide and also reduction in L-arginine, respectively, causing a relative reduction in vasodilatory effect.[14,29] PubMed:26337933
Resuscitation with SRBCs together with albumin did not alter plasma levels of hemoglobin, hemopexin, haptoglobin, or heme as compared to resuscitation with SRBCs alone (Figure 3C–E, I, Supplemental Material and Supplemental Figure II A–B). PubMed:27515135
Co-administration of haptoglobin with SRBCs results in a prolonged increase in plasma hemoglobin levels for more than 48 hours after transfusion. PubMed:27515135
Haptoglobin (Hp) is an abundant and conserved plasma glycoprotein, which binds acellular adult hemoglobin (Hb) dimers with high affinity and facilitates their rapid clearance from circulation following hemolysis. PubMed:24486321
Haptoglobin (Hp) is a Hb-scavenging plasma glycoprotein which binds non-covalently to hemoglobin dimers that are generated by dissociation of acellular Hb tetramers after hemolysis [6]. PubMed:24486321
Hp is the first-line scavenger that binds and accelerates the clearance of Hb in the circulation, although the macrophage CD163 receptor has also been the focus of several recent investigations [66– 68]. PubMed:24486321
Based on clinical observations the Hb and heme scavenger proteins haptoglobin (Hp) and hemopexin (Hx) have been characterized as a sequential defense system with Hp as the primary protector and Hx as a backup when all Hp is depleted during more severe intravascular hemolysis. PubMed:26475040
Free Hb is bound by the plasma protein haptoglobin, and the large molecular size Hb: Hp complexes are ultimately cleared by spleen and liver macrophages expressing the Hb scavenger receptor CD163.8 PubMed:26794659
Hp treatment prevented renal Hb exposure. PubMed:26794659
The prevention of renal Hb filtration by Hp may be a therapeutic strategy to block renal Hb exposure and to rescue renal function in patients with severe hemoglobinuria. PubMed:26794659
Thus, the interactions of hemoglobin with haptoglobin, and of heme with hemopexin, ensure safe disposal of potentially dangerous molecules [6,7,15–19] PubMed:26875449
However, patients who died had significantly higher plasma cell-free Hb and lower haptoglobin concentrations at all time points, preoperatively and immediately postoperatively and 6 and 12 hours postoperatively (Fig. 1 shows the 12-hr postoperative data). PubMed:29603246
Children undergoing open heart surgery experience a progressively increasing risk of postoperative infection and thrombosis, increasing need for mechanical ventilation and inotropes, increasing Day 1 through Day 2 peak blood lactate, and decreased nadir mean arterial pressure as the levels of free Hb increase and the levels of haptoglobin decrease. PubMed:29603246
free hemoglobin is rapidly cleared from the circulation by several scavenging mechanisms; however, we found that the plasma-free hemoglobin was high and haptoglobin levels were low in the patients examined (Table 1). PubMed:29929138
Normally, cellfree hemoglobin will dimerize and rapidly be bound by its hemoglobin scavengers haptoglobin and hemopexin [12]. PubMed:29956069
Hp is a plasma glyco-protein that normally circulates in within a concentration range of 0.3–2mg/ml and is the putative scavenger of cell-free Hb with a high affinity (KD¼10–12M) for Hb dimers (Fig. 1 A,B and Fig. 2 C [31]). PubMed:30281034
On the extracellular level, within the circulation, haptoglobin (Hp) and hemopexin (Hpx) are two of the most prominent scavenger proteins, with antioxidative properties through their capacity to remove cell-free Hb (by Hp) and heme (by Hpx). PubMed:30505280
The expression of A1M is up-regulated by elevated levels of free Hb, heme and ROS [23]. PubMed:24489717
This is consistent with our findings here that both heme and Hb were associated with increased levels of synovial fluid A1M. PubMed:30505280
High free hemoglobin was shown in patients with primary Cys89Tyr mutation in CD59 (Table 1) and it has been suggested in several ways that free hemoglobin may serve as a major mechanism for thrombophilia. PubMed:29929138
For instance, earlier studies have demonstrated that neutrophil elastase degrades the hemoglobin liberating free hemin that induces ROS production. PubMed:28716864
The same applies to hemolysin. For one thing, the pore-forming toxin hemolysin is one the pathogens’ tools of causing hemolysis or releasing hemoglobin and poorly available iron [139]; then again it trigger eryptosis, one mechanism of protecting against hemolysis [142]. PubMed:29956069
Endothelial injury may also be related to Free hemoglobin and its breakdown oxidative product heme, and MPs, which mediates direct proinflammatory, proliferative, and pro-oxidant effects on endothelial cells [22–24] both in PNH and congenital CD59 deficiency, but may be more pronounced in congenital CD59 deficiency and perhaps even more in the brain due to loss of CD59 in the endothelium of these patients. PubMed:29929138
Infusion of exogenous hemoglobin into SS-mice can markedly increase stasis compared to the amount of spontaneous stasis [5]. PubMed:29694434
Children undergoing open heart surgery experience a progressively increasing risk of postoperative infection and thrombosis, increasing need for mechanical ventilation and inotropes, increasing Day 1 through Day 2 peak blood lactate, and decreased nadir mean arterial pressure as the levels of free Hb increase and the levels of haptoglobin decrease. PubMed:29603246
Thus, in severe haemolytic diseases, such as paroxysmal nocturnal haemoglobinuria (PNH) and sickle cell disease (SCD), serum haptoglobin is typically undetectable and plasma haemoglobin is elevated (Tabbara, 1992). PubMed:25307023
In cases of congenital hemoglobinopathies such as sickle cell disease, deficiencies in complement system regulators such as paroxysmal nocturnal hemoglobinuria, and many other disorders, erythrocytes can lyse and liberate large quantities of hemoglobin. PubMed:26875449
Thus, in severe haemolytic diseases, such as paroxysmal nocturnal haemoglobinuria (PNH) and sickle cell disease (SCD), serum haptoglobin is typically undetectable and plasma haemoglobin is elevated (Tabbara, 1992). PubMed:25307023
Third, exposure to extracellular Hb, in the form of oxygen therapeutics or when Hb is released from old red blood cells, have also been reported to induce oxidative toxicity in kidney and brain tissues [65]. PubMed:24486321
Third, exposure to extracellular Hb, in the form of oxygen therapeutics or when Hb is released from old red blood cells, have also been reported to induce oxidative toxicity in kidney and brain tissues [65]. PubMed:24486321
Altogether, our best interpretation of these data is that increased levels of cell-free Hb and heme in synovial fluid early after injury triggered an increase in the synovial fluid A1M concentration that appeared to be protective of oxidative damage. PubMed:30505280
Plasma hemoglobin scavenges nitric oxide and causes vasoconstriction, platelet aggregation and inflammation9,22–24. PubMed:27515135
There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246
Hemolysis and the transfusion of banked blood or Hb-based therapeutics can result in varying quantities of circulating acellular Hb which can induce life threatening radical generating reactions in patients with a compromised vascular system [60]. PubMed:24486321
The anemia in CEP mice was severe with significant reduction of Hb levels and RBC number (Table 1), regenerative with marked reticulocytosis (28.8±4.2%) (Table 1), and microcytic and hypochromic with reduced mean cell Hb content (9.95±0.64 pg in CEP vs. 14.5±0.18 in WT mice) (Table 1). PubMed:28143953
By day 1 following injection, plasma Hb concentrations in the anemia group were reduced to 0.5 0.3 g/l, which was not significantly different from the control value of 0.5 0.3 g/l (n 6, unadjusted P 0.93; Fig. 3A). PubMed:29351418
The level of hemoglobin declined gradually over the time after the onset of ICH with a significant reduction at day 3. The contents of hemoglobin in the clot were 26.2 ± 5.2 mg/g at 4 hours, but were reduced to 13.9 ± 0.9 mg/g at day-3 (Fig. 2B, p<0.01). PubMed:27125525
We found that hemoglobin contents in hematoma were significantly higher in the DFX treated group compare to the vehicle-treated group (15.9 ± 1.8 vs. 11.8 ± 0.8 mg/g, p<0.05, Fig. 5A). PubMed:27125525
Moreover they have demonstrated that released Hb plays an important role in exacerbating RBC hemolysis, establishing a damaging hemolysis/ oxidative cycle that drives further red cell damage, vascular injury, and thrombosis. PubMed:19276082
Hemolysis and the transfusion of banked blood or Hb-based therapeutics can result in varying quantities of circulating acellular Hb which can induce life threatening radical generating reactions in patients with a compromised vascular system [60]. PubMed:24486321
Hemolysis increases the concentration of Hb which, under oxidative stress, releases free heme. PubMed:24904418
Haemoglobin and haem levels increase in plasma and urine when haptoglobin and haemopexin scavenging mechanisms are saturated during acute or chronic haemolysis. PubMed:25307023
Subsequent RBC lysis leads to release of acellular Hb, which, in turn, damages the alveolar epithelial cells. PubMed:26974230
The plasma hemoglobin levels at two and four hours after SRBC-transfusion were greater than the cell-free hemoglobin levels in the supernatant of the SRBCs before transfusion (Figure 1C, Supplemental Table I), providing evidence that hemolysis occurs in vivo during and after transfusion of SRBCs. PubMed:27515135
Red blood cell hemolysis in sickle cell disease (SCD) releases free hemoglobin. PubMed:28088643
During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. PubMed:29694434
Following MAC deposition on RBCs, intravascular hemolysis that leads to increasing levels of free hemoglobin was seen. PubMed:29929138
Excessive intravascular hemolysis saturates scavenger mechanisms, resulting in free hemoglobin in plasma that irreversibly reacts with nitric oxide (NO) to form nitrate and methemoglobin. PubMed:29929138
In infectious diseases, such as malaria and sepsis, high amounts of cell-free hemoglobin and heme were found [8], suggesting that hemolysis during sepsis and systemic inflammation is of pathophysiological relevance. PubMed:29956069
Finally, a bi-directional crosstalk between hemolysis and coagulation was postulated with induction of tissue factor by cell-free hemoglobin as potentially central mechanism for hemolysis to trigger coagulation [87]. PubMed:29956069
In addition to inflammation, cell-free hemoglobin (Hb) released via hemolysis is a potent inducer of oxidative stress. PubMed:30505280
Plasma hemoglobin scavenges nitric oxide and causes vasoconstriction, platelet aggregation and inflammation9,22–24. PubMed:27515135
There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246
Our findings in the complex setting of critically ill pediatric cardiac surgery patients demonstrate that higher levels of free Hb and lower levels of haptoglobin are associated with serious postoperative clinical complications (infection, thrombosis, death), immunomodulation, and inflammation. PubMed:29603246
During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. PubMed:29694434
In infectious diseases, such as malaria and sepsis, high amounts of cell-free hemoglobin and heme were found [8], suggesting that hemolysis during sepsis and systemic inflammation is of pathophysiological relevance. PubMed:29956069
High free hemoglobin was shown in patients with primary Cys89Tyr mutation in CD59 (Table 1) and it has been suggested in several ways that free hemoglobin may serve as a major mechanism for thrombophilia. PubMed:29929138
There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246
The median (and mean—data not shown) free Hb levels preoperatively and at all postoperative time points (immediately and 6 and 12 hr postoperatively) were higher (p50.057) in those who later developed a proven thrombosis (Fig. 3 displays the 12-hr data). PubMed:29603246
Our findings in the complex setting of critically ill pediatric cardiac surgery patients demonstrate that higher levels of free Hb and lower levels of haptoglobin are associated with serious postoperative clinical complications (infection, thrombosis, death), immunomodulation, and inflammation. PubMed:29603246
Children undergoing open heart surgery experience a progressively increasing risk of postoperative infection and thrombosis, increasing need for mechanical ventilation and inotropes, increasing Day 1 through Day 2 peak blood lactate, and decreased nadir mean arterial pressure as the levels of free Hb increase and the levels of haptoglobin decrease. PubMed:29603246
During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. PubMed:29694434
Hemolysis increases the concentration of Hb which, under oxidative stress, releases free heme. PubMed:24904418
Haemoglobin and haem levels increase in plasma and urine when haptoglobin and haemopexin scavenging mechanisms are saturated during acute or chronic haemolysis. PubMed:25307023
Analysis of Hb release from ex vivo vessel chamber experiments revealed a significant (p 0.05; n 4) increase in Hb levels following FeCl3 treatment of isolated aorta in the presence of flowing blood (157 45 g/ml), whereas FeCl3 pretreatment of vessels prior to blood perfusion caused no hemolysis (Fig. 2A). PubMed:19276082
Analysis of the time course of hemolysis in whole blood revealed a rapid linear increase in Hb levels, peaking 10 min after FeCl3 addition (Fig. 2B), a time course consistent with the rapid hemolysis and vascular injury observed in the ex vivo aortic thrombosis model. PubMed:19276082
Moreover they have demonstrated that released Hb plays an important role in exacerbating RBC hemolysis, establishing a damaging hemolysis/ oxidative cycle that drives further red cell damage, vascular injury, and thrombosis. PubMed:19276082
Hemolysis and the transfusion of banked blood or Hb-based therapeutics can result in varying quantities of circulating acellular Hb which can induce life threatening radical generating reactions in patients with a compromised vascular system [60]. PubMed:24486321
Subsequent RBC lysis leads to release of acellular Hb, which, in turn, damages the alveolar epithelial cells. PubMed:26974230
The plasma hemoglobin levels at two and four hours after SRBC-transfusion were greater than the cell-free hemoglobin levels in the supernatant of the SRBCs before transfusion (Figure 1C, Supplemental Table I), providing evidence that hemolysis occurs in vivo during and after transfusion of SRBCs. PubMed:27515135
Red blood cell hemolysis in sickle cell disease (SCD) releases free hemoglobin. PubMed:28088643
During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. PubMed:29694434
Following MAC deposition on RBCs, intravascular hemolysis that leads to increasing levels of free hemoglobin was seen. PubMed:29929138
In infectious diseases, such as malaria and sepsis, high amounts of cell-free hemoglobin and heme were found [8], suggesting that hemolysis during sepsis and systemic inflammation is of pathophysiological relevance. PubMed:29956069
Finally, a bi-directional crosstalk between hemolysis and coagulation was postulated with induction of tissue factor by cell-free hemoglobin as potentially central mechanism for hemolysis to trigger coagulation [87]. PubMed:29956069
In addition to inflammation, cell-free hemoglobin (Hb) released via hemolysis is a potent inducer of oxidative stress. PubMed:30505280
The results reported here indicate that, once exposed to oxidized plaque material, erythrocytes are lysed, the liberated hemoglobin is oxidized and heme dissociates from the resultant ferrihemoglobin. PubMed:20378845
Hemolysis and the transfusion of banked blood or Hb-based therapeutics can result in varying quantities of circulating acellular Hb which can induce life threatening radical generating reactions in patients with a compromised vascular system [60]. PubMed:24486321
Free hemoglobin (Hb) triggered vascular damage occurs in many hemolytic diseases, such as sickle cell disease, with an unmet need for specific therapeutic interventions. PubMed:26475040
Depending on the scale, rate, and site of hemolysis, the primary adverse effects triggered by free Hb are vascular dysfunction, oxidative tissue damage, and altered inflammatory response [1], PubMed:26475040
Several studies in animals have supported the idea that infusion of free Hb, stored RBC supernatant (preservation solution + plasma), and Hb-containing microvesicles causes vasoconstriction, vascular dysfunction, and vascular injury.12,16–18 PubMed:27308950
Third, exposure to extracellular Hb, in the form of oxygen therapeutics or when Hb is released from old red blood cells, have also been reported to induce oxidative toxicity in kidney and brain tissues [65]. PubMed:24486321
Third, exposure to extracellular Hb, in the form of oxygen therapeutics or when Hb is released from old red blood cells, have also been reported to induce oxidative toxicity in kidney and brain tissues [65]. PubMed:24486321
In that study, heme was shown to specifically bind to endothelial Toll-like receptors (TLR4) and trigger a cascade of inflammatory responses, which could be attributed to oxidation and degradation of cell-free Hb [73]. PubMed:24486321
Hemolysis increases the concentration of Hb which, under oxidative stress, releases free heme. PubMed:24904418
Exposure to Hb and its oxidized products increases heme overload on the AT1 cells. Heme overload induces the expression of HO-1 and iron-sequestering proteins, such as ferritin. PubMed:26974230
Toxicity of free hemoglobin is also caused by the release of cell-free heme, which produces lipid peroxidation and mitochondrial damage and increases the production of reactive oxygen species. PubMed:27515135
Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. PubMed:28088643
For instance, earlier studies have demonstrated that neutrophil elastase degrades the hemoglobin liberating free hemin that induces ROS production. PubMed:28716864
The expression of A1M is up-regulated by elevated levels of free Hb, heme and ROS [23]. PubMed:24489717
This is consistent with our findings here that both heme and Hb were associated with increased levels of synovial fluid A1M. PubMed:30505280
Because of its large molecular size, this complex is maintained in the intravascular space, preventing the association of otherwise free Hb with nitric oxide (NO; Reiter et al., 2002) and inhibiting the release of free heme (Melamed-Frank et al., 2001). PubMed:24904418
Thus, the antioxidant, anticoagulant, anti-proliferative and vasodilating effects of the HMOX1 and biliverdin reductase systems probably compensate for the nitric oxide (NO) scavenging, vasoconstrictive, proliferative, inflammatory and pro-oxidant effects of circulating free haemoglobin, haem and haem-iron, which are discussed below (Rother et al, 2005). PubMed:25307023
Thus, the antioxidant, anticoagulant, anti-proliferative and vasodilating effects of the HMOX1 and biliverdin reductase systems probably compensate for the nitric oxide (NO) scavenging, vasoconstrictive, proliferative, inflammatory and pro-oxidant effects of circulating free haemoglobin, haem and haem-iron, which are discussed below (Rother et al, 2005). PubMed:25307023
Thus, the antioxidant, anticoagulant, anti-proliferative and vasodilating effects of the HMOX1 and biliverdin reductase systems probably compensate for the nitric oxide (NO) scavenging, vasoconstrictive, proliferative, inflammatory and pro-oxidant effects of circulating free haemoglobin, haem and haem-iron, which are discussed below (Rother et al, 2005). PubMed:25307023
Free plasma haemoglobin and haem also scavenge NO and have multiple pro-inflammatory and pro-oxidant properties that mediate many of the adverse effects of haemolysis. PubMed:25307023
Depending on the scale, rate, and site of hemolysis, the primary adverse effects triggered by free Hb are vascular dysfunction, oxidative tissue damage, and altered inflammatory response [1], PubMed:26475040
Extracellular hemoglobin and heme are pro-oxidative, proinflammatory, and cytotoxic [10–12], and can contribute to the pathology of hemolytic diseases. PubMed:26875449
Plasma hemoglobin scavenges nitric oxide and causes vasoconstriction, platelet aggregation and inflammation9,22–24. PubMed:27515135
There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246
Our findings in the complex setting of critically ill pediatric cardiac surgery patients demonstrate that higher levels of free Hb and lower levels of haptoglobin are associated with serious postoperative clinical complications (infection, thrombosis, death), immunomodulation, and inflammation. PubMed:29603246
During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. PubMed:29694434
In infectious diseases, such as malaria and sepsis, high amounts of cell-free hemoglobin and heme were found [8], suggesting that hemolysis during sepsis and systemic inflammation is of pathophysiological relevance. PubMed:29956069
Thus, the antioxidant, anticoagulant, anti-proliferative and vasodilating effects of the HMOX1 and biliverdin reductase systems probably compensate for the nitric oxide (NO) scavenging, vasoconstrictive, proliferative, inflammatory and pro-oxidant effects of circulating free haemoglobin, haem and haem-iron, which are discussed below (Rother et al, 2005). PubMed:25307023
Free plasma haemoglobin and haem also scavenge NO and have multiple pro-inflammatory and pro-oxidant properties that mediate many of the adverse effects of haemolysis. PubMed:25307023
Free plasma haemoglobin and haem also scavenge NO and have multiple pro-inflammatory and pro-oxidant properties that mediate many of the adverse effects of haemolysis. PubMed:25307023
In addition to cell-free Hb, membrane structural modification, externalization of phosphatidylserine,21 decreased cell membrane deformability,22,23 and increased endothelial adherence24 could alter vascular NO homeostasis. PubMed:27308950
Plasma hemoglobin scavenges nitric oxide and causes vasoconstriction, platelet aggregation and inflammation9,22–24. PubMed:27515135
Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. PubMed:28088643
Extracellular Hb exhibits a highly toxic nature by scavenging Nitric Oxide (NO) that reduces its bioavailability [1]. PubMed:28088643
Some of the adverse effects caused by cell-free hemoglobin are a result of depletion of nitric oxide (NO), which may lead to vasoconstriction, inflammation, and platelet activation (10, 24). PubMed:28314763
Another mechanism for platelet activation by RBC lysate is extracellular hemoglobin, which enhances platelet activation by lowering NO bioavailability [ 29]. PubMed:28458720
Extracellular hemoglobin sequesters NO and thus promotes activation of endothelial cells and adhesion/aggregation of platelets [64]. PubMed:28458720
The first process links the nitric oxide (NO) reactivity of oxyHb to a cascade of cell-free Hb extravasation, hemolysis-associated NO-depletion, and vasoconstriction.21–23 PubMed:29610666
One of the mechanisms by which cell-free hemoglobin exerts its detrimental effects is its ability to effectively scavenge nitric oxide (NO), which in turn leads to perfusion disorders and an increased arterial and pulmonary arterial pressure [39, 40]. PubMed:29956069
Release of hemoglobin (and ultimately heme), and arginase-1 into the plasma results in binding of nitric oxide and also reduction in L-arginine, respectively, causing a relative reduction in vasodilatory effect.[14,29] PubMed:26337933
Release of hemoglobin (and ultimately heme), and arginase-1 into the plasma results in binding of nitric oxide and also reduction in L-arginine, respectively, causing a relative reduction in vasodilatory effect.[14,29] PubMed:26337933
Depending on the scale, rate, and site of hemolysis, the primary adverse effects triggered by free Hb are vascular dysfunction, oxidative tissue damage, and altered inflammatory response [1], PubMed:26475040
Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. PubMed:28088643
During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. PubMed:29694434
In addition to inflammation, cell-free hemoglobin (Hb) released via hemolysis is a potent inducer of oxidative stress. PubMed:30505280
Extracellular hemoglobin and heme are pro-oxidative, proinflammatory, and cytotoxic [10–12], and can contribute to the pathology of hemolytic diseases. PubMed:26875449
Many studies have explored basic mechanisms of Hb or heme triggered endothelial damage and have suggested that oxidative reactions of Hb generate multiple toxic species such as free heme that is released from ferric Hb, iron, free radicals, and globin aggregation products [15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25]. PubMed:26475040
Compared to wild-type (WT) mice, mice with 117 endothelial dysfunction have an increased vasoconstrictor response to infusion of 118 cell-free hemoglobin (25). PubMed:28314763
Sickle cell disease (SCD) and malaria are paradigmatic hemolytic disorders, in which alteration in the structure of red blood cells (RBCs) leads to the release of Hb and heme into the circulation. PubMed:26675351
This is the case in a mouse model of SCD, which is hallmarked by hemolysis, increased circulating Hb/heme, and low levels of Hp and Hx and shows elevated hepatic macrophage iron levels and M1 polarization. PubMed:26675351
Old blood transfusion resulted in systemic free Hb total exposure (AUC0–∞) of 4600 μmol heme-h/l, which was primarily cleared by the kidney within 24 h. PubMed:26794659
In old blood-transfused animals, strong Hb and iron deposition was observed in the tubule lumen and epithelial cells, respectively. PubMed:26794659
In mice resuscitated with SRBCs, plasma hemoglobin levels were greater than in mice resuscitated with FRBCs or in sham-treated mice at two, four, and 24 hours after transfusion (Figure 1C). PubMed:27515135
Old blood transfusion resulted in systemic free Hb total exposure (AUC0–∞) of 4600 μmol heme-h/l, which was primarily cleared by the kidney within 24 h. PubMed:26794659
Immunofluorescence confirmed that renal Hb exposure triggered overexpression of HMOX1 and the unfolded protein response (UPR) chaperone HSP70 in tubule epithelial cells (Figure 2d). PubMed:26794659
Immunofluorescence confirmed that renal Hb exposure triggered overexpression of HMOX1 and the unfolded protein response (UPR) chaperone HSP70 in tubule epithelial cells (Figure 2d). PubMed:26794659
In cases of congenital hemoglobinopathies such as sickle cell disease, deficiencies in complement system regulators such as paroxysmal nocturnal hemoglobinuria, and many other disorders, erythrocytes can lyse and liberate large quantities of hemoglobin. PubMed:26875449
Extracellular hemoglobin and heme are pro-oxidative, proinflammatory, and cytotoxic [10–12], and can contribute to the pathology of hemolytic diseases. PubMed:26875449
The second biochemical process relates to the ability of Hb to facilitate oxidative reactions outside of the reducing environment of the RBC, leading to the accumulation of ferric metHb(Fe3+) in tissue.24 PubMed:29610666
This is a principal requirement for hemoglobin and hemin to induce adverse reactivity in tissues, including nitric oxide and oxidative reactions, release of free hemin, and molecular-signaling effects of hemin (reviewed by Schaer DJ et al.) [13] and Hill A et al. [14]. PubMed:29929138
We also found that HbFe21 and HbFe31 activate NF-kB and mitogen-activated protein kinase pathways, as shown by phosphorylation of NF-kB p65 subunit and p44/42, respectively (Figure E3) as noted previously (31). PubMed:26974230
We found a significant enrichment of HO-1 in the mitochondrial, but not in the cytosolic fractions after exposure to HbFe21 and HbFe31 (Figures 3A and 3B). PubMed:26974230
Exposure to HbFe21 and HbFe31 did not alter the expression of cytochrome c oxidase IV protein (Figure 3A). PubMed:26974230
The level of hemoglobin declined gradually over the time after the onset of ICH with a significant reduction at day 3. The contents of hemoglobin in the clot were 26.2 ± 5.2 mg/g at 4 hours, but were reduced to 13.9 ± 0.9 mg/g at day-3 (Fig. 2B, p<0.01). PubMed:27125525
We found that hemoglobin contents in hematoma were significantly higher in the DFX treated group compare to the vehicle-treated group (15.9 ± 1.8 vs. 11.8 ± 0.8 mg/g, p<0.05, Fig. 5A). PubMed:27125525
We found that hemoglobin contents in hematoma were significantly higher in the DFX treated group compare to the vehicle-treated group (15.9 ± 1.8 vs. 11.8 ± 0.8 mg/g, p<0.05, Fig. 5A). PubMed:27125525
Free Hb and Hb present in microvesicles oxidize vascular nitric oxide (NO) much faster than RBC-encapsulated Hb to form nitrate.14,15 PubMed:27308950
These data suggest that co-administration of human haptoglobin or hemopexin does 276 not attenuate the conversion of NO to nitrate that is mediated by cell-free murine 277 hemoglobin. PubMed:28314763
Presence of any cell-free Hb limits NO diffusion from endothelium to smooth muscle cells for activation of guanylyl cyclase; as a consequence, mean arterial blood pressure increases.12,15 PubMed:27308950
SBP 315 increased 27±2 mmHg during the 40 minutes following infusion of hemoglobin in 316 db/db mice (Figure 4A). PubMed:28314763
Several studies in animals have supported the idea that infusion of free Hb, stored RBC supernatant (preservation solution + plasma), and Hb-containing microvesicles causes vasoconstriction, vascular dysfunction, and vascular injury.12,16–18 PubMed:27308950
Plasma hemoglobin scavenges nitric oxide and causes vasoconstriction, platelet aggregation and inflammation9,22–24. PubMed:27515135
Previous studies showed that db/db mice have enhanced 312 susceptibility to hemoglobin-induced vasoconstriction (25). PubMed:28314763
The cell-free Hb in stored RBCs should actually increase nitrate by oxidizing NO to nitrate. PubMed:27308950
Plasma hemoglobin scavenges nitric oxide and causes vasoconstriction, platelet aggregation and inflammation9,22–24. PubMed:27515135
Co-administration of haptoglobin with SRBCs results in a prolonged increase in plasma hemoglobin levels for more than 48 hours after transfusion. PubMed:27515135
Extracellular hemoglobin and its degradation products, free heme and iron, are highly toxic due to oxidative stress induction and decrease in nitric oxide availability. PubMed:28088643
Iron was also detected in the macrophages of the red pulp of CEP mice, while almost no iron deposit was observed in the spleen of Hjv–/– mice (Figure 4B), confirming that Hb and “free” heme are the likely source of macrophage iron accumulation. PubMed:28143953
Another pathogenic mechanism involves the release of iron from cell-free hemoglobin with consecutive radical formation, which in turn can modify lipids, proteins, and DNA, leading to inflammation [39]. PubMed:29956069
The anemia in CEP mice was severe with significant reduction of Hb levels and RBC number (Table 1), regenerative with marked reticulocytosis (28.8±4.2%) (Table 1), and microcytic and hypochromic with reduced mean cell Hb content (9.95±0.64 pg in CEP vs. 14.5±0.18 in WT mice) (Table 1). PubMed:28143953
Intravenous infusion of cell-free hemoglobin induces hypertension in mice 205 (24). PubMed:28314763
One of the mechanisms by which cell-free hemoglobin exerts its detrimental effects is its ability to effectively scavenge nitric oxide (NO), which in turn leads to perfusion disorders and an increased arterial and pulmonary arterial pressure [39, 40]. PubMed:29956069
When mice 347 are infused with extracellular hemoglobin that has been extensively crosslinked and 348 only contains a small fraction of monomeric hemoglobin (as in the HBOCs, 349 PolyHeme), scavenging of NO is markedly reduced (25). PubMed:28314763
Inhibition of extravasation of cross-linked extracellular 352 hemoglobin has been postulated as a possible mechanism of decreased NO353 scavenging in the muscular layer of arteries by high-molecular weight HBOCs. PubMed:28314763
Another mechanism for platelet activation by RBC lysate is extracellular hemoglobin, which enhances platelet activation by lowering NO bioavailability [ 29]. PubMed:28458720
There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246
When RBCs are damaged by high shear in continuous flow ventricular assist devices, free hemoglobin induces platelet aggregation, contributing to high risk of thrombotic complications [33]. PubMed:28458720
Extracellular hemoglobin sequesters NO and thus promotes activation of endothelial cells and adhesion/aggregation of platelets [64]. PubMed:28458720
Extracellular hemoglobin sequesters NO and thus promotes activation of endothelial cells and adhesion/aggregation of platelets [64]. PubMed:28458720
Besides the effects of intact RBCs, free extracellular hemoglobin prolongs clotting time of fibrinogen due to impaired polymerization [73]. PubMed:28458720
There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246
There are in vitro and animal model data linking increased free Hb, heme, and iron to inflammation, 6 infection,7 platelet (PLT) activation,8,9 vasculopathy, 10 and thrombosis. PubMed:29603246
The median (and mean—data not shown) free Hb levels preoperatively and at all postoperative time points (immediately and 6 and 12 hr postoperatively) were higher (p50.057) in those who later developed a proven thrombosis (Fig. 3 displays the 12-hr data). PubMed:29603246
Our findings in the complex setting of critically ill pediatric cardiac surgery patients demonstrate that higher levels of free Hb and lower levels of haptoglobin are associated with serious postoperative clinical complications (infection, thrombosis, death), immunomodulation, and inflammation. PubMed:29603246
Children undergoing open heart surgery experience a progressively increasing risk of postoperative infection and thrombosis, increasing need for mechanical ventilation and inotropes, increasing Day 1 through Day 2 peak blood lactate, and decreased nadir mean arterial pressure as the levels of free Hb increase and the levels of haptoglobin decrease. PubMed:29603246
During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. PubMed:29694434
However, patients who died had significantly higher plasma cell-free Hb and lower haptoglobin concentrations at all time points, preoperatively and immediately postoperatively and 6 and 12 hours postoperatively (Fig. 1 shows the 12-hr postoperative data). PubMed:29603246
Children undergoing open heart surgery experience a progressively increasing risk of postoperative infection and thrombosis, increasing need for mechanical ventilation and inotropes, increasing Day 1 through Day 2 peak blood lactate, and decreased nadir mean arterial pressure as the levels of free Hb increase and the levels of haptoglobin decrease. PubMed:29603246
Our findings in the complex setting of critically ill pediatric cardiac surgery patients demonstrate that higher levels of free Hb and lower levels of haptoglobin are associated with serious postoperative clinical complications (infection, thrombosis, death), immunomodulation, and inflammation. PubMed:29603246
Children undergoing open heart surgery experience a progressively increasing risk of postoperative infection and thrombosis, increasing need for mechanical ventilation and inotropes, increasing Day 1 through Day 2 peak blood lactate, and decreased nadir mean arterial pressure as the levels of free Hb increase and the levels of haptoglobin decrease. PubMed:29603246
Children undergoing open heart surgery experience a progressively increasing risk of postoperative infection and thrombosis, increasing need for mechanical ventilation and inotropes, increasing Day 1 through Day 2 peak blood lactate, and decreased nadir mean arterial pressure as the levels of free Hb increase and the levels of haptoglobin decrease. PubMed:29603246
The first process links the nitric oxide (NO) reactivity of oxyHb to a cascade of cell-free Hb extravasation, hemolysis-associated NO-depletion, and vasoconstriction.21–23 PubMed:29610666
The second biochemical process relates to the ability of Hb to facilitate oxidative reactions outside of the reducing environment of the RBC, leading to the accumulation of ferric metHb(Fe3+) in tissue.24 PubMed:29610666
Infusion of exogenous hemoglobin into SS-mice can markedly increase stasis compared to the amount of spontaneous stasis [5]. PubMed:29694434
High free hemoglobin was shown in patients with primary Cys89Tyr mutation in CD59 (Table 1) and it has been suggested in several ways that free hemoglobin may serve as a major mechanism for thrombophilia. PubMed:29929138
One mechanism that may contribute to enhanced platelet thrombus formation is inhibition of the metalloprotease ADAMTS13 by free hemoglobin [20]. PubMed:29929138
Endothelial injury may also be related to Free hemoglobin and its breakdown oxidative product heme, and MPs, which mediates direct proinflammatory, proliferative, and pro-oxidant effects on endothelial cells [22–24] both in PNH and congenital CD59 deficiency, but may be more pronounced in congenital CD59 deficiency and perhaps even more in the brain due to loss of CD59 in the endothelium of these patients. PubMed:29929138
Thus, the intravenous administration of hemoglobin in LPS-pretreated mice leads to a higher TNF- α concentration and an increased mortality; in turn, these effects could be inhibited by hemoglobin antibodies [33, 34]. PubMed:29956069
During DIC, fibrin strands within the fibrin mesh formed could cut red blood cells, resulting in the formation of schistocytes (strongly deformed red blood cells or fragments of red blood cells) and the release of hemoglobin. PubMed:29956069
Nevertheless, the crosstalk between glucose and heme metabolism in sepsis is bidirectional since an excessive accumulation of cell-free heme following hemolysis influences the glucose metabolism by iron-driven oxidative inhibition of the glucose-6-phosphatase (a liver enzymes being important for endogenous glucose production via gluconeogenesis and glycogenolysis) [14]. PubMed:29956069
Spontaneous decomposition of Hb via auto-oxidation leads to the formation of ROS, free heme groups and free iron, which are highly reactive and have the ability to damage lipids, proteins, and DNA (Olsson et al., 2012). PubMed:30505280
These novel data support a role for A1M in the protection against oxidative damage due to extracellular Hb and heme in the joint in various knee arthropathies. PubMed:30505280
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.