Free hemoglobin concentration in severe sepsis: methods of measurement and prediction of outcome

Adamzik, Michael; Hamburger, Tim; Petrat, Frank; Peters, Jürgen; Groot, Herbert de; Hartmann, Matthias

doi:10.1186/cc11425

Cited by 118 publications

(112 citation statements)

References 37 publications

Supporting

Mentioning

103

Contrasting

Unclassified

Order By: Relevance

“…The relationship between age of the stored blood, the volume of blood transfused, increases of CFH levels over time, and outcome, needs to be determined for septic patients and other critically ill patients. 37 There are limitations to the interpretation of our data; we only examined septic canines with pneumonia receiving massive transfusions and our findings might not be applicable to noninfectious illnesses, different types of infections, variation in the severity of infection we studied, or transfusions that are not massive in quantity. Although hemoglobin and RBCs across species are believed well preserved, [15][16][17] our results may be idiosyncratic to canines.…”

Section: Older Transfused Stored Blood Increases Mortality 1667mentioning

confidence: 96%

Mortality increases after massive exchange transfusion with older stored blood in canines with experimental pneumonia

Solomon

Wang

Sun

et al. 2013

Blood

154

243

View full text Add to dashboard Cite

Key Points• In canine S aureus pneumonia, first randomized blinded trial showing blood transfused at end of storage period increases mortality.• Increased in vivo hemolysis, cell-free hemoglobin, pulmonary hypertension, tissue damage, and gas exchange abnormalities each contributed.Two-year-old purpose-bred beagles (n ‫؍‬ 24) infected with Staphylococcus aureus pneumonia were randomized in a blinded fashion for exchange transfusion with either 7-or 42-day-old canine universal donor blood (80 mL/kg in 4 divided doses). Older blood increased mortality (P ‫؍‬ .0005), the arterial alveolar oxygen gradient (24-48 hours after infection; P < .01), systemic and pulmonary pressures during transfusion (4-16 hours) and pulmonary pressures for ϳ 10 hours afterward (all P < .02). Further, older blood caused more severe lung damage, evidenced by increased necrosis, hemorrhage, and thrombosis (P ‫؍‬ .03) noted at the infection site postmortem. Plasma cell-free hemoglobin and nitric oxide (NO) consumption capability were elevated and haptoglobin levels were decreased with older blood during and for 32 hours after transfusion (all P < .03). The low haptoglobin (r ‫؍‬ 0.61; P ‫؍‬ .003) and high NO consumption levels at 24 hours (r ‫؍‬ ؊0.76; P < .0001) were associated with poor survival. Plasma nontransferrin-bound and labile iron were significantly elevated only during transfusion (both P ‫؍‬ .03) and not associated with survival (P ‫؍‬ NS). These data from canines indicate that older blood after transfusion has a propensity to hemolyze in vivo, releases vasoconstrictive cell-free hemoglobin over days, worsens pulmonary hypertension, gas exchange, and ischemic vascular damage in the infected lung, and thereby increases the risk of death from transfusion. (Blood. 2013;121(9):1663-1672) IntroductionTransfusion of red blood cells (RBCs) is one of the most commonly used, potentially lifesaving medical therapies. Each year, some 80.7 million units of blood are collected in 167 countries worldwide, and approximately 15 million units are collected and transfused in the United States alone. 1,2 RBCs can be stored for up to 42 days to meet inventory needs, and by standard practice the oldest blood is usually used first ("first in, first out"). Food and Drug Administration (FDA) regulations only stipulate that at the end of the storage period 75% of the cells remain in the circulation at 24 hours after transfusion and that hemolysis in the storage bag does not exceed 1%, 3 no other product specification of quality is required. Although 6-week-old stored blood meets current FDA standards, laboratory and clinical studies have raised concerns that "older" blood may not be as safe as blood stored for a shorter duration. [4][5][6][7][8] Refrigerated storage of blood results in a "storage lesion" characterized by rheologic changes, metabolic derangements, changes in oxygen affinity and delivery, oxidative injury to lipids and proteins, RBC shape change, loss of membrane carbohydrates, and reduced RBC lifespan. [8][9][10] The storage lesion resu...

show abstract

Section: Older Transfused Stored Blood Increases Mortality 1667mentioning

confidence: 96%

Mortality increases after massive exchange transfusion with older stored blood in canines with experimental pneumonia

Solomon

Wang

Sun

et al. 2013

Blood

154

243

View full text Add to dashboard Cite

show abstract

“…Erythrocytes are severely damaged by HlyA and LtxA (5, 13), which both initially cause severe cell shrinkage and PS exposure in a protracted process before they finally swell and lyse (7,13). Because free hemoglobin has detrimental implications for the prognosis of, for example, sepsis (60,61), it is important that the damaged erythrocytes are recognized and phagocytosed before intravascular lysis occurs. In this context, it is important that THP-1 monocytes are able to recognize and phagocytose erythrocytes exposed to HlyA (8).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of P2X Receptors Protects Human Monocytes against Damage by Leukotoxin from Aggregatibacter actinomycetemcomitans and α-Hemolysin from Escherichia coli

et al. 2016

View full text Add to dashboard Cite

␣-Hemolysin (HlyA) from Escherichia coli and leukotoxin A (LtxA) from Aggregatibacter actinomycetemcomitans are important virulence factors in ascending urinary tract infections and aggressive periodontitis, respectively. The extracellular signaling molecule ATP is released immediately after insertion of the toxins into plasma membranes and, via P2X receptors, is essential for the erythrocyte damage inflicted by these toxins. Moreover, ATP signaling is required for the ensuing recognition and phagocytosis of damaged erythrocytes by the monocytic cell line THP-1. Here, we investigate how these toxins affect THP-1 monocyte function. We demonstrate that both toxins trigger early ATP release and a following increase in the intracellular receptors markedly reduces toxin-induced cytolysis. This pattern is paralleled in freshly isolated human monocytes from healthy volunteers. Interestingly, only a minor fraction of the toxin-damaged THP-1 monocytes eventually lyse. P2X 7 receptor inhibition generally prevents cell damage, except from a distinct cell shrinkage that prevails in response to the toxins. Moreover, we find that preexposure to HlyA preserves the capacity of THP-1 monocytes to phagocytose damaged erythrocytes and may induce readiness to discriminate between damaged and healthy erythrocytes. These findings suggest a new pharmacological target for protecting monocytes during exposure to poreforming cytolysins during infection or injury.␣ -Hemolysin (HlyA) is an important virulence factor frequently produced by strains of pathogenic Escherichia coli (1-3). The frequency with which HlyA-producing E. coli strains are isolated from patients increases with severity of the disease (for a review, see reference 2). HlyA is a pore-forming repeat in toxin (RTX) family member which inserts itself receptor independently into cell membranes (1). The cytotoxic effect of HlyA is massively amplified by ATP release, presumably through the HlyA pore (4) and following P2X receptor activation (5, 6). In erythrocytes, P2X 1 and P2X 7 receptors have been implicated in HlyA-induced hemolysis, and blocking of either of these receptors substantially reduces the hemolysis (5, 6). Interestingly, insertion of a HlyA pore does not cause immediate cell swelling and rupture but initially triggers a significant volume reduction that results from an increase in the intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) followed by activation of the Ca 2ϩ -sensitive K ϩ and Cl Ϫ channels K Ca 3.1 and TMEM16A (7). During erythrocyte shrinkage, cells expose phosphatidyl serine (PS) in the outer plasma membrane leaflet (7). Recently, we discovered that THP-1 monocytes are more likely to recognize and phagocytose erythrocytes that have been exposed to HlyA (8). This phagocytosis is prevented if HlyA-induced cell damage is diminished by P2X receptor antagonists or if cell shrinkage and PS exposure are blocked (8).Leukotoxin A (LtxA) is a virulence factor often released from Aggregatibacter actinomycetemcomitans in the periodontal connective tissue (9-11). ...

show abstract

“…We found that protease activity varied considerably in the different Hx preparations ( Figure 1), but that none of the Hx preparations altered neutrophil migration (Figures 2,5C,5D). In further hemoglobin correlated with mortality (17,18), and a common feature is endothelial cell dysfunction caused by cell-free hemoglobin (37) that may cause secondary organ failure in the lung. The reported sensitivity of endothelium to heme and the frequent physical presence of blood in alveoli may make the lung potentially and uniquely sensitive to heme-driven pathophysiology (38).…”

Section: Discussionmentioning

confidence: 99%

“…Hx has been proposed as a possible treatment for sepsis and sickle cell disease based upon studies finding that increased serum-free heme and decreased Hx were associated with worse outcomes (16)(17)(18) and that administration of Hx prevented the tissue damage and lethality in mouse models (15,16). However, questions have been raised as to the safety of Hx infusion because of possible protease activity of Hx (22)(23)(24) and possible effects of Hx on neutrophil chemotaxis in a different study (25).…”

Section: Amidolytic Assaymentioning

confidence: 99%

See 1 more Smart Citation

Purified and Recombinant Hemopexin: Protease Activity and Effect on Neutrophil Chemotaxis

Tian

Liu

Feng

et al. 2016

Mol Med

View full text Add to dashboard Cite

Infusion of the heme-binding protein hemopexin has been proposed as a novel approach to decrease heme-induced inflammation in settings of red blood cell breakdown, but questions have been raised as to possible side effects related to protease activity and inhibition of chemotaxis. We evaluated protease activity and effects on chemotaxis of purified plasma hemopexin obtained from multiple sources as well as a novel recombinant fusion protein Fc-hemopexin. Amidolytic assay was performed to measure the protease activity of several plasma-derived hemopexin and recombinant Fc-hemopexin. Hemopexin was added to the human monocyte culture in the presence of lipopolysaccharides (LPS), and also injected into mice intravenously (i.v.) 30 min before inducing neutrophil migration via intraperitoneal (i.p.) injection of thioglycolate. Control groups received the same amount of albumin. Protease activity varied widely between hemopexins. Recombinant Fc-hemopexin bound heme, inhibited the synergy of heme with LPS on tumor necrosis factor (TNF) production from monocytes, and had minor but detectable protease activity. There was no effect of any hemopexin preparation on chemotaxis, and purified hemopexin did not alter the migration of neutrophils into the peritoneal cavity of mice. Heme and LPS synergistically induced the release of LTB4 from human monocytes, and hemopexin blocked this release, as well as chemotaxis of neutrophils in response to activated monocyte supernatants. These results suggest that hemopexin does not directly affect chemotaxis through protease activity, but may decrease heme-driven chemotaxis and secondary inflammation by attenuating the induction of chemoattractants from monocytes. This property could be beneficial in some settings to control potentially damaging inflammation induced by heme.

show abstract

Free hemoglobin concentration in severe sepsis: methods of measurement and prediction of outcome

Cited by 118 publications

References 37 publications

Mortality increases after massive exchange transfusion with older stored blood in canines with experimental pneumonia

Mortality increases after massive exchange transfusion with older stored blood in canines with experimental pneumonia

Inhibition of P2X Receptors Protects Human Monocytes against Damage by Leukotoxin from Aggregatibacter actinomycetemcomitans and α-Hemolysin from Escherichia coli

Purified and Recombinant Hemopexin: Protease Activity and Effect on Neutrophil Chemotaxis

Contact Info

Product

Resources

About