Haem is associated with thrombosis in neonates and infants undergoing cardiac surgery for congenital heart disease

Stolla, Moritz; Henrichs, Kelly; Cholette, Jill M.; Pietropaoli, Anthony P.; Phipps, RP; Spinelli, Sherry L.; Blumberg, Neil

doi:10.1111/vox.12606

Cited by 5 publications

(4 citation statements)

References 9 publications

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“…Plasma hemoglobin, no longer surrounded by the reducing RBC milieu, is oxidatively destabilized, releasing its heme. Supporting this thesis are the clinical findings indicating release of hemoglobin from RBCs during acute coronary syndromes (17), increased plasma bilirubin levels (which correlate with the thrombus burden) following myocardial infarction (27), and increased plasma heme levels when thrombosis occurs after cardiopulmonary bypass (70).…”

Section: Discussionmentioning

confidence: 79%

Antithrombotic effects of heme-degrading and heme-binding proteins

Nath

Grande

Belcher

et al. 2020

American Journal of Physiology-Heart and Circulatory Physiology

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In the murine venous thrombosis model induced by ligation of the inferior vena cava (IVCL), genetic deficiency of heme oxygenase-1 (HO-1) increases clot size. This study examined whether induction of HO-1 or administration of its products reduces thrombosis. Venous HO-1 upregulation by gene delivery reduced clot size, as did products of HO activity, biliverdin, and carbon monoxide. Induction of HO-1 by hemin reduced clot formation, clot size, and upregulation of plasminogen activator inhibitor-1 (PAI-1) that occurs in the IVCL model, while leaving urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA) expression unaltered. The reductive effect of hemin on clot size required HO activity. The IVCL model exhibited relatively high concentrations of heme that peaked just before maximum clot size, then declined as clot size decreased. Administration of hemin decreased heme concentration in the IVCL model. HO-2 mRNA was induced twofold in the IVCL model (vs. 40-fold HO-1 induction), but clot size was not increased in HO-2−/− mice compared with HO-2+/+ mice. Hemopexin, the major heme-binding protein, was induced in the IVCL model, and clot size was increased in hemopexin−/− mice compared with hemopexin+/+ mice. We conclude that in the IVCL model, the heme-degrading protein HO-1 and HO products inhibit thrombus formation, as does the heme-binding protein, hemopexin. The reductive effects of hemin administration require HO activity and are mediated, in part, by reducing PAI-1 upregulation in the IVCL model. We speculate that HO-1, HO, and hemopexin reduce clot size by restraining the increase in clot concentration of heme (now recognized as a procoagulant) that otherwise occurs. NEW & NOTEWORTHY This study provides conclusive evidence that two proteins, one heme-degrading and the other heme-binding, inhibit clot formation. This may serve as a new therapeutic strategy in preventing and treating venous thromboembolic disease.

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Section: Discussionmentioning

confidence: 79%

Antithrombotic effects of heme-degrading and heme-binding proteins

Nath

Grande

Belcher

et al. 2020

American Journal of Physiology-Heart and Circulatory Physiology

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“…We observed an independent association between posttransfusion total plasma heme and mortality. The toxicity of cell‐free heme is supported by in vitro studies, animal models, and human subjects . The adverse effects include nitric oxide scavenging and vasoconstriction, increased vascular permeability, oxidative stress, inflammation, and immune dysregulation with increased risk of infection .…”

Section: Discussionmentioning

confidence: 99%

Total plasma heme concentration increases after red blood cell transfusion and predicts mortality in critically ill medical patients

et al. 2019

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BACKGROUND: Relationships between red blood cell (RBC) transfusion, circulating cell-free heme, and clinical outcomes in critically ill transfusion recipients are incompletely understood. The goal of this study was to determine whether total plasma heme increases after RBC transfusion and predicts mortality in critically ill patients. STUDY DESIGN AND METHODS:This was a prospective cohort study of 111 consecutive medical intensive care patients requiring RBC transfusion. Cellfree heme was measured in RBC units before transfusion and in the patients' plasma before and after transfusion.RESULTS: Total plasma heme levels increased in response to transfusion, from a median (interquartile range [IQR]) of 35 (26-76) μmol/L to 47 (35-73) μmol/L (p < 0.001). Posttransfusion total plasma heme was higher in nonsurvivors (54 [35-136] μmol/L) versus survivors (44 [31-65] μmol/L, p = 0.03). Posttransfusion total plasma heme predicted hospital mortality (odds ratio [95% confidence interval] per quartile increase in posttransfusion plasma heme, 1.76 [1.17-2.66]; p = 0.007). Posttransfusion total plasma heme was not correlated with RBC unit storage duration and weakly correlated with RBC unit cell-free heme concentration. CONCLUSIONS:Total plasma heme concentration increases in critically ill patients after RBC transfusion and is independently associated with mortality. This transfusion-associated increase in total plasma heme is not fully explained by RBC unit storage age or cell-free heme content. Additional studies are warranted to define mechanisms of transfusion-related plasma heme accumulation and test prevention strategies.R ed blood cell (RBC) transfusion is associated with increased risk of death in critically ill patients. 1 This risk may be explained by storage-related changes in banked RBCs. Such changes include depletion of adenosine triphosphate, nitric oxide, and 2,3diphosphoglycerate, excess cellular stiffness and fragility, and low-grade hemolysis. [2][3][4][5] The resulting cell-free hemoglobin (Hb; free in solution and contained in RBC microparticles) 3,4,6-8 can undergo oxidation and release cellfree heme. 9,10 These mediators may cause toxicity when transfused because cell-free Hb promotes circulatory dysfunction by scavenging nitric oxide 4,7,11,12 and cell-free ABBREVIATIONS: ICU = intensive care unit; IQR = interquartile range; MICU = medical intensive care unit; NTBI = non-transferrinbound iron; SOFA = sequential (sepsis-related) organ failure assessment. From the PIETROPAOLI ET AL.Fig. 5. Relationship between posttransfusion total plasma heme concentration and the pretransfusion plasma haptoglobin concentration. Box plots show the median (horizontal line) and 25th and 75th percentiles (lower and upper limits of the box).The dots represent outliers beyond the whiskers that designate the 10th and 90th percentiles. Comparison was made with Kruskal-Wallis test.

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“…It is known that routine transfusion service procedures, such as washing and apheresis , cause increased haemolysis of normal red cells, and that washing of longer stored donor red cells is associated with both increases in free haemoglobin and increases in poor patient outcomes . These new observations provide a rationale to move to animal model and clinical studies in various settings, including sickle cell anaemia, given the strong evidence that free haemoglobin and its metabolic products, such as heme and free iron are toxic.…”

Section: Discussionmentioning

confidence: 99%

Sickle red blood cells are more susceptible to in vitro haemolysis when exposed to normal saline versus Plasma‐Lyte A

et al. 2019

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Background Normal saline has been the fluid of choice for resuscitation, rehydration and fluid replacement during plasma or red cell exchange/cytapheresis. There are increased concerns about its clinical effects and data showing it causes more haemolysis in vitro than buffered solutions such as Plasma-Lyte A.Methods We investigated whether normal saline or Plasma-Lyte A was associated with greater haemolysis during hours of in vitro incubation with both normal red cells and samples from patients with sickle cell anaemia.Results Sickle red cells haemolysed more than normal red cells did in both crystalloid solutions. The results of 24-hour exposure to saline were particularly striking (median of 163 mg/dl (IQ range 105-247) for sickle red cells vs. 53 (48-92) for normal red cells (P < 0Á0001). In patient samples containing variable quantities of haemoglobin S red cells, increased haemoglobin S was associated with increased haemolysis. This effect was greater for normal saline than Plasma-Lyte A (P = 0Á12). ConclusionsThese in vitro models demonstrate that short-term ex vivo exposure of sickle red cells to normal saline leads to greater haemolysis than short-term exposure of normal red cells, and this effect is exacerbated by normal saline. Whether use of normal saline causes increased haemolysis in vivo is unknown. Given recent evidence that normal saline increases renal failure and mortality in critically ill patients, further studies are urgently needed.

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Haem is associated with thrombosis in neonates and infants undergoing cardiac surgery for congenital heart disease

Cited by 5 publications

References 9 publications

Antithrombotic effects of heme-degrading and heme-binding proteins

Antithrombotic effects of heme-degrading and heme-binding proteins

Total plasma heme concentration increases after red blood cell transfusion and predicts mortality in critically ill medical patients

Sickle red blood cells are more susceptible to in vitro haemolysis when exposed to normal saline versus Plasma‐Lyte A

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