Platelet Activation in Hemolytic Uremic Syndrome

Karpman, Diana; Manea, Minola; Vaziri-Sani, Fariba; Ståhl, Anna; Kristoffersson, Ann‐Charlotte

doi:10.1055/s-2006-939769

Cited by 53 publications

(45 citation statements)

References 145 publications

(171 reference statements)

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“…Hemoglobinemia, disordered platelet function, and thrombosis are features of paroxysmal nocturnal hemoglobinuria, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, and disseminated intravascular coagulation. There is evidence of platelet activation in these conditions, [52][53][54][55][56][57][58][59] but the potential contribution of NO scavenging by plasma hemoglobin to platelet activation and thrombosis has not yet been investigated. This mechanism is supported by evidence of NO scavenging by cell-free cross-linked hemoglobin artificial blood substitutes in rats, promoting platelet deposition at sites of subintimal injury.…”

Section: Discussionmentioning

confidence: 99%

Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin

Villagra

Shiva

Hunter

et al. 2007

Blood

332

277

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Increased platelet activation is recognized in patients with sickle cell disease (SCD), but its pathogenesis and clinical relevance remain uncertain. Pulmonary arterial hypertension (PAH), an important complication of SCD, is characterized by a proliferative pulmonary vasculopathy, in situ thrombosis, and vascular dysfunction related to scavenging of nitric oxide (NO) by hemoglobin released into blood plasma during intravascular hemolysis. We investigated links between platelet activation, PAH and NO scavenging in patients with SCD. Platelet activation marked by activated fibrinogen receptor correlated to the severity of PAH (r ‫؍‬ 0.58, P < .001) and to laboratory markers of intravascular hemolysis, such as reticulocyte count (r ‫؍‬ 0.44, P ‫؍‬ .02). In vitro exposure of platelets to pathologically relevant concentrations of cell-free hemoglobin promoted basal-and agonist-stimulated activation and blocked the inhibitory effects on platelet activation by an NO donor. In patients with SCD, administration of sildenafil, a phosphodiesterase-5 inhibitor that potentiates NO-dependent signaling, reduced platelet activation (P ‫؍‬ .01). These findings suggest a possible interaction between hemolysis, decreased NO bioavailability, and pathologic platelet activation that might contribute to thrombosis and pulmonary hypertension in SCD, and potentially other disorders of intravascular hemolysis. This supports a role for NO-based therapeutics for SCD vasculopathy. This trial was registered at www.clinicaltrials.gov as no. IntroductionA chronic state of hemostatic activation in sickle cell disease (SCD) has been well documented by several investigators. Some have highlighted the role of the sickle red cell 1,2 ; others have highlighted the contribution of abnormal tissue factor and secondary thrombin generation by a dysfunctional endothelium, 3 the depletion of endogenous anticoagulants, 4 or the activation of white blood cells. 5 It is likely that the increased expression of adhesion molecules, tissue factor, and thrombin generation, the result of chronic endothelial dysfunction or acute injury, are all important contributors to the coagulopathy of SCD. 6 Increased platelet activation is another known component of hemostatic activation in patients with SCD 1,7-9 Increased percentages of platelets are activated during steady state in patients with SCD, and this accelerates during vaso-occlusive crisis (VOC). [7][8][9] The exact inciting mechanism and clinical consequences of this process remain unknown, but platelet activation hypothetically might play a role in the development of chronic vascular complications, such as pulmonary arterial hypertension, by secreting mitogenic and vasoactive substances that promote intimal hyperplasia. In patients without SCD, platelet-derived growth factor plays a fundamental role in the pathogenesis of plexogenic pulmonary hypertension, and pathologic platelet activation likely contributes to the in situ thrombosis in pulmonary hypertension, which has recently been reviewed. 10 Pulmonary a...

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Section: Discussionmentioning

confidence: 99%

Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin

Villagra

Shiva

Hunter

et al. 2007

Blood

332

277

View full text Add to dashboard Cite

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“…In addition to its function in complement regulation, FH can act as an adhesion ligand for neutrophils and platelets and may also participate in immune adherence of various host tissues (1,13,20). Therefore, we used human cell lines, including those from both the upper and lower respiratory tracts, to investigate FH-mediated pneumococcal adherence to tissues in which PspC expression is important for infection (2).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its function in complement regulation, FH can act as an adhesion ligand for neutrophils and platelets and may also participate in immune adherence of various host tissues (1,13,20). In this study, we have investigated whether FH mediates adherence of pneumococci to human umbilical vein endothelial cells (HUVEC).…”

mentioning

confidence: 99%

Factor H Binding to PspC ofStreptococcus pneumoniaeIncreases Adherence to Human Cell Lines In Vitro and Enhances Invasion of Mouse Lungs In Vivo

Quin¹,

Onwubiko²,

Moore³

et al. 2007

Infect Immun

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Pneumococcal surface protein C (PspC) binds to both human secretory immunoglobulin A (sIgA) and complement factor H (FH). FH, a regulator of the alternative pathway of complement, can also mediate adherence of different host cells. Since PspC contributes to adherence and invasion of host cells, we hypothesized that the interaction of PspC with FH may also mediate adherence of pneumococci to human cells. In this study, we investigated FH-and sIgA-mediated pneumococcal adherence to human cell lines in vitro. Adherence assays demonstrated that preincubation of Streptococcus pneumoniae D39 with FH increased adherence to human umbilical vein endothelial cells (HUVEC) 5-fold and to lung epithelial cells (SK-MES-1) 18-fold, relative to that of D39 without FH on the surface. The presence of sIgA enhanced adherence to SK-MES-1 6-fold and to pharyngeal epithelial cells (Detroit 562) 14-fold. Furthermore, sIgA had an additive effect on adherence to HUVEC; specifically, preincubation of D39 with both FH and sIgA led to a 21-fold increase in adherence. Finally, using a mouse model, we examined the significance of the FH-PspC interaction in pneumococcal nasal colonization and lung invasion. Mice intranasally infected with D39 preincubated with FH had increased bacteremia and lung invasion, but they had similar levels of nasopharyngeal colonization compared to that of mice challenged with D39 without FH.

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“…of endothelium, 18 red cells, 19 and platelets. 20 Clinically, STEC-HUS can be nearly as severe as aHUS (with mortality of up to 5%), as exemplified during the wide outbreak in Germany and some other European countries in 2011. 21 The main reason why gastrointestinal infection particularly affects kidneys is thought to be the tissue tropism of Shiga-toxin on the basis of the strong expression of Gb3 on the glomerular endothelium.…”

Section: Introductionmentioning

confidence: 99%

“…40 Although platelets are normally protected from complement attack by the concerted action of factor H and membrane regulators, 94 this protection is impaired in aHUS. 20 We have recently shown that protection of platelets from complement attack by factor H requires sialic acids on the cell membrane in vitro. 59 Therefore, impaired alternative pathway regulation is a logical explanation for thrombocytopenia and could also contribute to formation of platelet-rich microvascular thrombi.…”

mentioning

confidence: 99%

HUS and atypical HUS

Jokiranta

2017

Blood

240

260

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Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by intravascular hemolysis, thrombocytopenia, and acute kidney failure. HUS is usually categorized as typical, caused by Shiga toxin–producing Escherichia coli (STEC) infection, as atypical HUS (aHUS), usually caused by uncontrolled complement activation, or as secondary HUS with a coexisting disease. In recent years, a general understanding of the pathogenetic mechanisms driving HUS has increased. Typical HUS (ie, STEC-HUS) follows a gastrointestinal infection with STEC, whereas aHUS is associated primarily with mutations or autoantibodies leading to dysregulated complement activation. Among the 30% to 50% of patients with HUS who have no detectable complement defect, some have either impaired diacylglycerol kinase ε (DGKε) activity, cobalamin C deficiency, or plasminogen deficiency. Some have secondary HUS with a coexisting disease or trigger such as autoimmunity, transplantation, cancer, infection, certain cytotoxic drugs, or pregnancy. The common pathogenetic features in STEC-HUS, aHUS, and secondary HUS are simultaneous damage to endothelial cells, intravascular hemolysis, and activation of platelets leading to a procoagulative state, formation of microthrombi, and tissue damage. In this review, the differences and similarities in the pathogenesis of STEC-HUS, aHUS, and secondary HUS are discussed. Common for the pathogenesis seems to be the vicious cycle of complement activation, endothelial cell damage, platelet activation, and thrombosis. This process can be stopped by therapeutic complement inhibition in most patients with aHUS, but usually not those with a DGKε mutation, and some patients with STEC-HUS or secondary HUS. Therefore, understanding the pathogenesis of the different forms of HUS may prove helpful in clinical practice.

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Platelet Activation in Hemolytic Uremic Syndrome

Cited by 53 publications

References 145 publications

Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin

Platelet activation in patients with sickle disease, hemolysis-associated pulmonary hypertension, and nitric oxide scavenging by cell-free hemoglobin

Factor H Binding to PspC ofStreptococcus pneumoniaeIncreases Adherence to Human Cell Lines In Vitro and Enhances Invasion of Mouse Lungs In Vivo

HUS and atypical HUS

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