Enhancement of Platelet Deposition by Cross-Linked Hemoglobin in a Rat Carotid Endarterectomy Model

Olsen, Stephen B.; Tang, Douglas B.; Jackson, Mark R.; Gomez, Edward R.; Ayala, Benjamin; Alving, Barbara M.

doi:10.1161/01.cir.93.2.327

Cited by 87 publications

(47 citation statements)

References 19 publications

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“…1,[6][7][8][9] The effect of free hemoglobin on platelet function and hypercoagulability and the recognized increase in thrombotic tendencies in PNH may be largely due to its ability to scavenge nitric oxide. [25][26][27][28][29][30][31][32] Other potential mechanisms of thrombosis in PNH include the generation of procoagulant platelet microvesicles due to the absence of the terminal complement inhibitor CD59, and the interaction of red cell microvesicles and soluble urokinase plasminogen activator receptor. 11,12,33,34 Terminal complement inhibition with eculizumab would be expected to have a beneficial effect on TE occurring through any of these mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria

Hillmen

Muus

Dührsen

et al. 2007

Blood

510

453

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Hemolysis and hemoglobinemia contribute to serious clinical sequelae in hemolytic disorders. In paroxysmal nocturnal hemoglobinuria (PNH) patients, hemolysis can contribute to thromboembolism (TE), the most feared complication in PNH, and the leading cause of disease-related deaths. We evaluated whether long-term treatment with the complement inhibitor eculizumab reduces the rate of TE in patients with PNH. Clinical trial participants included all patients in the 3 eculizumab PNH clinical studies, which recruited patients between 2002 and 2005 (n ‫؍‬ 195); patients from these studies continued treatment in the current multinational open-label extension study. Thromboembolism rate with eculizumab treatment was compared with the pretreatment rate in the same patients. The TE event rate with eculizumab treatment was 1.07 events/100 patient-years compared with 7.37 events/100 patient-years (P < .001) prior to eculizumab treatment (relative reduction, 85%; absolute reduction, 6.3 TE events/100 patient-years). With equalization of the duration of exposure before and during treatment for each patient, TE events were reduced from 39 events before eculizumab to 3 events during eculizumab (P < .001). The TE event rate in antithrombotic-treated patients (n ‫؍‬ 103) was reduced from 10.61 to 0.62 events/100 patient-years with eculizumab treatment (P < .001). These results show that eculizumab treatment reduces the risk of clinical thromboembolism in patients with PNH. This study is registered at http://clinicaltrials.gov (study ID no. NCT00122317). IntroductionIntravascular hemolysis and cell-free plasma hemoglobin have been implicated in the serious clinical sequelae of various hemolytic disorders. 1 Hemolysis is the primary clinical manifestation of the uncommon disease paroxysmal nocturnal hemoglobinuria (PNH) and has been shown to result in chronic disabling morbidities including anemia, severe fatigue, difficulty in functioning, pain, and thrombosis, all of which have a major effect on the patient's quality of life. 1-5 Paroxysmal nocturnal hemoglobinuria is defined by the acquired genetic deficiency of glycosylphosphatidylinositol (GPI)-linked proteins from the surface of blood cells. The absence of GPI-linked complement regulatory proteins on PNH erythrocytes renders them susceptible to terminal complement-mediated hemolysis.Hemolysis most likely contributes to thromboembolism (TE) in PNH, as patients with larger PNH clones have a higher incidence of TE and events have been temporally associated with increased hemolysis. 6-10 Although the mechanism is not fully understood, hemolysis has been implicated in the initiation of platelet activation and aggregation. 1 Additional in vitro studies have suggested that complement may directly activate platelets from PNH patients. 11,12 Thromboembolism is the leading cause of mortality in patients with PNH, 2,3,13-17 and an initial thrombotic event increases the relative risk of death in PNH 5-to 10-fold. 15,17 Retrospective studies suggest that, in non-Asian patients, TE accou...

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Section: Discussionmentioning

confidence: 99%

Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria

Hillmen

Muus

Dührsen

et al. 2007

Blood

510

453

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“…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. 60 Impaired NO bioavailability and platelet activation might play a general role in the predisposition to thrombosis in hemolytic anemias.…”

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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“…A cellular modified Hb developed as an oxygen carrier is known to cause vasoconstriction (23,24) and platelet stimulation (25) due to its NO scavenging action. Recently, new insights on the NO / Hb interaction have been proposed that NO covalently binds to a cysteine residue on the b-chain of Hb (Cysb93).…”

Section: Introductionmentioning

confidence: 99%

An S-Nitrosylated Hemoglobin Derivative Protects the Rat Hippocampus From Ischemia-Induced Long-Term Potentiation Impairment With a Time Window

et al. 2004

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Abstract. Evidence suggests that S-nitrosylation is a biological process involved in cerebral ischemia. The aim of the present study was to elucidate the effects of S-nitrosylated (SNO) polyethylene glycol-conjugated (PEG) hemoglobin (Hb) developed as an artificial oxygen carrier, which can absorb free NO and translocate NO to a sulfhydryl (SH) moiety, on ischemic cerebral dysfunction. Long-term potentiation (LTP) in the perforant path-dentate gyrus synapses of the rat hippocampus was evaluated as functional outcome 4 days after transient incomplete cerebral ischemia (2-vessel occlusion: 2VO, 10 min). SNO-PEG-Hb (250 mg / kg, i.v.) administered on Day 0, 1, 2, or 4 (immediately, 24 h, 48 h, or 96 h after reperfusion, respectively) alleviated 2VO-induced LTP impairment with a therapeutic time window. The effect was significant when SNO-PEG-Hb was administered on Day 1 or 2. SNO-PEG-Hb altered NOS features observed in the vehicle-treated 2VO rat, upregulation of eNOS, nNOS, and iNOS expressions at mRNA and protein levels; SNO-PEG-Hb further upregulated eNOS and nNOS and downregulated iNOS expressions. These findings suggest that SNO-PEG-Hb might have protective effects on the rat hippocampus from ischemia / reperfusion-induced functional damages, thereby increasing the therapeutic potential as an artificial oxygen carrier for use in the area of oxygen therapy.

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Enhancement of Platelet Deposition by Cross-Linked Hemoglobin in a Rat Carotid Endarterectomy Model

Abstract: These data suggest that in a rat endarterectomy model, alpha alpha Hb increases platelet deposition at sites of subintimal injury by binding NO. Increased deposition induced by alpha alpha Hb can be prevented by administration of L-arginine but not by pretreatment with aspirin.

Cited by 87 publications

References 19 publications

Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria

Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria

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

An S-Nitrosylated Hemoglobin Derivative Protects the Rat Hippocampus From Ischemia-Induced Long-Term Potentiation Impairment With a Time Window

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