Activated platelet aggregates in thrombotic thromboctyopenic purpura: decrease with plasma infusions and normalization in remission

Ahn, Yeon S.; Jy, Wenche; Kolodny, Luciano; Horstman, Lawrence L.; Mao, Wei; Valant, Peter A.; Duncan, Robert C.

doi:10.1046/j.1365-2141.1996.d01-1902.x

Cited by 27 publications

(28 citation statements)

References 17 publications

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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

328

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

328

277

View full text Add to dashboard Cite

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“…Approval by the Institutional Review Board of the University of Miami School of Medicine was obtained and all patients gave informed consent. Criteria for the diagnosis of TTP have been previously described (Ahn et al , 1996). Briefly, all patients with TTP presented with the following findings: severe thrombocytopenia (platelet count <20 × 10 9 /l), microangiopathic haemolytic anaemia, elevated lactate dehydrogenase (LDH) level and neurological dysfunction.…”

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confidence: 99%

Endothelial microparticles released in thrombotic thrombocytopenic purpura express von Willebrand factor and markers of endothelial activation

et al. 2003

Self Cite

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Summary. It has been suggested that endothelial apoptosis is a primary lesion in the pathogenesis of thrombotic thrombocytopenic purpura (TTP). We tested this hypothesis by examining the phenotypic signatures of endothelial microparticles (EMP) in TTP patients. In addition, the effect of TTP plasma on microvascular endothelial cells (MVEC) in culture was further delineated. EMP released by endothelial cells (EC) express markers of the parent EC; EMP released in activation carry predominantly CD54 and CD62E, while those in apoptosis CD31 and CD105. We investigated EMP release in vitro and in TTP patients. Following incubation of MVEC with TTP plasma, EMP and EC were analysed by flow cytometry for the expression of CD31, CD51, CD54, CD62E, CD105, CD106 and von Willebrand factor (VWF) antigen. EMP were also analysed in 12 TTP patients. In both EC and EMP, CD62E and CD54 expression were increased 3-to 10-fold and 8-to 10-fold respectively. However, CD31 and CD105 were reduced 40-60% in EC but increased twofold in EMP. VWF expression was found in 55 ± 15% of CD62E + EMP. Markers of apoptosis were negative. In TTP patients, CD62E+ and CD31 + /CD42b ) EMP were markedly elevated, and preceded and correlated well with a rise in platelet counts and a fall in lactate dehydrogenase. CD62E + EMP (60 ± 20%) co-expressed VWF and CD62E. The ratio of CD31 + /42b ) to CD62E + EMP exhibited a pattern consistent with activation. In conclusion, our studies indicate endothelial activation in TTP. EMP that co-express VWF and CD62E could play a role in the pathogenesis of TTP.

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“…Support for the hypothesis that circulating ULVWF causes shear‐induced PLT aggregation includes observations of increased PLT‐bound VWF 16 and circulating PLT aggregates 17 in TTP patients. Increased retention of PLTs suspended in TTP plasma has been demonstrated in a glass‐bead flow chamber model, suggesting that TTP plasma may have prothrombotic properties 18 .…”

Section: Is Ulvwf Pathogenic?mentioning

confidence: 92%

The pathogenicity of von Willebrand factor in thrombotic thrombocytopenic purpura: reconsideration of treatment with cryopoor plasma

Raife

Friedman²,

Dwyre³

2005

Transfusion

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New developments in the understanding of thrombotic thrombocytopenic purpura (TTP) provide opportunities for improved patient care. A widely held historical model of TTP microvascular thrombosis implicated circulating ultra large von Willebrand factor (ULVWF) in causing spontaneous platelet (PLT) aggregation. From this pathogenic model, concerns about ULVWF in fresh-frozen plasma (FFP) used to treat patients led to widespread use of cryopoor plasma (CPP) as an alternative. There is scant evidence, however, that circulating ULVWF contributes to microvascular thrombosis in TTP. New evidence suggests that the formation of PLT aggregates in TTP may be mediated by VWF in the process of being released from endothelium. Moreover, clinical studies do not demonstrate superior efficacy of CPP compared to FFP in the treatment of TTP. Because CPP may have reduced concentrations of factors important in the treatment of TTP, including ADAMTS13 metalloprotease, a reappraisal of the use of CPP in the treatment of TTP is warranted.

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Activated platelet aggregates in thrombotic thromboctyopenic purpura: decrease with plasma infusions and normalization in remission

Cited by 27 publications

References 17 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

Endothelial microparticles released in thrombotic thrombocytopenic purpura express von Willebrand factor and markers of endothelial activation

The pathogenicity of von Willebrand factor in thrombotic thrombocytopenic purpura: reconsideration of treatment with cryopoor plasma

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