Reliability of Thrombin Generation Assay on Frozen-Thawed Platelet-Rich Plasma: A Reply

Hézard, Nathalie; Remy, Marie-Geneviève; Florent, Bernadette; Nguyên, Philippe

doi:10.1373/clinchem.2006.074567

Cited by 2 publications

(2 citation statements)

References 7 publications

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“…The observed reduction of average albuminuria in type 2 diabetic patients suggests that the protective, FVL-mediated effect observed in the murine type 1 diabetes models is also relevant in the setting of type 2 diabetes mellitus. In contrast to the FVL mutation, which is associated with an increased thrombin-generation potential, 34 the PAI-1 4G/5G polymorphism, which increases the risk of thrombotic events without enhancing thrombin formation, is not associated with reduced albuminuria in type 1 or type 2 diabetic patients, as shown in previous studies [35][36][37][38] and in the current study.…”

Section: Discussionsupporting

confidence: 70%

Low but sustained coagulation activation ameliorates glucose-induced podocyte apoptosis: protective effect of factor V Leiden in diabetic nephropathy

Wang

Madhusudhan

et al. 2011

Blood

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Whereas it is generally perceived to be harmful, enhanced coagulation activation can also convey salutary effects. The high prevalence of the prothrombotic factor V Leiden (FVL) mutation in whites has been attributed to a positive selection pressure (eg, resulting from reduced blood loss or improved survival in sepsis). The consequences of enhanced coagulation activation, as observed in FVL carriers, on microvascular diabetic complications remain unknown. We therefore investigated the role of FVL in diabetic nephropathy. In heterozygous or homozygous diabetic FVL mice, albuminuria and indices of diabetic nephropathy were reduced compared with diabetic wild-type mice. This was associated with reduced glomerular apoptosis and preservation of podocytes in diabetic FVL-positive mice. In vitro, low-dose thrombin (50pM) prevented, whereas high-dose thrombin (20nM) aggravated, glucose-induced apoptosis in podocytes. In diabetic patients, the FVL mutation, but not the plasminogen activator inhibitor-1 4G/5G polymorphism, is associated with reduced albuminuria, which is consistent with a nephroprotective role of low but sustained thrombin generation. Consistently, anticoagulation of diabetic FVL-positive mice with hirudin abolished the nephroprotective effect. These results identify a nephroprotective function of low but sustained thrombin levels in FVL carriers, supporting a dual, context-dependent function of thrombin in chronic diseases. (Blood. 2011;117(19):5231-5242) IntroductionThe coagulation system provides an "on-demand" vascular repair system. After vascular injury, the coagulation system is activated, inducing fibrin formation and platelet activation, thus sealing the vascular leak and initiating a healing process leading in most cases to a restitutio ad integrum. As is evident in patients with severe hemophilia, this beneficial function of the hemostatic system is required for normal survival. Enhanced coagulation activation, however, is generally assumed to be disadvantageous for an individual's health, because some genetic polymorphisms associated with increased thrombin generation mediate an increased risk of venous thrombosis. 1 Considering the impending health risks associated with prothrombotic genetic polymorphisms, the high prevalence of some of them, in particular the factor V Leiden (FVL) mutation, led to the assumption that these genetic polymorphisms must be coupled with a positive selection pressure during evolution. 2 The FVL mutation is a missense mutation in the factor V gene (R506Q), resulting in the resistance of activated factor V to inactivation by activated protein C (aPC). The prevalence of the FVL mutation in whites is 4%-6%. 1 The potential benefits associated with FVL include a higher embryonic implantation rate, reduced puerperal maternal blood loss, and improved survival from severe infections. [3][4][5] The latter has been a matter of debate, because not all studies were able to reproduce the improved survival of FVL carriers in sepsis. [6][7][8][9][10][11] We have previously shown...

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Section: Discussionsupporting

confidence: 70%

Low but sustained coagulation activation ameliorates glucose-induced podocyte apoptosis: protective effect of factor V Leiden in diabetic nephropathy

Wang

Madhusudhan

et al. 2011

Blood

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“…Some authors believe that there are two good theoretical reasons for choosing frozen-thawed PRP to perform TGA (namely, physiologic environment, i.e., in the presence of autologous platelet phospholipids, and use of a biological material compatible with multicenter studies, i.e., a frozen sample). 45 However, some authors believe that assessing TG in frozen-thawed PRP would introduce a substantial bias in several measurements, especially lag-time and peak concentration. 46 Consequently, the ETP would appear to be the single variable that can be assessed in PRP, regardless of the storage conditions.…”

Section: Coagulation Factor Concentrationmentioning

confidence: 99%

Standardization and Clinical Utility of Thrombin-Generation Assays

Berntorp

Salvagno

2008

Semin Thromb Hemost

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Thrombin generation is a key process that determines the extent of a hemostatic plug or a thrombotic process. The ensuing thrombin burst is crucial for the formation of a stable fibrin clot. During its active life, thrombin exerts a multitude of highly regulated actions on the blood and the vessel wall, including the clotting of fibrinogen. The inappropriate generation of thrombin may lead to pathologic processes, foremost of which are hemorrhagic or thrombotic diseases. The coagulation system is usually investigated by means of two in vitro classic clotting tests, the activated partial thromboplastin time (APTT) and prothrombin time (PT), which assess only time to initiation of clot formation and do not entirely reflect global hemostatic balance. The APTT and PT permit identification of connectivity between the component activities identified as required for plasma coagulation and define the concept of intrinsic and extrinsic coagulation pathways, which converge at the point of formation of the prothrombinase complex. However, the mechanisms established by in vitro tests are not always mirrored in the human pathologies associated with bleeding or thrombosis. The recent development of newer tests based on the continuous registration of thrombin generation under in vitro conditions that mimic more closely what occurs in vivo prompt a reinvestigation of the balance between procoagulants and anticoagulants in patients with various hemostatic disorders. Thrombin-generation assays not only provide an overall assessment of hemostasis but also target potential extrahemostatic effects of the generated thrombin, a potent agonist of a multitude of cellular activation pathways. Moreover, estimation of an individual's thrombin-generation potential may correlate more closely with a hypercoagulable or hypocoagulable phenotype when compared with traditional coagulation tests. In this review, we discuss to what extent thrombin generation can be expected to reflect the clotting function of blood, the development and use of different thrombin-generation assay systems suitable for detecting changes in the kinetics of thrombin generation, and the clinical utility of thrombin generation.

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Reliability of Thrombin Generation Assay on Frozen-Thawed Platelet-Rich Plasma: A Reply

Cited by 2 publications

References 7 publications

Low but sustained coagulation activation ameliorates glucose-induced podocyte apoptosis: protective effect of factor V Leiden in diabetic nephropathy

Low but sustained coagulation activation ameliorates glucose-induced podocyte apoptosis: protective effect of factor V Leiden in diabetic nephropathy

Standardization and Clinical Utility of Thrombin-Generation Assays

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