Prothrombin activation on membranes with anionic lipids containing phosphate, sulfate and/or carboxyl groups

Gerads, Inge; Govers‐Riemslag, José W. P.; Tans, Guido; Zwaal, R.F.A.; Rosing, Jan

doi:10.1021/bi00486a027

Cited by 45 publications

(36 citation statements)

References 24 publications

(37 reference statements)

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“…Thus, one possible explanation for our results is that increased PTase activity is due to increased membrane disorder, at least to a point. This would be consistent with reports that oleate chains accelerate PTase activity (10,11), and it is compatible with the suggestion that PTase activity is sensitive to the precise way in which its components are juxtaposed on a membrane (6). Even if this is not the sole explanation for accelerated PTase, the relatively short acyl chains of DMPC/ DMPS may amplify the effects of the direct cause.…”

Section: Resultssupporting

confidence: 92%

“…This difference was evident even after accounting for changes in substrate transport due to altered lipid "fluidity" and was confirmed using the soluble substrate, prethrombin-1. Other investigators (6,11) have also used prethrombin-1 and found no such effect, but they nonetheless observed that PTase activity is accelerated by phosphatidylcholine vesicles if unsaturated acyl chains were present, especially at relatively low concentrations of phosphatidylserine.…”

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confidence: 98%

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Prothrombinase Acceleration by Oxidatively Damaged Phospholipids

Weinstein¹,

Li²,

Lawson³

et al. 2000

Journal of Biological Chemistry

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The optimally efficient production of thrombin by the prothrombinase complex relies on suitable positioning of its component factors and substrate on phosphatidylserine-containing lipid membranes. The presence of oxidatively damaged phospholipids in a membrane disrupts the normal architecture of a lipid bilayer and might therefore be expected to interfere with prothrombinase activity. To investigate this possibility, we prepared phosphatidylserine-containing lipid vesicles containing oxidized arachidonoyl lipids, and we examined their ability to accelerate thrombin production by prothrombinase. Oxidized arachidonoyl chains caused dosedependent increases in prothrombinase activity up to 6-fold greater than control values. These increases were completely attenuated by the presence of ␣-tocopherol, ␥-tocopherol, or ascorbate. Over the course of a 300-min oxidation, the ability of arachidonoyl lipids to accelerate prothrombinase peaked at 60 min and then declined to base-line levels. These results suggest that instead of being impeded by oxidative membrane damage, prothrombinase activity is enhanced by one or more products of nonenzymatic lipid oxidation.Thrombin production is controlled in vivo by a complex system of cascade and feedback mechanisms. By controlling thrombin production, these mechanisms regulate the various physiological activities of thrombin, including the maintenance of hemostasis, the signaling of smooth muscle and other cells, and the activation of platelets (1). Platelet plasma membranes are an especially important control point for thrombin production because upon activation they display anionic phosphatidylserine (PS) 1 lipids on their outer surface. PS-containing membranes accelerate thrombin production by facilitating the assembly of coagulation factors Va and Xa to form the prothrombinase complex (PTase), and the delivery of prothrombin to this complex for conversion into thrombin (2). To a large extent, PS lipids facilitate the assembly of PTase and the delivery of substrate by confining these factors to the membrane surface and reducing three-dimensional diffusional processes to two-dimensional processes. However, PS head groups can also accelerate PTase activity by functioning as a regulatory cofactor (3).There are compelling reasons to consider the possible effects of oxidative lipid damage on thrombin production. For instance, oxidation profoundly alters the architecture and chemical properties of phospholipid bilayers (4, 5), and the function of PTase is clearly sensitive to the physical state of the membrane (6). Many common cellular processes such as platelet activation release highly reactive oxygen species that can oxidize lipoproteins (7). Oxidation, in turn, dramatically increases the ability of lipoproteins to accelerate the activity of the PTase complex and produce more thrombin (8).The principal sites of both enzymatic and non-enzymatic oxidation in a membrane are the olefinic groups of unsaturated fatty acyl chains. Although the fatty acyl chains of membrane lipids have lon...

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Section: Resultssupporting

confidence: 92%

mentioning

confidence: 98%

Prothrombinase Acceleration by Oxidatively Damaged Phospholipids

Weinstein¹,

Li²,

Lawson³

et al. 2000

Journal of Biological Chemistry

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“…27 The rate of prothrombin activation is dependent on the assembly of tenase and prothrombinase complexes, which in turn depends on the presence of surfaces enriched in negativelycharged phospholipids. 28 The increased number of microparticles of platelet origin observed in association with large aneurysms is likely to provide the phosphatidylserine-enriched membranes required to favor thrombin generation. 29 Microparticles are the main link between platelet activation and thrombin generation.…”

Section: Touat Et Almentioning

confidence: 99%

Dilation-Dependent Activation of Platelets and Prothrombin in Human Thoracic Ascending Aortic Aneurysm

Touat

Lepage

Ollivier

et al. 2008

ATVB

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Objectives-The purpose of this study was to investigate whether thoracic ascending aortic aneurysm (TAAA) induces platelet activation as mural thrombus participates in aortic dilatation in abdominal aortic aneurysm and TAAA are associated with rheological factors favoring coagulation activation. Methods and Results-We studied the relation between coagulation activation and aortic diameter in Marfan patients (MFS) with various aortic diameters (nϭ52). We then studied patients presenting large aneurysms associated with bicuspid aortic valve (BAV) and degenerative form. Lastly, we used immunochemistry and biochemistry to investigate prothrombin/thrombin retention within the aortic wall. Microparticles, sGPV, tissue factor, and TAT complexes were increased in plasma from MFS with large aneurysms (Ն45 mm) compared to MFS with limited aortic dilatation (Ͻ45 mm). Similar elevations were observed in all patients with large aortic aneurysms, regardless of the etiology, the site of maximal aortic dilation, associated valvulopathy, risk factors, or treatments. P-selectin and platelet-bound fibrinogen were also increased, demonstrating platelet activation in large aneurysms. Significant increase in sCD146 plasma concentration suggested alteration of endothelium. Conclusions-Platelet activation occurs in patients with large aneurysms of the ascending aorta, is dependent on aortic dilation, and is associated with thrombin generation, part of which appears to be retained in mucoid degeneration areas. (Arterioscler Thromb Vasc Biol 2008;28:940-946)Key Words: thoracic aortic aneurysm Ⅲ coagulation Ⅲ Marfan Ⅲ platelets T horacic ascending aortic aneurysms (TAAA) are defined by an enlargement of the ascending aorta. TAAA can be observed in old patients without clear etiologic factors, in whom it represents a primary degenerative pathology of the ascending aorta. 1 But it can also occur in the younger population; it is then usually linked to a genetic or congenital disease. Marfan syndrome represents the majority of these cases. This is usually related to mutations in fibrillin1 2 and rarely to mutations in transforming growth factor (TGF)␤R 2, which can also be responsible for Loeys-Dietz Syndrome and familial aortic aneurysm. [3][4][5] Other molecular abnormalities have been implicated, such as mutations in myosin, 6 TGF␤R 1 , 5 ACTA2, 7 or other currently unknown genes. 8 Moreover, bicuspid aortic valves (BAV), which may be familial, 9 are associated with a high risk of aneurysm of the ascending aorta. 10 In contrast to their etiologic diversity, all localized aortic dilations share common rheological characteristics. In normal human aorta, the regular geometry (tubular shape and parallel walls) results in laminar blood flow and in a homogeneous shear rate, maintaining a physiological steady-state among the blood components and between the circulating blood and arterial wall. 11 Changes in arterial geometry considerably modify rheological parameters and therefore influence interactions between blood components. 11,12 The modu...

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“…Optimum prothrombinase activity has been reported for membranes that contain at least 10 mol % phosphatidylserine (11)(12)(13)(14). It is rationalized that this dependence is the result of the lower binding affinity of membranes with low phosphatidylserine content for the protein constituents of the enzyme complex (factor Xa and factor Va) as well as for its substrate prothrombin (15)(16)(17).…”

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confidence: 99%

Prothrombin Contributes to the Assembly of the Factor Va-Factor Xa Complex at Phosphatidylserine-containing Phospholipid Membranes

Billy¹,

Willems

Hemker

et al. 1995

Journal of Biological Chemistry

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The activation of prothrombin is catalyzed by prothrombinase, a complex of factor Xa and factor Va assembled on a negatively charged phospholipid membrane. We used a tubular flow reactor to identify the relative contributions of factor Va, prothrombin, and the negatively charged phosphatidylserine to the assembly of prothrombinase. Perfusion of phospholipidcoated capillaries with a mixture of factor Xa, factor Va, and prothrombin resulted in a steady-state rate of thrombin production that increased with (i) the phosphatidylserine content of the phospholipid bilayer, (ii) the factor Va concentration, and, most interestingly, (iii) the prothrombin concentration of the perfusion solution. Incorporation of 20 mol % phosphatidylethanolamine, a phospholipid with poor ability to promote prothrombinase activity, into a 5 mol % phosphatidylserine membrane also increased the steady-state rate of thrombin production. Direct measurements of the amount of prothrombinase in the flow reactor demonstrated that increased catalytic activities were the result of an increased steady-state amount of membrane-associated prothrombinase. Thus, similar turnover numbers of prothrombin activation (3100 min ؊1 ) were calculated, irrespective of the phosphatidylserine content of the membrane. We established for membranes with low phosphatidylserine content (<10 mol%) a linear relationship between the prothrombinase activity and the arithmetical product of the factor Va concentration in the perfusion solution and the prothrombin concentration near the catalytic surface. Our results indicate that, in addition to factor Va, prothrombin also is essential to the assembly of prothrombinase at macroscopic surfaces with low phosphatidylserine content. The data further suggest that the prothrombin concentration near the surface, controlled by the prothrombinase activity and mass transfer, is an important regulator of the prothrombinase surface density.

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Prothrombin activation on membranes with anionic lipids containing phosphate, sulfate and/or carboxyl groups

Cited by 45 publications

References 24 publications

Prothrombinase Acceleration by Oxidatively Damaged Phospholipids

Prothrombinase Acceleration by Oxidatively Damaged Phospholipids

Dilation-Dependent Activation of Platelets and Prothrombin in Human Thoracic Ascending Aortic Aneurysm

Prothrombin Contributes to the Assembly of the Factor Va-Factor Xa Complex at Phosphatidylserine-containing Phospholipid Membranes

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