Changes in Coagulation Factors Following Acute Myocardial Infarction in Man

Rennie, John; Ogston, D.

doi:10.1159/000214141

Cited by 10 publications

(7 citation statements)

References 16 publications

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“…[1][2][3][4][5][6][7][8] However, the role of FVIII in arterial thrombosis is controversial. In addition, for both venous and arterial thrombosis, it is unclear whether elevated FVIII is merely a proinflammatory biomarker, [14][15][16] a causative mechanism in the disease etiology, or both. We acutely elevated FVIII in mice and examined their susceptibility to thrombosis, and we used ex vivo and in vitro methods to elucidate biochemical mechanisms for the observed effects.…”

Section: Discussionmentioning

confidence: 99%

“…[9][10][11][12] However, associations between FVIII activity and CHD 13 or ischemic heart disease 12 were lost after multivariate adjustment for diabetes and von Willebrand factor (VWF) levels, respectively. Importantly, because FVIII is increased in diseases that induce an acute phase response, including myocardial infarction, 14 surgery, 15 and sepsis, 16 it is unclear whether FVIII's association with either venous or arterial thrombosis simply reflects an ongoing prothrombotic inflammatory process, or whether it is a direct, causative mechanism in the thrombosis etiology and therefore a therapeutic target, or both.…”

Section: Introductionmentioning

confidence: 99%

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Procoagulant activity induced by vascular injury determines contribution of elevated factor VIII to thrombosis and thrombus stability in mice

Machlus

Lin

2011

Blood

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Studies have correlated elevated plasma factor VIII (FVIII) with thrombosis; however, it is unclear whether elevated FVIII is a proinflammatory biomarker, causative agent, or both. We raised FVIII levels in mice and measured the time to vessel occlusion (TTO) after ferric chloride-induced injury. Compared with control (saline-infused) mice, elevated FVIII had no effect after longer (3-minute) carotid artery injury, but it shortened the TTO after shorter (2-minute) injury (P < .008). After injury, circulating thrombin-antithrombin (TAT) complexes were lower after short versus long injury (P < .04), suggesting short treatment produced less coagulation activation. TAT levels in FVIII-infused mice were higher than in controls after short, but not longer, injury. Accordingly, elevated FVIII had no effect on in vitro thrombin generation or platelet aggregation triggered by high tissue factor, but it increased thrombin generation rate and peak (2.4-and 1.5-fold, respectively), and it accelerated platelet aggregation (up to 1.6-fold) when initiated by low tissue factor. Compared with control mice, elevated FVIII stabilized thrombi (fewer emboli) after short injury, but it had no effect after longer injury. TTO and emboli correlated with TATs. These results demonstrate dependence of FVIII activity on extent of vascular injury. We propose elevated plasma FVIII is an etiologic, prothrombotic agent after moderate but not extensive vascular damage. (Blood. 2011;118(14):3960-3968) IntroductionElevated factor VIII (FVIII) levels have been consistently and positively associated with primary and recurrent venous thromboembolism (VTE; odds ratio [OR], 2.0-10.8]. [1][2][3][4][5][6][7][8] For example, the Leiden Thrombophilia Study 2 showed FVIII concentrations Ͼ 1.5 U/mL led to an OR Ͼ 5, and Kyrle et al 4 showed relative risk of VTE recurrence was 6.6 in patients with FVIII levels greater than 2.34 U/mL. FVIII concentrations Ͼ 2 U/mL have been associated with an OR of VTE recurrence as high as 10.8. 3 In contrast to VTE, the role of FVIII in arterial thrombosis is controversial. Using broad definitions of coronary heart disease (CHD) encompassing atherosclerosis, angina, transient ischemic attack, acute and nonacute myocardial infarction, and death, several studies have associated elevated FVIII with CHD, stroke, or both, with ORs ranging from 1.2-2.65. [9][10][11][12] However, associations between FVIII activity and CHD 13 or ischemic heart disease 12 were lost after multivariate adjustment for diabetes and von Willebrand factor (VWF) levels, respectively. Importantly, because FVIII is increased in diseases that induce an acute phase response, including myocardial infarction, 14 surgery, 15 and sepsis, 16 it is unclear whether FVIII's association with either venous or arterial thrombosis simply reflects an ongoing prothrombotic inflammatory process, or whether it is a direct, causative mechanism in the thrombosis etiology and therefore a therapeutic target, or both.Studies examining the role of elevated FVIII in murine thrombosi...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Procoagulant activity induced by vascular injury determines contribution of elevated factor VIII to thrombosis and thrombus stability in mice

Machlus

Lin

2011

Blood

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“…Human coagulation Factor VIII is increased in the circulation under conditions which induce the acute phase response, for example, after surgery (5), in association with a variety of acute and chronic disease states (6,7) or after experimental administration of LPS to volunteers (8). A recent report using IL-6 stimulation of the HepG2 and Chang hepatocyte cell lines as a model system has shown that this increase is at least partially due to an increase in Factor VIII mRNA, but the mechanisms by which this occurs have not yet been defined (9).…”

Section: Introductionmentioning

confidence: 99%

The Factor VIII Acute Phase Response Requires the Participation of NFκB and C/EBP

Notley¹,

Tinlin²,

Sawyer³

et al. 2000

Thromb Haemost

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SummaryCoagulation Factor VIII is an acute phase protein in humans that has recently been shown to be transcriptionally responsive to interleukin-6. In this study, we have demonstrated that the human Factor VIII promoter is activated in cultured hepatocytes exposed to bacterial lipopolysaccharide (LPS). Deletion analysis has narrowed the LPS-responsive element of the Factor VIII promoter to a small region which contains two C/EBP binding sites and an adjacent NFκB binding site. Mutation of the downstream C/EBP site reduces LPS-responsiveness by ∼50%, while mutation of the NFκB binding site completely eliminates LPS-responsiveness. While binding of C/EBPβ and NFκB is still observed in gel retardation studies using acute phase nuclear extracts and a probe containing mutations to the downstream C/EBP site, neither NFκB nor C/EBP appear to bind to a probe in which the NFκB site has been mutated. Conservation of this region of the Factor VIII promoter in species which exhibit an increase in Factor VIII levels in response to inflammatory stimuli suggests that these transcription factor binding sites are important for normal regulation of the Factor VIII gene under conditions of stress.

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“…4 -11 These side effects are important because of a procoagulant state in acute coronary syndromes. [12][13][14][15][16][17] In patients with AMI and thrombolytic therapy, markedly increased thrombin activation was associated with failure to open the occluded coronary artery and with a high reocclusion rate. 18 As one pathway of thrombin stimulation of thrombolytics, activation of the contact phase of the coagulation by plasmin has been found in vitro.…”

mentioning

confidence: 99%

Thrombolytic Therapy in Acute Myocardial Infarction

et al. 1998

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Background-Thrombolytic therapy in patients with acute myocardial infarction (AMI) is hampered by procoagulant effects. In vitro studies have indicated that plasmin stimulation activates the kallikrein-contact-phase system, resulting in thrombin activation. This prospective comparative study was designed to examine the procoagulant effects of streptokinase or alteplase in AMI. Methods and Results-Sixty-one patients with AMI received 1.5 million U of streptokinase or front-loaded alteplase (up to 100 mg) and systemic heparin. Twenty-four patients with AMI and no thrombolytic therapy and 30 control subjects were examined for comparison. Molecular markers of thrombin, plasmin activation, and coagulation activities were determined before therapy and serially for up to 10 days. Streptokinase and alteplase increase TAT to 50Ϯ17 and 51Ϯ18 g/L at 3 hours and to 50Ϯ17 and 33Ϯ14 g/L at 6 hours, respectively (PϽ0.01). Kallikrein activity is elevated (PϽ0.01) to 76Ϯ5 and 71Ϯ7 U/L at 3 hours and 64Ϯ6 and 47Ϯ5 U/L by streptokinase and alteplase, respectively, at 6 hours. Reductions in fibrinogen and increases in D-dimers and plasmin-antiplasmin complexes are more marked (PϽ0.05 and 0.01) after streptokinase versus alteplase. Correlations were found among TAT, kallikrein activity, and plasmin activation (PϽ0.01). Conclusions-The data indicate a more marked procoagulant action of the streptokinase regimen compared with front-loaded alteplase, thus supporting the hypothesis of a plasmin-mediated kallikrein activation with consecutive procoagulant action in vivo.

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Changes in Coagulation Factors Following Acute Myocardial Infarction in Man

Cited by 10 publications

References 16 publications

Procoagulant activity induced by vascular injury determines contribution of elevated factor VIII to thrombosis and thrombus stability in mice

Procoagulant activity induced by vascular injury determines contribution of elevated factor VIII to thrombosis and thrombus stability in mice

The Factor VIII Acute Phase Response Requires the Participation of NFκB and C/EBP

Thrombolytic Therapy in Acute Myocardial Infarction

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