Increased fibrinolytic activity after surgery induced by low dose heparin

Arnesen, Harald; Engebretsen, Lars; Ugland, O M; Seljeflot, Ingebjørg; Kierulf, Peter

doi:10.1016/0049-3848(87)90318-5

Cited by 31 publications

(16 citation statements)

References 10 publications

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“…These data are consistent with those of several investigations carried out in acute pa tients indicating increased levels of t-PA ag after treatments of more than 3 days with unfractionated heparin [2,[7][8][9]. In contrast, significant increases in t-PA ag, t-PA/PAI complexes and PAI-1 with no changes in ELT were reported by Vergnes et al [19] in elderly patients without thrombotic events after a more prolonged (30 and 60 days) prophylactic treatment with heparin.…”

Section: Effect O F Chronic Heparin Treatmentsupporting

confidence: 81%

“…Over the last years several in vitro and in vivo studies have suggested that the anti thrombotic activity of heparin may stem not only from the potentiation of the inhibitory activity of antithrombin III [1], but also from interactions with the fibrinolytic system [2][3][4][5], However, the results have been obtained with different preparations of heparin, and heparin was administered via differing routes to normal volunteers or patients and with reg imens varying from single doses to repeated daily doses [6], In in vivo studies performed in acute clinical conditions (such as deep vein thrombosis or in relation to surgical proce dures) a heparin-induced increase in fibrino lytic activity has been observed and found to be associated with an increase in plasma con centrations of tissue plasminogen activator (t-PA) [7][8][9][10] and/or a decrease in plasminogen activator inhibitor 1 (PAI-1) levels [11]. How ever, these studies were not suitable to investi gate the effect of heparin on the fibrinolytic system, because they were often performed in patients with acute conditions in whom sud den changes in haemostatic factors may arise.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Low-Dose Heparin Treatment on Fibrinolysis in Patients with Previous Myocardial Infarction

Prisco

Paniccia

Gensini

et al. 1993

Pathophysiol Haemos Thromb

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The present study was designed to investigate whether medium-term, low-dose heparin treatment is able to affect the fibrinolytic system. In a randomized cross-over study 10 asymptomatic patients with previous (1-6 years) myocardial infarction underwent two sequential 15-day treatments, respectively, on heparin and on placebo (saline solution), preceded and separated by 10-day wash-out periods. Heparin (as calcium heparin, 12,500 IU in 0.5 ml) and saline (0.5 ml) were subcutaneously administered once a day at 8 a.m. Blood samples for fibrinolysis studies were withdrawn on the first and 15th day of each period immediately before and 4 h after heparin or saline administration before and after 10 min venous occlusion (VO) respectively. Four hours after the first heparin administration tissue plasminogen activator antigen (t-PA ag) levels significantly increased with respect to saline administration (p < 0.01 and p < 0.05, respectively). After 15-day heparin treatment a decrease in euglobulin lysis time (p < 0.05) and an increase in t-PA activity (act) (p < 0.05) and in t-PA ag (p < 0.01) in comparison with placebo were observed before VO. No statistically significant changes in plasminogen activator inhibitor-1 (PAI-1) levels were found. The variations of fibrinolytic system activity induced by heparin treatment were more marked when evaluated after VO. These results indicate that medium-term low-dose heparin treatment increases t-PA ag formation and/or release with consequent t-PA act increase.

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Section: Effect O F Chronic Heparin Treatmentsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Effect of Low-Dose Heparin Treatment on Fibrinolysis in Patients with Previous Myocardial Infarction

Prisco

Paniccia

Gensini

et al. 1993

Pathophysiol Haemos Thromb

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“…The same conclusion was suggested by Arnesen et al, 9 who showed that patients receiving heparin during the pre-and postoperative periods exhibited a larger increase in t-PA activity and t-PA antigen after venous occlusion the third day after surgery than patients not receiving heparin.…”

supporting

confidence: 82%

Potentiation by Heparin Fragment CY 222 (CHOAY) of Thrombolysis Induced by Human Tissue-Type Plasminogen Activator

Juhan-Vague¹,

Stassen²,

Alessi³

et al. 1989

Semin Thromb Hemost

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Heparin is the standard treatment of deep vein thrombosis; the aim of this treatment is to prevent further thrombus growth, although minimal thrombolysis may be expected. In an animal thrombosis model, 1 ' 2 a significant reduction of the size of the thrombus has been obtained with low molecular weight heparins (LMWH), suggesting that these products may be of value in the curative treatment of thrombosis. A recent comparative study of standard heparin and LMWH showed a similar thrombolytic effect of both drugs but with the latter having no side effect. 3 In order to explain the reduction of the size of the thrombus obtained with heparin or LMWH, several studies attempted to demonstrate a profibrinolytic effect of these drugs. Investigations mainly concerned an effect on the release of tissue-type plasminogen activator (t-PA) by endothelial cells. The results of these studies are controversial.After a single injection of heparin or LMWH in human volunteers, an increase in euglobulin fibrinolytic activity (EFA) was observed 2 and 4 hours after the injection of LMWH, 1,4 and in one study the level of t-PA antigen was shown to be elevated after the injection. 5 However, the increase in EFA could have resulted from circadian fluctuations of the fibrinolytic activity with decrease of the PA inhibitor level in the early afternoon hours. 6 ' 7The observation of an increase in EFA in the eluate of organs perfused with heparin or LMWH 1,8 suggested an effect on the release of t-PA by the vascular bed.The same conclusion was suggested by Arnesen et al, 9 who showed that patients receiving heparin during the pre-and postoperative periods exhibited a larger increase in t-PA activity and t-PA antigen after venous occlusion the third day after surgery than patients not receiving heparin.In patients with deep vein thrombosis receiving high dose of the LMWH CY 222 (Choay, Paris, France), we looked for a relationship between the thrombolytic effect of CY 222 and the change in plasma fibrinolytic parameters: 10 a good thrombolytic effect evaluated by phlebography was obtained after 7 days of treatment but no change in EFA, t-PA antigen, and PA inhibitor occurred during treatment. These results were not consistent with the stimulating effect of CY 222 on the release of t-PA by endothelial cells, or with an effect on PA inhibitor. However, a direct effect of LMWH on the patient's own fibrinolytic system could be involved. To test this hypothesis, we looked for a direct effect of the LMWH CY 222 on t-PA activity and single chain urokinase PA (scu-PA) activity in animal studies: 11 in a model of jugular vein thrombosis in which rabbits received t-PA or scu-PA and standard heparin or LMWH, we found that CY 222 potentiated the thrombolytic effect of t-PA and to a lesser extent of scu-PA. THROMBOLYSIS AND PLASMA FIBRINOLYTIC PARAMETERS IN PATIENTS TREATED WITH CY 222Thirty patients with recently diagnosed (less than 7 days) deep vein thrombosis who had given their informed consent were randomized into three treatment groups and received 4...

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“…7 Tissue-type plasminogen activator may also be heparin releasable after its secretion from endothelial cells. 8 The heparinreleasable proteins are diverse in structure, function, and origin; however, with the exception of tumor necrosis factor-binding protein-1, they share the ability to bind heparin-like glycosaminoglycans on the surface of endothelial cells. 913 Intravenous heparin presumably competes for glycosaminoglycan binding sites and releases these proteins into the flowing blood.…”

mentioning

confidence: 99%

Identification of novel heparin-releasable proteins, as well as the cytokines midkine and pleiotrophin, in human postheparin plasma.

Novotny

Maffi

Mehta

et al. 1993

Arterioscler Thromb

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The heparin-releasable proteins are a group of proteins that are targeted to the endothelial surface by attachment to glycosaminoglycans and may have functions specific to the endothelium-blood interface. In this study, heparin-affinity chromatography of human postheparin plasma was used as a method to identify and study novel heparin-releasable proteins. Six proteins seen on sodium dodecyl sulfatepolyacrylamide gel electrophoresis gels have increased levels in plasma after intravenous heparin. The six proteins are platelet factor 4, midkine, pleiotrophin, and several novel proteins. Midkine and pleiotrophin are related cytokines that are developmentally regulated, neurotrophic, and mitogenic. Additional studies show that levels of midkine and pleiotrophin peak at 10 to 30 minutes after injection of heparin. Heparin-releasable midkine and pleiotrophin do not originate from blood cells or the kidney. Heparinreleasable midkine may originate from endothelial cells. Soft agar culture of an adenocarcinoma cell line (SW-13) demonstrates growth-stimulating activity similar to that described for pleiotrophin in the heparin-agarose eluate of postheparin plasma but not in the heparin-agarose eluate of preheparin plasma. It is concluded there are more heparin-releasable proteins than previously identified, including midkine and pleiotrophin, and that heparin-affinity chromatography of postheparin plasma is a useful technique for identifying novel heparin-releasable proteins.

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Increased fibrinolytic activity after surgery induced by low dose heparin

Cited by 31 publications

References 10 publications

Effect of Low-Dose Heparin Treatment on Fibrinolysis in Patients with Previous Myocardial Infarction

Effect of Low-Dose Heparin Treatment on Fibrinolysis in Patients with Previous Myocardial Infarction

Potentiation by Heparin Fragment CY 222 (CHOAY) of Thrombolysis Induced by Human Tissue-Type Plasminogen Activator

Identification of novel heparin-releasable proteins, as well as the cytokines midkine and pleiotrophin, in human postheparin plasma.

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