Early Heparin Administration Attenuates Tissue Factor-Mediated Thrombin Generation During Simulated Cardiopulmonary Bypass

Morizumi, Sei; Hiramatsu, Yuji; Matsuzaki, Kanji; Goto, Yukinobu; Sato, Shoko; Abe, Masakazu; Kato, Harumi; Matsubara, Muneaki; Sakakibara, Yuzuru

doi:10.1111/jocs.12254

Cited by 4 publications

(3 citation statements)

References 22 publications

(35 reference statements)

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“…Furthermore, in the lack of extrinsic coagulation pathway activation by the surgical field, heparin induces tissue factor pathway inhibitor (TFPI) elevation and attenuates tissue factor-mediated thrombin generation. 19 However, the elevation of C3 indicates the presence of an inflammatory response in agreement with the clinical setting or in vitro findings by others. 20,21 Our findings are in agreement with Pekna et al, who previously suggested that the blood-gas interface during cardiopulmonary bypass induces complement activation and increases in C3.…”

Section: Discussionsupporting

confidence: 87%

Ex vivo simulation of cardiopulmonary bypass with human blood for hemocompatibility testing

Teligui¹,

Dalmayrac

Corbeau

et al. 2015

Perfusion

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Section: Discussionsupporting

confidence: 87%

Ex vivo simulation of cardiopulmonary bypass with human blood for hemocompatibility testing

Teligui¹,

Dalmayrac

Corbeau

et al. 2015

Perfusion

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“…10,11 Tissue factor-dependent coagulation and inflammation, as a result of monocyte activation and surgical trauma, also occur during CPB. [12][13][14][15] In addition, coagulation proteases can cross-activate other plasma proteolytic cascades and vice versa. 16,17 Thus, the neonate undergoing CPB is susceptible to widespread and unregulated proteolysis with consumption of plasma protease inhibitors that regulate blood coagulation, fibrinolysis, complement and inflammation.…”

Section: Introductionmentioning

confidence: 99%

Plasma Proteolytic Cascade Activation during Neonatal Cardiopulmonary Bypass Surgery

et al. 2018

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The most striking changes were observed following heparin administration and were associated with the appearance of inactive forms of anti-thrombin and an increase in the plasma concentration of TFPI. Changes in anti-thrombin and TFPI remained evident throughout surgery and into the post-operative period but were not different between patients with or without post-operative bleeding. The concentration of antitrypsin decreased across surgery, but there was no significant accumulation of inactive conformations of any inhibitor besides anti-thrombin, indicating that widespread cross-activation of other plasma proteolytic cascades by coagulation proteases did not occur.

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“…TFPI attenuates procoagulant processes by targeting the extrinsic pathway by the inhibition of TF-FVIIa and FXa (37) and it has been previously shown to be significantly correlated with a prolonged TG lag time, and with a reduced ETP and peak height in healthy subjects (38). Additionally, Morizumi et al reported that a heparin-induced elevation of TFPI levels during CPB surgery indeed attenuates TG (39). An elevation of TFPI levels will result in decreased FX activation and increased prothrombinase activity, which is reflected in a reduced maximum rate of prothrombin conversion (19).…”

Section: Discussionmentioning

confidence: 98%

A reduction of prothrombin conversion by cardiac surgery with cardiopulmonary bypass shifts the haemostatic balance towards bleeding

Kremers¹,

Bosch²,

Bloemen

et al. 2016

Thromb Haemost

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Cardiac surgery with cardiopulmonary bypass (CPB) is associated with blood loss and post-surgery thrombotic complications. The process of thrombin generation is disturbed during surgery with CPB because of haemodilution, coagulation factor consumption and heparin administration. We aimed to investigate the changes in thrombin generation during cardiac surgery and its underlying pro- and anticoagulant processes, and to explore the clinical consequences of these changes using in silico experimentation. Plasma was obtained from 29 patients undergoing surgery with CPB before heparinisation, after heparinisation, after haemodilution, and after protamine administration. Thrombin generation was measured and prothrombin conversion and thrombin inactivation were quantified. In silico experimentation was used to investigate the reaction of patients to the administration of procoagulant factors and/or anticoagulant factors. Surgery with CPB causes significant coagulation factor consumption and a reduction of thrombin generation. The total amount of prothrombin converted and the rate of prothrombin conversion decreased during surgery. As the surgery progressed, the relative contribution of α2-macroglobulin-dependent thrombin inhibition increased, at the expense of antithrombin-dependent inhibition. In silico restoration of post-surgical prothrombin conversion to pre-surgical levels increased thrombin generation excessively, whereas co-administration of antithrombin resulted in the normalisation of post-surgical thrombin generation. Thrombin generation is reduced during surgery with cardiopulmonary bypass because of a balance shift between prothrombin conversion and thrombin inactivation. According to in silico predictions of thrombin generation, this new balance increases the risk of thrombotic complications with prothrombin complex concentrate administration, but not if antithrombin is co-administered.

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Early Heparin Administration Attenuates Tissue Factor-Mediated Thrombin Generation During Simulated Cardiopulmonary Bypass

Abstract: Heparin-induced TFPI elevation attenuates TF-mediated thrombin generation. Early heparin administration prior to the emergence of plasma TF may represent a novel strategy for controlling thrombin generation by the extrinsic coagulation pathway during CPB.

Cited by 4 publications

References 22 publications

Ex vivo simulation of cardiopulmonary bypass with human blood for hemocompatibility testing

Ex vivo simulation of cardiopulmonary bypass with human blood for hemocompatibility testing

Plasma Proteolytic Cascade Activation during Neonatal Cardiopulmonary Bypass Surgery

A reduction of prothrombin conversion by cardiac surgery with cardiopulmonary bypass shifts the haemostatic balance towards bleeding

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