Elsevier

Thrombosis Research

Volume 132, Issue 5, November 2013, Pages 584-591
Thrombosis Research

Regular Article
Lobectomy and postoperative thromboprophylaxis with enoxaparin improve blood hypercoagulability in patients with localized primary lung adenocarcinoma

https://doi.org/10.1016/j.thromres.2013.07.005Get rights and content

Abstract

Background

Patients with lung adenocarcinoma undergoing surgery are in high risk for VTE and receive routine post-operative thromboprophylaxis with LWMH.

Aim

We investigated markers of hypercoagulability in patients with primary localized adenocarcinoma and the modifications induced by lobectomy and postoperative administration of enoxaparin.

Materials and Methods

Patients suffering from localised primary lung adenocarcinoma (n = 15) scheduled for lobectomy were studied. The control group consisted of 15 healthy age and sex-matched individuals. Blood was collected before anaesthesia induction and after surgery, at several intervals until the 7th post-operative day. Samples were assessed for thrombin generation, phosphatidylserin expressing platelet derived microparticles expressing (Pd-MP/PS+), tissue factor activity (TFa), FVIIa and TFPI levels, procoagulant phospholipid dependent clotting time and anti-Xa activity.

Results

At baseline, patients showed increased thrombin generation and Pd-MP/PS+. After lobectomy thrombin generation significantly decreased. Administration of enoxaparin attenuated thrombin generation. In about 50% of samples collected post-operatively an increase of thrombin generation occurred despite the presence of the expected anti-Xa activity in plasma. At the 7th post-operative day, 3 out of 15 patients showed a significant increase of thrombin generation.

Conclusion

In patients with localized lung adenocarcinoma, hypercoagulability is characterized by high thrombin generation and increased concentration of Pd-MP/PS+. Tumor mass resection is related with attenuation of thrombin generation, which is inhibited by postoperative thromboprophylaxis with enoxaparin. The response to enoxaparin is not predicted by the concentration of the anti-Xa activity in plasma. The assessment of thrombin generation during prophylaxis with enoxaparin allows to identify patients with high residual plasma hypercoagulability.

Introduction

Cancer is linked with hypercoagulability and risk of thrombosis. Their close association has been recognized since the 19th century [1], [2], [3]. The risk of venous thromboembolism (VTE) is 6 to 7 fold higher in cancer patients [4], [5]. Venous thromboembolism (VTE) significantly affects morbidity and is the second most important cause of mortality in hospitalized cancer patients [6], [7]. The one-year cumulative incidence of VTE in patients with lung cancer not receiving thromboprophylaxis is estimated to be 5% to 6% [8].

Patients with lung adenocarcinoma have higher VTE risk as compared to those with squamous cell carcinoma [9], [10]. Surgery in cancer patients is a major triggering risk factor for VTE [11]. The incidence of asymptomatic deep vein thrombosis (DVT) after lobectomy or pneumonectomy has been reported to be 14% when thromboprophylaxis is not administered [12], [13]. In patients undergoing lung resection for cancer the incidence of symptomatic VTE is about 5% [14], [15]. Noteworthy, pulmonary embolism is fatal in up to 1.3% of cases [12]. In addition to surgery, patients undergoing pneumonectomy present other VTE risk factors during the post-operative period such as deshydratation, inflammation and prolonged bed-rest [16].

Low molecular weight heparins (LMWHs) are cornerstone drugs for thromboprophylaxis in surgical patients [17]. Lung-cancer patients undergoing surgery receive routine post-operative thromboprophylaxis with LWMH at the same dose as recommended for patients undergoing major abdominal surgery [18]. Low molecular weight heparins are pleiotropic anticoagulant drugs exerting their antithrombotic activity by inhibiting thrombin generation via the antithrombin dependent inhibition of factor Xa (FXa) and to a lesser extent by inhibiting thrombin [19]. In addition, LMWHs inhibit factor VIIa (FVIIa) generation and activity and induce Tissue Factor Pathway Inhibitor (TFPI) release that contribute to their antithrombotic effect [20], [21], [22]. These properties of LMWHs have been studied mainly in healthy volunteers, in patients undergoing major orthopedic surgery and in patients suffering from acute coronary syndromes [22], [23]. The mechanisms by which LMWHs exert their antithrombotic activity when administered postoperatively in cancer patients have not been fully elucidated.

Clinical trials and experimental studies elucidated many aspects of the interplay between cancer cells and blood coagulation [24], [25]. Tissue factor (TF) expressed by tumor cells as well as the formation of procoagulant microparticles derived from activated platelets are pivotal events leading to hypercoagulable state in patients with cancer [reviewed in [26], [27], [28]. The study of thrombin generation performed either with clotting based assays or with chromogenic substrates is an old and established tool in blood coagulation research [29], [30], [31], [32], [33], [34]. The Thrombogram-Thrombinoscope is the most recent version of thrombin generation assay that has been adequately standardized [35], [36], [37], [38]. This assay using a fluorogenic substrate allows to study thrombin generation in more physiologically relevant experimental conditions in platelet rich or poor plasma without any interference to fibrin formation. Parameters of thrombogram allow analysis of the initiation, amplification and inhibition phase of thrombin generation as well as the integral amount of generated thrombin [39]. The use of a standardized assay allowing to evaluate the entire blood coagulation process and the global antithrombotic effect of LMWHs in a physiologically relevant experimental system is expected to contribute in the understanding of the interplay between cancer cells and blood coagulation.

The present pilot study was conducted in patients with primary localized adenocarcinoma of the lung aiming to investigate the impact of lobectomy and postoperative administration of enoxaparin on thrombin generation and cellular markers of hypecoagulability.

Section snippets

Patients’ Group

Fifteen selected patients suffering from operable lung adenocarcinoma stage I or II were included in the study. Patients were recruited from December 2009 to Mai 2011. Lung cancer was diagnosed according to standard radiological and histological criteria and the stage of cancer was determined according to the TNM system [40]. All patients underwent lobectomy. None of the patients received any anti-cancer treatment before inclusion in the study. Patients were included to the study after

Demographics of the Studied Population

Patients (11 men and 4 women) included in the study were diagnosed with operable lung adenocarcinoma. They didn’t present previous personal history of VTE, atherothrombosis, diabetes or chronic arterial hypertension. The duration of surgery was 100 ± 30 min. All patients received routine post-operative thromboprophylaxis with a fixed daily dose of enoxaparin (4000 anti-Xa IU/day s.c.).

The control group consisted in 10 males and 5 females. The mean age of the control group was not significantly

Discussion

The present study demonstrates that in patients with localized primary adenocarcinoma of the lung the hypercoagulable state is characterized by increased thrombin generation, high levels of platelet derived microparticles and short phospholipid dependent clotting time. Lobectomy results in an attenuation of thrombin generation. Postoperative administration of thromboprophylaxis with enoxaparin further inhibits thrombin generation.

The studied cohort of patients was homogenous regarding the

Conflict of Interest

All authors except Dr. P Vandreden have no conflict of interest for this study. Dr. P. Vandreden is employee of Diagnositcia Stago.

Acknowledgement

The authors are grateful to Amir Khaterchi, Marie-Paule Roman and Severin Bouffard for the excellent technical assistance.

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