The effect of total hip/knee replacement surgery and prophylactic dabigatran on thrombin generation and coagulation parameters

doi:10.1016/j.thromres.2011.12.023

Thrombosis Research

Volume 130, Issue 5, November 2012, Pages 775-779

https://doi.org/10.1016/j.thromres.2011.12.023 Get rights and content

Abstract

Introduction

Total hip/knee replacement surgery (THR/TKR respectively) is associated with an increased risk of venous thromboembolism. Dabigatran is recommended as a thromboprophylactic agent post orthopaedic surgery. The aim of this study was to assess the post-operative (Day-1 and Day-2) effect of prophylactic Dabigatran on: the thrombin generation (TG) assay; prothrombin fragment 1.2 (F1.2); thrombin-antithrombin complexes (TAT); D-dimer (D-D); and other coagulation parameters.

Methods and samples

Nineteen patients (12 THR, 7 TKR) who received 110 mg dabigatran 4 hours post-operatively, then 220 mg the following day, were recruited. Blood was collected: pre-operatively (Pre-); peri-operatively (Peri-); 19 hours after 110 mg dabigatran (Day-1); and 17 hours after 220 mg dabigatran (Day-2). The TG assay was measured using the Calibrated Automated Thrombogram and a low concentration of tissue factor. Other coagulation parameters measured included activated partial thromboplastin time (APTT), thrombin-time (TT), ecarin-clotting time (ECT) and Hemoclot tests.

Results

From Pre- to Peri-, ETP/peak-thrombin, F1.2, TAT and D-D increased significantly. From Peri- to Day-1 and Day-2: TAT reduced progressively; D-D increased; F1.2 did not change significantly; lag-time and time-to-peak prolonged; ETP/Peak-thrombin increased spuriously, due to Dabigatran interfering with the α-2 macroglobulin:thrombin complex in the TG assay. APTT, TT, ECT and Hemoclot increased progressively post-operatively; good correlations were seen between these tests.

Conclusion

The effect of dabigatran on the TG assay, showed a spurious increase in ETP and Peak-thrombin due to its interference with the TG assay. Dabigatran reduced TAT, but not F1.2, suggesting that thrombin was still being generated after surgery, but was blocked by Dabigatran.

Introduction

The risk of venous thromboembolism (VTE) developing following total hip and knee replacement (THR and TKR respectively) surgery, if no chemical prophylaxis is administered, is 40-60% [1]. Activation of the coagulation system occurs during surgery, as indicated by increased in vitro thrombin generation (TG), prothrombin fragment 1.2 (F1.2), thrombin antithrombin complexes (TAT) and D-dimer (D-D) [2], [3], [4], [5], [6]. The increase in TG during surgery is also evidenced by the clinical development of VTE in the immediate post-operative period; in a study performed by Maynard and colleagues, ~ 85% of DVT that developed post TKR were evident venographically at 24 hours after the surgery, indicating that VTE had started in the peri-operative period [7].

Administering thromboprophylaxis after THR and TKR surgery has become the standard of care [1], [8] and dabigatran etexilate, an oral direct thrombin inhibitor, is one of the licensed agents for VTE prophylaxis after these surgeries. Approximately 80% of the drug is excreted unchanged via the kidney, with the remainder being eliminated via the biliary tract. In healthy subjects, the dabigatran plasma concentration peaks at 0.5-2 hours after administration whereas for patients undergoing THR, this is more prolonged due to the peri-operative changes in gastric pH/motility [9]. The slow absorption of dabigatran after surgery is the rationale for its early administration, starting 1-4 hours after surgery (110 mg once-daily) and increasing to 220 mg once-daily from the following day onwards. The estimated half-life for dabigatran is 8-10 hours following single-dose administration and 14-17 hours following multiple-dose administration [10]. For patients with a creatinine clearance (CrCl) of 30-50 ml/min or for those > 75 years, a reduced dose of 150 mg daily is advised. Due to the predictable dose-response relationship of dabigatran, laboratory monitoring is not recommended. However, in unusual circumstances (i.e. bleeding, renal/liver impairment, drug-to-drug interactions) monitoring or the ability to rule out a residual anticoagulant effect, could be crucial. Measurement of the anticoagulant effect of dabigatran can be assessed by the ecarin clotting time (ECT), thrombin time (TT), an optimised commercial TT where samples are diluted in normal plasma (Haemoclot test) and activated partial thromboplastin time (APTT), although the latter is less sensitive to supra-therapeutic doses [11], [12]. However these tests are not yet standardised for routine clinical laboratory use.

All anticoagulant agents, including dabigatran, directly or indirectly inhibit TG; thus it would appear that measuring their activity through the TG assay might be a suitable approach. Our group recently showed that at 24 hours after THR and TKR surgery, rivaroxaban inhibited TG more than dalteparin [6]. Further, several other studies have demonstrated that the TG assay may be more sensitive than current clotting tests at measuring the effect of anticoagulant therapies [13], [14], [15]. However, to our knowledge, no study has hitherto investigated the in vivo impact of prophylactic dabigatran on the TG assay, F1.2, TAT, D-D, as well as other coagulation parameters, following THR/TKR surgery. This is the gap which we aimed to fill in this study.

Section snippets

Patients

The study was approved by the Local Ethics and Research and Development Office at University College London Hospitals (UCLH) NHS Trust. The inclusion criterion for the study was the eligibility to receive thromboprophylaxis with dabigatran after elective, unilateral THR or TKR surgery. Exclusion criteria were: acquired/inherited bleeding disorders; history of VTE recurrence; platelet count < 100x10⁹/l; and active malignancy. Surgery was performed at UCLH by one team of three senior surgeons using

Methods

Full blood counts (FBC) were performed using a KX-21 analyser (Sysmex UK Ltd, Milton Keynes, UK). Unless otherwise stated, coagulation assays were performed on a CS-2000i automated coagulation analyser (Sysmex UK Ltd) and all reagents were from Siemens Healthcare Diagnostics (Marburg, Germany). Innovin and Actin FS were used in prothrombin time (PT) and APTT tests respectively. TT was performed by adding bovine thrombin (Thromboclotin reconstituted to 2.5NIH units/ml) to the plasma and the time

Results

No blood or platelet transfusions were administered during surgery to any patient. From Pre- to Peri- there was a significant reduction in haemoglobin (Hb), platelet count (PLT), haematocrit (HCt), PT and APTT (p < 0.01 for all) (Table 2). At Day-1, Hb and PLT reduced from the baseline, and from the time of drug administration to Day-1, only one patient received 2 units of red blood cells due to anaemia (Hb < 8 g/dl).

Discussion

Between July 2010 and January 2011, we recruited 19 patients who were undergoing elective unilateral THR and TKR. In order to assess the post-operative effect of dabigatran on the TG assay and other coagulation parameters, we felt that it was important to obtain the Pre- and the Peri-operative samples to enable a comparison. Patients for the study were recruited from one surgical team in order to help maintain constant surgical techniques and/or levels of trauma. The Peri- sample was taken at

Conflict of Interest Statement

The authors have no conflicts of interest.

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Regular ArticleThe effect of total hip/knee replacement surgery and prophylactic dabigatran on thrombin generation and coagulation parameters

Abstract

Introduction

Methods and samples

Results

Conclusion

Introduction

Section snippets

Patients

Methods

Results

Discussion

Conflict of Interest Statement

Thromb Res

J Arthroplasty

Thromb Res

J Thromb Haemost

J Thromb Haemost

J Thromb Haemost

Lancet

J Thromb Haemost

J Thromb Haemost

Lancet

The John Charnley Award. Thrombogenesis during total hip arthroplasty

Clin Orthop Relat Res

The impact of elective knee/hip replacement surgery and thromboprophylaxis with rivaroxaban or dalteparin on thrombin generation

Br J Haematol

Progression and regression of deep vein thrombosis after total knee arthroplasty

Clin Orthop Relat Res

Regular Article
The effect of total hip/knee replacement surgery and prophylactic dabigatran on thrombin generation and coagulation parameters