Int J Hematol DOI 10.1007/s12185-016-1954-x
ORIGINAL ARTICLE
Fibrin‑related markers for diagnosing acute‑, subclinical‑, and pre‑venous thromboembolism in patients with major orthopedic surgery Toshio Yamaguchi1 · Hideo Wada2 · Shinichi Miyazaki1 · Masahiro Hasegawa1 · Hiroki Wakabayashi1 · Kunihiro Asanuma1 · Naoki Fujimoto2 · Takeshi Matsumoto3 · Kohshi Ohishi3 · Akane Sakaguchi4 · Norikazu Yamada5 · Masaaki Ito5 · Yoshiki Yamashita6 · Naoyuki Katayama6 · Akihiro Sudo1 Received: 25 November 2015 / Revised: 25 January 2016 / Accepted: 2 February 2016 © The Japanese Society of Hematology 2016
Abstract Venous thromboembolism (VTE) is a common complication in patients who have undergone major orthopedic surgery, but there are few predictors of VTE after major orthopedic surgery treated with an anticoagulant. We measured levels of fibrin-related markers (FRMs), such as d-dimer, soluble fibrin (SF), and fibrinogen and fibrin degradation products (FDPs) in 66 patients with acutephase VTE, and 367 patients undergoing major orthopedic surgery. Plasma FDP, d-dimer, and SF levels were significantly higher in patients with acute VTE, but only FDP and d-dimer levels were significantly higher in subclinical VTE. Adequate cut-off levels of d-dimer were 2.2 μg/ ml for diagnosing acute VTE and 1.5 μg/ml for diagnosing subclinical VTE. d-dimer of less than 1.9 or 0.7 μg/ml ruled out acute VTE or subclinical VTE. d-dimer of more than 1.3 μg/ml preoperatively showed a moderate risk for postoperative VTE. Measurement of FRMs is useful for evaluating the risk of subclinical or postoperative VTE in
* Hideo Wada [email protected]‑u.ac.jp 1
Departments of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu, Japan
2
Departments of Molecular and Laboratory Medicine, Mie University Graduate School of Medicine, 2‑174 Edobashi, Tsu‑City, Mie‑ken 514‑8507, Japan
3
Blood Transfusion Service, Mie University Graduate School of Medicine, Tsu, Japan
4
Central Laboratory, Mie University Graduate School of Medicine, Tsu, Japan
5
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Japan
6
Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan
patients with major orthopedic surgery. In particular, FDP is the most valuable marker for diagnosing acute VTE, whereas d-dimer is the most valuable for diagnosing subclinical VTE or predicting VTE. Keywords VTE · Orthopedic surgery · FRMs · d-dimer · SF
Introduction Acute venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is one of the most prevalent cardiovascular diseases [1–3]. PE is a potentially fatal disease that is usually caused by DVT. As the patients with VTE have non-specific and highly variable symptoms, an early diagnosis of VTE is often difficult and imaging tests for a definitive diagnosis are expensive [4–6]. Fibrin-related markers (FRMs) such as d-dimer, soluble fibrin (SF) and fibrinogen and fibrin degradation products (FDPs) are reported to be useful for the diagnosis of thrombosis, such as disseminated intravascular coagulation [7] and VTE [8, 9]. d-dimer is used as an initial screening test in the emergency department to diagnose patients who have signs or symptoms suggestive of VTE. d-dimer is detectable in patients with DVT, as it is a marker of endogenous fibrinolysis [10]. The purpose of this test, which has a high negative predictive value (NPV), is to provide a fast and cost-effective way to triage patients with VTE [11]. Although the d-dimer has a high NPV and imaging tests could be omitted in patients with negative d-dimer, patients with positive d-dimer should undergo further imaging to determine whether or not they have VTE. Orthopedic surgery is associated with a high rate of postoperative VTE [12, 13]. The incidence of VTE ranges
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from 42 to 57 % after total hip arthroplasty (THA) and 41 to 85 % after total knee arthroplasty (TKA) [14] in the absence of thromboprophylaxis. Multiple studies [15–17] have established the efficacy of low-molecular-weight heparin (LMWH) for VTE prophylaxis in orthopedic surgery patients. New oral anticoagulants, such as edoxaban, have recently become available for prophylaxis after surgery [18]. Although measurements of the d-dimer and SF levels can be used to predict the incidence of DVT after THA or TKA [19], this ability is canceled following the administration of fondaparinux [20, 21]. These patients are treated with anti-Xa agents and monitored using anti- Xa activity, but there were few predictors of VTE after major orthopedic surgery [20–22]. In this study, we measured FRM levels in 66 patients with acute VTE and 367 patients undergoing major orthopedic surgery and examined the relationship between FRMs and DVT.
Materials and methods Three hundred and sixty-seven patients undergoing major orthopedic surgery [median age (25th–75th percentile), 65.0 years (57.0–74.5 years); 305 females and 62 males] treated with 30 mg of edoxaban (Daiichisankyo, Tokyo, Japan) and intermittent pneumatic compression for prophylaxis of DVT between January 1, 2013, and May 17, 2015, at Mie University Hospital were enrolled in this study. These patients received 30 mg of edoxaban orally administration once a day for 14 days beginning 24 h after lumbar anesthesia extubation. Although 17 patients [68.0 years (59.0–76.0 years), 15 females and 2 males] had no symptoms, they were diagnosed with distal DVT. These patients were considered to have subclinical VTE. After surgery, a further 57 patients [70 years (60–77 years), 51 females and 6 males] were newly diagnosed with distal DVT. These patients were considered to be in a pre-VTE state before surgery. These patients were generally treated with 30 mg of edoxaban until the day before surgery. The FDP, d-dimer and SF levels were measured in the 367 patients who underwent orthopedic surgery before surgery and at days 1, 4, 8 and 14 after surgery. Blood samplings on days 1a, 4a and 8a were carried out 1 h after the administration of edoxaban 30 mg. FRMs were also measured in 73 patients with acute VTE [69.0 years (51.3– 75.0 years), 57 females and 16 males)] and 90 healthy volunteers [20.0 years (19.0–24.0 years), 58 males and 32 females], which were compared to those in the patients with orthopedic surgery. The patients with acute VTE had some symptoms, and 30 patients had PE while 40 patients had proximal DVT. In these patients, blood sampling was performed within 3 days after the onset of VTE.
13
The presence of DVT in the patients who underwent orthopedic surgery was assessed by a whole-leg compression ultrasound examination using standardized ultrasound criteria for venous non-compressibility before surgery, as well as on day 4 and day 14 [20–22]. The PE and acute DVT were diagnosed by computed tomography. The study protocol was approved by the Human Ethics Review Committee of Mie University School of Medicine, and signed informed consent was obtained from each subject. This study was carried out in accordance with the principles of the Declaration of Helsinki. The plasma levels of FDP, d-dimer and SF were measured according to the latex agglutination method using Nanopia FDP, Nanopia d-dimer and Nanopia SF reagents, respectively (Sekisui Medical, Tokyo, Japan) [21, 22]. Statistical analysis The data are expressed as the median (25th–75th percentiles). Differences between groups were examined for significance using the Mann–Whitney U test. A P value of less than 0.05 was considered to indicate a significant difference. All statistical analyses were performed using the StatFlex, version 6, software package (Artec Co. Ltd., Osaka, Japan). In addition, the significance of differences in frequency was examined using a Chi square analysis and Fisher’s exact test.
Results Plasma FDP levels were significantly higher in the patients with acute VTE (18.7 μg/ml, 10.6–35.1 μg/ml, all p
ORIGINAL ARTICLE
Fibrin‑related markers for diagnosing acute‑, subclinical‑, and pre‑venous thromboembolism in patients with major orthopedic surgery Toshio Yamaguchi1 · Hideo Wada2 · Shinichi Miyazaki1 · Masahiro Hasegawa1 · Hiroki Wakabayashi1 · Kunihiro Asanuma1 · Naoki Fujimoto2 · Takeshi Matsumoto3 · Kohshi Ohishi3 · Akane Sakaguchi4 · Norikazu Yamada5 · Masaaki Ito5 · Yoshiki Yamashita6 · Naoyuki Katayama6 · Akihiro Sudo1 Received: 25 November 2015 / Revised: 25 January 2016 / Accepted: 2 February 2016 © The Japanese Society of Hematology 2016
Abstract Venous thromboembolism (VTE) is a common complication in patients who have undergone major orthopedic surgery, but there are few predictors of VTE after major orthopedic surgery treated with an anticoagulant. We measured levels of fibrin-related markers (FRMs), such as d-dimer, soluble fibrin (SF), and fibrinogen and fibrin degradation products (FDPs) in 66 patients with acutephase VTE, and 367 patients undergoing major orthopedic surgery. Plasma FDP, d-dimer, and SF levels were significantly higher in patients with acute VTE, but only FDP and d-dimer levels were significantly higher in subclinical VTE. Adequate cut-off levels of d-dimer were 2.2 μg/ ml for diagnosing acute VTE and 1.5 μg/ml for diagnosing subclinical VTE. d-dimer of less than 1.9 or 0.7 μg/ml ruled out acute VTE or subclinical VTE. d-dimer of more than 1.3 μg/ml preoperatively showed a moderate risk for postoperative VTE. Measurement of FRMs is useful for evaluating the risk of subclinical or postoperative VTE in
* Hideo Wada [email protected]‑u.ac.jp 1
Departments of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu, Japan
2
Departments of Molecular and Laboratory Medicine, Mie University Graduate School of Medicine, 2‑174 Edobashi, Tsu‑City, Mie‑ken 514‑8507, Japan
3
Blood Transfusion Service, Mie University Graduate School of Medicine, Tsu, Japan
4
Central Laboratory, Mie University Graduate School of Medicine, Tsu, Japan
5
Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Japan
6
Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan
patients with major orthopedic surgery. In particular, FDP is the most valuable marker for diagnosing acute VTE, whereas d-dimer is the most valuable for diagnosing subclinical VTE or predicting VTE. Keywords VTE · Orthopedic surgery · FRMs · d-dimer · SF
Introduction Acute venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is one of the most prevalent cardiovascular diseases [1–3]. PE is a potentially fatal disease that is usually caused by DVT. As the patients with VTE have non-specific and highly variable symptoms, an early diagnosis of VTE is often difficult and imaging tests for a definitive diagnosis are expensive [4–6]. Fibrin-related markers (FRMs) such as d-dimer, soluble fibrin (SF) and fibrinogen and fibrin degradation products (FDPs) are reported to be useful for the diagnosis of thrombosis, such as disseminated intravascular coagulation [7] and VTE [8, 9]. d-dimer is used as an initial screening test in the emergency department to diagnose patients who have signs or symptoms suggestive of VTE. d-dimer is detectable in patients with DVT, as it is a marker of endogenous fibrinolysis [10]. The purpose of this test, which has a high negative predictive value (NPV), is to provide a fast and cost-effective way to triage patients with VTE [11]. Although the d-dimer has a high NPV and imaging tests could be omitted in patients with negative d-dimer, patients with positive d-dimer should undergo further imaging to determine whether or not they have VTE. Orthopedic surgery is associated with a high rate of postoperative VTE [12, 13]. The incidence of VTE ranges
13
T. Yamaguchi et al.
from 42 to 57 % after total hip arthroplasty (THA) and 41 to 85 % after total knee arthroplasty (TKA) [14] in the absence of thromboprophylaxis. Multiple studies [15–17] have established the efficacy of low-molecular-weight heparin (LMWH) for VTE prophylaxis in orthopedic surgery patients. New oral anticoagulants, such as edoxaban, have recently become available for prophylaxis after surgery [18]. Although measurements of the d-dimer and SF levels can be used to predict the incidence of DVT after THA or TKA [19], this ability is canceled following the administration of fondaparinux [20, 21]. These patients are treated with anti-Xa agents and monitored using anti- Xa activity, but there were few predictors of VTE after major orthopedic surgery [20–22]. In this study, we measured FRM levels in 66 patients with acute VTE and 367 patients undergoing major orthopedic surgery and examined the relationship between FRMs and DVT.
Materials and methods Three hundred and sixty-seven patients undergoing major orthopedic surgery [median age (25th–75th percentile), 65.0 years (57.0–74.5 years); 305 females and 62 males] treated with 30 mg of edoxaban (Daiichisankyo, Tokyo, Japan) and intermittent pneumatic compression for prophylaxis of DVT between January 1, 2013, and May 17, 2015, at Mie University Hospital were enrolled in this study. These patients received 30 mg of edoxaban orally administration once a day for 14 days beginning 24 h after lumbar anesthesia extubation. Although 17 patients [68.0 years (59.0–76.0 years), 15 females and 2 males] had no symptoms, they were diagnosed with distal DVT. These patients were considered to have subclinical VTE. After surgery, a further 57 patients [70 years (60–77 years), 51 females and 6 males] were newly diagnosed with distal DVT. These patients were considered to be in a pre-VTE state before surgery. These patients were generally treated with 30 mg of edoxaban until the day before surgery. The FDP, d-dimer and SF levels were measured in the 367 patients who underwent orthopedic surgery before surgery and at days 1, 4, 8 and 14 after surgery. Blood samplings on days 1a, 4a and 8a were carried out 1 h after the administration of edoxaban 30 mg. FRMs were also measured in 73 patients with acute VTE [69.0 years (51.3– 75.0 years), 57 females and 16 males)] and 90 healthy volunteers [20.0 years (19.0–24.0 years), 58 males and 32 females], which were compared to those in the patients with orthopedic surgery. The patients with acute VTE had some symptoms, and 30 patients had PE while 40 patients had proximal DVT. In these patients, blood sampling was performed within 3 days after the onset of VTE.
13
The presence of DVT in the patients who underwent orthopedic surgery was assessed by a whole-leg compression ultrasound examination using standardized ultrasound criteria for venous non-compressibility before surgery, as well as on day 4 and day 14 [20–22]. The PE and acute DVT were diagnosed by computed tomography. The study protocol was approved by the Human Ethics Review Committee of Mie University School of Medicine, and signed informed consent was obtained from each subject. This study was carried out in accordance with the principles of the Declaration of Helsinki. The plasma levels of FDP, d-dimer and SF were measured according to the latex agglutination method using Nanopia FDP, Nanopia d-dimer and Nanopia SF reagents, respectively (Sekisui Medical, Tokyo, Japan) [21, 22]. Statistical analysis The data are expressed as the median (25th–75th percentiles). Differences between groups were examined for significance using the Mann–Whitney U test. A P value of less than 0.05 was considered to indicate a significant difference. All statistical analyses were performed using the StatFlex, version 6, software package (Artec Co. Ltd., Osaka, Japan). In addition, the significance of differences in frequency was examined using a Chi square analysis and Fisher’s exact test.
Results Plasma FDP levels were significantly higher in the patients with acute VTE (18.7 μg/ml, 10.6–35.1 μg/ml, all p
