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Fibrin monomer could be a useful predictor of pulmonary embolism after total hip arthroplasty: preliminary report
J Orthop Sci (2001) 6:119–122
Fibrin monomer could be a useful predictor of pulmonary embolism after total hip arthroplasty: preliminary report Toshikazu Kubo1, Isao Kitajima2,3, Atsushi Makinodan1, Sadanobu Niratsuka4, Shigehiro Inoue1, Goro Otsuka1, Suzuyo Ohashi1, Keiichiro Ueshima1, and Yasusuke Hirasawa1 1
Department of Orthopaedic Surgery, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan 2 Department of Laboratory and Molecular Medicine, Kagoshima University School of Medicine, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan 3 Department of Laboratory Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan 4 Nissui Pharmaceutical Co., Ltd., Research Department, 1075-2 Hokunanmoro, Yuki, Ibaraki 307-0036, Japan
Abstract We examined 17 total hip arthroplasty patients in order to develop a method for the predictive diagnosis of pulmonary embolism (PE) after joint arthroplasty. Scintigraphy revealed the presence of PE in 4 patients. Prothrombin time (PT), activated partial thromboplastin time (aPTT), antithrombin III (ATIII), and thrombin-AT III complex (TAT) did not show significant differences between patients with and without PE. D-dimer 7 days after surgery showed significant differences between patients with and without PE. Fibrin monomer (FM) increased sharply after surgery, and it was significantly different between the patients with and without PE immediately after surgery and 2 days after surgery. Our findings suggest the importance of FM in the predictive diagnosis of pulmonary embolism after total hip arthroplasty, and 40 µg/ml or higher levels with our measurement method could represent a high-risk condition. Key words Total hip arthroplasty · Pulmonary embolism · Fibrin monomer · D-dimer · Thrombin-antithrombin complex · Pulmonary scintigraphy
Introduction The incidence of deep vein thrombosis (DVT) after orthopaedic surgery is relatively high, and the rates are reported to be 34%–63% after total hip arthroplasty (THA)4,6 and 41%–88% after total knee arthroplasty.10,11 DVT patients frequently develop pulmonary embolism (PE). When severe PE occurred, fatal outcome was reported in 0.1%–5% of the cases.9 More than 90% of PEs are derived from thromboses of deep veins in the legs and pelvic cavity. Therefore, it is
Offprint requests to: T. Kubo Received: June 12, 2000 / Accepted: November 27, 2000 The work was done at Kyoto Prefectural University of Medicine.
important to establish method for the predictive diagnosis of thrombosis that may result in PE after joint arthroplasty. Hematologic tests are simple examinations, and if they were applicable for predictive diagnosis after surgery, appropriate treatments for high-risk patients could be started at an earlier time. Fibrin monomer (FM) has attracted attention as a quick and useful factor to detect thrombophilia. We prepared a new FMspecific antibody and utilized it with a latex coagulation method.5 In this study, blood samples of THA patients were collected periodically for the measurement of blood coagulation parameters, including FM. The findings were examined in relation to the results of pulmonary scintigraphy, and useful parameters for the prediction of PE after THA were examined.
Subjects and methods The subjects were 17 patients (2 men and 15 women) who underwent THA. Their ages ranged between 47 and 73 years (mean, 63.1 years). All patients had received aspirin for 28 days after surgery, and had had pulmonary scintigraphy between days 7 and 14 in order to examine for the occurrence of PE. Venous blood was sampled 1 day before surgery, within 3 h after surgery, and on postoperative days 2, 7, 14, 21, and 28. The samples were citrated and used in blood coagulation tests. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were measured using a light scattering method; D-dimer was measured with a latex photometric immunoassay method; antithrombin III (AT III) was measured by a composite substrate method; and thrombin-AT III complex (TAT) was measured by an enzyme immunoassay method. For the measurement of FM, we prepared a new FM-specific antibody, F504 (Nissui Pharmaceutical, Tokyo, Japan). This monoclonal antibody to FM reacts
120
T. Kubo et al.: Fibrin monomer as a predictor of pulmonary embolism
when FM is formed in the process in which fibrinogen changes to fibrin through the action of thrombin, and this reaction does not require a dissociation process. Therefore, this method has a higher specificity in comparison with conventional measurement methods which require a dissociation process, and can detect substances that will develop into a thrombus, and, thus, would be useful in the prediction of thrombosis. This latex agglutination method is simple and rapid.5 Statistical analysis was performed by the MannWhitney U-test.
Results
patients with and without PE (Tables 2, 3). On the other hand, postoperative increases were observed in aPTT, TAT, D-dimer, and FM. aPTT increased immediately after surgery and then decreased in all patients, and increased in patients with PE on postoperative days 14 and 21, although there were no significant differences between groups (Table 4). TAT (Table 5) increased sharply after surgery, then decreased, but the levels were not significantly different between the patients with and without PE. D-dimer (Table 6) decreased after the sharp postoperative increase, but increased again on or after postoperative day 7. The second peak was significantly higher in the patients with PE (P , 0.05). FM (Table 7) in patients with PE also increased sharply after surgery, and there was a significant difference
Pulmonary scintigraphy (Fig. 1) and arterial oxygen concentration measurement (Table 1) detected PE in 4 of the 17 patients, although none of these 4 patients had any clinical symptoms such as dyspnea. Postoperative changes in coagulative factors were examined comparatively in the patients with and without PE. PT and AT III decreased after surgery and then increased, but there were no differences between
Table 1. Arterial oxygen concentration in four patients with pulmonary embolism (PE), measured when pulmonary scintigram was taken PaO2 (mmHg) Case 1 Case 2 Case 3 Case 4
66.9 60.0 66.9 79.0
Fig. 1. Pulmonary embolism occurred after total hip arthroplasty. Pulmonary scintigram showing embolism
Table 2. Changes in prothrombin time (PT) after total hip arthroplasty (%) Postoperative days
With PE Without PE
Before surgery
Immediately after surgery
2
7
14
21
28
84.3 6 11.4 95.8 6 30.4
66.5 6 5.8 63.6 6 15.5
76.7 6 7.6 77.8 6 8.6
86.8 6 10.0 88.9 6 19.1
73.5 6 12.6 85.5 6 9.2
89.8 6 21.4 77.8 6 17.0
81.0 6 12.2 82.3 6 20.3
Values are means 6 SD. Venous blood was sampled 1 day before surgery, within 3 h after surgery, and on postoperative days 2, 7, 14, 21, and 28. With PE (n 5 4); without PE (n 5 13)
Table 3. Changes in anti-thrombin III (AT III) after total hip arthroplasty (%) Postoperative days
With PE Without PE
Before surgery
Immediately after surgery
2
7
14
21
28
103.0 6 9.4 100.4 6 20.3
77.5 6 8.9 77.2 6 17.5
99.7 6 23.9 85.9 6 24.5
117.8 6 7.9 100.7 6 16.5
113.0 6 9.4 97.0 6 16.1
106.5 6 18.0 89.6 6 19.4
92.0 6 36.8 94.4 6 24.0
Values are means 6 SD. Venous blood was sampled 1 day before surgery, within 3 h after surgery, and on postoperative days 2, 7, 14, 21, and 28. With PE (n 5 4); without PE (n 5 13)
T. Kubo et al.: Fibrin monomer as a predictor of pulmonary embolism
121
Table 4. Changes in activated partial thromboplastin time(s) (aPTT) after total hip arthroplasty (sec) Postoperative days
With PE Without PE
Before surgery
Immediately after surgery
2
7
14
21
28
36.4 6 5.9 47.3 6 42.1
65.4 6 31.9 72.0 6 56.0
38.8 6 2.2 39.4 6 6.5
35.5 6 4.8 35.9 6 4.9
73.2 6 71.0 36.2 6 3.5
77.3 6 71.9 52.5 6 40.8
40.1 6 0.6 36.7 6 1.7
Values are means 6 SD. Venous blood was sampled 1 day before surgery, within 3 h after surgery, and on postoperative days 2, 7, 14, 21, and 28. With PE (n 5 4); without PE (n 5 13)
Table 5. Changes in thrombin-AT III complex (TAT) after total hip arthroplasty (µg/l) Postoperative days
With PE Without PE
Before surgery
Immediately after surgery
2
7
14
21
28
6.4 6 8.9 10.6 6 17.5
60.0 6 0.0 47.7 6 16.5
24.9 6 8.8 23.6 6 19.1
14.8 6 7.5 19.6 6 21.8
13.4 6 5.2 9.3 6 5.0
21.5 6 25.8 19.4 6 25.2
4.9 6 1.1 20.1 6 16.8
Values are means 6 SD. Venous blood was sampled 1 day before surgery, within 3 h after surgery, and on postoperative days 2, 7, 14, 21, and 28. With PE (n 5 4); without PE (n 5 13)
Table 6. Changes in D-dimer after total hip arthroplasty (µg/ml) Postoperative days
With PE Without PE
Before surgery
Immediately after surgery
2
7
14
21
28
1.2 6 0.8 3.9 6 6.5
31.4 6 3.3 20.8 6 13.3
14.8 6 14.9 6.0 6 5.5
27.7 6 14.3* 12.3 6 10.6*
20.6 6 8.2 13.0 6 10.2
13.9 6 8.2 7.5 6 3.5
8.9 6 0.6 11.9 6 8.1
* P , 0.05 Values are means 6 SD. Venous blood was sampled 1 day before surgery, within 3 h after surgery, and on postoperative days 2, 7, 14, 21, and 28. With PE (n 5 4); without PE (n 5 13)
Table 7. Changes in fibrin monomer (FM) after total hip arthroplasty (µg/ml) Postoperative days
With PE Without PE
Before surgery
Immediately after surgery
2
7
14
21
28
6.0 6 11.4 10.6 6 16.1
46.9 6 11.6* 21.7 6 14.6*
18.1 6 14.8* 2.7 6 1.2*
22.2 6 30.3 12.8 6 16.0
20.6 6 21.7 9.0 6 10.8
25.8 6 28.2 6.1 6 4.8
5.5 6 3.7 9.8 6 15.6
* P , 0.05 Values are means 6 SD. Venous blood was sampled 1 day before surgery, within 3 h after surgery, and on postoperative days 2, 7, 14, 21, and 28. With PE (n 5 4); without PE (n 5 13)
between the patients with and without PE immediately after surgery and 2 days after surgery (P , 0.05). FM in the patients with PE reached 40 µg/ml or higher, whereas FM did not reach 40 µg/ml in 11 of the 13 patients without PE during the 2 days after surgery.
Discussion The activation of the coagulation system immediately after surgery could be attributable to surgical manipulation. A cause of PE following DVT after THA is thought to be the increased thrombophilia due to the
influx of tissue factor (TF) into the blood stream.2 Because of the surgical invasion for hip arthroplasty, TF and cell fragments are released into the venous blood, and this could, first, cause thrombosis in capillary vessels of the lung, and then induce PE. The values for PT, APTT, AT III, and TAT did not differ significantly between patients with and without PE. Therefore, these factors were concluded to be inapplicable in the diagnosis of PE. The usefulness of fibrin and its metabolites in the evaluation of acute and chronic hypercoagulable states was recently reported.3 D-dimer, which has been monitored as an indicator of the cleavage products of fibrin,
122
T. Kubo et al.: Fibrin monomer as a predictor of pulmonary embolism
has been used in the diagnosis of disseminated intravascular coagulation, and D-dimer with an enzyme immunoassay was reported to be useful in the diagnosis of DVT.8,14 In the present study, the D-dimer value immediately after surgery increased significantly in all patients, but a significant difference between patients with and without PE was observed only 7 days after surgery. This indicates that the D-dimer level in patients at a very early stage of DVT or PE would not be useful for the prediction of PE,15 and this also suggests the necessity to develop more sensitive measurement techniques or to find another suitable factor for the detection of a hypercoagulable state at the very early stage. Fibrin is produced as a result of the interaction between thrombin or thrombin-like protease and fibrinogen.7 FM is a component of soluble fibrin, and it is produced when thrombin sequentially cleaves fibrinopeptide A and B from the aminoterminals of Aα- and Bβ-chains of fibrinogen, respectively.1 In the current study, we prepared a new FM-specific antibody and utilized it with a latex coagulation method.5 As a result, FM was found to be the factor which related significantly to PE. FM increased sharply after surgery and was significantly different between the patients with and without PE immediately after surgery and 2 days after surgery (P , 0.05). Vogel et al.12 conducted blood coagulation tests and venography of the legs in 156 patients whose bone fractures were treated surgically, and they reported increased FM levels in 34 of 36 patients (94%) with DVT and in 31 of 120 patients (26%) without DVT. They also examined 129 patients who had had abdominal surgery,12 and found that 12 of them developed DVT after surgery. They conducted blood coagulation tests in these 12 patients, and found that FM was most closely related to the occurrence of DVT, i.e., positivity was 91.7% for FM, 75.0% for D-dimer, and 41.7% for TAT. In addition, the FM level increased sharply from 1 day prior to the appearance of clinical symptoms of DVT in all the FM-positive patients.13 Our findings, together with those of previous studies, show that FM would be a useful predictive factor for PE, and it could indicate a high risk for DVT and PE. With our FM measurement method, FM levels of 40 µg/ ml or higher could represent a high-risk condition, although this point should be confirmed in a larger number of patients. These high-risk patients should be
monitored carefully with other examinations, such as ultrasonography, for the legs, and should receive prophylaxis for thrombosis. Acknowledgments. This study was supported by the fund of the Ministry of Health and Welfare.
References 1. Caliezi C, Funfsin N, Maruran T, et al. Performance of a new fibrin monomer assay to exclude deep vein thrombosis in symptomatic outpatients. Thromb Haemost 1999;81:50–3. 2. Dahl OE. The role of the pulmonary circulation in the regulation of coagulation and fibrinolysis in relation to major surgery. J Cardiothorac Vasc Anesth 1997;11:322–8. 3. Dempfle CE. The use of soluble fibrin in evaluating the acute and chronic hypercoagulable state. Thromb Haemost 1999;82:673–83. 4. Evarts CM, Feil EJ. Prevention of thromboembolic disease after elective surgery of the hip. J Bone Joint Surg Am 1971;53:1271– 80. 5. Hamano A, Tanaka S, Ueno Y, et al. Measurement of soluble fibrin in plasma by using a monoclonal antibody to fibrin monomer. Jpn J Thromb Hematosis 1999;10:357 (abstract in Japanese). 6. Harris WH, Salzman EW, Athanasouils CA, Waltman AC, DeScanctics RW. Aspirin prophylaxis of venous thromboembolism after total hip replacement. N Engl J Med 1977;297:1246– 9. 7. Janmey PA, Erdile L, Bale MD, et al. Kinetics of fibrin oligomer formation observed by electron microscopy. Biochemistry 1983; 22:4336–40. 8. Koopman MM, van Beek EJ, ten Cate JW. Diagnosis of deep vein thrombosis. Prog Cardiovasc Dis 1994;37:1–12. 9. Leclerc JR. Venous thromboembolic disorders. Philadelphia: Lea and Febiger; 1991. pp. 303–65. 10. Lynch AF, Bourne RB, Rorabeck CH, et al. Deep-vein thrombosis and continuous passive motion after total knee arthroplasty. J Bone Joint Surg Am 1988;70:11–4. 11. Stringer MD, Steadman CA, Hedges AR, et al. Deep vein thrombosis after elective knee surgery. An incidence study in 312 patients. J Bone Joint Surg Br 1989;71:492–7. 12. Vogel G, Spanuth E. Predictive value of fibrin monomers in postoperative deep vein thrombosis. Klin Wochenschr 1990;68: 1020–6. 13. Vogel G, Dempfle CE, Spannagel M, et al. The value of quantitative fibrin monomer determination in the early diagnosis of postoperative deep vein thrombosis. Thromb Res 1996;81:241– 51. 14. Wells PS, Brill-Edwards P, Stevens P, et al. A novel and rapid whole-blood assay for D-dimer in patients with clinically suspected deep vein thrombosis. Circulation 1995;91:2184–7. 15. Yamada N, Wada H, Nakase T, et al. Hemostatic abnormalities in patients with pulmonary embolism compared with that in deep vein thrombosis. Blood Coagul Fibrinosis 1995;6:627–33.
Fibrin monomer could be a useful predictor of pulmonary embolism after total hip arthroplasty: preliminary report Toshikazu Kubo1, Isao Kitajima2,3, Atsushi Makinodan1, Sadanobu Niratsuka4, Shigehiro Inoue1, Goro Otsuka1, Suzuyo Ohashi1, Keiichiro Ueshima1, and Yasusuke Hirasawa1 1
Department of Orthopaedic Surgery, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan 2 Department of Laboratory and Molecular Medicine, Kagoshima University School of Medicine, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan 3 Department of Laboratory Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan 4 Nissui Pharmaceutical Co., Ltd., Research Department, 1075-2 Hokunanmoro, Yuki, Ibaraki 307-0036, Japan
Abstract We examined 17 total hip arthroplasty patients in order to develop a method for the predictive diagnosis of pulmonary embolism (PE) after joint arthroplasty. Scintigraphy revealed the presence of PE in 4 patients. Prothrombin time (PT), activated partial thromboplastin time (aPTT), antithrombin III (ATIII), and thrombin-AT III complex (TAT) did not show significant differences between patients with and without PE. D-dimer 7 days after surgery showed significant differences between patients with and without PE. Fibrin monomer (FM) increased sharply after surgery, and it was significantly different between the patients with and without PE immediately after surgery and 2 days after surgery. Our findings suggest the importance of FM in the predictive diagnosis of pulmonary embolism after total hip arthroplasty, and 40 µg/ml or higher levels with our measurement method could represent a high-risk condition. Key words Total hip arthroplasty · Pulmonary embolism · Fibrin monomer · D-dimer · Thrombin-antithrombin complex · Pulmonary scintigraphy
Introduction The incidence of deep vein thrombosis (DVT) after orthopaedic surgery is relatively high, and the rates are reported to be 34%–63% after total hip arthroplasty (THA)4,6 and 41%–88% after total knee arthroplasty.10,11 DVT patients frequently develop pulmonary embolism (PE). When severe PE occurred, fatal outcome was reported in 0.1%–5% of the cases.9 More than 90% of PEs are derived from thromboses of deep veins in the legs and pelvic cavity. Therefore, it is
Offprint requests to: T. Kubo Received: June 12, 2000 / Accepted: November 27, 2000 The work was done at Kyoto Prefectural University of Medicine.
important to establish method for the predictive diagnosis of thrombosis that may result in PE after joint arthroplasty. Hematologic tests are simple examinations, and if they were applicable for predictive diagnosis after surgery, appropriate treatments for high-risk patients could be started at an earlier time. Fibrin monomer (FM) has attracted attention as a quick and useful factor to detect thrombophilia. We prepared a new FMspecific antibody and utilized it with a latex coagulation method.5 In this study, blood samples of THA patients were collected periodically for the measurement of blood coagulation parameters, including FM. The findings were examined in relation to the results of pulmonary scintigraphy, and useful parameters for the prediction of PE after THA were examined.
Subjects and methods The subjects were 17 patients (2 men and 15 women) who underwent THA. Their ages ranged between 47 and 73 years (mean, 63.1 years). All patients had received aspirin for 28 days after surgery, and had had pulmonary scintigraphy between days 7 and 14 in order to examine for the occurrence of PE. Venous blood was sampled 1 day before surgery, within 3 h after surgery, and on postoperative days 2, 7, 14, 21, and 28. The samples were citrated and used in blood coagulation tests. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were measured using a light scattering method; D-dimer was measured with a latex photometric immunoassay method; antithrombin III (AT III) was measured by a composite substrate method; and thrombin-AT III complex (TAT) was measured by an enzyme immunoassay method. For the measurement of FM, we prepared a new FM-specific antibody, F504 (Nissui Pharmaceutical, Tokyo, Japan). This monoclonal antibody to FM reacts
120
T. Kubo et al.: Fibrin monomer as a predictor of pulmonary embolism
when FM is formed in the process in which fibrinogen changes to fibrin through the action of thrombin, and this reaction does not require a dissociation process. Therefore, this method has a higher specificity in comparison with conventional measurement methods which require a dissociation process, and can detect substances that will develop into a thrombus, and, thus, would be useful in the prediction of thrombosis. This latex agglutination method is simple and rapid.5 Statistical analysis was performed by the MannWhitney U-test.
Results
patients with and without PE (Tables 2, 3). On the other hand, postoperative increases were observed in aPTT, TAT, D-dimer, and FM. aPTT increased immediately after surgery and then decreased in all patients, and increased in patients with PE on postoperative days 14 and 21, although there were no significant differences between groups (Table 4). TAT (Table 5) increased sharply after surgery, then decreased, but the levels were not significantly different between the patients with and without PE. D-dimer (Table 6) decreased after the sharp postoperative increase, but increased again on or after postoperative day 7. The second peak was significantly higher in the patients with PE (P , 0.05). FM (Table 7) in patients with PE also increased sharply after surgery, and there was a significant difference
Pulmonary scintigraphy (Fig. 1) and arterial oxygen concentration measurement (Table 1) detected PE in 4 of the 17 patients, although none of these 4 patients had any clinical symptoms such as dyspnea. Postoperative changes in coagulative factors were examined comparatively in the patients with and without PE. PT and AT III decreased after surgery and then increased, but there were no differences between
Table 1. Arterial oxygen concentration in four patients with pulmonary embolism (PE), measured when pulmonary scintigram was taken PaO2 (mmHg) Case 1 Case 2 Case 3 Case 4
66.9 60.0 66.9 79.0
Fig. 1. Pulmonary embolism occurred after total hip arthroplasty. Pulmonary scintigram showing embolism
Table 2. Changes in prothrombin time (PT) after total hip arthroplasty (%) Postoperative days
With PE Without PE
Before surgery
Immediately after surgery
2
7
14
21
28
84.3 6 11.4 95.8 6 30.4
66.5 6 5.8 63.6 6 15.5
76.7 6 7.6 77.8 6 8.6
86.8 6 10.0 88.9 6 19.1
73.5 6 12.6 85.5 6 9.2
89.8 6 21.4 77.8 6 17.0
81.0 6 12.2 82.3 6 20.3
Values are means 6 SD. Venous blood was sampled 1 day before surgery, within 3 h after surgery, and on postoperative days 2, 7, 14, 21, and 28. With PE (n 5 4); without PE (n 5 13)
Table 3. Changes in anti-thrombin III (AT III) after total hip arthroplasty (%) Postoperative days
With PE Without PE
Before surgery
Immediately after surgery
2
7
14
21
28
103.0 6 9.4 100.4 6 20.3
77.5 6 8.9 77.2 6 17.5
99.7 6 23.9 85.9 6 24.5
117.8 6 7.9 100.7 6 16.5
113.0 6 9.4 97.0 6 16.1
106.5 6 18.0 89.6 6 19.4
92.0 6 36.8 94.4 6 24.0
Values are means 6 SD. Venous blood was sampled 1 day before surgery, within 3 h after surgery, and on postoperative days 2, 7, 14, 21, and 28. With PE (n 5 4); without PE (n 5 13)
T. Kubo et al.: Fibrin monomer as a predictor of pulmonary embolism
121
Table 4. Changes in activated partial thromboplastin time(s) (aPTT) after total hip arthroplasty (sec) Postoperative days
With PE Without PE
Before surgery
Immediately after surgery
2
7
14
21
28
36.4 6 5.9 47.3 6 42.1
65.4 6 31.9 72.0 6 56.0
38.8 6 2.2 39.4 6 6.5
35.5 6 4.8 35.9 6 4.9
73.2 6 71.0 36.2 6 3.5
77.3 6 71.9 52.5 6 40.8
40.1 6 0.6 36.7 6 1.7
Values are means 6 SD. Venous blood was sampled 1 day before surgery, within 3 h after surgery, and on postoperative days 2, 7, 14, 21, and 28. With PE (n 5 4); without PE (n 5 13)
Table 5. Changes in thrombin-AT III complex (TAT) after total hip arthroplasty (µg/l) Postoperative days
With PE Without PE
Before surgery
Immediately after surgery
2
7
14
21
28
6.4 6 8.9 10.6 6 17.5
60.0 6 0.0 47.7 6 16.5
24.9 6 8.8 23.6 6 19.1
14.8 6 7.5 19.6 6 21.8
13.4 6 5.2 9.3 6 5.0
21.5 6 25.8 19.4 6 25.2
4.9 6 1.1 20.1 6 16.8
Values are means 6 SD. Venous blood was sampled 1 day before surgery, within 3 h after surgery, and on postoperative days 2, 7, 14, 21, and 28. With PE (n 5 4); without PE (n 5 13)
Table 6. Changes in D-dimer after total hip arthroplasty (µg/ml) Postoperative days
With PE Without PE
Before surgery
Immediately after surgery
2
7
14
21
28
1.2 6 0.8 3.9 6 6.5
31.4 6 3.3 20.8 6 13.3
14.8 6 14.9 6.0 6 5.5
27.7 6 14.3* 12.3 6 10.6*
20.6 6 8.2 13.0 6 10.2
13.9 6 8.2 7.5 6 3.5
8.9 6 0.6 11.9 6 8.1
* P , 0.05 Values are means 6 SD. Venous blood was sampled 1 day before surgery, within 3 h after surgery, and on postoperative days 2, 7, 14, 21, and 28. With PE (n 5 4); without PE (n 5 13)
Table 7. Changes in fibrin monomer (FM) after total hip arthroplasty (µg/ml) Postoperative days
With PE Without PE
Before surgery
Immediately after surgery
2
7
14
21
28
6.0 6 11.4 10.6 6 16.1
46.9 6 11.6* 21.7 6 14.6*
18.1 6 14.8* 2.7 6 1.2*
22.2 6 30.3 12.8 6 16.0
20.6 6 21.7 9.0 6 10.8
25.8 6 28.2 6.1 6 4.8
5.5 6 3.7 9.8 6 15.6
* P , 0.05 Values are means 6 SD. Venous blood was sampled 1 day before surgery, within 3 h after surgery, and on postoperative days 2, 7, 14, 21, and 28. With PE (n 5 4); without PE (n 5 13)
between the patients with and without PE immediately after surgery and 2 days after surgery (P , 0.05). FM in the patients with PE reached 40 µg/ml or higher, whereas FM did not reach 40 µg/ml in 11 of the 13 patients without PE during the 2 days after surgery.
Discussion The activation of the coagulation system immediately after surgery could be attributable to surgical manipulation. A cause of PE following DVT after THA is thought to be the increased thrombophilia due to the
influx of tissue factor (TF) into the blood stream.2 Because of the surgical invasion for hip arthroplasty, TF and cell fragments are released into the venous blood, and this could, first, cause thrombosis in capillary vessels of the lung, and then induce PE. The values for PT, APTT, AT III, and TAT did not differ significantly between patients with and without PE. Therefore, these factors were concluded to be inapplicable in the diagnosis of PE. The usefulness of fibrin and its metabolites in the evaluation of acute and chronic hypercoagulable states was recently reported.3 D-dimer, which has been monitored as an indicator of the cleavage products of fibrin,
122
T. Kubo et al.: Fibrin monomer as a predictor of pulmonary embolism
has been used in the diagnosis of disseminated intravascular coagulation, and D-dimer with an enzyme immunoassay was reported to be useful in the diagnosis of DVT.8,14 In the present study, the D-dimer value immediately after surgery increased significantly in all patients, but a significant difference between patients with and without PE was observed only 7 days after surgery. This indicates that the D-dimer level in patients at a very early stage of DVT or PE would not be useful for the prediction of PE,15 and this also suggests the necessity to develop more sensitive measurement techniques or to find another suitable factor for the detection of a hypercoagulable state at the very early stage. Fibrin is produced as a result of the interaction between thrombin or thrombin-like protease and fibrinogen.7 FM is a component of soluble fibrin, and it is produced when thrombin sequentially cleaves fibrinopeptide A and B from the aminoterminals of Aα- and Bβ-chains of fibrinogen, respectively.1 In the current study, we prepared a new FM-specific antibody and utilized it with a latex coagulation method.5 As a result, FM was found to be the factor which related significantly to PE. FM increased sharply after surgery and was significantly different between the patients with and without PE immediately after surgery and 2 days after surgery (P , 0.05). Vogel et al.12 conducted blood coagulation tests and venography of the legs in 156 patients whose bone fractures were treated surgically, and they reported increased FM levels in 34 of 36 patients (94%) with DVT and in 31 of 120 patients (26%) without DVT. They also examined 129 patients who had had abdominal surgery,12 and found that 12 of them developed DVT after surgery. They conducted blood coagulation tests in these 12 patients, and found that FM was most closely related to the occurrence of DVT, i.e., positivity was 91.7% for FM, 75.0% for D-dimer, and 41.7% for TAT. In addition, the FM level increased sharply from 1 day prior to the appearance of clinical symptoms of DVT in all the FM-positive patients.13 Our findings, together with those of previous studies, show that FM would be a useful predictive factor for PE, and it could indicate a high risk for DVT and PE. With our FM measurement method, FM levels of 40 µg/ ml or higher could represent a high-risk condition, although this point should be confirmed in a larger number of patients. These high-risk patients should be
monitored carefully with other examinations, such as ultrasonography, for the legs, and should receive prophylaxis for thrombosis. Acknowledgments. This study was supported by the fund of the Ministry of Health and Welfare.
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