The Journal of Arthroplasty Vol. 27 No.

1 2012

Risk of Deep Venous Thrombosis in Drain

Clamping With Tranexamic Acid and
Carbazochrome Sodium Sulfonate Hydrate in
Total Knee Arthroplasty
Tomohiro Onodera, MD, PhD,* Tokifumi Majima, MD, PhD,y
Naohiro Sawaguchi, MD, PhD,* Yasuhiko Kasahara, MD, PhD,*
Takayuki Ishigaki, MD,* and Akio Minami, MD, PhD*

Abstract: The aim of this randomized prospective study was to clarify risks associated with a
drain-clamping method using tranexamic acid and carbazochrome sodium sulfonate hydrate after
total knee arthroplasty (TKA). Subjects comprised 100 patients scheduled to undergo TKA,
randomized into 2 groups: 50 patients received the drain-clamping method using tranexamic acid
and carbazochrome sodium sulfonate hydrate and 50 patients received drain-clamping with saline.
Although bleeding volume was significantly lower in the group with tranexamic acid and
carbazochrome sodium sulfonate hydrate, risk of asymptomatic deep venous thrombosis as
detected by ultrasonography was comparable between groups. Tranexamic acid and carbazo-
chrome sodium sulfonate hydrate in the drain-clamping method help reduce bleeding after TKA
without increasing the risk of deep venous thrombosis. Keywords: total knee arthroplasty, deep
venous thrombosis, drain-clamping method, tranexamic acid.
© 2012 Elsevier Inc. All rights reserved.

Patients undergoing total knee arthroplasty (TKA) have
a risk of substantial bleeding for which blood transfusion
might be necessary. Various methods have been
reported to reduce blood loss after TKA such as
hypotensive anesthesia [1], fibrin tissue adhesive [2,3],
compression bandaging and cryotherapy [4], and drain
clamping [5-8].
A recent meta-analysis demonstrated no major benefit
to the routine use of a drain after TKA [9]. A minor
advantage associated with drain use is a reduction in
early bloody wound drainage and extremity bruising
[10-12]. A disadvantage to drain use is an increase in the
total blood loss.
In an attempt to reduce the blood loss associated with
drain use, drain clamping has been reported [7]. Further-
From the *Department of Orthopaedic Surgery, Hokkaido University
Graduate School of Medicine, Sapporo, Japan; and yDepartment of Joint
Replacement and Tissue Engineering, Hokkaido University Graduate School of
Medicine, Sapporo, Japan.
Submitted August 26, 2010; accepted February 7, 2011.
The Conflict of Interest statement associated with this article can be
found at doi:10.1016/j.arth.2011.02.004.
Reprint requests: Tokifumi Majima, MD, PhD, Department of Joint
Replacement and Tissue Engineering, Hokkaido University Graduate
School of Medicine, North 15 West 7, Kita–Ku, Sapporo 060–8638, Japan.
© 2012 Elsevier Inc. All rights reserved.
0883-5403/2701-0017$36.00/0
doi:10.1016/j.arth.2011.02.004
more, drain-clamping techniques has been modified to
include the use of adrenaline [6,8,13] and tranexamic acid
[14]. Both methods have been reported to decrease blood
loss after TKA.
Tranexamic acid is an antifibrinolytic agent that is
administered to enhance hemostasis. Although a recent
systematic review showed no difference in deep
venous thrombosis (DVT) rates when using tranexamic
acid after TKA [15], intravenous tranexamic acid has
been associated with an increased risk of DVT in
patients with other bleeding diseases such as menor-
rhagia [16], suggesting that the use of intravenous
tranexamic acid has the potential to increase the risk of
DVT after TKA. However, little is known about the risk
of asymptomatic DVT development during drain clamp-
ing with/without tranexamic acid. The aim of the
present study was to determine the risk of asymptomatic
DVT in the drain-clamping method using tranexamic
acid after TKA.
Methods
Subjects comprised 100 consecutive patients who were
scheduled to undergo primary TKA between 2006 and
2009. In the tranexamic acid group, 50 mL of saline
containing 50 mg of carbazochrome sodium sulfonate
hydrate for increasing capillary resistance [17] and 1 g of
tranexamic acid was injected immediately after wound

105
106 The Journal of Arthroplasty Vol. 27 No. 1 January 2012

Table 1. Patient Demographics operations were performed by a single surgeon (T.M.).

Variables Group T
TKAs n = 50
Age (y) 70.4 ± 10.1
Sex (Female/Male) 42/8
Diagnosis (OA/others) 34/16
BMI (kg/m2) 25.3 ± 4.6
Operation time (min) 117.0 ± 41.5
OA indicates osteoarthritis; BMI, body mass index, defined as the
weight in kilograms divided by the square of the height in meters.
closure through a 3.2-mm diameter drain (group T). In
the saline group, 50 mL of saline was applied for drain
clamping (group N). To prevent infection, 200 mg of
antibiotic (amikacin sulfate) was mixed into both
solutions. This tube was clamped and closed completely
for 60 minutes, then the clamp was released. Patients
were randomly assigned to the 2 groups using a random
number list. Before the start of this randomized study, all
study protocols were approved by the institutional
review board at the Hokkaido University School of
Medicine. No autologous blood was used in any patient.
This study focused on blood loss and the risk of
asymptomatic DVT development between a group
using drainage clamping with tranexamic acid and a
group using drainage clamping with saline. Bilateral
ultrasonography of the lower extremities (LOGIQ E9;
General Electric Company, CT) was performed preop-
eratively and 10 days postoperatively. Ultrasonography
was scheduled preoperatively and for 10 days postoper-
atively. Proximal DVT was defined as the thrombosis of
the popliteal, femoral, deep femoral, common femoral
and iliac veins and of the inferior vena cava. Distal DVT
was defined as thrombosis in any of the following veins:
anterior and posterior tibial, peroneal, gastrocnemial,
and soleal veins. Patients showing DVT preoperatively
were excluded, as were those with known coagulation
disorders, abnormal coagulation test values, or receiving
anticoagulation medication.
Under general anesthesia, the air tourniquet was
inflated to 280 mm Hg in all cases during surgery.
Total knee arthroplasty was performed through a
midline skin incision with a subvastus approach using
the same TKA in all patients. In all cases, a computed
tomography–guided navigation system (Vector Vision;
Brain LAB, Heimstetten, Germany) was used, and all
Group N All surgeries were performed with a single air tourni-
n = 50 quet, and the bone cement and cementing technique
70.5 ± 8.3 were identical in all cases. The same external 3.2-mm
41/9 diameter drain and closed suction drainage system were
39/11
used. A single drain was placed subfascially and pulled
25.9 ± 5.1
111.2 ± 21.3 through the skin laterally/proximally. Drains were
removed when the amount of drained blood in 24
hours was less than 50 mL. After drain removal,
continuous passive motion was initiated. To prevent
DVT, an arteriovenous impulse system (Venostream;
Terumo, Tokyo, Japan) and elastic compression stock-
ings were used in all patients.
Data are represented as mean ± SD. Significant
differences among groups were assessed using 2-tailed
Student t tests. All differences were considered signifi-
cant at a probability level of 95% (P b .05).
Results
During the 2-year period, we prospectively analyzed
100 consecutive patients who underwent cemented
TKA at our hospital. Demographic data for patients
are shown in Table 1. The 2 groups of patients were
well-matched, showing no significant differences
between groups.
The mean postoperative volume of drained blood was
380.4 ± 271.2 mL in the tranexamic acid and
carbazochrome sodium sulfonate hydrate group and
676.4 ± 306.2 mL in the saline group (P b .05) (Table 2).
Mean postoperative reduction of hemoglobin level was
2.20 ± 1.11 g/dL in the tranexamic acid and carbazo-
chrome sodium sulfonate hydrate group and 3.11 ±
1.26 g/dL in the saline group (P b .05). Allogeneic blood
transfusion was required for 2 patients (4%) in the
tranexamic acid and carbazochrome sodium sulfonate
hydrate group and 1 patient (2%) in the saline acid
group (P = .56). Mean duration of drainage was 3.36 ±
1.16 days in the tranexamic acid and carbazochrome
sodium sulfonate hydrate group and 3.24 ± 0.82 days in
the saline group (P = .55).
Preoperative and postoperative D-dimer levels and
frequency of DVT are shown in Table 3. Mean
preoperative/postoperative level of D-dimer was 1.68 ±
2.35 μg/mL per 8.41 ± 7.60 μg/mL in the tranexamic
acid and carbazochrome sodium sulfonate hydrate
group and 1.97 ± 3.08 μg/mL per 8.17 ± 6.86 μg/mL
in the saline group (P = .87). Proximal DVT occurred in

Table 2. Postoperative Blood Loss

Group T Group N P Table 3. Preoperative and Postoperative D-dimer Levels and
Frequency of DVT
Total blood loss (mL) 380.4 ± 271.2 676.4 ± 306.2 b.05
Reduction in hemoglobin 2.20 ± 1.11 3.11 ± 1.26 b.05 Group T Group N P
level (g/dL) Preoperative D-dimer 1.68 ± 2.35 1.97 ± 3.08 NS
Nontransfused/total 48/50 (96%) 49/50 (98%) NS Induction in D-dimer 8.41 ± 7.60 8.17 ± 6.86 NS
Drainage period 3.36 ± 1.16 3.24 ± 0.82 NS Proximal DVT/total 2/50 (4%) 1/50 (2%) NS
NS indicates not significant. Distal DVT/total 20/50 (40%) 22/50 (44%) NS
 Risk of DVT in Drain Clamping in TKA  Onodera et al
2 patients (4%) in the tranexamic acid and carbazo-
chrome sodium sulfonate hydrate group and 1 patient
(2%) in the saline group (P = .56). Distal DVT occurred
for 20 patients (40%) in the tranexamic acid and
carbazochrome sodium sulfonate hydrate group and 22
patients (44%) in the saline acid group (P = .69). No
cases of symptomatic DVT or pulmonary embolism
were encountered.
Discussion
Antifibrinolytic agents such as tranexamic acid
potentially reduce blood loss and the need for
transfusion. Tranexamic acid is a synthetic amino
acid derivative that binds reversibly to plasminogen,
inhibiting binding to fibrin and activation to plasmin
[18,19]. Although a recent literature review showed
no increase in the risk of DVT when using intravenous
tranexamic acid [15,20], many studies have evaluated
only symptomatic DVT. The number of asymptomatic
DVT events and DVT markers (such as D-dimer levels)
needs to be evaluated as well. In addition, intravenous
tranexamic acid has been associated with an increased
risk of DVT in patients with other bleeding diseases
[16], suggesting that the use of intravenous tranexa-
mic acid may increase the risk of DVT after TKA.
Intra-articular administration of tranexamic acid po-
tentially decreases the risk of DVT compared with
intravenous injection.
This study demonstrated that the volume of blood loss
after TKA surgery using the drain-clamping method
with tranexamic acid and carbazochrome sodium
sulfonate hydrate was significantly reduced compared
with using saline solution. However, the incidence of
asymptomatic DVT did not increase when using tra-
nexamic acid and carbazochrome sodium sulfonate
hydrate. Despite the statistically significant reduction in
the postoperative blood loss using this technique, there
was no difference in the need for allogeneic blood
between groups. To the best of our knowledge, this
represents the first report to evaluate the risk of
asymptomatic DVT using tranexamic acid and carbazo-
chrome sodium sulfonate hydrate.
This study has some limitations. First, the patient
cohort was small. Although this study was a
prospective, randomized study, further investigation
is required to clarify the risk of DVT in the drain-
clamping method with tranexamic acid and carbazo-
chrome sodium sulfonate hydrate. Second, the diag-
nostic accuracy of ultrasonography is not optimal.
Although compression ultrasonography has largely
replaced venography to diagnose DVT in the lower
extremity, contrast venography remains the diagnostic
reference standard.
In conclusion, the present study showed that using
tranexamic acid and carbazochrome sodium sulfonate
hydrate with the drain-clamping method significantly
107
decreases blood loss after TKA without increasing the
risk of asymptomatic DVT.
Acknowledgment
We would like to thank Mutsumi Nishida and her
team in the Diagnostic Center for Sonography at
Hokkaido University Hospital for their efforts and
contributions in data acquisition.
References
1. Juelsgaard P, Larsen UT, Sorensen JV, et al. Hypotensive
epidural anesthesia in total knee replacement without
tourniquet: reduced blood loss and transfusion. Reg
Anesth Pain Med 2001;26:105.
2. Levy O, Martinowitz U, Oran A, et al. The use of fibrin
tissue adhesive to reduce blood loss and the need for blood
transfusion after total knee arthroplasty. A prospective,
randomized, multicenter study. J Bone Joint Surg Am
1999;81:1580.
3. Wang GJ, Hungerford DS, Savory CG, et al. Use of
fibrin sealant to reduce bloody drainage and hemoglo-
bin loss after total knee arthroplasty: a brief note on a
randomized prospective trial. J Bone Joint Surg Am
2001;83-A:1503.
4. Gibbons CE, Solan MC, Ricketts DM, et al. Cryotherapy
compared with Robert Jones bandage after total knee
replacement: a prospective randomized trial. Int Orthop
2001;25:250.
5. Kiely N, Hockings M, Gambhir A. Does temporary
clamping of drains following knee arthroplasty reduce
blood loss? A randomised controlled trial. Knee 2001;
8:325.
6. Ryu J, Sakamoto A, Honda T, et al. The postoperative
drain-clamping method for hemostasis in total knee
arthroplasty. Reducing postoperative bleeding in total
knee arthroplasty. Bull Hosp Jt Dis 1997;56:251.
7. Sakihara H. A method to control postoperative
bleeding after total knee replacement. Seikeisaigaigeka
1988;31:543.
8. Yamada K, Imaizumi T, Uemura M, et al. Comparison
between 1-hour and 24-hour drain clamping using diluted
epinephrine solution after total knee arthroplasty. J
Arthroplasty 2001;16:458.
9. Parker MJ, Roberts CP, Hay D. Closed suction drainage for
hip and knee arthroplasty. A meta-analysis. J Bone Joint
Surg Am 2004;86-A:1146.
10. Holt BT, Parks NL, Engh GA, et al. Comparison of closed-
suction drainage and no drainage after primary total knee
arthroplasty. Orthopedics 1997;20:1121.
11. Kim YH, Cho SH, Kim RS. Drainage versus nondrainage in
simultaneous bilateral total hip arthroplasties. J Arthro-
plasty 1998;13:156.
12. Kim YH, Cho SH, Kim RS. Drainage versus nondrainage in
simultaneous bilateral total knee arthroplasties. Clin
Orthop Relat Res 1998;188.
13. Tsumara N, Yoshiya S, Chin T, et al. A prospective
comparison of clamping the drain or post-operative
salvage of blood in reducing blood loss after total knee
arthroplasty. J Bone Joint Surg Br 2006;88:49.
108 The Journal of Arthroplasty Vol. 27 No. 1 January 2012
14. Akizuki S, Yasukawa Y, Takizawa T. A new method of
hemostasis for cementless total knee arthroplasty. Bull
Hosp Jt Dis 1997;56:222.
15. Kagoma YK, Crowther MA, Douketis J, et al. Use of
antifibrinolytic therapy to reduce transfusion in patients
undergoing orthopedic surgery: a systematic review of
randomized trials. Thromb Res 2009;123:687.
16. Sundstrom A, Seaman H, Kieler H, et al. The risk of venous
thromboembolism associated with the use of tranexamic
acid and other drugs used to treat menorrhagia: a case-
control study using the General Practice Research Data-
base. BJOG 2009;116:91.
17. Matsumoto Y, Hayashi T, Hayakawa Y, et al. Carbazo-
chrome sodium sulphonate (AC-17) decreases the accu-
mulation of tissue-type plasminogen activator in culture
medium of human umbilical vein endothelial cells. Blood
Coagul Fibrinolysis 1995;6:233.
18. Mannucci PM. Hemostatic drugs. N Engl J Med 1998;339:
245.
19. Prentice CR. Basis of antifibrinolytic therapy. J Clin Pathol
Suppl (R Coll Pathol) 1980;14:35.
20. Zufferey P, Merquiol F, Laporte S, et al. Do antifibrinolytics
reduce allogeneic blood transfusion in orthopedic surgery?
Anesthesiology 2006;105:1034.