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C OPYRIGHT
2018 BY T HE J OURNAL OF B ONE AND J OINT S URGERY, I NCORPORATED

A commentary by Joshua M. Pahys, MD, is

linked to the online version of this article at
jbjs.org.

Effect of Tranexamic Acid on Blood Loss,

D-Dimer, and Fibrinogen Kinetics in Adult
Spinal Deformity Surgery
Ryan P. Pong, MD, Jean-Christophe A. Leveque, MD, Alicia Edwards, MBA, Vijay Yanamadala, MD, Anna K. Wright, PhD,
Megan Herodes, BS, CSP, and Rajiv K. Sethi, MD

Investigation performed at Virginia Mason Medical Center, Seattle, Washington

Background: Antifibrinolytics such as tranexamic acid reduce operative blood loss and blood product transfusion re-
quirements in patients undergoing surgical correction of scoliosis. The factors involved in the unrelenting coagulopathy
seen in scoliosis surgery are not well understood. One potential contributor is activation of the fibrinolytic system during a
surgical procedure, likely related to clot dissolution and consumption of fibrinogen. The addition of tranexamic acid
during a surgical procedure may mitigate the coagulopathy by impeding the derangement in D-dimer and fibrinogen
kinetics.
Methods: We retrospectively studied consecutive patients who had undergone surgical correction of adult spinal de-
formity between January 2010 and July 2016 at our institution. Intraoperative hemostatic data, surgical time, estimated
blood loss, and transfusion records were analyzed for patients before and after the addition of tranexamic acid to our
protocol. Each patient who received tranexamic acid and met inclusion criteria was cohort-matched with a patient who
underwent a surgical procedure without tranexamic acid administration.
Results: There were 17 patients in the tranexamic acid cohort, with a mean age of 60.7 years, and 17 patients in the
control cohort, with a mean age of 60.9 years. Estimated blood loss (932 ± 539 mL compared with 1,800 ± 1,029 mL; p =
0.005) and packed red blood-cell transfusions (1.5 ± 1.6 units compared with 4.0 ± 2.1 units; p = 0.001) were
significantly lower in the tranexamic acid cohort. In all single-stage surgical procedures that met inclusion criteria, the rise
of D-dimer was attenuated from 8.3 ± 5.0 mg/mL in the control cohort to 3.3 ± 3.2 mg/mL for the tranexamic acid cohort
(p < 0.001). The consumption of fibrinogen was 98.4 ± 42.6 mg/dL in the control cohort but was reduced in the
tranexamic acid cohort to 60.6 ± 35.1 mg/dL (p = 0.004).
Conclusions: In patients undergoing spinal surgery, intravenous administration of tranexamic acid is effective at re-
ducing intraoperative blood loss. Monitoring of D-dimer and fibrinogen during spinal surgery suggests that tranexamic acid
impedes the fibrinolytic pathway by decreasing consumption of fibrinogen and clot dissolution as evidenced by the
reduced formation of D-dimer.
Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

C
omplications in adult spinal deformity surgery range as
high as 80% in some series1-6, and intraoperative blood
loss remains one of the largest contributing factors. The
surgical literature contains several reports that document blood
loss exceeding a patient’s baseline total estimated blood volume
sustained during a corrective spinal fusion for idiopathic sco-
liosis7-12, and, more recently, with adult spinal deformity as
well13,14, particularly with the use of pedicle subtraction oste-
otomy. In 1 large series, 10.2% of intraoperative adverse events
occurred in cases in which estimated blood loss exceeded 5 L13.

Disclosure: There was no source of external funding for this study. The Disclosure of Potential Conflicts of Interest forms are provided with the online
version of the article (http://links.lww.com/JBJS/E657).

J Bone Joint Surg Am. 2018;100:758-64 d http://dx.doi.org/10.2106/JBJS.17.00860

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Numerous studies have examined perioperative blood loss
associated with adult spinal deformity surgery and have dem-
onstrated the mitigating effects of blood transfusion on the
lower-than-normal perioperative limits of hemoglobin and
hematocrit1,3,7,9-11,14. Furthermore, efforts at reducing perioper-
ative blood loss and transfusion requirements have led to in-
corporation of multiple blood conservation strategies,
including an intraoperative blood cell salvage system, antifi-
brinolytic agents, and recombinant factor VIIa15-17.
Antifibrinolytic agents such as e-aminocaproic acid and
tranexamic acid have been used to reduce hemorrhage following
severe trauma and in surgical procedures in which blood loss is
expected to be high18-23. The use of tranexamic acid in the context
of orthopaedic and cardiac surgery has been extensively studied
with multiple prospective randomized controlled trials as well
as a recently published meta-analysis24-38. For patients undergoing
total knee arthroplasty, tranexamic acid administration reduced
intraoperative blood loss by >50% and the number of patients
requiring blood transfusions by two-thirds. In a systematic review
on the use of tranexamic acid in spine surgery, Winter et al.
demonstrated a similar effect as a hemostatic agent39.
Antifibrinolytic agents decrease blood loss by inhibiting
the ability of plasmin to break down fibrin, thereby acting to
decrease clot dissolution40. Products of clot dissolution include
D-dimer, and, despite widespread use of intravenous tranexa-
mic acid in many types of surgery, its effect on D-dimer gen-
eration in the surgical patient has not been investigated. In a
recent study, Bosch et al. reported on the coagulation profiles of
patients with adolescent idiopathic scoliosis undergoing pos-
terior spinal fusion41. The point-of-care hourly testing utilized
in their study indicated a correlation among higher blood loss,
increased length of the surgical procedure, and higher rates of
consumptive coagulopathy as evidenced by the increase in the
disseminated intravascular coagulation (DIC) score, which
included a dichotomous measure of D-dimer.
Most efforts at reducing intraoperative blood loss during
adult spinal deformity surgery have focused on formation of the
clot, ensuring that adequate levels of clotting factors are available
(plasma and cryoprecipitate transfusions); only recently, with
the addition of antifibrinolytics, has the dissolution of the clot
been a target of therapy. Although antifibrinolytic use has gained
momentum and is becoming common, very little quantifiable
data exist to demonstrate the mechanism by which antifibri-
nolytics promote reduced blood loss. The kinetics of fibrinolysis
and the effect that tranexamic acid has on the process remain to
be characterized, and the utility of serial and routine measure-
ments of D-dimer has not been evaluated. To better understand
clot dissolution and fibrinolysis, we performed a retrospective
study of our complex spine population focusing our attention on
markers of clot dissolution, D-dimer, consumption of substrate
to make a clot, and fibrinogen.
Materials and Methods
T his retrospective study was approved by our institutional
review board and granted a waiver of informed consent.
T R A N E X A M I C A C I D E F F E C T O N B L O O D L O S S , D-D I M E R , AND
F I B R I N O G E N I N S P I N A L D E F O R M I T Y S U R G E RY
Patient Inclusion
All patients undergoing multilevel complex spinal fusions be-
tween January 2010 and July 2016 were reviewed for study
inclusion. Cases were excluded from the study cohort if they
had <6 levels of fusion, were undergoing fusion of the cervical
spine, required fusion for cases of trauma or malignancy, had
<2 intraoperative measurements of fibrinogen or D-dimer, or
were staged (Fig. 1).
Data Collection
All clinical information was abstracted from our electronic
medical records. Data collected include sex, age, body mass
index (BMI), American Society of Anesthesiologists (ASA)
score, hematological parameters, operative times, estimated
blood loss, transfusion records, surgical staging, pedicle sub-
traction osteotomy, 30-day complications, and postoperative
length of stay for each case.
Anesthesia Protocol for Adult Spinal Deformity Surgery
Since 2010, our group has utilized and previously reported on a
standardized perioperative protocol for adult spinal deformity
surgery42. In brief, our protocol includes a robust multidisci-
plinary preoperative assessment, the use of 2 attending spine
surgeons, and a standardized approach to intraoperative anes-
thesia and patient assessment. Baseline laboratory measures,
including prothrombin time, international normalized ratio
(INR), hematocrit, platelet count, arterial blood gas, fibrinogen,
and D-dimer, are taken immediately after induction of anes-
thesia and every hour thereafter. After laboratory results are
reported, a brief pause and team huddle occur between the
anesthesiologists and spine surgeons to discuss the current
physiologic state of the patient and to make the decision to
proceed as planned or to stage the procedure. The estimation of
blood loss is part of our intraoperative protocol, which initially
relies on adding the suction canister totals and adding the esti-
mates from the lap sponges. After the Cell Saver (Haemonetics)
Fig. 1
Study cohort diagram. TXA = tranexamic acid.
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TABLE I Patient Characteristics for Single-Stage Adult Deformity Surgery with and without Tranexamic Acid

Cohort without Tranexamic Acid Cohort with Tranexamic Acid P Value

No. of patients* 57 18
Male sex* 10 (17.5%) 3 (16.7%) >0.99
Age† (yr) 64.0 ± 13 61.4 ± 15 0.52
Surgical time† (min) 365 ± 60 363 ± 64 0.81
No. of levels fused† 8.9 ± 2.2 11 ± 3.2 0.002
Pedicle subtraction osteotomy* 3 5
Length of stay† (days) 7.6 ± 4.6 8.4 ± 5.1 0.51
BMI† (kg/m2) 27.9 ± 5.3 27.5 ± 6.5 0.76
Deep vein thrombosis or pulmonary embolism* 3 1 >0.99
ASA score† 2.5 ± 0.5 2.3 ± 0.7 0.17

*The values are given as the number of patients, with or without the percentage in parentheses. †The values are given as the mean and the
standard deviation.

is utilized, the estimated blood loss from the Cell Saver was
calculated as previously described43. In April 2015, our team
added intraoperative tranexamic acid to our standardized pro-
tocol, with a bolus preoperative dose of 10 mg/kg followed by an
intraoperative infusion at a rate of 1 mg/kg/hr.
Statistical Analysis
All variables were reported as the mean and the standard
deviation, and univariate analysis was performed using the
Wilcoxon rank-sum test, with significance defined as p £ 0.05.
To account for confounding variables, we statistically matched
patients who received tranexamic acid during a single-stage
adult spinal deformity surgical procedure with those who
underwent this procedure without tranexamic acid adminis-
tration. Cohort matching was based on the following clinically
relevant confounders: number of spine levels fused (within 3
levels), BMI (within 5 kg/m2 on the BMI scale), and age (within
5 years) at the time of procedure. Comparisons of the resultant
estimated blood loss, units of packed red blood cells transfused,
and units of thawed plasma transfused were performed using
case-control matching and the paired t test for continuous
variables, and significance was set at p £ 0.05. The time course
of the change in hematological parameters was plotted for all
eligible cases before and after administration of tranexamic
acid. Both STATA/IC version 13.1 for Windows (StataCorp)
and SPSS Statistics 23 (IBM) were used for statistical analysis.

TABLE II Cohort-Matched Transfusion Data for Single-Stage Adult Deformity Surgery with and without Tranexamic Acid

Cohort without Tranexamic Acid Cohort with Tranexamic Acid P Value

No. of patients 17 17
Male sex* 1 (5.9%) 3 (17.7%) 0.601
Age† (yr) 60.9 ± 14.1 60.7 ± 15.7 0.840
Surgical time† (min) 376.7 ± 56.8 363.8 ± 67.3 0.487
No. of levels fused† 10.5 ± 3.0 10.8 ± 3.2 0.111
Pedicle subtraction osteotomy* 0 4
Length of stay† (days) 8.2 ± 6.0 8.2 ± 5.1 0.973
BMI† (kg/m2) 30.2 ± 4.4 27.8 ± 6.5 0.058
ASA score† 2.4 ± 0.5 2.3 ± 0.7 0.496
Estimated blood loss† (mL) 1,800.0 ± 1,029.3 932.35 ± 539.4 0.005
Packed red blood cells† (units) 4.00 ± 2.1 1.53 ± 1.6 0.001
Thawed plasma† (units) 3.71 ± 2.1 1.41 ± 1.8 0.001

*The values are given as the number of patients, with or without the percentage in parentheses. †The values are given as the mean and the
standard deviation.
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Fig. 2 Fig. 3
Fig. 2 Kinetics of platelets during the surgical course of a single-stage procedure without and with tranexamic acid (TXA). Error bars indicate the standard
error. Fig. 3 Kinetics of fibrinogen during the surgical course of a single-stage procedure without and with tranexamic acid (TXA). Error bars indicate the
standard error.

Results
O f 312 consecutive surgical procedures screened, 237 pa-
tients were excluded on the basis of our inclusion criteria,
allowing 75 surgical procedures for final analysis (Fig. 1). These
were completed in a single stage, with 18 patients (24%) receiving
tranexamic acid and the remaining 57 (76%) undergoing a sur-
gical procedure without tranexamic acid administration. Patient
characteristics for all eligible cases are presented in Table I. In all
single-stage surgical procedures, no significant differences were
seen in age, sex, or surgical time when comparing patients with
and without intravenous tranexamic acid.
To account for clinically relevant confounding variables,
17 patients (14 female patients and 3 male patients) who un-
derwent single-stage adult spinal deformity surgery were
matched with 17 patients who underwent this procedure with-
out tranexamic acid (16 female patients and 1 male patient)
(Table II). The control cohort, compared with the study cohort,
had a similar number of levels of fusion (10.5 ± 3.0 compared
with 10.8 ± 3.2 levels), surgical time (376.7 ± 56.8 compared
with 363.8 ± 67.3 minutes), and age (60.9 ± 14.1 compared with
60.7 ± 15.7 years). The addition of tranexamic acid decreased the
total estimated blood loss from 1,800 ± 1,029 mL in the control
cohort to 932 ± 539 mL in the tranexamic acid cohort (p =
0.005). The reduction in estimated blood loss was mirrored by a
reduction in blood component transfusion, as the packed red
blood-cell transfusions were 4.0 ± 2.1 units of blood in the
control cohort and 1.5 ± 1.6 units of blood in the tranexamic
acid cohort (p = 0.001). Thawed plasma transfusion saw a
similar reduction, with 3.7 ± 2.1 units in the control cohort and
1.4 ± 1.8 units in the tranexamic acid cohort (p = 0.001) (Table
II). These results further validated our initial findings presented
in Table I.
Hemostatic parameters were monitored during the sur-
gical procedure. However, for 46 patients, hemostatic param-
eters were not captured because of shorter surgical time. Patient
characteristics for this group can be seen in the Appendix.
Measures of the INR to evaluate for coagulopathy showed
no difference with and without tranexamic acid administration,
with an INR at incision of 1.1 ± 0.08 in the tranexamic acid cohort
compared with 1.1 ± 0.06 (p = 0.7) in the control cohort and an

TABLE III Hemostatic Parameters During a Single-Stage Surgical Procedure with and without Tranexamic Acid*

Cohort without Tranexamic Acid Cohort with Tranexamic Acid P Value

Increase in D-dimer (mg/mL) 8.3 ± 5.0 3.3 ± 3.2 <0.001

D-dimer maximal hourly increase 340% ± 280% 113% ± 54% <0.001
Time of D-dimer maximal hourly increase (minutes after incision) 187 ± 71 257 ± 81 <0.001
Decrease in fibrinogen (mg/dL) 98.4 ± 42.6 60.6 ± 35.1 0.004
Decrease in platelets (·103/mL) 75.4 ± 59.4 41.2 ± 80.2 0.146
Increase in INR 0.20 ± 0.09 0.18 ± 0.19 0.242

*The values are given as the mean and the standard deviation.
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Fig. 4
Kinetics of D-dimer during the surgical course of a single-stage procedure
without and with tranexamic acid (TXA). Error bars indicate the standard
error.
INR after closure of 1.3 ± 0.1 in the tranexamic acid cohort
compared with 1.3 ± 0.2 (p = 0.3) in the control cohort. The effect
of intravenous tranexamic acid on the substrates of clot formation
was evaluated by comparing the kinetics of platelets and fibrin-
ogen (Figs. 2 and 3). Those patients who underwent a surgical
procedure without the tranexamic acid protocol had a mean
decrease in platelet count of 75 ± 59 · 103/mL compared with a
decrease in platelet count of 41 ± 80 · 103/mL in those who had
tranexamic acid as part of their intraoperative management
(p = 0.15). Fibrinogen levels decreased 98 ± 43 mg/dL in the
group without tranexamic acid and that reduction was atten-
uated to 61 ± 35 mg/dL in the group with tranexamic acid (p =
0.004) (Table III).
To evaluate clot dissolution during the surgical proce-
dures, we studied D-dimer kinetics (Fig. 4). The absolute in-
crease in D-dimer went from 8.3 ± 5.0 mg/mL without the
tranexamic acid protocol to 3.3 ± 3.2 mg/mL in the group with
tranexamic acid (p < 0.001). The time at which the maximal
increase in D-dimer occurred was delayed by intravenous tra-
nexamic acid administration from 187 ± 71 to 257 ± 81 min-
utes after incision (p < 0.001). The maximal percentage
increase in D-dimer also was reduced from 340% ± 280% in
the control cohort to 113% ± 54% in the tranexamic acid
cohort (p < 0.001) (Table III).
Discussion
B lood loss during complex spine surgery can be both in-
sidious and profuse. This blood loss can lead to hypoten-
sion, lack of oxygen-carrying capacity, and end organ ischemia
if not detected and treated. The treatment of anemia and depletion
of coagulation substrates can itself lead to the morbidity of the
patient in the form of transfusion-related circulatory overload44,
transfusion-related lung injury45, transfusion-related reactions,
and a host of other untoward sequelae related to blood product
transfusion46.
T R A N E X A M I C A C I D E F F E C T O N B L O O D L O S S , D-D I M E R , AND
F I B R I N O G E N I N S P I N A L D E F O R M I T Y S U R G E RY
Monitoring coagulation through prothrombin time and
INR evaluates the presence of clot-forming substrates and their
effectiveness. However, using these measures is extremely in-
sensitive to the presence of clot dissolution, such that the
presence of accelerated clot dissolution can only be detected
upon severe depletion of these clot-forming substrates. Clot
dissolution mediated by activated plasmin results in the pro-
duction of fibrin degradation products such as D-dimer40. The
genesis of coagulopathy in complex spine surgery can be mul-
tifactorial; however, disseminated intravascular coagulation
during scoliosis surgery has long been a putative mechanism11.
The measurement of D-dimer longitudinally during a
complex elective surgical procedure is not usually undertaken
and has rarely been previously reported. The data presented
here are striking for the magnitude and speed at which D-dimer
levels increase during the course of the surgical procedure
(Fig. 4). In patients without tranexamic acid, our observed peak
of 14.8 mg/mL greatly exceeds other reports in the literature for
such procedures as laparoscopic cholecystectomy (peak of 0.5
mg/mL), open cholecystectomy (peak of 0.6 mg/mL)47, arthro-
plasty (1.4 mg/mL)48, coronary bypass surgery (<1.5 mg/mL),
cardiac valve surgery (approximately 1.0 mg/mL), or thoracic
surgery (between 1.5 and 2.0 mg/mL) with peak values usually
observed postoperatively rather than intraoperatively49.
Because antifibrinolytics such as tranexamic acid act to
inhibit the activation of plasmin and subsequent clot dissolu-
tion, the effect on D-dimer generation should be demonstrable
and might therefore serve as a preventative measure for
avoiding the coagulopathy during complex spine surgery sec-
ondary to clot lysis. This effect of tranexamic acid was dem-
onstrated within our study population, as those patients who
received tranexamic acid had lower absolute levels of D-dimer
and a decreased rate of production measured by the maximal
percentage hourly increase. This finding suggests that tra-
nexamic acid is reducing intraoperative blood loss by inhibiting
the breakdown of a formed cross-linked clot. In our popula-
tion, this reduction in the D-dimer elevation was by a factor of
3, from 340% in the group that did not receive tranexamic acid
to 113% in the group that received tranexamic acid, and was
greater in absolute magnitude but similar in quality to that seen
in the arthroplasty population (a change in D-dimer of 68% in
the group that did not receive tranexamic acid and 14% in the
group that received tranexamic acid)48.
The clinical utility of monitoring D-dimer levels during
surgical procedures is not well defined. To our knowledge, this
study is the first to profile the intraoperative kinetics of D-
dimer generation with and without tranexamic acid. Anec-
dotally, our surgical team has noted that there are time periods
toward the end of the surgical case in which hemostasis seems
less responsive to targeted blood component administration,
and these time periods correlate with the accelerated rise in D-
dimer observed at those same time points. This correlation may
therefore be helpful in decisions with regard to staging of
surgical procedures. If the operative course is approaching a
point of no return such as an osteotomy or destabilizing ma-
neuver and the D-dimer has entered its exponential rise phase,
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the team might consider staging the procedure, allowing the
hemostatic system to recover, and then returning to the oper-
ating room at a future time. This use of the D-dimer cascade
and its time course will require more study before such clinical
algorithms can be stated explicitly, but these initial data
suggest a promising approach. However, one confounder to
this measure is the attenuation of the D-dimer cascade when
operating with tranexamic acid present, as the reduction in the
slope of the D-dimer rise may prevent the ability to determine
the inflection point at which a DIC-like state has begun.
Measuring the substrates of clotting, including fibrinogen
and platelets, in the presence or absence of tranexamic acid allows
examination of the upstream effects that tranexamic acid had
on the coagulation system. When tranexamic acid was utilized, the
decrease in platelets was diminished, reaching significance in the
first stage of 2-stage surgical procedures. More impressive was
the reduction in fibrinogen, which was lessened in all of our groups
when tranexamic acid was added, indicating that less substrate
was utilized to make a clot in the presence of the antifibrinolytic.
INR, as a functional measure of substrates for coagulation, did
not demonstrate any changes in any of our groups, suggesting that
adequate coagulation factors were present in both surgical pro-
cedures with and without tranexamic acid.
Our study had several limitations. Our retrospective
study design, with the addition of tranexamic acid in 2015
delineating our 2 populations, could have led to a time bias, as
other parts of the surgical procedure may have evolved over
time, which could have altered the surgical course and blood
loss. This date coincided with the increased utilization of ex-
treme lateral interbody fusion. We attempted to limit the effect
of the ever-evolving surgical technique by removing staged
procedures from our study, introducing a more even distri-
bution of patients treated with pedicle subtraction osteotomy
in the single-stage group, and controlling for surgical time in a
matched cohort analysis. Our responses to the change in D-
dimer were also not fully standardized over time in terms of
transfusion of blood products. Patients typically underwent
transfusion on the basis of total estimated blood loss during the
surgical procedure, but, to characterize this more effectively,
more discrimination in our data as to the hourly blood loss that
was associated with the elevation in D-dimer would have been
useful. We do chart real-time hourly laboratory values and
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T R A N E X A M I C A C I D E F F E C T O N B L O O D L O S S , D-D I M E R , AND
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Appendix
A table showing patient characteristics for patients un-
dergoing adult spinal deformity surgery excluded because
of missing D-dimer or fibrinogen values is available with the
online version of this article as a data supplement at jbjs.org
(http://links.lww.com/JBJS/E658). n
Ryan P. Pong, MD1
Jean-Christophe A. Leveque, MD1
Alicia Edwards, MBA2
Vijay Yanamadala, MD3
Anna K. Wright, PhD1
Megan Herodes, BS, CSP1
Rajiv K. Sethi, MD1
1Virginia Mason Medical Center, Seattle, Washington
2ChicagoMedical School, Rosalind Franklin University,
North Chicago, Illinois
3Department
of Neurosurgery, Massachusetts General Hospital,
Boston, Massachusetts
E-mail address for R.P. Pong: ryan.pong@virginiamason.org
ORCID iD for R.P. Pong: 0000-0003-2459-0677
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