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Prevention of postpartum hemorrhage using antifibrinolytics – concern for a
hypercoaguable effect?
Fellow: Homa K. Ahmadzia
Faculty Mentors: Amy P. Murtha, Geeta K. Swamy and Chad A. Grotegut
Homa K. Ahmadzia MD, MPH,1 Evelyn L. Lockhart MD2, Chad A. Grotegut MD1,
Samantha M. Thomas MB3, Ian J. Welsby MB, BS4, Maureane R. Hoffman MD, PhD5,
Amy P. Murtha MD1, Geeta K. Swamy MD1
1Department
of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Duke
University
2Department
of Pathology, Division of Pathology Clinical Services, Duke University
3Department
of Biostatistics, Duke University
4Department
of Anesthesiology, Division of Cardiac Anesthesiology, Duke University
5Department
of Pathology, Division of General Pathology, Duke University
Corresponding author:
Homa K. Ahmadzia MD, MPH
Department of Obstetrics and Gynecology
Duke University School of Medicine
Durham, NC 27710
Work Phone: 919-681-5220
Cell Phone: 703-622-6524
Email: [email protected]
Financial support: Duke Charles B. Hammond Fund
Short title/running foot: Antifibrinolytics and effect on coagulation
Fax: 919-681-7861
Precis
Addition of antifibrinolytic agents to whole blood in vitro does not increase clot firmness
or decrease clotting time using thromboelastometry in healthy pregnant women.
Abstract
Objectives: Antifibrinolytic agents are used in the setting of hemorrhage but concern
exists about potential to increase risk for venous thromboembolism. Our study sought to
determine the impact of tranexamic acid (TXA) and ε-aminocaproic acid (EACA) on in
vitro clotting properties during pregnancy.
Methods: Whole blood (WB) was obtained from healthy pregnant, obese and
preeclamptic pregnant women (n=10 in each group) prior to delivery as well as healthy
non-pregnant controls (n=10). Maximum clot firmness (MCF) and clotting time (CT)
were measured using rotation thromboelastometry in the presence of TXA (3, 30, or
300µg/mL) or EACA (30, 300, or 3000µg/mL). ANOVA and regression analyses were
performed.
Results: Among healthy pregnant women, there was no significant difference between
mean MCF (WB alone, WB with TXA doses = 66.5, 66.1, 66.4, 66.3 mm, respectively;
p=0.25) or mean CT (409, 412, 420, 424 sec; p=0.30) after TXA treatment. Similar
results were found using EACA. Preeclampsia group demonstrated increase in MCF
with addition of EACA and TXA compared to whole blood alone (p=0.05 and p=0.04,
respectively) but not CT (p=0.19 and 0.43). Compared to healthy non-pregnant controls,
the mean WB MCF was significantly higher in healthy pregnant women (57.8 vs. 66.5
mm, p<0.0001).
Conclusions: Pregnancy is a hypercoaguable state, as reflected in our finding of
increased MCF in pregnant compared to non-pregnant women. Addition of
antifibrinolytic therapy in vitro does not appear to increase MCF or CT for non-pregnant,
pregnant and obese women. Whether antifibrinolytics are safe in preeclampsia may
require further study.
Introduction
Postpartum hemorrhage (PPH), commonly defined as blood loss greater than
500mL after a vaginal delivery and greater than 1000mL after a cesarean delivery, is a
significant contributor to maternal morbidity and mortality worldwide.1 According to WHO
estimates from 2003-2012, obstetric hemorrhage was the single leading cause and
accounted for 27.1% maternal deaths (661,000 deaths).2 Furthermore, morbidity from
severe hemorrhage includes blood transfusions, profound anemia and loss of
productivity and longer hospital stays. Between 1994 and 2006, the incidence of PPH in
the US increased by 26%3 likely due to rising cesarean section rates, abnormal
placentation and higher order pregnancies.
During an acute hemorrhage, both clot formation and clot break-down
(fibrinolysis) occur. Fibrinolysis is the process by which tissue plasminogen activator
(tPA) enables plasmin to breakdown fibrin into fibrin degradation products (Figure 1).
Inadequate clot formation or excessive fibrinolysis will lead to a coagulopathic state and
uncontrolled hemorrhage. Antifibrinolytic agents such as Tranexamic acid (TXA) and εamniocaproic acid (EACA), competitively inhibit lysine binding sites of the plasminogen
molecule to stabilize fibrin levels and prevent fibrinolysis, thereby resulting in reduced
blood loss.4
Reductions in morbidity are well proven for prophylactic use of TXA and EACA in
cardiac and orthopedic surgery, without increased risk of thrombotic complications. 5-7
Antifibrinolytic therapy shows great potential in the field of obstetrics, especially in the
primary prevention of PPH. Peripartum administration of TXA in a few randomized
controlled trials reduced estimated blood loss at the time of delivery.
8-11
Furthermore,
the ongoing WOMAN trial will determine if TXA reduces mortality or odds of
hysterectomy in the setting of PPH.12
Given that pregnancy is a known hypercoaguable state, 13 the use of
antifibrinolytics in pregnancy has raised concerns about a potentially increased risk of
thrombosis associated with TXA or EACA in the peripartum period. A recent Cochrane
meta-analysis showed that TXA and EACA in non-pregnant patients do not increase the
risk of thromboembolic complications.14 Unfortunately, the existing clinical studies in
pregnancy using TXA are small, are not powered to assess safety, and only include
healthy pregnant patients. 8, 11 Studies using EACA during pregnancy in the English
literature are limited to case reports of use in patients with rare coagulopathies.
15, 16
The in vitro study design is optimal for studying theoretical risks of these drugs at
various concentrations, especially in pregnant women at higher risk for associated
complications. Specifically, obese women have elevated baseline fibrinogen levels and
increased risk for venous thromboembolism.17, 18 In addition, women with preeclampsia
are at an increased risk for seizures and venous thromboembolism.19 Thus, women with
preeclampsia and concerns for postpartum hemorrhage may be better treated with
EACA over TXA because of the association of TXA and seizures at high doses in
cardiac patients.20
Our overall hypothesis is that antifibrinolytic agents, TXA and EACA, do not
incrementally increase the hypercoaguable state in pregnant women. The overall
objective of this study was to determine if antifibrinolytic agents increase blood clotting
properties in whole blood as measured by thromboelastometry. We compared
viscoelastic clotting parameters in whole blood samples with and without addition of
varying doses of antifibrinolytics among 1) healthy pregnant, 2) obese pregnant women,
3) preeclamptic pregnant women, and 4) healthy non-pregnant women.
Materials and Methods
Following Duke University IRB approval (IRB# Pro00047007) study participants
were recruited including healthy volunteers to serve as non-pregnant controls. Pregnant
women in the third trimester (greater than 31 weeks) who were delivering at Duke
University Hospital and planning a repeat cesarean delivery or labor induction were
eligible for participation. Eligible pregnant women were divided into three groups: 1)
healthy pregnant, 2) obese pregnant women and 3) pregnant women with
preeclampsia. Obesity was defined as a body mass index (BMI) of greater than 35.0
kg/m2 and was selected based a prior study showing hypercoaguable effect with TEG in
obese versus non-obese pregnant women.21 Maternal weight for BMI categorization
was based on weight at time of recruitment. Preeclampsia was defined by a blood
pressure of at least 140/90 and proteinuria >300mg on 24 urine collection or a
protein/creatinine ratio >0.3. All women were between 18 and 45 years old and English
speaking. Women were excluded if they had a personal/family history of thrombophilia,
bleeding disorder or hemoglobinopathies; maternal cardiovascular disorder or diabetes
not well controlled on medications (with the exception of women in preeclampsia group);
use of anticoagulants or chronic NSAIDs (other than baby aspirin) within the last 4
weeks; any condition suspected to put them at risk for PPH (i.e. placental abruption,
starting hematocrit <30, history of PPH, chorioamnionitis, preterm premature rupture of
membranes, abnormal placentation). Data collection included maternal age, parity,
gestational age, body mass index (BMI) and preoperative automated blood cell count,
including hematocrit and platelet count.
Thromboelastography/thromboelastometry (TEG/ROTEM) measures viscoelastic
changes in whole blood under low shear conditions as the clot forms and then as the
clot undergoes fibrinolysis. Among the various ROTEM parameters, as illustrated in
Figure 2, we focused on the following two parameters: clotting time (CT, seconds),
which is the time from start of measurement until initiation of clotting and maximum clot
firmness (MCF, mm). These two parameters are good measures of hypercoagulability
and have been used previously in studies examining viscoelastic properties.22, 23 We
used the NATEM option of ROTEM, in which no additional coagulation reagents are
added, so that it would best simulate in vivo conditions. NATEM is the recalcification of
whole blood without the addition of other reactivating reagents such as ellagic acid
(used for INTEM) or tissue factor (used for EXTEM).
For each subject, whole blood was collected during admission for delivery using
a 21 gauge needle or larger. Whole blood samples were then processed using ROTEM,
in the presence of three different concentrations of the antifibrinolytic drug, TXA or
EACA. The concentrations of each antifibrinolytic agent used were determined based
on the mean in vivo concentrations observed or targeted in cardiac bypass patients who
received prophylactic doses of the drugs during surgery (37.4 µg/ml for TXA and 260
µg/ml for EACA).24, 25 In order to establish a dose response curve, a 10-fold lower and a
10-fold higher concentration around this expected level were used for each sample
(TXA 3, 30, 300 µg/ml and EACA 30, 300, 3000 µg/ml). ROTEM allows for four samples
to be processed simultaneously. For each subject’s sample, 300µl of whole blood was
placed into each of the four ROTEM chambers for MCF and CT measurements. One
chamber was WB alone (plus phosphate buffer solution vehicle) and the other three
chambers contained dose response model antifibrinolytic drug concentrations, 20µl drug
volume added to the 300µl WB. All ROTEM runs were performed within 4 hours of
sample collection by a single investigator (H.K.A.), who was trained by the
manufacturer.
In addition, citrated plasma samples were centrifuged at 3000g for 12 minutes
and supernatant was stored at -70oC until assayed for fibrinogen concentrations. Serum
fibrinogen levels were measured from each subject using standard laboratory testing
from thawed samples. Fibrinogen levels were then incorporated into our final regression
model as a potential confounding variable, given that fibrinogen affects blood clotting
properties and can be elevated in pregnancy and obesity.26
To ensure that the antifibrinolytic drugs were active within our in vitro model, both
antifibrinolytic drugs were tested to determine if they could reverse tPA-induced
hyperfibrinolysis. For these control experiments, WB was placed into the ROTEM
chambers with 0.3 µg/ml tPA and 3 µg/mL of TXA or 30 µg/mL EACA.
According to Rheenen-Flach et al.27 , the mean INTEM MCF for pregnant women
at 32-41 weeks gestation was 71 mm, with a standard deviation of 4 mm using
EXTEM/INTEM. Another study publishing reference ranges in pregnancy found some
wider variation in the INTEM MCF.28 Therefore, we used an expected mean of 71 mm
and standard deviation of 5 mm among our healthy pregnant women. For 90% power,
alpha=0.05, and the maximal allowable difference that results in equivalence estimated
at 10 mm, the expected sample size using bioequivalence means power analysis is 10
subjects in each group. Although the studies we used for sample size estimation are
based on INTEM/EXTEM, we would not expect much difference in MCF values in
NATEM.
A generalized estimating equation (GEE) approach was used to examine withingroup differences in MCF and CT at different concentrations of TXA or Amicar. This
type of model was used because it is able to account for the correlation between
observations made on the same patient. Between-group differences in MCF and CT at
baseline and each concentration of TXA or Amicar were examined using analysis of
variance (ANOVA) and analysis of covariance (ANCOVA). A pre-specified significance
level of 0.05 was used for all statistical tests. All statistical analyses were performed
using SAS, version 9.4 (SAS Institute, Cary, NC).
Results
Whole blood was collected from 10 healthy, 10 obese and 10 preeclamptic
women as well as 10 non-pregnant women. There was no difference in maternal age
between the four groups, Table 1. Women with preeclampsia had a lower mean
gestational age of 36.7 ± 2.7 weeks when compared to healthy and obese pregnant
women (p=0.002). The mean BMI in the healthy pregnant group was 26.6 ± 3.6 kg/m2,
compared to the obese pregnant group of 42.6 ± 6.4 kg/m2. Hematocrit and platelet
count were not statistically different in any of the pregnant groups. Mean serum
fibrinogen levels were significantly higher among each of the pregnant groups when
compared to non-pregnant women (p<0.001), but there was no difference in mean
fibrinogen levels between the three pregnant groups (p=0.51).
TXA reversed tPA-induced fibrinolysis with 3 µg/ml of TXA, to illustrate that our
antifibrinolytic drugs were active in our in vitro model, (Figure 3).
In vitro experiments showing the effect of increasing doses of each antifibrinolytic
drug on MCF and CT are shown in Tables 2 and 3, respectively. Compared to whole
blood alone, higher doses of TXA and EACA did not significantly change the MCF within
non-pregnant, healthy pregnant and obese pregnant women. Pregnant women with
preeclampsia showed a significant increase in their MCF values with increasing
concentrations of TXA (p=0.04) and EACA (p=0.05) compared to WB alone. Figure 4
illustrates the findings for TXA on both viscoelastic parameters. Figures for Amicar
results were not included as they were similar (see supplemental Figure I). As
fibrinogen is known to increase blood clotting properties and is affected by pregnancy,
we controlled for this in the within-group comparisons. Our findings did not change after
adjusting for fibrinogen, gestational age and BMI (based on univariable analyses in
Table 1), so we report only adjusted comparisons.
Table 3 shows the impact of antifibrinolytic drugs on CT (initiation of clot
formation) within each group. There were no differences seen in the CT with addition of
either drug compared to WB alone, within any of the four clinical groups.
Next, we evaluated whether baseline viscoelastic parameters differed between
clinical groups, or if viscoelastic parameters with the addition of antifibrinolytic agents
differed between clinical groups. Baseline MCF values were significantly lower among
non-pregnant women when compared to any of the three pregnancy groups (unadjusted
p<0.001), Figure 5. Adjusting for BMI and fibrinogen, baseline values were still different
between non-pregnant and healthy pregnant (p=0.03) or obese pregnant (p=0.03) but
not preeclampsia (p=0.13). After adding antifibrinolytic agents at any concentration,
between-group comparisons of non-pregnant women to pregnant women were all
significant (p≤0.01). Finally, between each of the pregnant group comparisons (healthy
pregnant, obese pregnant and preeclamptic pregnant) there was no difference in mean
MCF value at baseline, or with additional antifibrinolytic agents (Figure 5). This
relationship remained true after adjusting for BMI, fibrinogen and gestational age.
Baseline non-pregnant versus healthy pregnant CT values were significantly
different (p=0.02), Figure 6. This relationship persisted after adjustment for BMI and
fibrinogen (p=0.03). Addition of antifibrinolytic agents did not affect between-group CT
comparisons among non-pregnant and pregnant women. Mean baseline CT between
the groups of pregnant women showed no difference (p=0.17), Figure 6.
Discussion
Our study showed that in vitro addition of the antifibrinolytic agents, TXA and
EACA, to whole blood of non-pregnant, healthy pregnant and obese pregnant women
did not increase maximum clot firmness as measured by thromboelastometry baseline
differences by pregnancy status. These findings persisted after adjusting for covariates
of serum fibrinogen, BMI and gestational age, which are known to affect blood clotting
properties. We found that within each of the four clinical groups, clotting time was not
affected by the addition of either antifibrinolytic agent. However, women with
preeclampsia demonstrated significantly increased maximum clot firmness with TXA
and EACA compared to whole blood alone. Although this was a statistically significant
difference, the clinical significance of this observation is unknown.
The major advantage of ROTEM over plasma coagulation assays is ability to
measure whole blood and not individual blood fraction components such as proteins in
plasma, which may not accurately reflect in vivo conditions.29 While some normative
data exists for ROTEM during pregnancy,27, 28, 30 there are no published data on the
effect of antifibrinolytic therapy on ROTEM values in pregnancy.
Our study is novel in that it explores an in vitro model and antifibrinolytic agents
in pregnancy. Recently, an in vitro model using thromboelastography explored
transfusion principles in postpartum hemorrhage.31 Other studies have utilized in vitro
addition of hemostatic agents to whole blood in the setting of factor deficiency to guide
optimal preoperative adjunct therapy.32 Further animal studies have shown that an in
vitro model can identify therapeutic ranges for antifibrinolytics needed to reverse a
hyperfibrinolytic state.33
We demonstrate that NATEM can identify pregnancy as a hypercoaguable state,
as reflected in our finding of increased baseline MCF and decreased CT in pregnant
compared to non-pregnant women. These findings are consistent with prior studies
using thromboelastography.27 Although our study did not show a significant difference in
MCF between obese pregnant and healthy pregnant women, other larger studies using
pregnant women have demonstrated ROTEM hypercoagulability parameters (MCF and
AUC) are affected by obesity.34
Similarly, preeclampsia is thought to increase the risk for hypercoagulability in
pregnancy, but we did not show increased MCF values or decreased CT values
compared to healthy pregnant women. A recent study demonstrated similar findings
where 30 women with preeclampsia, compared to 60 gestational-age matched healthy
controls, also showed no difference in mean MCF NATEM values (64 vs. 61 mm;
p=0.07) between the two groups.35 However, this same study demonstrated significant
differences when using the activated INTEM (ellagic acid) and EXTEM (tissue factor)
tests between the two groups.
The WOMAN study12 aims to demonstrate the safety and efficacy of TXA but will
not be completed until May 2016. Our findings possibly suggest that TXA and EACA are
not ideal for prophylactic use in women with preeclampsia. However, our model was in
vitro based and in vivo studies would be helpful to confirm this relationship.
Furthermore, in a severe hemorrhage situation, a clinician would need to weigh the risks
and benefits of hemorrhage versus thrombosis.
Our study is not without limitations. We are assuming that the clotting cascade is
only initiated from the contact activation of the pin rotating in the cup, rather than the
other dynamic intrinsic and extrinsic components of the clotting cascade. In addition, we
did not find a specific agent or condition to induce a hypercoaguable state beyond that
found in our patient’s samples for a ‘positive control.’ However, other studies have
reported ROTEM references ranges for normal pregnancy higher than our values,27, 28
indicating that the machine has a wider range of sensitivity for detecting
hypercoagulability.
In conclusion, our study evaluated in vitro whole blood coagulation profiles of
pregnant women in the setting of antifibrinolytic therapy. It is reassuring that the
addition of antifibrinolytic agents to whole blood from both healthy pregnant women and
obese pregnant women did not produce a hypercoaguable ROTEM profile, although
caution for prophylactic use may be prudent in preeclampsia. Finally, further in vivo
studies are needed in the obstetric population to further demonstrate the efficacy and
safety of antifibrinolytic therapy to both treat and prevent postpartum hemorrhage.
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Table 1. Demographic data and baseline laboratory values.*
Non-
Healthy
Obese
Preeclampsia
Pregnant,
Pregnant,
Pregnant,
Pregnant,
NP
HP
OP
PP
(n=10)
(n=10)
(n=10)
(n=10)
31.3 ± 4.6
31.6 ± 3.2
29.0 ± 5.7
31.6 ± 5.5
0.58
-
39.4 ± 0.7
39.3 ± 0.9
36.7 ± 2.7
0.002
White
Black
10
-
5
2
6
4
4
5
Hispanic
-
2
-
-
Asian
-
1
-
1
BMI (kg/m2)
28.5 ± 11.3
26.6 ± 3.6
42.6 ± 6.4
35.3 ± 9.3
<0.001
Hematocrit
-
36.3 ± 2.0
34.7 ± 2.9
36.1 ± 3.8
0.44
-
227 ± 35
243 ± 82
188 ± 59
0.15
524 ± 85
525 ± 108
<0.001
p-value
Age (years)
Gest. age
(weeks)
Ethnicity (n)
Pre-delivery
(%)
Platelet
count (K)
Fibrinogen
320 ± 60
486 ± 53
(mg/dL)
*Reported as mean ± standard deviation (SD)
Table 2. Effect of Tranexamic acid (TXA) and ε-aminocaproic acid (EACA) on maximum clot firmness (MCF), mm,
within each of four clinical groups.*
EACA
TXA
3
30
300
Adj. £
µg/ml
µg/ml
µg/ml
p-value
57.8
57.2
58.5
57.8
0.07
(2.9)
(3.5)
(3.0)
(2.5)
66.5
66.1
66.4
66.3
(2.2)
(2.6)
(2.3)
(2.3)
67.7
68.9
69.0
69.1
(4.5)
(3.1)
(2.6)
(3.3)
66.3
67.7
68.2
67.5
(3.8)
(3.9)
(3.5)
(4.1)
Control
30
300
3000
Adj. £
µg/ml
µg/ml
µg/ml
p-value
57.1
56.7
57.7
58.0
0.11
(2.6)
(2.1)
(2.4)
(2.9)
66.5
66.2
66.5
66.5
(2.9)
(3.1)
(3.0)
(2.8)
68.8
68.5
69.3
69.8
(3.3)
(3.1)
(3.2)
(2.9)
66.5
67.1
67.8
68.5
(4.7)
(4.1)
(4.0)
(4.1)
Control
Non-Pregnant
0.25
0.77
Healthy Pregnant
0.11
0.06
Obese Pregnant
0.04
Preeclampsia Pregnant
*Numbers reported as MCF mean (SD)
£Adjusted
for fibrinogen, gestational age (if pregnant) and BMI
0.05
Table 3. Effect of Tranexamic acid (TXA) and ε-aminocaproic acid (EACA) on clotting time (CT), sec, within each of four
clinical groups.*
TXA
Control
Non-Pregnant
Healthy
501
EACA
3
30
300
Adj. £
µg/ml
µg/ml
µg/ml
p-value
537
529
529
300
3000
Adj. £
µg/ml
µg/ml
µg/ml
p-value
532
554
554
534
(54)
(61)
(59)
(52)
413
418
416
404
(49)
(44)
(43)
(36)
391
384
382
388
(87)
(81)
(81)
(89)
448
447
437
434
(70)
(82)
(69)
(72)
Control
0.06
(62)
(74)
(61)
(72)
409
412
420
424
0.13
0.30
Pregnant
(71)
(67)
(70)
(69)
Obese
388
395
390
398
0.13
0.29
Pregnant
(67)
(90)
(70)
(71)
Preeclampsia
444
443
443
431
Pregnant
30
0.10
0.43
(58)
(59)
(57)
(48)
0.19
*Numbers reported as CT mean (SD)
£
Adjusted for fibrinogen, gestational age (if pregnant) and BMI
Ahmadzia
Figure 1. Normal fibrinolysis and site of action of antifibrinolytic agents. TXA =
Tranexamic acid, EACA = ε-aminocaproic acid, tPA = tissue plasminogen activator,
FDPs = fibrin degradation productions
Figure 2. Typical ROTEM diagram and parameters (reproduced from www.rotem.de).
25
Ahmadzia
Figure 3. Actual ROTEM demonstrating reversal of tPA hyperfibrinolysis with TXA.
26
Ahmadzia
Figure 4. Effect of TXA on MCF and CT in dose response model.
27
Ahmadzia
Figure 5. Comparing mean MCF between four groups at baseline and with the addition
of the middle dose of TXA and EACA. The middle concentration dose for each drug was
chosen to represent in the figure since within-group comparisons for most groups did
not show a significant impact with TXA and EACA on MCF.**
* p=<0.001, unadjusted; p=0.03, adjusted for BMI and fibrinogen
**all other comparisons between pregnant groups NS, adjustments included BMI,
fibrinogen and gestational age
28
Ahmadzia
Figure 6. Comparing mean CT between four groups at baseline and with the addition of
the middle dose of TXA and EACA. The middle concentration dose for each drug was
chosen to represent in the figure since within-group comparisons did not show a
significant impact with TXA and EACA on CT.**
* p=0.02, unadjusted; p=0.03, adjusted for BMI and fibrinogen
**all other comparisons between pregnant groups NS, adjustments included BMI,
fibrinogen and gestational age
29
Ahmadzia
Supplemental Figure I. Effect of EACA on MCF and CT in dose response model.
30