Thrombosis Research 134 (2014) 837845

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Thrombosis Research
journal homepage: www.elsevier.com/locate/thromres

Regular Article

Increased activation of blood coagulation in pregnant women with the

Factor V Leiden mutation
Ulla Kjellberg a,b,, Marianne van Rooijen c,d, Katarina Bremme c,d, Margareta Hellgren a,b,e
a

Department of Obstetrics, Sahlgrenska University Hospital, Gothenburg, Sweden

Section for the Health of Women and Children, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden
Department of Obstetrics and Gynaecology, Karolinska University Hospital, Stockholm, Sweden
d
Department of Womens and Childrens Health, Karolinska Institutet, Stockholm, Sweden
e
Department of Antenatal Care, Nrhlsan Primary Care, Vstra Gtaland, Sweden
b
c

a r t i c l e

i n f o

Article history:
Received 13 December 2013
Received in revised form 9 July 2014
Accepted 31 July 2014
Available online 9 August 2014
Keywords:
D-dimer
Factor V Leiden
Pregnancy
Prothrombin fragments 1 + 2
Soluble brin

a b s t r a c t
Background: The risk of venous thromboembolism is enhanced in pregnant carriers of the Factor V Leiden mutation. The primary aim of the study was to compare prothrombin fragments 1 + 2, soluble brin and D-dimer
levels in pregnant Factor V Leiden mutation carriers with those in non-carriers. Secondary aims were to evaluate
whether these biomarkers could predict placenta-mediated complications or venous thromboembolism, and to
study blood coagulation after caesarean section with thromboprophylaxis and after vaginal delivery without
thromboprophylaxis.
Material/Methods: Prothrombin fragments 1 + 2, soluble brin and D-dimer levels were studied longitudinally in
476 carriers with singleton pregnancies from gestational weeks 2325 until 810 weeks postpartum.
Results: Prothrombin fragments 1 + 2 and D-dimer levels gradually increased during pregnancy. D-dimer levels
were higher in carriers, both during pregnancy and puerperium, compared to non-carriers. D-dimer levels above
0.5 mg/l were found in about 30% and 20% of the heterozygous carriers at 45 and 810 weeks postpartum,
respectively. Soluble brin levels were mainly unchanged during pregnancy, with no difference between carriers
and non-carriers. Biomarker levels were similar in carriers with uncomplicated and complicated pregnancies.
Conclusion: Higher D-dimer levels indicate increased blood coagulation and brinolysis activity in carriers. The
high proportion of carriers with D-dimer levels exceeding 0.5 mg/l postpartum must be considered when
assessing the probability of venous thromboembolism. Large overlaps in biomarker levels in normal and complicated pregnancies suggest that these biomarkers cannot be used as predictors. Thromboprophylaxis following
caesarean section may prevent increased activation of blood coagulation.
2014 Elsevier Ltd. All rights reserved.

Introduction
During pregnancy and postpartum, the haemostatic system changes
into a state of hypercoagulability. The brinolytic system remains active
and compensates for increased brin formation, although plasminogen
Abbreviations: APC, activated protein C; c.s, caesarean section; CV, coefcient of variation; DIC, disseminated intravascular coagulation; DVT, deep vein thrombosis; ELISA,
enzyme-linked immunosorbent assay; FVL, Factor V Leiden; F1 + 2, prothrombin fragments 1 + 2; IUFD, intrauterine fetal death; LMHW, low molecular weight heparin; r,
Pearsons correlation coefcient; SD, standard deviation; SGA, small for gestational age;
SF, soluble brin; VTE, venous thromboembolism.
Authors contributions: All authors researched the literature, planned the study, developed the protocol and recruited participants. MH and UK applied for ethical approval.
UK undertook the data analysis and wrote the rst draft of the manuscript. All authors contributed to data analysis, reviewed and edited the manuscript and approved the nal
version.
Corresponding author at: Department of Obstetrics and Gynaecology, SU/stra, S-416
85 Gteborg, Sweden. Tel.: +46 31 3434129.
E-mail address: ulla.kjellberg@hotmail.se (U. Kjellberg).

http://dx.doi.org/10.1016/j.thromres.2014.07.037
0049-3848/ 2014 Elsevier Ltd. All rights reserved.

activator inhibitor 1 and 2 levels are increased and basal tissue-type

plasminogen activator activity is decreased [13]. The most common
thrombophilia among Caucasians is hereditary activated protein C
(APC) resistance, caused by the Factor V Leiden (FVL) mutation [4,5].
The related increased risk of venous thromboembolism (VTE) during
pregnancy and puerperium in FVL carriers, compared to non-carriers,
is well known [6,7]. However, the inuence of the FVL mutation on
placenta-mediated complications, including preeclampsia, small for
gestational age (SGA) and placental abruption, is still controversial.
In order to study the activity of the blood coagulation and brinolysis systems, different biomarkers of blood coagulation activation, brin
formation and brin degradation, such as prothrombin fragments 1 + 2
(F1 + 2), soluble brin (SF) complexes and D-dimers, can be analysed
in plasma [810]. Only two longitudinal studies concerning F1 + 2
and D-dimer in FVL carriers with normal pregnancies, and none
concerning SF [11,12], have been published.
The primary aim of this study was to determine F1 + 2, SF and Ddimer levels in pregnant FVL carriers, as well as to evaluate differences

838

U. Kjellberg et al. / Thrombosis Research 134 (2014) 837845

between carriers and non-carriers. Secondary aims were to evaluate

whether these biomarkers could serve as predictors for placentamediated complications or VTE during pregnancy and whether there
was any difference among heterozygous carriers in activation of
blood coagulation and brinolysis following caesarean section (c.s.)
with thromboprophylaxis, compared to vaginal delivery without
thromboprophylaxis. Prophylactic anticoagulant regimes might be of interest if increased activation of blood coagulation is found in women
with the FVL mutation.

Leuven, Belgium). The blood was handled as previously described and

stored at 70 C until analysed [3].
Samples taken during treatment with low-dose aspirin, dextran or
LMWH were excluded from the statistical analyses, except from the
comparison between women delivered with c.s. and those delivered
vaginally.
Criteria for Diagnosis of Complications
Blood pressure was measured in the sitting subjects left arm at heart
level after a 20-minute rest.

Materials and Methods

Participants
Random screening of 6000 pregnant women for APC resistance was
performed in connection with the routine ultrasound at gestational
week 1718 in Gothenburg and Stockholm. 484 healthy carriers of the
FVL mutation with no history of VTE and with singleton pregnancies
were identied, and 476 agreed to participate in the study (Fig. 1).
The prothrombin gene (Factor II) mutation was routinely analysed in
women with APC resistance in one of the study regions (n = 300), while
it was analysed in the other study region only if there was heredity for
VTE or if a complication occurred (n = 133.) The women were followed
longitudinally, as previously described [10]. Short-term low molecular
weight heparin (LMHW) was administered, according to routine, to
women at transient increased risk of VTE during pregnancy.
Thromboprophylaxis with LMHW was also given for six weeks
postpartum to homozygous women and to women with additional
thrombophilia and for one week postpartum to all carriers delivered by
c.s.. Women who contracted VTE or supercial thrombophlebitis were
treated with LMWH in therapeutic doses.
The local Ethics Committee for Medical Research at the University of
Gothenburg approved the study.
Blood Sampling
Blood samples were taken, through careful venipuncture of a cubital
vein following a 20-minute rest, between 7.30 and 10.00 a.m. at 2325,
3234 and 3840 gestational weeks and at one day, 45 weeks and
810 weeks postpartum. Blood was collected in Vacutainer tubes containing 0.5 ml trisodium citrate (0.13 mol/l) (Venoject, Terumo,

Gestational hypertension: 90 mm Hg diastolic blood pressure on

two occasions, at minimum six-hour interval, after gestational
week 20
Mild preeclampsia: 90 mm Hg diastolic blood pressure on two
occasions and proteinuria (1+ reading on dipstick) on two occasions, at minimum six-hour interval, and negative urine culture
Severe preeclampsia: as mild preeclampsia but with one of the
following additional ndings:
120 mm Hg diastolic blood pressure once or 110 mm Hg
diastolic blood pressure on two occasions, at minimum sixhour interval
proteinuria 3 g per 24 hours
symptoms/signs of organ dysfunction, such as renal insufciency, pulmonary edema, eclampsia, visual disturbances,
IUGR or platelet count b 100x109/L
Small for gestational age (SGA): birth weight below two standard
deviations (SD)
Placental abruption: abdominal pain, uterine tenderness, frequent
small contractions and elevated uterine tone, together with vaginal
bleeding or a retroplacental clot, i.e. a condition leading to immediate delivery
VTE: deep vein thrombosis (DVT) was diagnosed by triplex ultrasonography (combination of venous compression, color Doppler and
pulsed Doppler ultrasonography), magnetic resonance venography
or phlebography. Pulmonary embolism was diagnosed by spiral
computed tomography or ventilation-perfusion lung scintigraphy
according to Biello.

Study group
6000 pregnant women

484 healthy FVL carriers

8 did not approve to participate
476 healthy FVL carriers

458 heterozygous

408 normal pregnancies

11 homozygous
6 heterozygous F VL combined
with heterzygous F II mutation
1 pseudo-homozygous carrier

50 complicated
pregnancies

18 normal pregnancies

Fig. 1. Flow chart of Factor V Leiden carriers. FVL: Factor V Leiden, FII: Factor II.

U. Kjellberg et al. / Thrombosis Research 134 (2014) 837845

Supercial thrombophlebitis: diagnosed clinically, i.e. palpable, tender vein, accompanied by a surrounding area of localized inammation. If the thrombophlebitis was located near a perforating vein,
DVT was ruled out by triplex ultrasonography.
Blood loss: routinely estimated and recorded by the midwife at
delivery.

839

of SF, D-dimer Latex and D-dimer ELISA were used. Comparisons

between caesarean and non-caesarean delivery were performed with
the MannWhitney U-test. Fisher's exact test was used when comparing D-dimer Latex postpartum. Mean, SD, median, min and max for originally measured values are presented in the tables. All signicance tests
were two-tailed and conducted at the 0.05 signicance level.
Pearsons correlation coefcient (r) was used to measure correlations and r is given with the 95 % condence interval.

Laboratory Methods
Results
APC resistance was analysed with COATEST APC Resistance V,
Chromogenix AB, Mlndal, Sweden. The FVL and prothrombin gene
mutations were diagnosed by polymerase chain reaction technique
[14,15]. F1 + 2 was analysed with a quantitative enzyme-linked immunosorbent assay technique (ELISA) (Enzygnost F1 + 2 micro, Dade
Behring, Marburg, Germany). SF was analysed with a latex
immunoturbidometric assay (LPIA-Iatro, Mitsubishi Kagaku Iatron Inc,
Japan) [16]. D-dimer ELISA was analysed with an immunologic technique (Asserachrome D-Di/ Diagnostica Stago, France).D-dimer
Latex was analysed with a latex agglutination assay (STA-Liatest DDI, Diagnostica Stago, France).
According to the participating laboratories, the inter-assay coefcients of variation (CV) were: APC resistance test: 4% at APC ratio 2.4;
F1 + 2 test: 20% at 0.13-0.29 nmol/l and 15% at 117 nmol/l; SF-test:
10% at 10 mg/l and 6% at 35 mg/l; D-dimer ELISA test: 10% at 0.081.0 mg/l; D-dimer Latex test: 20% at 0.5 mg/l and 10% at 2.0 mg/l.
All analyses were performed in series. If absorbance was above the
top standard, the sample was re-tested after dilution so that the results
were read on the linear part of the calibration curve.
Lupus anticoagulants was analysed with the Dilute Russel Viper
Venom Time test, according to routine.
F1 + 2, D-dimer ELISA and D-dimer Latex were analysed at the
Department of Clinical Chemistry, Sahlgrenska University Hospital,
Gothenburg, and SF was analysed at the Department of Clinical Chemistry, Malm University Hospital, Malm. Both laboratories are accredited
(ISO 15189).
Controls for F1 + 2 consisted of 42 randomly selected healthy noncarriers with normal pregnancies, followed longitudinally, as previously
reported [3].
Controls for SF and D-dimer Latex consisted of another randomly
selected 43 healthy non-carriers with normal pregnancies, followed
longitudinally. These latter controls are those remaining after exclusion
of women with APC resistance from a previous study [17].
The number of women studied with regard to SF and D-dimer Latex
had to be limited for economic reasons. Thus, 52 of the healthy heterozygous FVL carriers with normal pregnancies were matched for age,
parity and body mass index with FVL carriers with placenta-mediated
complications, VTE, supercial thrombophlebitits, homozygosity for
FVL or heterozygosity for FVL with additional thrombophilia, in order
to obtain a smaller but representative group for comparison.
Statistics
All variables showed a positive skewed distribution and the statistical analyses were thus performed on data transformed by Bloms transformation method. For analyses within carriers, change over time was
examined by mixed model repeated measures analysis with timepoint specied as xed effect. The Toeplitz covariance structure proved
(tested by likelihood ratio test) to be the most appropriate for this analysis. For comparisons between carriers and non-carriers, mixed model
repeated measures analysis was used, specifying FVL status, timepoint and interaction between FVL status and time-point as xed
effects. The Toeplitz covariance structure, allowing for heterogeneity
between groups, proved to be the most appropriate for this analysis.
By default, this method adjusts p-values and condence limits for all
pairwise differences. For graphical purposes, log2 of F1 + 2 and log10

Pregnancy was uncomplicated in 408 of the 458 heterozygous

women, in all eleven homozygous women, in all six women with double
heterozygosity and in the woman with pseudohomozygous APC resistance. Thirty-four heterozygous women had placenta-mediated complications, or contracted VTE or supercial thrombophlebitis (Table 1).
None of these women were taking LMHW at the time of complication.
Lupus anticoagulants was detected after pregnancy in one woman
who contracted severe preeclampsia, intrauterine fetal death and postpartum pulmonary embolism. Sixteen women contracted gestational
hypertension. More details on the respective clinical course have been
reported previously [13]. Demographics for all groups are shown in
Table 2.
Planned and acute c.s. were performed in 6.7% and 7.1% of heterozygous carriers with normal pregnancy, respectively. In the control group
for F1 + 2, planned and acute c.s. rates were 4.6% and 7.0%, respectively.
In the control group for SF and D-dimer Latex, the corresponding
respective rates were 4.7% and 7.0%. Eleven of the women who
contracted placenta-mediated complications were delivered by acute
c.s. and two by planned c.s. Two of the FVL-homozygous women were
delivered by planned c.s. and one woman with the FVL mutation and
prothrombin mutation was delivered by acute c.s.
Due to technical errors, six outliers of F1 + 2, one of SF and one of Ddimer ELISA were excluded, all among the heterozygous FVL carriers
with normal pregnancies. The most common reasons for missing samples were forgotten appointment, vacation and sick-listing. Twentyseven women delivered before gestational week 38 and nine women
gave birth at hospitals outside our regions.
Biomarker levels in women during treatment with anticoagulants, as well as in women at one day postpartum who bled more
than 1000 ml, are excluded from comparisons but they did not differ

Table 1
Placenta-mediated complications, gestational hypertension, venous thromboembolism
and supercial thrombophlebitis in carriers of the Factor V Leiden mutation.
Complications (n = 50)

Placental abruption
Placental abruption + SGA
SGA
SGA and supercial thrombophlebitis
Severe preeclampsia
Severe preeclampsia + SGA
Mild preeclampsia
Lupus anticoagulants + pulmonary
embolism + IUFD + severe
preeclampsia
Deep vein thrombosis
Pulmonary embolism
Supercial thrombophlebitis
Gestational hypertension

Heterozygous
FVL carriers
(n = 458)

Homozygous FVLcarriersa
(n = 12) or heterozygous
FVL carriers with
heterozygous FII
mutation (n = 6)

2
1
6
1
6
3
6
1

0
0
0
0
0
0
0
0

2
1
5
16

0
0
0
0

n, number; SGA, small for gestational age; IUFD, intrauterine fetal death; FVL, Factor V Leiden; FII, Factor II.
a
including one woman with pseudohomozygous APC resistance.

a
A smaller group of the heterozygous FVL carriers with normal pregnancies matched for age, parity and BMI with heterozygous carriers with placenta-mediated complications, venous thromboembolism, supercial thrombophlebitis, homozygosity
or heterozygosity with additional thrombophilia for comparisons of soluble brin and D-dimer Latex. bone women had more than one complication. creference [3]. dreference [17]. FVL, Factor V Leiden; VTE, venous thromboembolism; F1 + 2, prothrombin fragment 1 + 2; BMI, body mass index.
See separate le.

29.8(5.4)
23-40
24
18
22.8(3.6)
19.0-32.4
31(3.4)
24-36
8
8
27(6.2)
20-41
30.7(4.1)
20-44
260
148
23.6(3.8)
16.2-44.8
Age years
(SD) range
Nulliparous, n
Parous, n
BMI (SD)
range

30.4(4.5)
19-41
40
12
25.1(4.5)
20-39

30(4.2)
21-41
28
6
26(4.9)
19-39

31(5.6)
19-39
12
6
24(3.6)
20-31

Non-carrier controls
for F1 + 2 c
n = 42
Homozygous FVL carriers (n = 11)
Double mutation FVL and Factor II (n = 6)
Pseudohomozygous FVL (n = 1)
with normal pregnancy
n = 18
Heterozygous FVL carriers
with gestational hypertension
n = 16
Heterozygous FVL carriers with
placenta-mediated complications
(n = 26) or VTE (n = 4) or supercial
thrombophlebitis(n = 5)
n = 34b
Matcheda heterozygous
FVL carriers with normal
pregnancy
n = 52
Heterozygous FVL
carriers with normal
pregnancy
n = 408
Demography

Table 2
Demography. Age, parity and body mass index.

30.0(4.2)
21-40
23
20
24.1(4.0)
17.9-32.4

U. Kjellberg et al. / Thrombosis Research 134 (2014) 837845

Non-carrier controls
for soluble brin and
D-dimer Latex d
n = 43

840

from those not treated with anticoagulants or those who bled less
than 1000 ml (data not shown). Biomarker levels in women who
contracted gestational hypertension, which has not proven to be
placentally mediated, or supercial thrombophlebitis were in the
same intervals as the corresponding levels in carriers with normal
pregnancies (data not shown).
Heterozygous FVL Carriers with Normal Pregnancies
Fl + 2 levels in heterozygous carriers increased signicantly and
gradually during pregnancy (Table 3) but were not higher at one day
postpartum than during the late third trimester. F1 + 2 levels in carriers
did not differ from those in non-carriers in the second and early third
trimester. Non-carriers had higher levels of F1 + 2 in the late third trimester, compared to carriers, who had higher levels than non-carriers
at eight weeks postpartum (Table 3).
The levels of SF in carriers were the same during pregnancy, at
45 weeks and at 810 weeks postpartum (Table 3) but higher at one
day postpartum than in the late third trimester. Carriers had higher
levels in the second trimester but not in the third trimester or at
810 weeks postpartum (Table 3).
D-dimer ELISA and D-dimer Latex levels in carriers increased gradually during pregnancy and were higher at one day postpartum than in
the late third trimester (Table 3). The D-dimer ELISA exceeded
0.5 mg/l in 31% and 15% of the heterozygous carriers at 45 and
810 weeks postpartum, respectively. D-dimer Latex levels were higher
in carriers during both pregnancy and puerperium (Table 3). D-dimer
Latex levels exceeded 0.5 mg/l in 36% and 23% of the carriers at 45
and 810 weeks postpartum, respectively. D-dimer Latex levels
exceeded 0.5 mg/l in 11% of the non-carriers at eight weeks postpartum
[17]. This difference between carriers and non-carriers at eight weeks
postpartum was not statistically signicant.
The correlation between D-dimer Latex and D-dimer ELISA was high
throughout pregnancy and at one day postpartum (r = 0.89 (0.810.94), 0.90 (0.81-0.94), 0.95 (0.90-0.97)) and 0.94 (0.90-0.97),
respectively), but low at 45 and 810 weeks postpartum (r = 0.72
(0.5-0.9) and 0.40 (0.1-0.6), respectively). There was a weak correlation
between F1 + 2 and SF levels during the second and early third trimester (r b 0.5) but no correlation during the late third trimester and
postpartum. The correlations between SF and D-dimer ELISA were
high during pregnancy and at one day postpartum, (r = 0.70 (0.540.81), 0.71 (0.55-0.81), 0.61(0.39-0.76), 0.75 (0.58-0.86)) but not significant at 45 and 810 weeks postpartum.
Heterozygous FVL Carriers Contracting Placenta-mediated Complications
or VTE
Only heterozygous FVL carriers contracted any placenta-mediated
complications or VTE. The levels of the biomarkers during pregnancy
and at eight weeks postpartum in these women did not differ from
those in heterozygous carriers with normal pregnancies (Fig. 2).
Heterozygous FVL Carriers Delivered by Caesarean Section
F1 + 2, SF and D-dimer Latex levels were the same in heterozygous
FVL carriers delivered with c.s. and given thromboprophylaxis as in
those vaginally delivered and not given thromboprophylaxis (Table 4).
D-dimer ELISA levels were higher in the women delivered with c.s.
than in those vaginally delivered at 45 weeks postpartum, but not at
one day or 810 weeks postpartum (Table 4).
Homozygous FVL Carriers and Women with Additional Thrombophilia
All pregnancies were normal. F1 + 2 and D-dimer ELISA levels were
signicantly higher in FVL-homozygous women and in women with

Table 3
Prothrombin fragments 1 + 2, soluble brin, D-dimer ELISA and D-dimer Latex in heterozygous Factor V Leiden carriers and in non-carriers during normal pregnancy and postpartum.
F1 + 2 nmol/l

Matched heterozygous
FVL carriers with normal
pregnancies

p-valuea

Mean (SD)
Median
(Min - Max)
n

p-valueb

Mean (SD)
Median
(Min - Max)
n

1.6 (0.6)
1.6 (0.9 - 4.0)
n = 41
2.6 (0.8)
2.4 (0.9 - 5.1)
n = 40
3.2 (1.3)
2.7 (1.2 - 6.4)
n = 37

0.16

19.3 (33.1)
4.2 (0.4 - 176.0)
n = 52
12.6 (19.2)
3.4 (0.7 - 67.6)
n = 52
12.2 (17.8)
4.2 (0.2 - 67.8)
n = 42
31.8 (35.4)
14.8 (1.6 - 131.0)
n = 38
4.7 (2.8)
3.7 (1.9 - 15.5)
n = 48
3.7 (1.7)
3.4 (1.8 - 11.2)
n = 48

(1) 2325
gestational
weeks
(2) 2830
gestational
weeks
(3) 3840
gestational
weeks
(4) 1 day
postpartum

1.7 (0.7)
1.6 (0.9 - 9.0)
n = 402
2.5 (1.1)
2.0 (1.2 - 10.3)
n = 388
2.8 (1.2)
2.5 (1.1 - 10.2)
n = 323
3.0 (1.8)
2.4 (0.7 - 14.3)
n = 275
1.2 (0.4)
1.2 (0.5 - 3.9)
n = 296
1.0 (0.3)
1.0 (0.4 - 1.9)
n = 328

2vs1:b0.001

3vs1:b0.001
3vs2:b0.001

0.16

0.048

4vs1:b0.001
4vs3:0.80
5vs1:b0.001
5vs4:b0.001
6vs1:b0.001
6vs5:b0.001

0.8 (0.2)
0.8 (0.5 - 1.5)
n = 40

b0.001

p-valuea

2vs1:0.08

3vs1:0.93
3vs2:0.12

Non-carriers
with normal
pregnancies

Test

Matched heterozygous
FVL carriers with normal
pregnancies

Mean (SD)
Median
(Min - Max)
n

p-valueb

Mean (SD)
Median
(Min - Max)
n

7.8 (13.1)
3.8 (0.1 - 56.4)
n = 40
7.1 (9.9)
3.9 (0.1 - 48.4)
n = 41
8.7 (9.9)
5.7 (1.8 - 48.1)
n = 37

0.040

1.4 (1.2)
1.0 (0.4 - 6.0)
n = 44
1.7 (1.2)
1.3 (0.6 - 5.8)
n = 43
2.5 (2.0)
1.8 (0.9 - 9.2)
n = 40
5.5 (4.9)
3.8 (1.0 - 20.0)
n = 35
0.6 (0.6)
0.4 (0.2 - 3.0)
n = 41
0.4 (0.4)
0.3 (0.2 - 2.3)
n = 43

0.79

0.51

4vs1:b0.001
4vs3:b0.001
5vs1:0.61
5vs4:b0.001
6vs1:0.12
6vs5:0.11

4.8 (3.2)
3.6 (0.2 - 15.1)
n = 41

0.46

p-valuea

2vs1:0.002

3vs1:b0.001
3vs2:0.001

D-dimer ELISA mg/l

Non-carriers
with normal
pregnancies

Test

Heterozygous FVL carriers

with normal pregnancies

Mean (SD)
Median
(Min - Max)
n

p-valueb

Mean (SD)
Median
(Min - Max)
n

0.7 (0.6)
0.5 (0.1 - 3.2)
n = 42
0.8 (0.6)
0.7 (0.2 - 3.2)
n = 41
1.4 (1.0)
1.1 (0.3 - 5.6)
n = 36

b0.001

1.3 (1.6)
0.8 (0.3 - 13.0)
n = 403
1.5 (1.4)
1.1 (0.2 - 12.0)
n = 388
2.0 (1.4)
1.5 (0.6 - 10.0)
n = 323
7.9 (10.1)
4.8 (0.4 - 64.0)
n = 275
0.6 (0.5)
0.4 (0.2 - 4.6)
n = 298
0.4 (0.3)
0.3 (0.2 - 3.6)
n = 330

b0.001

b0.001

4vs1:b0.001
4vs3:b0.001
5vs1:b0.001
5vs4:b0.001
6vs1:b0.001
6vs5:b0.001

0.4 (0.6)
0.1 (0.1 - 3.2)
n = 42

b0.001

p-valuea

2vs1:b0.001

3vs1:b0.001
3vs2:b0.001
4vs1:b0.001
4vs3:b0.001
5vs1:b0.001
5vs4:b0.001
6vs1:b0.001
6vs5:b0.001

U. Kjellberg et al. / Thrombosis Research 134 (2014) 837845

Test

Mean (SD)
Median
(Min - Max)
n

(6) 810 weeks

postpartum

D-dimer Latex mg/l

Non-carriers
with normal
pregnancies

Time point

(5) 45 weeks
postpartum

SF mg/l

Heterozygous FVL carriers

with normal pregnancies

FVL, factor V Leiden; F1 + 2, prothrombin fragments 1 + 2; SF, soluble brin; n, number; SD, standard deviation.
a
Test within group is performed by using mixed model repeated measures analysis with the Toeplitz covariance structure, specifying time point as xed effect. Outcome variables F1 + 2, SF, D-dimer Latex and D-dimer ELISA are transformed to
normal distribution in this analysis by Blom's transformation.
b
Test between groups is performed by using mixed model repeated measures analysis, with the Toeplitz covariance structure allowing for heterogeneity between groups, specifying FVL status, time point and interaction between FVL status and
time point as xed effects. Outcome variables F1 + 2, SF and D-dimer Latex are transformed to normal distribution in this analysis by Blom's transformation.

841

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U. Kjellberg et al. / Thrombosis Research 134 (2014) 837845

Fig. 2. Prothrombin fragments 1 + 2 (F1 + 2), soluble brin (SF) and D-Dimer ELISA during pregnancy in Factor V Leiden (FVL) carriers with normal and complicated pregnancies and
non-carriers with normal pregnancies. The boxes show the 25%, 50% and 75% cumulative relative frequencies. The whiskers go 1.5 box lengths from the edge of the box or to the minimum
or maximum values within the fences. Extreme values are shown as small dots. The mean values are shown as dots for carriers and squares for non-carriers. The y-axis has a log2 scale for
F1 + 2 and a log10 scale for SF and D-dimers ELISA. Figures under the plots denote number of women. F1 + 2, prothrombin fragments 1 + 2; SF, soluble brin; C1 and C3, heterozygous
women with uneventful pregnancies. N-C, non-carriers; PMC, carriers with placenta-mediated complications, including preeclampsia, small for gestational age and placental abruption; T:
carriers with homozygosity for FVL or with additional thrombophilia; VTE, carriers with venous thromboembolism.

additional thrombophilia than in heterozygous carriers with normal

pregnancies (Fig. 2, Table 5).
Discussion
Increased blood coagulation and brinolysis were found in FVL
carriers, compared to non-carriers. About one-third and one-fth of
the heterozygous carriers with normal pregnancies had increased levels
of D-dimer Latex at 45 and 810 weeks postpartum, respectively.
There were no considerable differences between carriers and noncarriers in the activation of early blood coagulation steps, measured
with F1 + 2, or with brin formation, determined as SF. Large overlaps
in biomarker levels between normal and complicated pregnancies suggest that these biomarkers cannot be used as predictors for placentamediated complications. There was no difference among heterozygous
carriers in activation of blood coagulation or brinolysis following c.s.
with thromboprophylaxis, compared to vaginal delivery without
thromboprophylaxis.
The strength of this study is the very large number of women with
the FVL mutation followed prospectively and longitudinally. The only
previous longitudinal studies concerning these biomarkers in FVL
carriers during pregnancy are one study of F1 + 2 and D-dimers in 11
women [11] and one study of F1 + 2 in 25 women [12].
One weakness of the study was the relatively small groups of noncarriers, which may have impaired the possibility to detect signicant
changes. Albeit rather small, the control groups were nonetheless
regarded as appropriate since it is difcult to motivate women to participate in longitudinal studies during pregnancy and postpartum. Crosssectional studies with large numbers of participants are easier to

conduct but they generate weaker results than longitudinal studies.

There were 67 missing prothrombin mutation tests. From a statistical
perspective, we missed one positive test, which, in our opinion, did
not affect the results.
The CV of the SF and F1 + 2 methods were about 20% in the low
ranges of the methods, which probably had little inuence on the
results.
Blood samples taken during anticoagulant treatment and after
bleeding at delivery were excluded because these two factors have
quite major effects on haemostasis. Also, our aim was to study normal
pregnancy and in women without treatment.
The increase in F1 + 2 levels during pregnancy is in accordance with
previous longitudinal studies of non-carriers or non-genotyped women
[11,12,18,19]. Levels of F1 + 2 were not signicantly higher the day
after delivery than in the late third trimester, which may be due to
their shorter plasma half-life. However, a more plausible explanation
is that F1 + 2 molecules, which remain attached to the phospholipids
on the platelet surface, escape detection, as the assay we used is performed on platelet-poor plasma [20].
There were no major alterations in SF levels during pregnancy, in
agreement with a cross-sectional study of SF in non-genotyped women
[21]. The low-grade disseminated intravascular coagulation (DIC) that
exists in normal pregnancy may not result in increased SF levels as fulminant DIC does [22]. Perhaps SF is a better biomarker of thromboembolism and DIC than D-dimer because of the lower rate of false positivity,
as proposed earlier [21,22]. SF levels were signicantly higher the day
after delivery than in the late third trimester, indicating more pronounced activation of haemostasis in connection with delivery. The
low variation in SF levels and the low correlation between F1 + 2 and

U. Kjellberg et al. / Thrombosis Research 134 (2014) 837845

843

Table 4
Prothrombin fragments 1 + 2, soluble brin, D-dimer ELISA and D-dimer Latex postpartum in heterozygous Factor V Leiden carriers with normal pregnancies delivered vaginally or by
caesarean section.

F1 + 2 (nmol/l)
1 day postpartum

4-5 weeks postpartum

8-10 weeks postpartum

SF (mg/l)
1 day postpartum

4-5 weeks postpartum

8-10 weeks postpartum

D-dimer ELISA (mg/l)

1 day postpartum

4-5 weeks postpartum

8-10 weeks postpartum

D-dimer Latex (mg/l)

1 day postpartum

4-5 weeks postpartum

8-10 weeks postpartum

Vaginal delivery

Caesarean section

n = 352
3.0 (1.8)
2.4 (0.7; 14.3)
n = 274
1.2 (0.4)
1.2 (0.5; 3.9)
n = 257
1.0 (0.3)
1.0 (0.4; 1.9)
n = 281
n = 45
31.8 (35.4)
14.8 (1.6; 131.0)
n = 38
4.9 (2.9)
3.6 (1.9; 15.5)
n = 41
3.8 (1.8)
3.4 (1.9; 11.2)
n = 42
n = 352
7.9 (10.2)
4.7 (0.4; 64.0)
n = 274
0.5 (0.5)
0.4 (0.2; 4.6)
n = 259
0.4 (0.3)
0.3 (0.2; 3.6)
n = 283
n = 45
5.5 (4.9)
3.8 (1.0; 20.0)
n = 35
0.5 (0.4)
0.4 (0.2; 2.4)
n = 35
0.4 (0.4)
0.3 (0.2; 2.3)
n = 37

n = 56
7.5 (30.4)
1.9 (1.2; 210.0)
n = 47
1.2 (0.3)
1.1 (0.7; 2.0)
n = 42
1.0 (0.3)
0.9 (0.6; 1.8)
n = 47
n=7
37.8 (42.6)
24.0 (1.2; 96.0)
n=6
3.7 (0.7)
3.8 (2.8; 5.0)
n=7
2.6 (0.7)
2.4 (1.8; 3.9)
n=6
n = 56
11.0 (24.9)
5.5 (1.1; 169.0)
n = 47
0.6 (0.5)
0.5 (0.3; 3.0)
n = 42
0.4 (0.2)
0.4 (0.2; 0.9)
n = 47
n=7
10.0 (7.9)
9.0 (1.8; 20.0)
n=5
1.0 (1.0)
0.6 (0.4; 3.0)
n=6
0.6 (0.6)
0.4 (0.2; 1.8)
n=6

p-value
0.08

0.57

0.20

0.62

0.73

0.038

0.20

0.011

0.09

0.22

0.11

0.57

Mean (SD) / Median (Min; Max) / n = are presented for continuous variables.
For comparison between groups, the MannWhitney U-test was used for continuous variables. F1 + 2, prothrombin fragments 1 + 2; SF, soluble brin; ELISA, enzyme-linked immunosorbent assay technique.

SF levels might be explained by the fact that SF is an intermediate product in multi-step processes. The fact that the F1 + 2 level is a measure of
thrombin generation, while the SF level is a measure of brin product
generation, but is also inuenced by inhibitors of coagulation (antithrombin, 2-macroglobulin and 1-antitrypsin) and brinogen, may
be another explanation.
The increase in D-dimer ELISA and D-dimer Latex levels during pregnancy concurs with the only previously reported longitudinal study of
D-dimer [11].
D-dimer Latex levels were increased (above 0.5 mg/l) in heterozygous carriers postpartum: 36% (45 weeks postpartum) and 23%
(810 weeks postpartum), respectively. This has not been reported
before.
Currently, there are controversies about the utility of D-dimer as a
biomarker for VTE during pregnancy [23]. The generally increased Ddimer levels during pregnancy have led to a suggestion that higher cutoff levels for normality during pregnancy and postpartum should be determined, making it possible to use D-dimer, alone or together as part of
a scoring system, to diagnose VTE. The differences between the D-dimer
levels in DVT-positive and DVT- negative women decreased as pregnancy progressed in a study with a relatively small number of DVT [24]. The
higher D-dimer levels in FVL carriers reported in this study must be
taken into consideration in a population with a high percentage of FVL
carriers. The overlap between D-dimer levels in DVT-negative carriers

and DVT-positive non-carriers might be substantial both during pregnancy and in the puerperium. D-dimer levels must be tested and
interpreted with substantial caution in pregnancy and the puerperium.
We found no considerable differences in F1 + 2, SF, D-dimer ELISA
or D-dimer Latex levels in heterozygous women delivered with c.s.
and given thromboprophylaxis, compared with heterozygous women
delivered vaginally and not given thromboprophylaxis. This may be a
result of the thromboprophylaxis. However, the low number of c.s.
may have contributed to the lack of statistical signicance.
The absence of a correlation between SF and D-dimer ELISA levels
postpartum strengthens the evidence that these two assays do not detect the same substances. In a previous study, a low correlation between
these SF and D-dimer ELISA assays was taken as proof that the antibody
that detects SF does not recognize cross-linked brin degradation products [9]. The high correlations between SF and D-dimer ELISA during
pregnancy could be due to the fact that changes in haemostasis and brinolysis inuence both variables in the same direction.
The correlation between the D-dimer Latex and D-dimer ELISA assays during pregnancy and at one day postpartum were high, in accordance with another study [9]. The low correlation postpartum
between D-dimer Latex and D-dimer ELISA can be explained by a
small absolute difference in levels.
The number of placenta-mediated complications in the carriers was
the same as in the general population during the same time period,

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U. Kjellberg et al. / Thrombosis Research 134 (2014) 837845

Table 5
Prothrombin fragments 1 + 2, soluble brin and D-dimer ELISA in heterozygous Factor V Leiden carriers during normal pregnancy and postpartum and in homozygous Factor V Leiden
carriers and in heterozygous Factor V Leiden carriers with additional thrombophilia.

F1 + 2 (nmol/l)
23-25 g w

32-34 g w

38-40 g w

8-10 weeks postpartum

D-dimer ELISA (mg/l)

23-25 g w

32-34 g w

38-40 g w

8-10 weeks postpartum

SF (mg/l)
23-25 g w

32-34 g w

38-40 g w

8-10 weeks postpartum

Heterozygous FVL Carriers

n = 408
1.7 (0.7)
1.6 (0.9; 9.0)
n = 402
2.5 (1.1)
2.0 (1.2; 10.3)
n = 388
2.8 (1.2)
2.5 (1.1; 10.2)
n = 323
1.0 (0.3)
1.0 (0.4; 1.9)
n = 328
n = 408
1.3 (1.6)
0.8 (0.3; 13.0)
n = 403
1.5 (1.4)
1.1 (0.2; 12.0)
n = 388
2.0 (1.4)
1.5 (0.6; 10.0)
n = 323
0.4 (0.3)
0.3 (0.2; 3.6)
n = 330
n = 52
19.3 (33.1)
4.2 (0.4; 176.0)
n = 52
12.6 (19.2)
3.4 (0.7; 67.6)
n = 52
12.2 (17.8)
4.2 (0.2; 67.8)
n = 42
3.7 (1.7)
3.4 (1.8; 11.2)
n = 48

n = 19
2.0 (0.5)
1.8 (1.3; 3.6)
n = 19
3.2 (1.0)
3.2 (1.6; 4.4)
n = 19
3.5 (1.2)
3.2 (2.0; 5.6)
n = 16
1.1 (0.4)
1.0 (0.7; 2.1)
n = 14
n = 19
1.5 (1.1)
1.1 (0.5; 5.6)
n = 19
2.7 (1.7)
1.9 (0.8; 5.8)
n = 19
3.6 (2.8)
3.2 (1.2; 11.0)
n = 16
0.6 (0.5)
0.4 (0.2; 1.9)
n = 14
n = 19
11.6 (14.6)
5.3 (2.1; 50.5)
n = 19
17.0 (18.8)
7.3 (0.6; 57.1)
n = 19
16.7 (18.8)
8.3 (0.5; 60.0)
n = 15
4.3 (2.2)
3.7 (1.9; 9.7)
n = 13

p-value
0.007

0.002

0.008

0.75

0.008

b.001

0.002

0.12

0.36

0.041

0.10

0.43

Mean (SD) / Median (Min; Max) / n = are presented for continuous variables. For comparison between groups, the MannWhitney U-test was used for continuous variables. T, homozygous FVL carriers or heterozygous FVL carriers with additional thrombophilia; FVL, factor V Leiden F1 + 2, prothrombin fragments 1 + 2; SF, soluble brin; ELISA, enzyme-linked immunosorbent assay technique; g w, gestational weeks.

based on Swedish Medical Birth Register data. There were 20 women

with placental abruption, SGA or severe preeclampsia. When planning
the study, we expected an increased rate of placenta-mediated complications in FVL carriers, compared to non-carriers. The incidences of
complications in FVL carriers were unexpectedly low. However, there
was a marked overlap between biomarker levels in heterozygous carriers with and without complications, which suggests that the biomarkers analysed in this study cannot be used as predictors. In
previous studies reporting higher levels of F1 + 2 [25,26] and D-dimer
[2730] in non-genotyped women with severe preeclampsia, early
SGA or placental abruption, the tests were performed in women already
diagnosed with the respective complications. One study [27] found no
difference between SF levels in women with severe preeclampsia and
women with normal pregnancies, while another study [31] found
higher levels in the former group.
The number of women with VTE was as expected but too small to
permit any conclusions about the usefulness of these biomarkers as predictors of VTE.

overlaps in biomarker levels between heterozygous carriers with normal and complicated pregnancies suggest that these biomarkers cannot
be used as predictors for placenta-mediated complications. In heterozygous carriers, D-dimer levels above 0.5 mg/L were found in about 30 % at
45 weeks postpartum and in about 20 % at 810 weeks postpartum.
These results must be taken into consideration when assessing the probability of VTE during pregnancy and the puerperium. D-dimer levels are
unsuitable for assessing VTE in obstetric patients. Thromboprophylaxis
may prevent increased activation of blood coagulation and brinolysis
following caesarean section.

Conict of Interest Statement

We declare that we have no conicts of interest. The sponsors did
not inuence the study design or the interpretation of results.

Funding
Conclusion
Blood coagulation and brinolysis are more activated in FVL carriers
than in non-carriers during pregnancy and early postpartum. Large

This study was supported by grants from Region Vstra Gtaland,

the Gteborg Medical Society, Karolinska Institutet Foundations, Elsa
and Gustav Lindhs Foundation and Chromogenix AB.

U. Kjellberg et al. / Thrombosis Research 134 (2014) 837845

Acknowledgements
We wish to express our gratitude to the women participating in
our study; the midwives who enrolled them; the research midwives
at Karolinska University Hospital, for technical assistance; Marianne
Dahlberg, the Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, and Andreas Hillarp, Department of Clinical Chemistry, Malm University Hospital, Malm, for laboratory
supervision; Steffen Rosn, Haemochrom Diagnostica AB, Gothenburg, Sweden, for constructive discussions; Sture Holm, Biostatistic,
the University of Gothenburg, Nils-Gunnar Pehrsson and Aldina
Pivodic, Statistiska konsultgruppen, Gothenburg for support with
statistics; and Joy Ellis, for language review.
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