Thrombosis Research 185 (2020) 72–77

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

Review Article

Diagnosis and management of congenital thrombophilia in the era of direct T

oral anticoagulants
R. Alameddinea, R. Nassabeina, G. Le Galb, P. Siéc, F. Mullierd, N. Blaisa,
⁎

a
Department of Hematology and Transfusion Medicine, Centre Hospitalier de l'Université de Montréal, Montreal University, Canada
b
Department of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Canada
c
Hematology Lab., Université Paul Sabatier et CHU de Toulouse, Toulouse, France
d
Université catholique de Louvain, CHU UCL Namur, Namur Thrombosis and Hemostasis Center (NTHC), NARILIS, Yvoir, Belgium

ARTICLE INFO ABSTRACT

Keywords: Direct oral anticoagulants (DOAC)s are often preferred to other anticoagulants as they are more practical and do
DOAC not require routine laboratory monitoring. Less is known about their use in congenital thrombophilia. Efficacy of
Thrombosis DOACs in congenital thrombophilia, effect of DOACs and other anticoagulants on diagnostic tests as well as
Congenital thrombophilia efficacy and safety of anticoagulant use in this population is still a matter of debate. In this review we intended to
Thrombophilia testing
analyze the potential pitfalls of testing for thrombophilia in patients using DOACs and vitamin K antagonists
Vitamin K antagonists
(VKA)s as well as to suggest strategies to improve diagnostic accuracy in this setting. We also reviewed the
literature for evidence regarding the safety and efficacy of DOACs in patients with congenital thrombophilia.
Some evidence was found supporting the use of DOACs in low risk thrombophilia, although evidence for their
use in high risk thrombophilia is limited to small series and case reports. Our findings support the generation of
better evidence to support DOAC use for congenital thrombophilia, especially in the high risk subgroups.

1. Introduction
Direct oral anticoagulants (DOAC)s have been gradually introduced
to clinical practice since a decade. The indications span over a wide
spectrum and started with stroke prevention in patients with atrial fi-
brillation and have more recently been extended to primary thrombo-
prophylaxis in selected patients with cancer. Nonetheless, little is
known about the role of DOACs in congenital thrombophilia (CT) [1].
The latter encompasses a heterogeneous group of patients with muta-
tions affecting different coagulation factors, which are at varied risks
for thrombosis. Patients with CT also do have a varied pathophysiology
where DOACs may theoretically provide advantages and disadvantages
over standard anti-vitamin K therapy. In this review, we address the-
oretical and practical arguments regarding use of DOACs in CT and
review the emerging body of evidence of safety and efficacy of DOACs
in CT.
2. Methods
databases. We used the key terms direct oral anticoagulants or novel
oral anticoagulants or apixaban or rivaroxaban or edoxaban or dabi-
gatran and hereditary thrombophilia or inherited thrombophilia or
congenital thrombophilia. Results were limited to English literature.
The search end date was February 15, 2019. We also reviewed the in-
dividual articles and their references and citing articles. Low risk
thrombophilia was defined by low cumulative recurrence rates and
included heterozygous Factor V Leiden mutation, heterozygous pro-
thrombin G20210A mutation, or high Factor VIII levels [2]. For this
group, we were able to identify studies comparing DOAC to warfarin as
a result of randomized trials or retrospective database analysis. Con-
sidering the existence of higher level data for this group, we rejected
publications limited to non-comparative case studies. High risk
thrombophilia was defined by high cumulative recurrence rates, and
included antithrombin, protein C or protein S deficiency along with
combined/homozygous defects [2]. For this group, we elected to in-
clude all the identified data, even case reports of single patients, in
order to provide as much guidance as possible for this subgroup.

We conducted a literature review using Pubmed and Google Scholar

Abbreviations: CT, congenital thrombophilia; DOAC, direct oral anticoagulant; VKA, vitamin K antagonist
⁎
Corresponding author at: Department of Hematology and Transfusion Medicine, Centre Hospitalier de l'Université de Montréal, Montreal University, 1000 Rue
saint Denis, Montreal, QC H2X 0C1, Canada.
E-mail address: n.blais@umontreal.ca (N. Blais).

https://doi.org/10.1016/j.thromres.2019.11.008
Received 5 September 2019; Received in revised form 31 October 2019; Accepted 11 November 2019
Available online 12 November 2019
0049-3848/ © 2019 Elsevier Ltd. All rights reserved.
R. Alameddine, et al.
Fig. 1. Effect of DOACs on coagulation cascade in three scenarios illustrating A) non-thrombophilic state, B) in PC or PS deficiency as well as with the Factor V Leiden
mutation, Factor II and factor X inhibitors are downstream inhibitors relative to the genetic variant and C) in AT deficiency, factor X inhibitors act upstream from the
genetic variant whereas factor II inhibitors are effective downstream. D) In factor II prothrombin G20210A polymorphism, Factor II inhibitors act downstream; aPC:
activated Protein C; PS: Protein S.
3. Pathophysiology of thrombosis risk in CT – theoretical
interactions with DOACs
The clinical relevance of thrombophilia assessment in the manage-
ment of patients who have developed provoked or idiopathic venous
thromboembolic disease remains controversial. Routine screening cur-
rently has not been proven to be clinically useful for most patients and
is not recommended for patients who have major transient risk factors
[3].
The lack of a recommendation supporting systematic thrombophilia
assessment for unprovoked thrombosis implies that the option of DOAC
or VKA therapy should not be influenced by thrombophilia test results.
Nonetheless, several questions emerge, especially for patients with
previously identified congenital thrombophilia mutations.
The efficacy of DOACs may not be equivalent to VKAs in every
disease state as recently pointed out by the results of the TRAPS study
and the Spanish trial recently published from Ordi-Ros et al. [4,5] These
trials suggest that in the antiphospholipid antibody syndrome, rivar-
oxaban was associated with a higher risk of thromboembolic events
compared to VKAs. In the TRAPS trial, the recurrent events were mostly
arterial events. Three out of 7 arterial thrombotic events occurred in
patients originally diagnosed with venous thromboembolism [4]. In the
Spanish study, rivaroxaban did not show non-inferiority to dose ad-
justed VKA in thrombotic APS, with a thrombotic recurrence rate of
11.6% and 6.3% respectively [5]. This difference was mainly due to the
occurrence of 9 stroke events with rivaroxaban and 0 event with VKAs.
Such a concern may then be well applicable to high-risk inherited
thrombophilias, which are potentially associated with an increased risk
of arterial events as well. This potential risk of arterial thrombosis has
been suggested in some case reports but requires further investigation
[6,7].
The longer half-life of the anticoagulant effect of vitamin K an-
tagonists such as warfarin, that is mainly used in North America, may
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Thrombosis Research 185 (2020) 72–77
be advantageous in situations of sub-optimal compliance to treatment.
In this regard, patients with high-risk thrombophilias may be more
sensitive to transient loss of treatment protection from DOACs con-
sidering their short half-life, which would be further aggravated by
suboptimal compliance. In the real-world setting, this may lead to re-
currence especially when long-term treatment of young adults is man-
dated. A series evaluated the use of DOACs in 33 patients with
thrombophilia and reported a recurrence rate of 9%, which was mainly
due to dose interruption [8]. A retrospective observational cohort
aimed to assess real world adherence and compliance with DAOCs in
adults with atrial fibrillation demonstrated that the mean adherence in
anticoagulation-naive versus anticoagulation-experienced patients at 6
and 12 months of follow-up was 72.3% versus 83.3% (p < 0.001) and
63.7% versus 79.9% (p < 0.001), respectively. Main predictors of
lower adherence were higher number of comorbidities and antic-
oagulation-naive user status, whereas predictors of higher adherence
were old age and higher number of concomitant medications. Thus,
young patients with no comorbidities are more prone to skip doses
during their long duration of treatment [9]. Regular monitoring of
VKAs allows closer contact to the health care management team, which
could potentially reduce issues related to drug-drug interactions and
long-term compliance.
Mechanisms for an increased risk of thrombosis in CT may vary
according to genotype. Antithrombin binds to heparin or endogenous
heparan sulfate to inhibit factors IIa and Xa. The prothrombin G20210A
mutation is linked to an increase in the synthesis of normal factor II.
Finally, decrease in coagulation inhibitors such as protein C and S or
insensitivity to activated protein C by the Factor V Leiden mutation
slow the rate of inactivation of factors Va and VIIIa activity. Different
effects of CT on factor Xa and IIa theoretically suggests that some an-
ticoagulants may be better suited in some situations. For example,
DOACs have the advantage of not reducing Protein C/S function as
compared with VKAs. Anti-Xa and anti-IIa agents both affect the
R. Alameddine, et al. Thrombosis Research 185 (2020) 72–77

coagulation cascade downstream to protein C/S and factor V and
therefore seem particularly relevant for protein C/S deficiencies as well
as factor V Leiden mutation (Fig. 1, panel B). On the other hand, anti-IIa
or VKAs could theoretically prove to be more effective than anti-Xa
inhibitors in the setting of antithrombin deficiency as this defect leads
to unopposed thrombin activity (Fig. 1, panel C). Similarly, the pro-
thrombin G20210A mutation is associated with increased levels of ge-
netically intact prothrombin that may be better antagonized by anti-IIa
agents or by the inhibition of factor II gamma-carboxylation induced by
VKAs (Fig. 1, panel D). In a systematic review by Elsebaie et al., in-
cluding mostly patients with factor V Leiden mutation and antipho-
spholipid antibodies, the risk reduction for thrombosis recurrence with
anti-IIa vs VKAs (RR, 0.50; 95% CI, 0.19 to 1.34) appeared greater than
that observed for anti-Xa vs VKAs (RR, 1.02; 95% CI, 0.35 to 2.97),
although not statistically significant [10]. Although not definitive, these
results open the possibility that certain patients with CT may derive
better protection from thrombosis with specific agents.
the absence of gamma-carboxylation. Since some genetic deficits in
protein C and S are defined by an isolated functional defect of the
protein, an evaluation of the activity of these proteins is essential and is
not possible while on VKAs. It should be noted that the INR of a patient
can normalize after stopping VKAs well before the functional levels of
each factor are returned to their optimal level. It is therefore very
challenging to make a diagnosis of protein C and S deficiency in a pa-
tient recently treated with a VKA. The adequate timing of Protein C/S
testing in relation to the discontinuation of VKAs is unknown and may
be up to 3 weeks [17], especially for protein S in the absence of vitamin
K supplementation. In case of recent VKA intake, the concurrent vali-
dation of normal activities of factors II, VII, IX and X while dosing
Protein C/S activity may be used as a surrogate to the absence of any
residual vitamin K effect and may allow a more accurate evaluation
[18].
4.2. Patients on DOACs

4. Pitfalls in the diagnosis of CT in anticoagulated patients
Many patients referred to specialists for the management of her-
editary thrombophilia are incorrectly diagnosed. A false diagnosis
based on inappropriate testing conditions leads to inappropriate patient
counselling as well as worries for potentially concerned family mem-
bers. Anticoagulants, either VKAs or DOACs, are well known to affect
thrombophilia screening assays. It is therefore important that testing be
adequately performed either to rule out a previous incorrect diagnosis
of CT or to confirm diagnosis in an anticoagulated patient. The fol-
lowing section details the potential effects of anticoagulants on
thrombophilia screening assays (summarized in Table 1).
4.1. Patients on VKAs
Genetic testing for factor V Leiden and prothrombin G20210A
mutations is not influenced by VKAs.
Screening for FVL with the protein C resistance assay: the APCR is
based on the prolongation of the aPTT induced by the addition of ac-
tivated protein C to a plasma sample, whose effect is blunted in the
presence of the factor V Leiden mutation. A modified version of the
original protein C resistance assay with preserved sensitivity for the
factor V Leiden mutation, incorporates the presence of normal pool
plasma to correct for the potential deficiencies in factors II, IX and X
induced by VKAs.
Measurement of antithrombin activity is not influenced by VKA.
Measurement of proteins C and S activity: VKAs reduce the activity
of the vitamin K dependent hepatic gamma-carboxylase. Activities of
factors II, VII, IX and X as well as proteins C and S are thus reduced.
Antigenic levels of proteins C and S are generally not affected by VKA
since the protein is still present but these proteins lose their activity in
Genetic testing for factor V Leiden and prothrombin G20210A
mutations is not influenced by DOACs.
Screening for Factor V Leiden with the APCR assay: in this aPTT
based assay, inhibitors of factors IIa and Xa counteract the blunting
effect of the Factor V Leiden mutation and masks its presence causing a
false negative result. Therefore, DOACs can lead to a false diagnosis of
resistance. Douxfils et al. investigated the impact of rivaroxaban on
coagulation assays including the APC resistance assay, showed that
results are influenced but depending on the assay type. The Pefakit APC
resistance Factor V Leiden® test that uses Russell Viper Venom from
Daboia Russelli to activate prothrombinase complex showed no inter-
ference with rivaroxaban [15]. Another report demonstrated no effect
of apixaban on aPTT based APC resistance test below concentrations of
447 ng/ml [19]. Though, as the utility of this assay outside of screening
for Factor V Leiden is still controversial, its use should be replaced by
genetic testing of the factor V mutation or used after the elimination of
DAOC interference (see below).
Measurement of antithrombin activity: Antithrombin potentiates
the effect of heparin in order to inhibit the activity of factors IIa and Xa.
Factor IIa and Xa inhibitors will cause a direct interference with some
testing techniques. The test most widely used in the laboratory and
considered more sensitive for antithrombin deficiency is dependent on
antithrombin induced factor Xa inhibition. In a recent publication, the
authors demonstrate that Xa-based techniques lead to a false elevation
of antithrombin by anti-Xa anticoagulants [20]. In this setting, a IIa
inhibition based technique would be preferable although suboptimal.
Similarly, dabigatran was not found to interfere with the measurement
of antithrombin with an anti-Xa technique. Thus, depending on the
assay used by the laboratory, DOACs have the potential to falsely in-
crease antithrombin levels and thus mask a deficiency.
Measurement of proteins C and S: The measurement of antigenic

Table 1
Interference of VKA and DOACs with thrombophilia testing.
Adapted from Favaloro et al. [11], Frater et al. [12], Bonar et al. [13], Douxfils et al. [14,15] and Marlar et al. [16].
VKA Anti-IIa (Dabigatran) Anti-Xa
(Edoxaban-Apixaban-Rivaroxaban)

FVL genotyping ↔ ↔ ↔
FII genotyping ↔ ↔ ↔
Activated Protein c Resistance (APCR) ↔ ↑ ↑ or ↔
AT activity (anti-Xa method) ↔ ↔ ↑
AT activity (anti-IIa method) ↔ ↑ ↔
Chromogenic protein C activity ↓ ↔ ↔
Antigenic protein C ↓ ↔ ↔
Protein S activity ↓ ↔ ↑ or ↔
Total and free protein S ↓ ↔ ↔
PT-based clotting factors/inhibitors ↑ ↓ ↓
PTT-based clotting factors/inhibitors ↔ ↓↓↓ ↓

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R. Alameddine, et al.
Protein C or functional protein C by a chromogenic method is not af-
fected by DOACs. It is the same for the measurement of the antigenic
total and free S protein. On the other hand, there is a false elevation of
functional protein S (which is based on a coagulating method) with
increasing levels of an anti-Xa agent. Therefore, the measurement under
DOAC has the potential to cause a false increase in the levels of the
activity of the protein S and thus mask a state of deficiency.
In conclusion, it is preferable to stop taking DOACs at least 2 days
before antithrombin and functional protein S assays or when drug levels
are completely absent (potentially confirmed by drug level assays).
Interruption of anticoagulation in these patients can be problematic as
there is risk of thromboembolic recurrence. DOAC-Stop® is a method
described to overcome this problem. Coagulation tests were performed
on 135 patients taking different DOACs after adding these adsorbent
tablets to their blood samples. The study demonstrated its efficacy in
overcoming interferences, thus facilitating interpretation of thrombo-
philia screening tests in patients taking DOACs [21]. Another method
was published using activated carbon. In the 29 patients, activated
carbon using a dose of 20 mg/ml removed DOAC interference on coa-
gulation tests evaluated (PT and aPTT and lupus assays) [22]. These
particularities underscore the necessity to communicate adequately
with the laboratory in order to plan the most appropriate testing
strategy and the best timing according to the anticoagulant used.
5. Efficacy of DOACs in low risk CTs (isolated heterozygous factor
V Leiden and prothrombin G20210A mutation)
DOACs have become widely used for the prevention and treatment
of venous thromboembolism and their approved indications are ex-
panding. Many large-scale randomized trials have now convincingly
shown the efficacy and safety of DOACs as suitable alternatives to VKAs
for the acute treatment and secondary prophylaxis of VTE (Table 2).
The presence of CT has not been a criterion for selection or strati-
fication of patients enrolled in these studies. Most of the information
about efficacy and safety of DOAC in patients with CT is derived from
post-hoc analysis of patients with previously known thrombophilia, as
none of these studies have included baseline screening for CT.
Elsebaie et al. conducted a recent meta-analysis of large RCT of
DOACs for VTE in CT [10]. They evaluated the risks for VTE in patients
with CT included in the large RCTs and found that the treatment effect
of DOACs in terms of VTE recurrence was not different between patients
with CT compared to those without CT with a RR of 1.02; 95% CI,
0.80–1.30; (I2 = 46%). The presence or absence of thrombophilia was
not a significant interaction factor affecting outcomes for patients re-
ceiving DOACs vs VKA (p = 0.35). Similarly, the risk of major bleeding
or clinically relevant non major bleeding were not different between
DOACs and VKA arms in patients with CT with (RR, 0.84; 95% CI, 0.32
to 2.19; I2 = 0%) and (RR, 0.92; 95% CI, 0.62 to 1.36; I2 = 23%) re-
spectively. Thrombophilia did not alter the risk of major bleeding or
clinically relevant non major bleeding in the whole population with
Table 2
Current evidence on the use of DOACs in low risk thrombophilia.
Type of thrombophilia Treatment arms Study population (n)
Randomized controlled trials [10]
Prothrombin gene mutation DOAC 38
Warfarin/heparin 37
Factor V Leiden DOAC 217
Warfarin/heparin 239
Total DOAC 255
Warfarin/heparin 276
Retrospective database analysis [23]
Congenital thrombophilia Rivaroxaban 403
Warfarin 403
95% CI: 95% confidence interval; RR: risk ratio; MB/CRNMB: major bleeding/clinically relevant non-major bleeding events, HR: hazard ratio.
Thrombosis Research 185 (2020) 72–77
(p = 0.64 for major bleeding, and p = 0.29 for clinically relevant non
major bleeding).
Coleman et al. performed a review of the MarketScan database
consisting of a commercial database and Medicare [23]. They identified
patients with baseline thrombophilia including factor V Leiden, pro-
thrombin G20210A gene mutation and protein C, S and antithrombin
deficiency. Using a 1:1 propensity score, they matched 403 patients
receiving rivaroxaban and 403 patients on VKAs. There was no statis-
tical difference in recurrent VTE and major bleeding among the two
groups with HRs of 0.70, (95% CI = 0.33–1.49) and 0.55 (95%
CI = 0.16–1.86), respectively.
6. Efficacy of DOACs in high risk CT (AT, PC, PS, compound/
homozygous abnormalities)
Elsebaie et al. examined the efficacy of DOACs in patients with high
risk thrombophilias enrolled in RCTs. Only one recurrent event was
noted in 92 patients on DOACs and none in 79 patients on warfarin. The
relative risk of major bleeding or CRNMB was 0.97 (CI: 0.39–2.38) [10]
(Table 3).
Undas et al. reported a retrospective series of 33 patients with high-
risk thrombophilia. Twenty-five (76%) had a family history of VTE. All
patients had a history of VTE, mostly unprovoked (n = 22, 67%).
Almost one half of patients had isolated inherited thrombophilia in-
cluding protein C deficiency in 9%, antithrombin deficiency in 15% and
protein S deficiency in 12%, Factor V Leiden homozygous carrier in 3%
and Prothrombin G20210A mutation in 9%. The other half of patients
had combined mutations, combined heterozygous Factor V Leiden and
prothrombin G20210A was the most common combination (18%).
After a median of 28 months of treatment with VKA, 94% of patients
were transitioned to DOACs. Most patients (70%) received rivaroxaban
at a dose of 20 mg/day and the others received dabigatran and apix-
aban. Three recurrent episodes were observed. Two recurrences oc-
curred after voluntary withdrawal of the DOAC and one recurrence of
DVT occurred on treatment in an obese patient on rivaroxaban with
mixed Protein S deficiency/Factor V Leiden mutation after a 10-hour
flight [8].
McBride et al. reported a series of 13 patients with CT including 4
with concomitant cancer treated with DOACs. The majority of patients
had Factor V Leiden heterozygous and thus only 5 patients were re-
ported with severe thrombophilias. Patients had a median follow up of
2 years. One patient had recurrent DVT on rivaroxaban after 40 days
and did not recur after switching to apixaban. Further details are not
provided in this abstract publication [31].
Nojima et al. reported the case of a 40-year old man with antith-
rombin deficiency who presented with multiple thrombosis in the su-
perior mesenteric vein, inferior vena cava (IVC), right common iliac
vein, and pulmonary emboli treated with an IVC filter and started on
apixaban. Follow up after 6 months on CT scan demonstrated almost
complete resolution of previously described clots [26].
VTE recurrence (n) RR; 95% CI MB/CRNMB (n) RR; 95% CI
0 3
2 4
5 17
3 19
5 RR = 1.10; [0.31–3.86] 20/254 RR = 0.93; [0.52–1.67]
5 23/275
HR = 0.70, (0.33–1.49) HR = 0.55, (0.16–1.86)
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Table 3
Current evidence on the use of DOACs in high risk thrombophilia.
Pooled data from large randomized controlled trials [10]

Type of thrombophilia Treatment arm Study population (n) VTE recurrence (n) RR; 95% CI MB/CRNMB (n) RR; 95% CI

Antithrombin deficiency DOAC 15 0 2

Warfarin/heparin 11 0 1
Protein C deficiency DOAC 40 0 3
Warfarin/heparin 28 0 3
Protein S deficiency DOAC 37 1 4
Warfarin/heparin 40 0 4
Total DOAC 92 1 RR = 2.58 [0.11–62.47] 9/92 RR = 0.97 [0.39–2.38]
Warfarin/heparin 79 0 8/79

Case reports

Thrombophilia Medications Key findings

Van Bruwaene et al. [24] AT deficiency: 5 Rivaroxaban, Apixaban, During a median 21 (range 8–34) months follow-up, only one on treatment VTE
PC deficiency: 3 Dabigatran recurrence (9%) was observed
PS deficiency: 4
FVL homozygous: 1
FII homozygous: 3
Mixed defects: 17
Hermans et al. [25] PC and PS deficiency: 2 Rivaroxaban Apixaban Rivaroxaban and Apixaban safe and effective in 5 patients with CT
PS deficiency: 1
PC deficiency: 1
FVL and PC deficiency: 1
Menon et al. [26] AT deficiency Apixaban Apixaban safe and effective for more than 6 months after an extensive VTE.
Cook et al. [27] AT deficiency Rivaroxaban Rivaroxaban effective in preventing recurrent VTE after hip fracture surgery
Menon et al. [28] Protein C deficiency Rivaroxaban Rivaroxaban safe and effective in a child with warfarin induced skin necrosis.
Yagi et al. [29] Protein S deficiency Edoxaban Recurrence of VTE attributed to non-adherence.
Sakai et al. [30] AT deficiency Edoxaban Successful treatment and prevention of VTE after extensive femoral-inferior vena cava
thrombosis with PE treated by pregnancy interruption and Edoxaban. Patient successfully
continued edoxaban for 55 weeks until subsequent pregnancy.

95% CI: 95% confidence interval; RR: risk ratio; MB/CRNMB: major bleeding/clinically relevant non-major bleeding events.

Kawai et al. reported the case of a 90-year-old woman with familial
antithrombin deficiency who was successfully managed with antith-
rombin replacement and post-operative rivaroxaban after undergoing a
right femoral fracture repair [32].
In a 13-year-old child with warfarin induced skin necrosis and
thrombosis involving the inferior vena cava, left external iliac vein, and
popliteal vein, rivaroxaban was used as further treatment at the un-
conventional dose of 22.5 mg daily. Treatment was effective without
recurrence after three years of therapy [28].
Yagi et al., reported a 70-year-old man with unprovoked venous
thromboembolism, known for poor adherence, treated with edoxaban.
He developed an inferior vena cava thrombosis, was diagnosed with
Protein S deficiency and successfully switched to high dose apixaban
therapy thereafter [29].
Sakai et al. describe a 30-year-old patient experiencing an extensive
femoral-inferior vena cava thrombosis with PE during her fourth
pregnancy. A concurrent diagnosis of AT deficiency was made.
Treatment included heparin, a temporary IVC filter and pregnancy
termination. After hospital discharge the patient was treated success-
fully with edoxaban for 55 weeks. This treatment was replaced by un-
fractionated heparin and antithrombin concentrates at a further preg-
nancy discovered at 5 weeks gestational age [30].
7. Discussion
Diagnosis of CT in patients using anticoagulants is complex and
needs close interaction between the laboratory and the clinician. The
reliability of the results will vary according to the anticoagulant used,
the timing of the last dose and the particular assay performed in the
laboratory. It is therefore paramount that a previous diagnosis of CT be
validated by the integration of all these factors. Similarly, a diagnostic
work-up for CT must be planned in conjunction with a laboratory
physician aware of these issues.
This review provides some reassurance towards the efficacy and
safety of DOACs with either heterozygous factor V Leiden or the pro-
thrombin G20210A mutations. For other rarer types of high-risk CT, the
current literature has provided some successful experiences with DOAC
use, although the comparison to warfarin is not possible at this time.
The advantages of VKA are a greater clinical experience, a longer
duration of action of 2–5 days, which ensures sustained anticoagulation
even in case of missed doses, and the regular monitoring provided by
INR determination which may be associated with improved treatment
compliance. Although warfarin is not the only VKA used in many
countries, the current literature does not allow comparing its efficacy
with other VKAs with potentially important differences in their phar-
macologic profile such as phenprocoumon, phenindione and aceno-
coumarol.
In contrast, DOACs have the advantage of simple dosing, no need for
monitoring, limited drug and food interactions, no need for initial
parenteral course of anticoagulation (dabigatran and edoxaban ex-
cepted) and offer greater flexibility in situations in which a short in-
terruption or decrease in the intensity of anticoagulation might be
warranted, e.g. transiently high risk of bleeding such as menorrhagia.
Similarly to the differences in the VKAs, different DOACs have different
pharmacologic profiles and some are potentially more effective than
others. As well, differences in bleeding complication have been sug-
gested in network meta-analyses, more specifically in the management
of atrial fibrillation [33]. Therefore, clinical decisions should therefore
be individualized based on the overall clinical situation. Finally, no
data is available on reduced doses of DOACs for secondary prophylaxis
specifically in CT. Thus, low-dose long-term treatment with DOACs as
reported in EINSTEIN-CHOICE [34] and AMPLIFY-EXT [35] may not be
suited to all patients, especially in high-risk situations. Patients known
to have a high-risk CT were probably very infrequently enrolled in these

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trials given that their design included an aspirin or placebo arm. It
could be argued that in large randomized control trials of DOAC, pa-
tients with CT and APS were not excluded per se. Nonetheless, the
absence of categorisation of specific CTs in these studies precludes any
conclusion particularly in the rare and high risk thrombophilia sub-
groups. An effort should be made to gather further information on these
patients, especially in the form of sub-group studies from the available
clinical trials. The identification of the exact type of CT in these studies
would be helpful to further assess their impact on treatment selection.
8. Conclusion
Diagnosis of CT can often be erroneous if knowledge of the testing
conditions is not taken into account. Patients with heterozygous factor
V Leiden and prothrombin G20210A mutation seem to derive similar
benefits from DOACs as the general population without known CT. In
the setting of other types of CT, the use of DOACs might not be optimal
for patients with high-risk thrombophilias, as demonstrated for patients
with triple positive antiphospholipid syndrome. Nonetheless, DOACs
have the advantage over VKAs that they can be temporary interrupted
in some cases of bleeding (for example menorrhagias) or in situations of
a temporary high risk of bleeding (for example high risk sport activity).
Pending more detailed information, the final choice of long-term
treatment should therefore emanate from an informed discussion with
patients including the assessment of the risk of long-term non-com-
pliance and the presence of specific risk factors for bleeding.
In conclusion, there is a need for high-level of evidence regarding
the comparative efficacy and safety of DOACs compared to VKAs in CT
as most of the data stem from either post-hoc subgroup analysis of large
RCTs or small case series.
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