Journal of Thrombosis and Haemostasis, 16: 634–645
13970
REVIEW ARTICLE
The influence of thyroid function on the coagulation system
and its clinical consequences
L . P . B . E L B E R S , * 1 E . F L I E R S † and S . C . C A N N E G I E T E R ‡ §
*Department of Internal Medicine, MC Slotervaart; †Department of Endocrinology and Metabolism, Academic Medical Center, University of
Amsterdam, Amsterdam; ‡Department of Clinical Epidemiology, Leiden University Medical Center; and §Department of Internal Medicine,
Section of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands
To cite this article: Elbers LPB, Fliers E, Cannegieter SC. The influence of thyroid function on the coagulation system and its clinical conse-
quences. J Thromb Haemost 2018; 16: 634–45.
Summary. Several studies indicate that low plasma levels
of thyroid hormone shift the hemostatic system towards a
hypocoagulable and hyperfibrinolytic state, whereas high
levels of thyroid hormone lead to more coagulation and
less fibrinolysis. Low levels of thyroid hormone thereby
seem to lead to an increased bleeding risk, whereas high
levels, by contrast, increase the risk of venous thromboem-
bolism. Hypothyroidism leads to a higher incidence of
acquired von Willebrand’s syndrome and with increasing
levels of free thyroxine, levels of fibrinogen, factor VIII
and von Willebrand factor, amongst others, increase grad-
ually, to the extent that they may lead to symptomatic
venous thromboembolism in patients with hyperthy-
roidism. Here, we discuss the literature on the effect of
thyroid hormone on the hemostatic system and the associ-
ated risk of bleeding and venous thromboembolism.
Patients with hypothyroidism are at increased risk of
developing bleeding complications, which could be rele-
vant in patients undergoing invasive procedures. Further-
more, physicians should be aware of the possibility of
hyperthyroidism as an underlying risk factor for venous
thromboembolism, especially in unexplained cases. Clini-
cal studies are needed to further investigate the signifi-
cance for general practice of these findings. Besides the
effects of hyperthyroidism on venous thromboembolism,
its effects on embolism secondary to atrial fibrillation are
described.
Correspondence: Laura P. B. Elbers, Medical Centre Slotervaart,
Department of Internal Medicine, Louwesweg 6, 1066 EC Amster-
dam, the Netherlands
E-mail: Elbers.L@zaansmc.nl
1
Present address: Zaans Medisch Centrum, Zaandam, the Netherlands
Received: 12 July 2017
Manuscript handled by: P. H. Reitsma
Final decision: P. H. Reitsma, 9 January 2018
DOI: 10.1111/jth.
Keywords: blood coagulation; fibrinolysis; hemorrhage;
hyperthyroidism; hypothyroidism; venous thrombosis.
Introduction
Thyroid hormone affects several cardiovascular parame-
ters. Hypothyroidism is associated with an unfavorable
lipid profile because thyroid hormone stimulates the clear-
ance of cholesterol in the liver [1]. Overt and subclinical
hypothyroidism increase the risk of cardiovascular disease
and mortality [2,3]. Hyperthyroidism increases the risk of
atrial fibrillation [4,5] and overt and subclinical hyperthy-
roidism are associated with an increased risk of arterial
thrombosis and mortality, at least partly mediated by
atherosclerosis [6–9]. Although less known, thyroid hor-
mone also influences the coagulation system. Several stud-
ies indicate that low levels of thyroid hormone shift the
hemostatic system towards a hypocoagulable and hyperfib-
rinolytic state, whereas high levels of thyroid hormone lead
to more coagulation and less fibrinolysis. Low levels of thy-
roid hormone thereby seem to lead to a higher bleeding
risk, whereas high levels, on the other hand, increase the
risk of venous thromboembolism. The clinical implications
of the effects of thyroid hormone on the hemostatic system,
however, have received relatively little attention. Therefore,
for this review we set out to evaluate and discuss the effect
of plasma thyroid hormone concentrations on the hemo-
static system and its associated risk of bleeding and venous
thromboembolism. Because the level of free thyroxin
(FT4), and not thyroid stimulating hormone (TSH), is the
best reflection of the directly available amount of thyroid
hormone, this is the measurement that was focused on [10].
Effects of thyroid hormone on markers of coagulation
and fibrinolysis
As early as 1965, Simone et al. showed significantly
reduced levels of factor (F) VIII, FIX and FXI in
hypothyroid patients [11]. More recently, increased
© 2018 International Society on Thrombosis and Haemostasis

bleeding time, prothrombin time (PT) and activated par-
tial thromboplastin time (APTT), and decreased FVIII
activity as well as von Willebrand factor (VWF) activity
were observed in patients with overt hypothyroidism
when compared with controls [12]. These abnormalities
were reversed after treatment with levothyroxine. These
results were supported by a prospective study showing
that severe short-term hypothyroidism in patients follow-
ing a total thyroidectomy for thyroid cancer was associ-
ated with significantly lower levels of VWF and FVIII
compared with these levels in the same patients when they
were in a euthyroid state [13]. Nevertheless, these results
should be interpreted with caution, because both the
malignancy as well as the surgical procedure could have
altered the thrombotic environment. An observational
cohort study showed that hypothyroidism resulted in
hyperfibrinolysis (shorter clot lysis time) and a reduced
activated thrombin-activatable fibrinolysis inhibitor
(TAFIa)-dependent prolongation of clot lysis [14]. Other
analyses in this study showed lower clot maximum absor-
bance, shorter clot lysis time, smaller clot lysis area and
less compact fibrin clots; all of these abnormalities were
resolved upon restoration of a euthyroid state [15].
In subclinical hypothyroidism, there does seem to be a
net prothrombotic effect with higher levels of FVII, PAI-
1 and tissue plasminogen activator (t-PA), compared with
healthy controls, whereas these levels were reduced after
6 months of therapy with levothyroxine [16]. TAFI levels
appeared to be increased in subclinical hypothyroidism
[17] and another study showed that global fibrinolytic
capacity was significantly lower in patients with subclini-
cal hypothyroidism, compared with a control group [18].
The effect of hyperthyroidism on procoagulant, antico-
agulant and fibrinolytic factors has been described in sev-
eral studies in the past decades. A recent systematic
review and meta-analysis reported the influence of hyper-
thyroidism on the coagulation and fibrinolytic system
in vivo [19]. A total of 29 articles consisting of 51 studies
were included. The studies were of varying quality. Five
cross-sectional studies (hyperthyroid subjects and euthy-
roid controls), four intervention studies (before and after
treatment in hyperthyroid patients) and four experimental
studies (before and after use of thyroid hormone in
euthyroid subjects) of medium/high quality were used for
meta-analysis. In the four medium-quality observational
cross-sectional studies, levels of VWF, fibrinogen and
D-dimer were significantly increased in persons with sub-
clinical hyperthyroidism compared with euthyroid con-
trols [20–22]. In patients with overt hyperthyroidism, only
fibrinogen levels had been measured, which were slightly
increased [23]. In the four medium-quality intervention
studies, increased levels of plasma fibrinonectin, VWF,
thrombomodulin and PAI-1, and decreased levels of
t-PA, were observed during hyperthyroidism when com-
pared with a euthyroid state after anti-thyroid treatment
[24–27]. Four experimental studies investigated laboratory
© 2018 International Society on Thrombosis and Haemostasis
Thyroid and coagulation 635
parameters in healthy volunteers taking thyroid hormone
for a specific period of time and this exogenous thyrotoxico-
sis led to increased plasma levels of tissue factor, FVIII,
FIX, FX, VWF, fibrinogen, D-dimer and PAI-1, and
resulted in a prolongation of clot lysis time and shortening
of APTT [28–30]. In the meta-analysis, it was concluded
that hyperthyroidism shifts the hemostatic balance towards
a hypercoagulable and hypofibrinolytic state, which was
observed in both endogenous and exogenous hyperthy-
roidism, and in both subclinical and overt hyperthyroidism.
After publication of this systematic review, another study of
experimental hyperthyroidism added that the procoagulant
factors XIII subunit B, FII, FV and FXI also positively cor-
related with higher FT4 levels (regression coefficient ≥ 0.8)
[31]. Also, a positive correlation could be found for FIX.
Concomitantly, plasminogen, the main enzyme promoting
fibrinolysis, was decreased. Others investigated patients
who shifted from severe hypothyroidism to mild hyperthy-
roidism during thyroid cancer treatment and showed
in vitro that during levothyroxine treatment, the activation
times of platelet adhesion and aggregation after stimulation
with collagen and epinephrine/adenosine-diphosphate were
significantly shortened [32]. The previously shown effects of
increasing levels of thyroid hormone on VWF and FVIII
were confirmed in this study. Platelet plug formation was
also studied as collagen-epinephrine-induced closure time
(CEPI-CT) in a cohort of 120 patients with overt hyperthy-
roidism, patients with subclinical and overt hypothy-
roidism, and euthyroid controls [33]. Hyperthyroidism was
associated with shortened CEPI-CT values and thus
increased platelet plug formation. Platelet plug formation
decreased during therapy with thiamazole. The effect of
exogenous hyperthyroidism on TAFI was studied in healthy
volunteers who were randomized to receive levothyroxine
or no medication for 14 days in a crossover design [14].
Thyroid hormone excess resulted in a hypofibrinolytic con-
dition and in an enhanced TAFIa-dependent prolongation
of clot lysis. In addition, a trend towards decreased plasma
TAFI levels was observed. Hooper et al. showed that
hyperthyroid subjects displayed higher clot maximum
absorbance compared with controls and longer clot lysis
time [34], which correlated with FT4 levels. Plasma levels of
fibrinogen and PAI-1 were significantly higher in patients
compared with controls. These effects of FT4 on fibrinogen
and PAI-1 were also observed in the study of Horacek et al.
[32]. In Fig. 1, a simplified schematic representation of
coagulation and fibrinolysis pathways is represented, as well
as the effect of endogenous hyperthyroidism on its parame-
ters. In Table 1, we summarized the available evidence on
the influence of thyroid hormone status on hemostatic bal-
ance.
Bleeding
In line with the observed effects on the coagulation sys-
tem in patients with hypothyroidism, a notable incidence
636 L. P. B. Elbers et al

Plasma
Intrinsic Extrinsic Vessel
pathway VWF wall
pathway
(tissue factor)
FXII
FXI FV FVII
FIX FX
FVIII

Prothrombin Thrombin

F1+2 Plasminogen PAI-1

Fibrinogen Fibrin t-PA

Plasmin

D-dimer

Fig. 1. Simplified schematic representation of coagulation and fibrinolysis pathways, and the effect of endogenous hyperthyroidism on its
parameters in medium or high-quality studies. F indicates Factor. Von Willebrand factor (VWF), present in plasma by constitutive or induced
release from endothelial cells, facilitates adhesion and aggregation of platelets to the injured vessel wall (primary hemostasis). The coagulation
system (secondary hemostasis) can be activated via two pathways leading to fibrin formation. The intrinsic pathway is initiated by exposure to
negatively charged molecules such as polyphosphates, neutrophil extracellular traps, DNA or RNA. The extrinsic pathway is initiated by the
exposure of tissue factor after injury of the endothelium. F1 + 2 is the activation peptide that is cleaved during thrombin formation, and can
therefore be considered a marker for thrombin generation. Plasmin is the enzyme that degrades fibrin clots. Plasminogen activator inhibitor-1
(PAI-1) inhibits tissue-type plasminogen activator (t-PA). D-dimer is a degradation product of fibrin and therefore a marker of both coagula-
tion and fibrinolysis.

of acquired von Willebrand syndrome (aVWS) has been
observed in hypothyroid patients, which could be relevant
in patients undergoing invasive surgical procedures. This
association was first addressed by several case reports. In
a systematic review on hypothyroidism and aVWS, pub-
lished in 2008, several epidemiological studies of low to
medium quality were identified, and no studies of high
quality [35]. Still, the results supported a pivotal role of
VWF in the bleeding tendency in patients with overt
hypothyroidism. The bleeding episodes were mainly
mucocutaneous, the bleeding tendency was ameliorated
by desmopressin administration and laboratory tests
showed low levels of VWF and low FVIII levels. In 2012,
the first prospective study on aVWS in patients with
newly diagnosed overt hypothyroidism was published
[36]. In this study consecutive hypothyroid patients were
enrolled before or within the first 48 hours of replacement
therapy. Patients were divided into severe (VWF:antigen
[Ag] and/or VWF:ristocetin [RCo] ≤ 10%), moderate
(VWF:Ag and/or VWF: RCo between 10% and 30%) or
mild aVWS (VWF:Ag and/or VWF:RCo between 30%
and 50%). Among 90 hypothyroid patients, an incidence

Table 1 Available evidence on the influence of thyroid hormone status on hemostatic balance, risk of bleeding and risk of venous thromboem-
bolism

Thyroid function Hemostatic balance Increased risk

Overt hypothyroidism Hypocoagulable state [11–15] Bleeding [38]

Possibly abnormal vaginal bleeding [40,41,62]
Subclinical hypothyroidism Possibly hypercoagulable state [18–20] Possibly abnormal vaginal bleeding [42]
Lower levels of FT4 within reference ranges Possibly hypocoagulable state [48] Possibly bleeding [43]
Higher levels of FT4 within reference ranges Possibly hypercoagulable state [25] VTE [10,48,49]
Subclinical hyperthyroidism Possibly hypercoagulable state [22–24] Unknown
Overt hyperthyroidism Hypercoagulable state [14,26–34,36] VTE [9,53–55,57,58]

VTE indicates venous thromboembolism; FT4, free thyroxine.

© 2018 International Society on Thrombosis and Haemostasis


of aVWS of 33% was found. There were no patients with
severe aVWS, 9% had moderate aVWS and 23% had
mild aVWS. Bleeding score was negatively correlated with
both VWF:Ag and VWF:RCo. After restoration of
euthyroidism, VWF:Ag had significantly increased by
44%, VWF:RCo by 36%, FVIII by 39%, and endoge-
nous thrombin potential by 10%.
Although it is commonly accepted among clinicians
that hypothyroidism leads to an increased risk of abnor-
mal vaginal bleeding [37], the available data are scarce.
One study found that menorrhagia was more common in
171 women with hypothyroidism than in 214 healthy con-
trols (7% vs. 1%). Another study reported that the inci-
dence of menstrual disturbances was similar among 586
women with hyperthyroidism (18.3%) and 111 women
with hypothyroidism (15.3%) compared with 105 healthy
controls (23.8%) [38]. However, patients with severe
hypothyroidism had a higher incidence (34.8%) of men-
strual disturbances than mild-moderate cases (10.2%).
Others stated that hypothyroidism may be greatly under-
diagnosed as a cause of menorrhagia [39], but this was
based on a study in women using an intrauterine device
and suffering from increased menstrual bleeding in whom
FT4 and TSH levels were all in the normal range whereas
thyrotropin-releasing hormone (TRH) stimulation tests
were consistent with occult hypothyroidism in the 10
women having the highest TSH levels [40]. Of note, all
had significant improvement in bleeding symptoms within
3 months after treatment with levothyroxine.
Recently, it was suggested that low plasma levels of FT4
within the reference range also influence the risk of bleed-
ing. The FACTORS (Factors in Oral Anticoagulant
Safety) study is a case–control study in patients receiving
vitamin K antagonist (VKA) treatment, including 110
cases with major hemorrhage and 220 matched controls
treated with VKA without major hemorrhage [41]. In this
study, the risk of major hemorrhage was increased 5-fold
in patients with an FT4 level below 13 pmol L 1, compared
with patients with an FT4 level above 13 pmol L 1 (odds
ratio [OR], 5.1; 95% confidence interval [CI], 0.9–28.6). At
a cut-off of 14 pmol L 1, the risk was increased 3-fold
(OR, 2.9; 95% CI, 1.0–8.5). However, an increased risk of
major bleeding with low levels of FT4 within the reference
range was not observed in patients undergoing bariatric
surgery [42]. Seventy-two cases (2.5%) with major bleeding
were identified in a cohort of 2872 consecutive patients
undergoing bariatric surgery, and 288 controls were
selected. The median plasma level of FT4 was 13 pmol L 1
(interquartile range, 12–14) in the cases as well as in the
controls. No clear effect was observed of low levels of FT4
on the risk of major bleeding: odds ratio 1.48 (95% CI,
0.46–4.80) for patients with an FT4 level < 11 pmol L 1,
1.03 (0.49–2.18) for patients with an FT4 level < 12
pmol L 1 and 1.12 (0.65–1.94) for patients with an FT4
level < 13 pmol L 1 as compared to patients with FT4 val-
ues greater than or equal to these cut-off levels. There are
© 2018 International Society on Thrombosis and Haemostasis
Thyroid and coagulation 637
several potential explanations for the differences observed
in the study in patients undergoing bariatric surgery and
the study in patients receiving VKA treatment. First, both
populations were clearly different: the bariatric population
was younger and, most importantly, in the FACTORS
study all patients were on VKAs, whereas these patients
were excluded in the study in patients undergoing bariatric
surgery. Furthermore, the bariatric population consisted of
patients with obesity, which is in itself associated with
hypercoagulability and an increased VTE risk [43]. All
major bleeding events were attributed to a surgical proce-
dure, in contrast to the (mainly) spontaneous bleeding
events in patients on VKAs. Second, an explanation for
the increased risk of major bleeding in the FACTORS
study could be that lower levels of FT4 influence VKA sta-
bility, which was observed in a pilot study [44]. However,
the same study observed that patients with subclinical
hypothyroidism had a diminished sensitivity for VKAs,
which would make them less prone to bleeding. The litera-
ture on overt hypothyroidism also argues against this
explanation because overt hypothyroidism seems to dimin-
ish the effect of VKAs by decreasing the clearance of coag-
ulation factors [45].
Venous thromboembolism
Even within the normal range, higher plasma levels of
FT4 are associated with an increased risk of VTE (deep
vein thrombosis [DVT] and pulmonary embolism [PE]) in
a dose–response manner [10,46,47] (Fig. 2). Interestingly,
two studies observed odds ratios (ORs) below 1 for low
levels of FT4, suggesting that low levels of FT4 could pro-
tect against VTE [10,46]. In a case–control study on leg
vein thrombosis (the ACT study), parameters of thyroid
function were assessed at time of presentation in 190 cases
and 379 sex-matched controls [10]. For several cut-off
levels, it was observed that the risk of VTE gradually
increased with increasing levels of FT4. FT4 levels above
17 pmol/l yielded a sex- and age-adjusted OR of 2.2
(95% CI, 1.2–4.2) for unprovoked DVT, which further
increased up to an OR of 13.0 (95% CI, 1.1–154.1) for
FT4 levels above reference range. Likewise, in a prospec-
tive case–cohort study performed within the HUNT2
cohort in Norway, where blood was sampled some time
before the thrombotic event, the risk of VTE clearly
increased gradually with increasing levels of FT4 (OR 2.5
[95% CI, 1.3–5.0] for FT4 levels exceeding 17.3 pmol/l
relative to levels below this cut-off) [47]. This risk was
even higher with shorter time between blood sampling
and thrombosis (up to an OR of 9.9 [95% CI, 2.9–34.0]
when the period between blood sampling and thrombosis
was less than 0.5 years). In a third study, a large popula-
tion-based case–control study (MEGA study) designed to
identify risk factors for VTE, the aims were (i) to study
the effect of thyroid hormone levels on the levels of coag-
ulation proteins, and (ii) to assess the role of the latter in
638 L. P. B. Elbers et al

ACT MEGA
100 5

4
10
3
OR

OR
2
1
1

0.1 0
10 15 20 25 18 20 22 24 26
FT4 (pmol/L) FT4 (pmol/L)

HUNT2
100
10

10

OR
1
OR

ACT
1 MEGA
HUNT2
0.1
0.1 10 12 14 16 18 20 22 24
10 12 14 16 18 FT4 (pmol/L)
FT4 (pmol/L)

Fig. 2. Risk of venous thromboembolism (VTE) according to plasma levels of free thyroxine in the ACT study, the MEGA study and HUNT2
cohort. Risks are expressed as odds ratio (OR) (95% confidence interval). FT4 indicates free thyroxine. The analyses of the ACT study were
adjusted for age and gender. For each cut-off level below the 50th percentile, subjects below the cut-off were compared to subjects above this
level with the use of the latter as reference, and vice versa for cut-off levels above the 50th percentile. The analyses of the MEGA study were
adjusted for age, sex, body mass index and smoking. Serum FT4 levels of 15.5–18.9 pmol L 1 were chosen as the reference group. Analyses in
the HUNT2 cohort were adjusted for age and gender and restricted to the cases with VTE within 0.5 years from blood sampling. As cut-off
points for FT4, the 2nd, 5th, 10th, 90th, 95th and 98th percentiles in the control group were used. For the lower percentiles, the numbers of
case and control subjects below the cut-off percentile were compared with the numbers above this cut-off percentile. For the higher percentiles,
the opposite was done.

the association between FT4 and VTE [46]. Blood was
donated at a median of 10 months after the event. High
levels of FT4 were associated with increased concentra-
tions of procoagulant factors (i.e. FVIII, FIX, fibrinogen
and VWF; see Figs 3 and 4 for effects of different levels
of FT4 on FVIII and VWF in controls), and also with an
increased risk of VTE, up to an OR of 2.2 (95% CI, 1.0–
4.6) for levels above 24.4 pmol L 1 relative to FT4 levels
between 15.5 and 18.9 pmol L 1. In 11 cases and one
control, clinical hyperthyroidism was diagnosed shortly
before or after the thrombotic event, leading to a 17-fold
increased risk of VTE (OR, 17.0; 95% CI, 2.2–133.0).
The ORs approached unity after adjustment for FVIII
and VWF, suggesting that the effect was mediated by
these factors.
Several studies investigated the risk of VTE in patients
with overt hyperthyroidism. These studies are summarized
in Table 2. At first, numerous case reports, the first of
which was published already in 1927 [48], addressed the
possible association between hyperthyroidism and
cerebral venous thrombosis (CVT) [49,50]. One of these
case reports pointed out that the incidence reported in the
literature of the combination of CVT and thyrotoxicosis
was already significantly higher than expected by chance
alone (0.1 9 10 6 per year vs. 0.0032 9 10 6 year 1),
suggesting that thyrotoxicosis, possibly through a factor
VIII-mediated hypercoagulability, is a predisposing factor
for the development of CVT [49]. This conclusion was
based on the finding that except for an increased factor
VIII clotting activity there were no thrombophilic abnor-
malities. From the seven published papers on this topic,
six studies have shown an increased risk of VTE in
patients with hyperthyroidism [51–56] and one did not
find such an association [57]. In a cohort study of 428
hyperthyroid patients without a control population, three
patients (0.7%) had a documented episode of VTE within
6 months of diagnosing hyperthyroidism [52]. Although it
was concluded that the absolute risk of VTE in acute
hyperthyroidism was low, the incidence of VTE in this
study was much higher than in the general population

© 2018 International Society on Thrombosis and Haemostasis

 Thyroid and coagulation 639

Factor VIII activity 8903 patients with hyperthyroidism and a control cohort
of 44 515 persons without hyperthyroidism. Here, hyper-
FVIII:C (IU/mL) (means [95% CI])

thyroidism was associated with a 2.3 times greater risk

200
(95% CI, 1.20–4.45) of PE compared with controls during
a 5-year follow-up period and after adjusting for con-
founding factors [53]. During this 5-year follow-up per-
iod, a substantial proportion of the patients had probably
150
become euthyroid, which may have resulted in an under-
estimation of the short-term risk. Recently, a nationwide
population-based cohort study was performed using data
100
from the Danish Civil Registration System and the Dan-
ish National Patient Registry. In this study, data from
85 856 patients diagnosed with hyperthyroidism and
10 –1
2
–1
5
–1
8
–2
1
–2
4 24 847 057 age- and sex-matched general population com-
< >
10 13 16 19 22 parison cohort members were evaluated [9]. Patients with
FT FT
4 4
= = = = =
FT FT FT FT FT
4 4 4 4 4
hyperthyroidism had a 3-fold increased risk of a first
Serum free thyroxine (pmol/L) occurrence of VTE within 3 months after diagnosis of
hyperthyroidism (hazard ratio, 3.28; 95% CI, 2.71–3.97).
Fig. 3. Effect of different levels of FT4 on factor VIII activity Diagnoses of hyperthyroidism and VTE were retrieved
(FVIII:C) (IU mL 1) in controls of the MEGA study (means with
from ICD codes. The fifth and sixth studies investigated
95% confidence intervals). FT4 indicates serum free thyroxine
(pmol L 1). the risk of VTE in patients with autoimmune disease, one
of which was Graves’ disease [55,56]. One was a large
cohort study achieved using three databases of linked sta-
tistical records of hospital admissions in England, which
Von Willebrand factor antigen
concluded that Graves’ disease was associated with an
VWF antigen (U/dL) (means [95% CI])

increased risk of VTE with a rate ratio of 1.56 (95% CI,

200
150
100
10 –1
< >
10
FT
4 4
= =
FT
4 4
Fig. 4. Effect of different levels of FT4 on von Willebrand factor
antigen (VWF) (U dL 1) in controls of the MEGA study (means
with 95% confidence intervals). FT4 indicates serum free thyroxine
(pmol L 1).
(0.7% vs. 0.072% in 6 months in the general population
[58]). Another cohort study among patients with hyper-
thyroidism caused by Graves’ disease, multinodular goiter
or toxic adenoma investigated the occurrence of VTE
between 6 months before and 6 months after the diagno-
sis of hyperthyroidism [51]. Out of 587 patients, five
patients experienced a VTE during the study period,
resulting in an incidence rate of 8.7 per 1000 person-
years, which is also much higher than in the general pop-
ulation. The third study was a large population study in
1.23–1.95) compared with a reference cohort of subjects
without autoimmune disease [55]. The Swedish Hospital
Discharge Register was used to perform a cohort study
with a control group with 50 954 individuals with Graves’
disease, again based on diagnostic codes. It was con-
cluded that Graves’ disease was associated with a high
risk of PE in the first year after hospital admission (stan-
dardized incidence ratio, 6.50; 95% CI, 5.84–7.23; com-
pared with the total population of Sweden) [56].
However, the design of these two studies limits allocation
as to whether the disease was active (overt hyperthy-
2
–1
5
–1
8
–2
1
–2
4 24 roidism) or already treated at time of the diagnosis of
13 16 19 22
FT
= = = VTE. The final study, the only one that did not find an
FT FT FT FT
4 4 4
association between hyperthyroidism and VTE risk,
Serum free thyroxine (pmol/L) aimed to explore a possible role of thyroid dysfunction in
VTE using the National Hospital Discharge Survey
(NHDS) in the USA. The authors concluded that hyper-
thyroidism was not associated with an increased risk of
VTE, but these results are hard to interpret because the
identification of patients with hyperthyroidism was based
on diagnostic codes after discharge and it was unknown
whether patients were already treated at the time of VTE
[57]. Also, information on thyroid hormone status at the
time of VTE was lacking.
Atrial fibrillation and hyperthyroidism
Effects of thyroid hormone on the heart may indirectly
influence hemostasis. Increased action of thyroid hormone
causes a hyperdynamic cardiovascular state with higher

© 2018 International Society on Thrombosis and Haemostasis

 Table 2 Clinical endpoint studies in hyperthyroidism

Study
Author, year [ref] design Cohort; objective Sample Clinical endpoints Results Conclusions

Danescu, 2009 [57] Cohort National Discharge Survey; to study the Exposed: 633 000 patients with PE and DVT Relative risk 0.98, 95% CI Hyperthyroidism is not
incidence of VTE in patients discharged hyperthyroidism* 0.96–1.01 associated with an
from short-stay hospitals in the USA Unexposed: 908 172 patients increased risk of VTE
640 L. P. B. Elbers et al

between 1979 and 2005 with or without without thyroid dysfunction

hyperthyroidism
Lin, 2010 [53] Cohort The Taiwan Longitudinal Health
Insurance Database; to estimate the risk
of PE among hyperthyroid patients
compared with non-hyperthyroid
patients
Ramagopalan, Cohort Three databases of linked statistical
2011 [55] records of hospital admissions in
England; to study the risk of VTE in
patients admitted to the hospital with
immune-mediated diseases
Kootte, 2012 [51] Cohort Hospital records of three hospitals in the
Netherlands between 2003 and 2009; to
determine the risk of VTE in all
patients with overt hyperthyroidism
Z€
oller, 2012 [56] Cohort The Swedish Hospital Discharge
Register; to study the risk of VTE after
hospital admission for autoimmune
disorders
Kim, 2013 [52] Cohort Consecutive outpatients presenting to the
endocrinology clinic at two district
hospitals in New Zealand from 2006 to
2008; to identify all occurrences of
objectively proven symptomatic VTE in
the 6 months following the diagnosis
of hyperthyroidism
Dekkers [9] Cohort The Danish Civil Registration System
and the Danish National Patient
Registry; to compare the rate of all-
cause mortality as well as first
occurrence of VTE, acute myocardial
infarction, ischemic and non-ischemic
stroke, arterial embolism, atrial
fibrillation and percutaneous coronary
intervention in the two cohorts
Exposed: 8903 patients with
hyperthyroidism*
Unexposed: 44 515 patients
without thyroid dysfunction
Exposed: 101 402 individuals with
hyperthyroidism*
Unexposed: 313 716 individuals
without hyperthyroidism
Exposed: 587 patients with overt
hyperthyroidism†
Exposed: 50 954 individuals with
Graves’ disease*
Unexposed: total population of
Sweden
Exposed: 428 patients with acute
hyperthyroidism†
Exposed: 85 856 patients
diagnosed with hyperthyroidism*
Unexposed: 847 057 general
population comparison cohort
PE Relative risk 2.31, 95% CI
1.20–4.45
PE and DVT Rate ratio 1.56, 95% CI
1.23–1.95
PE and DVT 5/587 had VTE, resulting
in an incidence rate of 8.7
per 1000 person-years,
95% CI 2.8–20.2
PE Standardized incidence
ratio 6.50, 95% CI 5.84–
7.23
PE and DVT 3/428 (0.7%) had VTE
and CVT
PE and DVT Hazard ratio 3.28, 95% CI
2.71–3.97, within
3 months after diagnosis
of hyperthyroidism
Patients with
hyperthyroidism are at
increased risk of PE
Graves’ disease is
associated with an
increased risk of VTE
The incidence of VTE in
patients with
hyperthyroidism is higher
than expected
Graves’ disease is
associated with a high
risk of PE in the first year
after hospital admission
The absolute risk of VTE
in acute hyperthyroidism
is low
Patients with
hyperthyroidism are at
increased risk of VTE

VTE, venous thromboembolism; PE, pulmonary embolism; DVT, deep venous thrombosis; CI, confidence interval; CVT, cerebral venous thrombosis. *Based on diagnostic codes. †Biochemi-
cally confirmed.

© 2018 International Society on Thrombosis and Haemostasis


cardiac output and a faster heart rate, increased left ven-
tricular function and increased incidence of supraventricu-
lar tachyarrhythmias. Hyperthyroidism leads to a higher
incidence (4.6% to 25%) of atrial fibrillation and atrial
flutter [4,5,9,59] and, at least partly by that mechanism, a
higher risk of cerebral arterial thrombosis [7–9]. A 5-year
follow-up study in young adults found that the hazard of
having ischemic stroke during the 5-year follow up period
was 1.44-times greater for patients with hyperthyroidism
than for patients in the comparison cohort [7]. Siu et al.
found that in hyperthyroid patients who presented with
new onset AF, there was an increased risk of ischemic
stroke. Ischemic stroke was observed in 15 hyperthyroid
patients with AF (9.4%) vs. five patients with non-thyroid
AF (3.1%, P = 0.02) and one hyperthyroid patient with-
out AF (0.6%, P < 0.001) [8].
Discussion and concluding remarks
From the available literature it can be concluded that low
levels of FT4 lead to a hypocoagulable and hyperfibri-
nolytic state and to an increased risk of bleeding. Also,
low levels of FT4 may protect against VTE. With increas-
ing levels of thyroid hormone, more coagulation and less
fibrinolysis are present and the risk of VTE is increased
in a dose–response kind of way, resulting in increased
VTE risk in overt hyperthyroidism.
Despite the increase in body weight, hypertension and
dyslipidemia, which are associated with a prothrombotic
environment, an increased bleeding tendency is observed
in some patients with overt hypothyroidism. Observed
bleedings were mucocutaneous and related to aVWS.
Also, less compact fibrin networks with enhanced fibrinol-
ysis were observed in hypothyroidism. Low levels of FT4
within the normal range may also lead to a higher risk of
bleeding [41] but this association was not found in
patients undergoing bariatric surgery [42].
In the literature, it is suggested that (subclinical)
hypothyroidism could lead to an increased risk of menor-
rhagia [37] but the available evidence is scarce [38–40,60].
Considering the effect of thyroid hormone on hemostasis,
theoretically, it is likely that hypothyroidism could lead
to more vaginal blood loss. One could speculate that this
is also caused by a direct effect of thyroid hormone on
muscle contractility and connective tissue. At present, it
seems that low levels of FT4 lead to an increased inci-
dence of menorrhagia. Because this is a clinically relevant
problem, this should be investigated in more detail.
With higher levels of FT4, the risk of VTE is increased in
a dose–response kind of way. The study within the HUNT2
cohort demonstrated a second dose–response relation (i.e.
that the relative risk for VTE was higher when the time
between VTE and blood sampling became shorter). Such
dose–response associations are suggestive of a causal rela-
tion. Likewise, in studies investigating the relation between
VTE and FT4, a longer time between thyroid function
© 2018 International Society on Thrombosis and Haemostasis
Thyroid and coagulation 641
measurement and blood sampling could cause an underesti-
mation of the relation. One could debate whether the
observed increased risk of VTE with higher levels of FT4 is
influenced by so-called non-thyroidal illness syndrome
(NTIS). The most common and earliest change in this syn-
drome is inhibition of thyroxin (T4)-to-triiodothyronine
(T3) conversion, with a resulting decrease in the circulating
T3 level [61]. The analyses in the study of van Zaane et al.
showed that cases had higher T3 levels compared with con-
trols, whereas there was a clear association between T3 and
VTE, making it highly unlikely that the findings are a
reflection of NTIS [10].
Due to lack of a control group in the majority of the
studies investigating patients with overt hyperthyroidism
[51–53], it is impossible to calculate relative risks for VTE
in these studies. In some studies investigating the risk of
VTE in overt hyperthyroidism, it is likely that patients
who already achieved euthyroidism were also included,
which probably dilutes the observed risk of VTE. Some
studies investigating patients with overt hyperthyroidism
also included recurrent hyperthyroidism, which could fur-
ther dilute the risk of VTE because in general, patients
with recurrent hyperthyroidism are diagnosed earlier, and
are therefore exposed to high levels of FT4 to a lesser
extent and for a shorter duration of time. Studies that
used ICD codes to investigate the risk of VTE in hyper-
thyroidism may not have provided reliable data on the
underlying cause of diagnosed hyperthyroidism and thy-
roid function at the time of diagnosis of VTE, and may
also have underestimated the relation. In our opinion, the
most important explanation for the somewhat contradic-
tory results in these studies, is the lack of data on thyroid
function (truly overt hyperthyroidism?) at time of diagno-
sis of the venous thromboembolism. Until now, there
have been no clinical endpoint studies in patients with
biochemically confirmed hyperthyroidism that included a
control group (Table 2), except for the MEGA-study and
the ACT study, but these studies included only a few
patients with overt hyperthyroidism [10,46]. Nevertheless,
high relative risks were found in both studies (i.e. of 17
and 13). At present, the limitations of the currently avail-
able evidence hamper the formulation of specific recom-
mendations for clinical practice. Thus, a study in a cohort
of consecutive patients with newly diagnosed and bio-
chemically confirmed hyperthyroidism, with a control
group of patients without hyperthyroidism, is warranted.
Thyroid function parameters will need to be collected at
several timepoints to justify the classification of VTE as
provoked by hyperthyroidism. Such a design would allow
for the calculation of absolute and relative risks for VTE
in hyperthyroidism and would provide information on
the time relation between the diagnoses of hyperthy-
roidism and VTE, as hyperthyroidism may be present
some time before it is diagnosed.
Only when such evidence is present can we really deter-
mine implications for clinical practice. At the moment it
642 L. P. B. Elbers et al
is not clear whether we should just be cautious for VTE
in patients with hyperthyroidism, or should screen for
hyperthyroidism in patients with VTE, or both. If hyper-
thyroidism is to be established as a risk factor for VTE,
this should imply a shorter duration of treatment with
anticoagulants. Recently, the Scientific and Standardiza-
tion Committees of the International Society on Throm-
bosis and Haemostasis (ISTH) proposed criteria to
categorize episodes of VTE as provoked by a transient
risk factor [62]. Based on these criteria, hyperthyroidism
could be considered as a minor (yet important) transient
risk factor during the 2 months before diagnosis of VTE,
because it leads to a 3- to 10-fold increase in risk of a
first VTE, comparable to risk factors like pregnancy or
puerperium. VTE is considered as a multi-causal disease
in which several determinants combine to cross a so-
called ‘thrombotic threshold’ [63] and a high level of FT4
could contribute to development of VTE, mainly by
increasing levels of FVIII and VWF. For future research,
it would be interesting to investigate the safety and effec-
tiveness of thromboprophylactic treatment in high-risk
hyperthyroid patients.
In almost all studies on VTE in overt hyperthyroidism,
this solely concerned DVT and PE (Table 2). However,
the literature described the co-occurrence of CVT and
hyperthyroidism in >30 case reports, suggesting that
hyperthyroidism could also be a risk factor for developing
CVT. This is a potentially life-threatening condition and
a difficult clinical diagnosis to make, also because thyro-
toxic storm can be accompanied by neurological symp-
toms. The association between hyperthyroidism and
CVT, however, is even harder to study due to the very
low incidence of CVT.
Only a few studies have been performed that tried to
elucidate the mechanism by which hyperthyroidism
increases the risk of VTE (Table 3). Because autoimmune
diseases are associated with an increased risk of develop-
ing venous thrombosis [55,56], one could hypothesize that
its autoimmune process (such as lupus anticoagulant in
systemic lupus erythematosus) and the associated inflam-
matory response could modulate the thrombotic environ-
ment. However, the effect of hyperthyroidism on markers
of coagulation and the risk of VTE is also observed in
hyperthyroidism that is not caused by an autoimmune
disease (e.g. toxic multinodular goiter). The effect of thy-
roid hormone on hemostasis seems to be a direct effect on
gene transcription of coagulation proteins [64–66].
Recently, the hypothesis was tested that the hypercoagula-
ble state in hyperthyroidism is mediated via the thyroid
hormone receptor b (TRb) [67]. Patients with resistance to
thyroid hormone (RTH) due to defective TRb were used,
because these patients exhibit elevated circulating thyroid
hormones with refractoriness to thyroid hormone action in
TRb-expressing tissues. Eighteen patients with RTH due
to defective TRb, 16 patients with hyperthyroidism and 18
euthyroid subjects were included. Parameters of
Table 3 Proposed mechanisms by which hyperthyroidism increases
the risk of venous thromboembolism
Proposed mechanism
A direct effect on gene transcription of coagulation proteins [64–66],
more specifically via the thyroid hormone receptor b [67]
Altered clot structure/lysis [34]
Contact system activation and abundant neutrophil extracellular
trap formation [69]
Autoimmune process/inflammatory response (evidence solely from
studies investigating the risk of autoimmune disease and the risk of
venous thrombosis [55, 56])
coagulation and fibrinolysis were elevated in hyperthyroid
patients compared with patients with RTH due to defec-
tive TRb, whereas these parameters were not different
between euthyroid controls and RTH patients, despite ele-
vated FT4 concentrations in RTH patients. This indicates
that the procoagulant effects observed in hyperthyroidism
are mediated via the TRb. For future research, it might be
interesting to also investigate the role of the other thyroid
hormone receptor, the thyroid hormone receptor a in
patients with resistance to thyroid hormone due to a speci-
fic mutation in this receptor [68]. In addition to stimula-
tion of coagulation factors mediated via the TRb, altered
clot structure/lysis may be another mechanism for
increased thrombotic risk in hyperthyroidism [34]. How-
ever, as exogenous hyperthyroidism in healthy volunteers
had no effect on any of the clot structure parameters, addi-
tional mechanisms for the effects on hemostasis observed
in healthy volunteers using levothyroxine must be present.
The final study demonstrated that contact system activa-
tion and abundant neutrophil extracellular trap formation
occurred in the high thrombin generation state in hyper-
thyroidism and were correlated with FT4 level [69].
Another consequence of the hypercoagulable state
induced by hyperthyroidism is the possibility that thy-
romimetics that are currently investigated may increase
the risk of VTE. These compounds specifically stimulate
the TR b to lower cholesterol levels in dyslipidemia [70].
It is important that future prospective clinical trials assess
the effect of this class of agents on coagulation and fibri-
nolysis markers, and on the risk of thrombotic events.
The same applies for patients treated with relatively high
doses of levothyroxine for several reasons, including dif-
ferentiated thyroid cancer.
Other topics of interest for further research are whether
thyroid function can be used as a continuous variable in
prediction studies on bleeding and/or VTE risk. Also, it
would be interesting to investigate whether hyperthy-
roidism leads to the same increase in risk of DVT as for
PE. Risk factors for DVT are shown not to be always the
same as for PE. A well-known example is the factor V
Leiden (FVL) paradox: the FVL mutation poses a clearly
higher risk for DVT than for PE [71]. Because hyperthy-
roid patients display firmer clots, one could hypothesize
that the risk is higher for DVT than for PE.
© 2018 International Society on Thrombosis and Haemostasis

In summary, low levels of thyroid hormone shift the
hemostatic system to a hypocoagulable and hyperfibri-
nolytic state, whereas high levels of thyroid hormone lead
to a more prothrombotic state. Fibrinogen, FVIII and
VWF are important players in this interaction. Patients
with hypothyroidism are at increased risk of developing
bleeding complications due to impaired coagulation and
fibrinolysis, and this could be relevant in patients under-
going invasive surgical procedures. With increasing levels
of FT4, levels of, amongst others, fibrinogen, FVIII and
VWF increase gradually. Physicians should be aware of
the possibility of hyperthyroidism as an underlying risk
factor for venous thromboembolism, especially in unex-
plained cases. Clinical studies are needed to further inves-
tigate the consequences for general practice of the
influence of thyroid hormone on the hemostatic system.
Addendum
L. Elbers wrote the manuscript. All authors were involved
in interpreting the literature and designing the figures,
and all authors commented on the manuscript.
Acknowledgements
We thank V.E.A. Gerdes (MC Slotervaart) for carefully
reviewing this manuscript.
Disclosure of Conflict of Interests
The authors state that they have no conflict of interest.
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