Clinical Endocrinology (2016) 84, 473–484
12767
CLINICAL PRACTICE UPDATE
The effects of pituitary and thyroid disorders on haemostasis:
potential clinical implications
Nikolaos Kyriakakis*, Julie Lynch*, Ramzi Ajjan*,† and Robert D. Murray*,†
*Department of Endocrinology, Leeds Centre for Diabetes & Endocrinology, Leeds Teaching Hospitals NHS Trust, and †Division of
Cardiovascular and Diabetes Research, Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM), University of Leeds,
Leeds, UK
Summary
Disturbances of coagulation and fibrinolysis are usually multifac-
torial and growing evidence suggests that endocrinopathies mod-
ulate the haemostatic balance. The thrombotic alterations in
endocrine disorders range from mild laboratory clotting abnor-
malities with little clinical significance to serious thrombotic and
bleeding disorders directly related to hormonal disturbances.
This literature review focuses on presenting the current data on
the effects of thyroid and pituitary disorders on various parame-
ters of the haemostatic system. With the exception of overt
hypothyroidism which appears to cause a bleeding tendency, the
rest of the endocrinopathies discussed in this review (subclinical
hypothyroidism, hyperthyroidism, endogenous hypercortisola-
emia, growth hormone deficiency, acromegaly, prolactinoma/hy-
perprolactinaemia and hypogonadotrophic hypogonadism) are
associated with a hypercoagulable and hypofibrinolytic state,
increasing the overall cardiovascular risk and thromboembolic
potential in these patients. In most studies, the haemostatic
abnormalities seen in endocrine disorders are usually reversible
with successful treatment of the underlying condition and bio-
chemical disease remission. High-quality studies on larger
patient cohorts are needed to produce robust evidence on the
effects of endocrine disorders and their therapeutic interventions
on coagulation and fibrinolysis, as well as on the long-term
mortality and morbidity outcomes in association with endo-
crine-related haemostatic imbalance. Given the rarity of some of
the endocrine disorders, multicentre studies are required to
achieve this target.
(Received 11 November 2014; returned for revision 9 December
2014; finally revised 2 March 2015; accepted 3 March 2015)
Correspondence: Robert D. Murray, Leeds Centre for Diabetes & Endo-
crinology, Leeds Teaching Hospitals NHS Trust, St James’s University
Hospital, Beckett Street, Leeds LS9 7TF, UK. Tel.: +44 (0)113 206 4931;
Fax: +44 (0)113 206 6257; E-mail: robertmurray@nhs.net
© 2015 John Wiley & Sons Ltd
doi: 10.1111/cen.
Introduction
Endocrinopathies have been associated with abnormalities of
various parameters of coagulation and fibrinolysis. The degree
of disturbance to the overall haemostatic balance and the
effects on the long-term cardiovascular and thromboembolic
risk that these abnormalities cause remain debatable. This
review article summarizes the currently available data focusing
on the effects of pituitary and thyroid disorders on haemosta-
sis. We initially present a brief overview of the clot formation
and clot lysis pathways, followed by a narrative description of
the main effects of thyroid and pituitary disorders on parame-
ters of coagulation, fibrinolysis and fibrin network structure.
Clinical implications of these laboratory abnormalities and
effects of successful therapeutic interventions in restoring the
haemostatic balance are also analysed. Due to limited data and
absence of appropriate studies, this review does not cover
platelet abnormalities in endocrinopathies except for the poten-
tial direct effect of hyperprolactinaemia on platelet function.
Pathologies to be discussed in this review article include
hypothyroidism, hyperthyroidism, Cushing’s disease/endogenous
hypercortisolaemia, growth hormone deficiency, acromegaly,
prolactinoma/hyperprolactinaemia and hypogonadotrophic
hypogonadism.
Overview of haemostasis
The haemostatic equilibrium is the result of a complex interac-
tion between cellular and protein phases of coagulation. Follow-
ing vessel injury, platelets and coagulation factors are activated
and this culminates in the formation of the fibrin network,
which forms the skeleton of the blood clot. During formation of
the fibrin network, the fibrinolytic system is activated to limit
blood clot formation and avoid widespread vascular occlusion.
The clotting process and fibrinolysis are schematically shown in
Fig. 1.
The coagulation system
The initial trigger for thrombus formation is usually an injury
to the blood vessel wall. At the site of injury, collagen exposure
473
474 N. Kyriakakis et al.

Intrinsic pathway
Clot formation Extrinsic pathway (amplification of thrombin production)
Pathway (initiation of thrombin
production)
Endothelial Platelet activation
Trauma unknown trigger
FXII FXIIa
Thrombin

Platelet FXI FXIa Thrombin

aggregation and
coagulation factor FIX FIXa FVIIIa FVIII
Tissue Factor (TF)
release
TFPI FVIIa
Protein S
FIXa -FVIIa
FIX Prothrombin
TF - FVIIa
Antithrombin Protein C

FIXa FX FXa Activated Protein C

FXa -FV FXa FX
FXa -FVa
FV (Prothombinase Protein S Thrombomodulin
complex) FVa FV

Antithrombin
Thrombin Thrombin

Clot lysis
Pathway t-PA PAI - 1

FXIII TAFI

Plasmin Plasminogen
FXIIIa

α2-antiplasmin

Fibrinogen Fibrin Fibrin Fibrin

(soluble) (stabilized) Degradation
Products

Inhibitory factor
Activation
Inhibition

Fig. 1 Schematic diagram of the coagulation and fibrinolysis pathways illustrating the various interactions between promoters and inhibitors of
haemostasis. Endothelial trauma is usually the trigger that activates platelets and initiates the coagulation cascade, with the production of thrombin,
which augments the coagulation signals via activation of various procoagulant factors, leading to further thrombin production. Thrombin catalyses
conversion of fibrinogen to fibrin. TFPI, antithrombin and the protein C/protein S/thrombomodulin systems, on the other hand, act by inhibiting
several clotting factors. Clotting formation process is terminated via activation of plasmin (through the actions of t-PA and plasminogen), which
degrades fibrin, promoting clot lysis. TAFI, t-PA and a2-antiplasmin are the main inhibitors of fibrinolysis. A2-antiplasmin inhibits clot lysis both by
inactivating plasmin, by forming a complex with it and also by becoming incorporated into the fibrin clot increasing its resistance to the action of
plasmin. ADP, adenosine diphosphate; F, factor; a, activated; PAI-1, plasminogen activator inhibitor-1; TAFI, thrombin-activatable fibrinolysis
inhibitor; TF, tissue factor; TFPI, tissue factor pathway inhibitor; t-PA, tissue plasminogen activator.

leads to platelet adhesion and aggregation, while exposed tissue extrinsic pathway, which, via activation of factors IX (FIX) and
factor (TF) forms a complex with circulating factor VIIa (FVIIa) X (FX), leads to the formation of the factor Xa-V complex (pro-
initiating blood coagulation.1 This is the traditionally described thrombinase complex) catalysing the conversion of prothrombin

© 2015 John Wiley & Sons Ltd

Clinical Endocrinology (2016), 84, 473–484

to thrombin.1 However, it is now well accepted that division
into extrinsic and intrinsic pathway is an artificial laboratory
phenomenon that does not apply to the in vivo environment.2
Generation of thrombin represents a key step in the regulation
of the coagulation system as it (i) mediates platelet activation
(resulting in the release of ADP, serotonin and thromboxane A2,
which in turn promote further platelet recruitment), (ii) cataly-
ses conversion of fibrinogen to fibrin (a key component of stable
fibrin clots) and (iii) activates several coagulation factors of the
intrinsic pathway [factors V, VIII and XI (FV, FVIII, FXI)],
potentiating fibrin production further and amplifying the coagu-
lation signals.1 A number of anticoagulant factors, including tis-
sue factor pathway inhibitor (TFPI), proteins C and S,
antithrombin and thrombomodulin, inhibit different parts of
the coagulation cascade, to downregulate the fibrin production
and maintain the haemostatic balance.
The fibrinolytic system
Synthesized fibrin is degraded by the fibrinolytic system. Tissue
plasminogen activator (t-PA) and urokinase-like plasminogen
activator convert plasminogen to plasmin. Plasmin is the pivotal
enzyme of the fibrinolytic system, responsible not only for the
degradation of fibrin, but also for the hydrolysis of factors V,
VIII, XIII and von Willebrand factor (vWF).3 Fibrinolytic activ-
ity is reduced by the physiological inhibitors of fibrinolysis,
which include plasminogen activator inhibitor-1 (PAI-1), which
inhibits t-PA; a2-antiplasmin, which is incorporated into the
fibrin network to inhibit plasmin action, thereby increasing fibri-
nolysis resistance4; and thrombin-activatable fibrinolysis inhibi-
tor (TAFI), which suppresses fibrinolysis by removing carboxy-
terminal lysines from partially degrading fibrin, thus compro-
mising plasminogen activator binding and subsequent activation
of plasminogen to plasmin.5 Table 1 summarizes the main
plasma factors that regulate coagulation and fibrinolysis.
The clinical relevance of haemostatic abnormalities has been
demonstrated in a number of studies. Elevated factor VIII, IX,
XI and TAFI levels, reduced TFPI, protein C and S, and certain
PAI-1 polymorphisms have been associated with thrombotic
conditions, such as venous thromboembolism, ischaemic stroke
and myocardial infarction.6–9 Additionally, high fibrinogen has
been identified as an independent risk factor for atherosclerotic
and cardiovascular disease.10 In the light of the above, the hae-
mostatic abnormalities associated with endocrinopathies cannot
be considered as a benign condition.
Table 1. Summary of the main promoters and inhibitors of coagulation and fibrinolysis
Procoagulant factors Anticoagulant factors
• Tissue factor (TF) • Tissue factor pathway
• Clotting factors (FII-FXIII) inhibitor (TFPI)
• Thrombin • Protein C/protein
• Von Willebrand factor (vWF) S/thrombomodulin system
• Antithrombin
© 2015 John Wiley & Sons Ltd
Clinical Endocrinology (2016), 84, 473–484
Hormones & Clotting 475
Thyroid disorders
Hypothyroidism
Clotting abnormalities in hypothyroidism range from abnormal
laboratory findings to clinically significant episodes of bleeding.
A defect of primary haemostasis in the form of acquired von
Willebrand syndrome (AVWS) type 1 has been the main coagul-
opathy described in hypothyroidism. In almost all case reports,
this has been associated with mucocutaneous bleeding11
although it is generally believed that AVWS does not cause clini-
cally significant coagulopathy, potentially making AVWS an un-
derdiagnosed complication of hypothyroidism. However, this
should be taken into account when hypothyroid patients
undergo invasive procedures, due to the clinically significant risk
of bleeding.12 In a cohort of 90 patients with clinically overt
hypothyroidism, Stuijver et al. found that the prevalence of
AVWS was 33%. All patients with AVWS had either mild or
moderate AVWS, which was reversible after restoring euthyroid
status.13
The effects of hypothyroidism on the rest of the coagulation
and fibrinolytic markers have been investigated in a number of
studies, often producing conflicting results, indicating that
hypothyroidism may affect the haemostatic mechanisms in a
more complicated way than originally anticipated. An overall
hypocoagulable state was found by Gullu et al. who assessed 15
patients with overt hypothyroidism, indicated by prolongation
of activated partial thromboplastin time (aPTT), prothrombin
time (PT) and clotting time, in combination with reduction in
FVIII activity, vWF and platelet levels, compared with healthy
controls. Levothyroxine treatment reversed these abnormalities.14
In favour of the bleeding diathesis in hypothyroidism are the
results published by Simone15 that showed significantly reduced
levels of factors VIII, IX and XI in hypothyroid patients. Simi-
larly, Yango et al.16 found prolonged aPTT, reduced FVIII, vWF
activity and antigen levels in 22 patients who had previous thy-
roidectomy, 4–6 weeks after discontinuing levothyroxine replace-
ment therapy.
Contrary to the previous studies, results from other research
groups suggest that hypothyroidism is associated with a hyper-
coagulable and hypofibrinolytic state. Impaired fibrinolysis due
to increased TAFI levels has been found by Akinci et al.,17
reporting positive correlation between TAFI antigen levels and
severity of hypothyroidism, and reversibility of this abnormality
with thyroxine replacement therapy. It should be noted,
Fibrinolytic factors Antifibrinolytic factors
• Tissue plasminogen • Thrombin-activatable fibrinolysis
activator (t-PA) inhibitor (TAFI)
• Urokinase plasminogen • Plasminogen activator inhibitor-1
activator (u-PA) (PAI-1)
• Plasmin • Alpha-2-antiplasmin
476 N. Kyriakakis et al.

however, that the hypothyroid group had increased waist
circumference and an unfavourable lipid profile compared with
the control group, which may have accounted for the throm-
botic environment documented in the study. A mixed picture
of coagulation and fibrinolytic abnormalities was found by
Erem et al. in two studies. The initial study showed increased
levels of FVII, thrombomodulin and TAFI, reduced levels of
TFPI, protein C and S, and reduced concentrations of vWF
and factors V and VIII.18 The second study revealed increased
fibrinogen, antithrombin III (AT-III) and PAI-1 levels with
reduced activity of FVIII and FX.19
The variable effect of thyroid hormone deficiency on haemo-
stasis has been more clearly illustrated in a prospective study by
Chadarevian et al., who compared 24 patients with moderate
hypothyroidism (TSH 10–50mIU/l) and 27 patients with severe
hypothyroidism (TSH >50mIU/l) with 25 healthy controls. The
results revealed increased thrombotic potential for patients with
moderate hypothyroidism (elevated levels of PAI-1, a2-antiplas-
min, t-PA and reduced D-dimer level), while completely oppo-
site results were found for patients with severe hypothyroidism,
indicating that hypothyroidism may have a biphasic effect on
fibrinolysis, depending on disease severity.20 The three groups
were well matched for cardiovascular risk factors, including
BMI, LDL cholesterol, triglycerides, blood pressure (systolic and
diastolic) and fasting glucose, indicating the haemostatic
alteration observed was related to the thyroid status of the
patients.20
Clot parameters in patients with severe hypothyroidism (mean
TSH 92
3  17
2mIU/l) were assessed in an interventional study
by Stuijver et al., both before and after treatment with levothy-
roxine. Results showed lower clot maximum absorbance, shorter
clot lysis time, smaller clot lysis area and less compact fibrin
clots when the patients were in the hypothyroid state. This is
consistent with the formation of less compact clots that are eas-
ier to breakdown, consequently increasing the bleeding risk. The
mechanisms for these findings appeared to be related to lower
levels of fibrinogen, resulting in the formation of less compact
clots, and reduced PAI-1 levels, making the fibrinolytic process
more efficient.21 These abnormalities were resolved upon resto-
ration of euthyroid state.
In contrast to overt hypothyroidism, a hypercoagulable and
hypofibrinolytic state has been consistently reported in patients
with subclinical hypothyroidism. The main findings from differ-
ent studies include reduced global fibrinolytic capacity,22
increased TAFI levels17 and increased FVII, PAI-1 and fibrinogen
concentrations.23 Overall data suggest that subclinical hypothy-
roidism cannot be regarded as a benign condition. The beneficial
effect of treatment with levothyroxine in restoring the haemo-
static balance by reducing the levels of TAFI, PAI-1 and FVII
has also been shown.17,23
In summary, data about the effects of hypothyroidism on hae-
mostasis remain controversial as both hypercoagulable and hy-
pocoagulable states have been described. Overall it appears that
severe hypothyroidism is associated with a bleeding tendency,

Table 2. Summary of the current evidence on the main effects of thyroid and pituitary disorders on several parameters of coagulation and fibrinolysis
and their clinical significance

Main coagulation/fibrinolytic Overall effect on

Endocrine disorder abnormalities haemostasis Clinical relevance

Hypothyroidism
Overt ↓vWF, FVIII, FIX, FXI, Bleeding tendency Acquired von Willebrand
↓PAI-1, antiplasmin, fibrinogen syndrome type 1
↑aPPT, PT
Subclinical/moderate ↑FVII, fibrinogen Possible mild Uncertain, possibly thrombotic
↑PAI-1, TAFI, antiplasmin hypercoagulability

Hyperthyroidism ↑vWF, FVIII, FIX, fibrinogen Probable mild Possibly increased VTE risk
↑PAI-1, TAFI hypercoagulability
↓t-PA, plasminogen, protein C&S, ↓TFPI, aPTT
↑clot lysis time

Endogenous hypercortisolaemia ↑FII, FV, FVII, FIX, FX, FXII, vWF Mild/moderate Confirmed increased risk of VTE
↑fibrinogen, ↓aPTT hypercoagulability
↑PAI-1, TAFI, antiplasmin

Growth hormone deficiency ↑fibrinogen, PAI-1 Possible mild Uncertain

↓t-PA hypercoagulability

Acromegaly ↑fibrinogen, PAI-1 Possible mild Uncertain

↓t-PA, TFPI hypercoagulability

Prolactinoma/hyperprolactinaemia ↑fibrinogen, PAI-1, ↓TFPI Data inconsistent Uncertain

? ↑platelet activation

Hypogonadotrophic hypogonadism ↑FV, FX, PAI-1, ↓antithrombin Possible mild Uncertain

hypercoagulability

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Clinical Endocrinology (2016), 84, 473–484

whereas subclinical or moderate hypothyroidism predisposes to
hypercoagulable state (Table 2). Therefore, in addition to the
‘type’ of hormonal anomaly, the ‘degree’ of change can dictate
the thrombotic phenotype of an individual.
Hyperthyroidism
Overt hyperthyroidism has been traditionally associated with a
hypercoagulable and hypofibrinolytic state. The association
between thromboembolism and overt hyperthyroidism is well
recognized, with the cerebral venous system being the most
common site of venous thrombosis reported in the literature.24
In a retrospective study of 428 hyperthyroid patients, only 3
patients (0
7%) had a documented episode of venous thrombo-
sis within 6 months of diagnosing hyperthyroidism, suggesting a
low absolute risk for VTE.25 In contrast, in a large population
study involving 53,418 patients, hyperthyroidism was associated
with 2
31 times greater risk for pulmonary embolism compared
with controls, during a 5-year follow-up period and after adjust-
ing for confounding factors.26
To elucidate the potential mechanism through which thyroid
hormones affect haemostasis, Shih et al. assessed the effects of
T3 in the regulation of various genes in hepatoma cells overex-
pressing TRa receptors. The authors demonstrated that T3-
induced expression of genes responsible for the production of
fibrinogen, thrombin and Factor X.27 In accordance with the
above results, an in vivo study in rats following thyroidectomy
showed higher levels of fibrinogen in rats receiving T3 postoper-
atively, compared with rats left without thyroid hormone
replacement.27 These findings are consistent with the hypercoag-
ulable potential associated with hyperthyroidism and the bleed-
ing diathesis seen in overt hypothyroidism.
A number of studies have demonstrated reduced fibrinolytic
potential in hyperthyroidism, with reduced levels of t-PA,28–30
plasminogen28 and increased levels of PAI-128–30 and TAFI29
being the main findings suggestive of hypofibrinolysis. Regarding
the coagulation markers, elevated fibrinogen, vWF, factor IX and
AT-III levels, along with reduced concentrations of protein C
and S, TFPI antigen, FV and FX, have been reported in two
studies by Erem and colleagues,29,31 alterations indicative of a
hypercoagulable state which may increase the total cardiovascu-
lar risk of hyperthyroid patients. Li et al.30 have reported that
thyroid hormone levels were correlated positively with PAI-1
and vWF concentrations and inversely with basal and released t-
PA following venous occlusion. These changes are consistent
with increased risk of thrombotic disorders in individuals with
hyperthyroidism, particularly venous thrombotic and embolic
events. Normalization of thyroid function has been shown to
reverse some of these haemostatic abnormalities.30
A cross-sectional population study by D€ orr et al. revealed
higher fibrinogen levels in subjects with subclinical and overt
hyperthyroidism. Low TSH was found to be an independent risk
factor for elevated fibrinogen.32 The described association
between low TSH and raised fibrinogen becomes more signifi-
cant in the context of other data showing that elevated fibrino-
gen is an independent risk factor for cardiovascular diseases.10
© 2015 John Wiley & Sons Ltd
Clinical Endocrinology (2016), 84, 473–484
Hormones & Clotting 477
The effects of short-term exposure of healthy individuals to
exogenous thyroid hormones have been investigated in a small
number of studies. Verkleij et al.33 showed that exogenous
hyperthyroxinaemia in healthy volunteers results in a hypofibrino-
lytic state, with enhanced activated-TAFI-dependent prolongation
of clot lysis time. Van Zaane et al. conducted a two-stage trial, ini-
tially inducing mild hyperthyroxinaemia and after a period of
washout rendering the participants profoundly hyperthyroid.
During the first stage of the study, a significant rise in the vWF
antigen level and activity was noted. Increase in the FVIII and
PAI-1 levels, along with prolongation of clot lysis time, was also
observed but failed to reach statistical significance. During the sec-
ond stage, overt exogenous hyperthyroidism resulted in a more
extensive derangement of coagulation and fibrinolysis, including
increase in the levels of vWF antigen and activity, FVIII, FIX, FX,
PAI-1 and fibrinogen, prolongation of clot lysis time and shorten-
ing of aPTT. Remarkably, the research group found no change in
the prothrombin fragment 1 + 2 (which represents ongoing coag-
ulation activation in vivo) or in the endogenous thrombin poten-
tial (which reflects the potential thrombin-forming capacity of the
plasma ex vivo).34 The results of this study, although indicating
exogenous hyperthyroxinaemia is associated with a hypercoagula-
ble and hypofibrinolytic state, also suggested that the alterations
in the haemostatic parameters cannot entirely explain the
increased thromboembolic potential seen in patients with endoge-
nous hyperthyroidism.
Hooper and colleagues recently produced novel data relating
to clot structure parameters in patients with hyperthyroidism.
Higher clot maximum absorption, indicating more compact
clots, prolonged lysis time and larger lysis area, along with ele-
vated fibrinogen, and PAI-1 levels were observed in patients with
untreated hyperthyroidism compared with controls (Figs 2 and
3). These changes were partially reversed after treatment with
antithyroid medications and normalization of thyroid hormone
levels. On the other hand, short-term exogenous hyperthyroid-
ism did not alter any of the clot structure parameters, indicating
that endogenous hyperthyroidism has a different effect on clot
structure compared with exogenous hyperthyroxinaemia.35
In summary, there are congruent data that hyperthyroidism is
associated with hypercoagulable and hypofibrinolytic milieu
(Table 2), although the clinical consequences of these changes
have not been entirely recognized, mainly due to the lack of
large prospective studies. Reversibility of the haemostatic abnor-
malities with antithyroid therapy has been shown.
Pituitary disorders
Cushing’s disease/endogenous hypercortisolaemia
Cushing’s disease (CD) is the commonest cause of endogenous
glucocorticoid excess, resulting in chronic hypercortisolaemia
under the direct effect of an ACTH-secreting pituitary adenoma.
Cushing’s syndrome (CS) in general has been considered a hy-
percoagulable state, and although complications related to CS
such as obesity, insulin resistance, hypertension and hyperlipida-
emia may contribute to the clotting and fibrinolytic abnormali-
478 N. Kyriakakis et al.
(a)
(b)
(c)
ties seen, data suggest that glucocorticoid excess is directly
involved in modulating haemostasis.
CS has been associated with increased risk of VTE during active
disease and postoperatively. The non-surgically provoked VTE
risk has been estimated at 1
9–2
5%, while the estimated range of
postoperative risk has been 0
0–5
6%, being comparable to major
orthopaedic surgery under standard thromboprophylaxis.36 In a
large cohort study of 473 patients with CS, Stuijver and colleagues
found an incidence rate of VTE of 14
6 per 1000 person-years,
which was considerably higher than the general population.37
Another interesting finding from the same study was that the inci-
dence rates of VTE in patients with ACTH-dependent and ACTH-
independent CS were similar before treatment; however, none of
the patients with ACTH-independent CS had any VTE episodes
following adrenalectomy, compared with a risk of 3
4% for
patients with ACTH-dependent CS who had undergone pituitary
surgery, raising questions about the potential role of ACTH in the
haemostatic balance. Additionally, none of the patients with non-
functioning pituitary adenomas developed VTE following pitui-
tary surgery, further supporting the hypothesis that the increased
VTE risk seen in the patients with ACTH-dependent CS is gluco-
corticoid excess-related, with a potential effect from either excess
or sudden drop of ACTH following pituitary surgery.37 Boscaro
et al. performed a retrospective analysis of postoperative data of
patients with CS and demonstrated increased mortality and mor-
Fig. 2 Visualization of ex vivo fibrin clots from
healthy controls and subjects with hyperthyroidism
at baseline and after normalizing thyroid function.
(a) and (b), Laser scanning confocal microscopy
and scanning electron microscopy, respectively,
showing fibrin networks made from pooled plasma
of controls and hyperthyroid subjects (pool of 10
random samples from each group). A denser clot is
evident in hyperthyroidism, with partial reversal of
the changes after normalization of thyroid
function. (c), Fibre thickness in a total of 240 fibres
from control, hyperthyroid and euthyroid clots (30
fibres were measured in eight different clot areas
from each group). Reproduced from Ref. [35].
bidity rates related to thromboembolic events in the patient group
that did not receive thromboprophylaxis following pituitary or
adrenal surgery. Similarly to the results from Stuijver, the majority
of the thromboembolic episodes occurred in patients who were
treated for pituitary-dependent CS (27 of the 29 patients who
developed postoperative thrombotic complications had pituitary-
dependent CS).38
The exact pathogenesis of the hypercoagulable state seen in CS
remains yet to be fully elucidated, although cumulative data from
various studies suggest that this is related to increased production
of clotting factors and impairment of the fibrinolytic mecha-
nisms. Activation of the intrinsic clotting pathway, as reflected by
shortening of the aPTT and increase in the levels of clotting fac-
tors II, V, VIII, IX, XI, XII, vWF and fibrinogen, is the main coag-
ulation abnormality described in patients with CS.39–41
Abnormalities of the fibrinolytic parameters in patients with
hypercortisolaemia include elevated PAI-1, TAFI and a2-antiplas-
min levels.38,39,41 These changes are compatible with the prolon-
gation of clot lysis time found in patients with CS,41 as a result of
the reduced fibrinolytic capacity. On the other hand, a rise in the
concentrations of plasmin that promotes fibrinolysis, and anti-
thrombin and protein C and S that inhibit the coagulation
cascade, has also been reported. The authors hypothesize this is
probably a compensatory mechanism against the overall hyperco-
agulable state of CS.40
© 2015 John Wiley & Sons Ltd
Clinical Endocrinology (2016), 84, 473–484
 Hormones & Clotting 479

(a)

(b)
Fig. 3 Microscopic lysis of fully formed ex vivo
fibrin clots from healthy controls and subjects with
hyperthyroidism at baseline and after normalizing
thyroid function. (a), One representative
experiment demonstrating lysis of fully formed
clots made from pooled plasma of healthy controls
or hyperthyroid subjects after the addition of tissue
plasminogen activator and plasminogen to the edge
of the clot; (b), mean lysis time (four independent
experiments) of clots made from pooled plasma of
healthy controls and hyperthyroid subjects (pool of
10 random samples from each group). Reproduced
from Ref. [35].

Increased levels of vWF are another haemostatic abnormality
in CS. Indeed, in vitro studies have shown elevated levels of
vWF mRNA expression after exposing human endothelial cells
to high-dose dexamethasone.42 In addition to increased vWF
levels, others reported larger vWF multimers in CS, along with
increased responsiveness to ristocetin and spontaneous platelet
aggregation. These abnormalities began to normalize following
surgery, but not until 3 months postoperatively.40 Given the fact
that elevated vWF levels were not consistently seen in all patients
with CS, further studies have illustrated the role of genetic fac-
tors and in particular the importance of polymorphisms of the
vWF gene promoter in the glucocorticoid-induced increase in
the vWF levels. Studies have shown that the haplotype 1 of vWF
gene promoter was encountered more frequently among patients
with CS with elevated vWF levels, compared with haplotype 2,
mainly found in patients with normal vWF levels.43,44
It has been argued that the abnormalities in coagulation and
fibrinolysis seen in CS can also be associated with obesity, which
is one of the predominant clinical features in these patients.
Correlation between obesity and increased levels of vWF, FVII
and PAI-1 has been previously shown45; however, some of the
clotting abnormalities seen in CS, such as shortening of aPTT
and prolongation of clot lysis time, persist when comparing
patients with CS with controls matched for body mass index
(BMI), indicating that hypercortisolaemia is an independent fac-
tor leading to deranged clotting.41 Additionally, Boscaro et al.
has shown that there is a significant inverse correlation between
urinary free cortisol levels and aPTT values38; however, not all
studies have demonstrated this.41
Reversal of haemostatic and fibrinolytic imbalance caused by
CS has been demonstrated in a number of studies. Manetti et al.
assessed 40 patients with CS at diagnosis and 12 months follow-
ing surgery and found significant reduction in almost all param-
eters of coagulation and inhibitors of fibrinolysis
postoperatively. However, patients with active disease after sur-
gery had significantly elevated concentrations of vWF, PAI-1,

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Clinical Endocrinology (2016), 84, 473–484
480 N. Kyriakakis et al.
a2-antiplasmin, fibrinogen, ATIII and reduced aPTT values.46
Similarly, normalization of clotting factors in patients who
achieved disease remission 6 months after surgery was demon-
strated by Kastelan et al.,47 with post-treatment values showing
no difference compared with controls. On the other hand, van
der Pas et al.41 showed no statistically significant change in the
parameters of coagulation and fibrinolysis after biochemical con-
trol of CS in 15 patients, 80 days after a stepwise escalation of
medical treatment with pasireotide, cabergoline and ketoconaz-
ole. The discrepancy seen in the results of the last study com-
pared with the previous ones is probably related to the shorter
period of follow-up. This possibly reflects that the hypercoagula-
bility related to active CS persists for a prolonged period of time
after biochemical remission has been achieved. In favour of this
hypothesis are the clinical observations in Stuijver’s cohort,
showing that the majority of the thrombotic events occurred
within the first 2 months following surgery.36 Additionally, in
another study, serial measurements of FVIII following surgical
or medical treatment of CS showed a gradual decrease, taking
3–4 months to fully normalize.48
The above data reasonably raise the issue of thromboprophylax-
is in patients with CS during the peri- and postoperative period.
Despite some authors recommending the need for VTE prophy-
laxis,37,41 no specific guidelines exist about the duration or the
intensity of thromboprophylaxis in such cases. However, taking
into account the previously presented data, it would be reasonable
to consider thromboprophylaxis in patients with active CS until
definitive treatment, which in the subgroup of patients with
ACTH-dependent CS could be extended in the postoperative per-
iod for a period of 2–3 months. The need for thromboprophylaxis
would be even more important if additional risk factors for
thromboembolism coexist (i.e. active malignancy, dehydration,
sepsis, inflammatory conditions, obesity, previous history of VTE,
etc.). Ideally randomized controlled studies should be conducted
to investigate the benefit of antithrombotic therapy, which may
have practical limitations given the rarity of these cases.
In summary, CS is associated with a hypercoagulable state
with increased risk for VTE. This seems to be multifactorial,
although hypercortisolaemia appears to be an independent fac-
tor, affecting the haemostatic balance (Table 2). The thrombo-
embolic risk persists during the immediate postoperative period,
even after biochemical remission. Further studies are required to
produce robust evidence for developing clear guidelines about
thromboprophylaxis in these patients; however, the low preva-
lence of the condition is a significant inhibitory factor.
Growth hormone deficiency
Growth hormone deficiency (GHD) has been associated with
reduced survival and increased cardiovascular risk. The results of
several studies have demonstrated the unfavourable effects of
GHD on body composition, lipid profile, insulin resistance and
arterial blood pressure.
A number of studies have been conducted on small patient
cohorts to investigate the effects of GHD on haemostasis. Over-
all, these studies suggest that GHD predisposes to a thrombo-
genic environment, mainly affecting fibrinolysis. Alterations of
the fibrinolytic parameters seen in patients with GHD include
elevated fibrinogen and PAI-1 antigen and activity.49,50 Treat-
ment with recombinant human growth hormone (rh-GH) leads
to a reduction in the PAI-1 activity, PAI-1 antigen and t-PA
antigen levels, resulting in a more favourable fibrinolytic state.51
Minno et al. found amelioration in the clotting and fibrinolytic
profile of GHD patients in whom reduction in the insulin levels
occurred during GH replacement. In this subgroup, levels of
protein C and S, t-PA, PAI-1 and FVIII activity dropped signifi-
cantly after 6 months of therapy. Regardless of the change to the
insulin level, no difference was seen in the levels of the coagula-
tion factors II, IX and VII antigen before and after GH treat-
ment. The authors suggested that the reduction seen in the
protein C and S values reflected the overall improvement of
the haemostatic profile after GH replacement.52 Contrary to the
previous studies, no difference in fibrinogen concentrations and
no change in fibrinolytic markers, following 1 year of GH
replacement were found by Gomez et al., when comparing 10
GHD patients with 25 healthy controls.53
Devin and colleagues measured the circadian plasma PAI-1
antigen and t-PA activity values, along with the fibrinolytic
potential using the venous occlusion test in 12 adults with
GHD. They found a mean 62% increase in PAI-1 antigen, with
a mean 24% reduction in t-PA activity, loss of the circadian var-
iation in the PAI-1 production (which normally results in higher
levels in the morning), and impaired fibrinolytic response after
venous occlusion in the patient group. This defect in the fibri-
nolytic mechanisms has been proposed by the authors to con-
tribute to the increased cardiovascular risk seen in patients with
GHD.54 Contrary to the previous studies, results from an animal
model study showed that mice homozygous for a point muta-
tion in the GH-releasing hormone receptor gene and effectively
GH deficient demonstrate prolonged blood clotting times when
compared with mice heterozygous for the above mutation. In
the pulmonary embolism (PE) model, homozygous male and
female mice had lower mortality and longer survival period
when thromboplastin was injected compared with heterozygous
mice, with the authors concluding that GHD is protective
against thrombosis in vivo.55
There are a small number of studies concerning the effects of
GHD and GH replacement on biomarkers of coagulation and
fibrinolysis in children and young adolescents. In a study by Reis
and colleagues, GHD children who had previously been treated
with GH, but remained GH deficient 2 years after treatment was
stopped, demonstrated increased collagen and ADP-induced
platelet aggregation. The authors proposed that platelet hyperac-
tivation could be a therapeutic target for primary prevention, to
minimize the future cardiovascular risk in these individuals.56
Data derived from a cohort of 36 prepubertal children with
GHD showed higher levels of fibrinogen and activated PAI-1
compared with controls. Reduction in PAI-1 concentrations, but
not in fibrinogen and vWF levels, was observed after 6 months
of GH replacement therapy.57
In summary, GHD causes a thrombogenic milieu, mainly
related to hypofibrinolysis (Table 2). Replacement with GH
© 2015 John Wiley & Sons Ltd
Clinical Endocrinology (2016), 84, 473–484

seems to reverse, at least partially, the haemostatic abnormalities,
although further studies on larger patient cohorts are required
to investigate the long-term effects of GH therapy on mortality
and morbidity outcomes.
Acromegaly
Acromegaly has been associated with a twofold increase in mor-
tality rate, mainly due to cardiovascular and cerebrovascular dis-
ease, primarily related to the unfavourable metabolic profile seen
in these patients.58
Abnormalities of coagulation and fibrinolysis have been con-
sidered to contribute to the increased risk of cardiovascular dis-
ease in patients with acromegaly. Elevated levels of plasma
fibrinogen have been consistently reported by various research
groups in patients with active disease.59–61 A significant decrease
in hyperfibrinogenaemia was found following treatment of acro-
megaly and achievement of biochemical remission.60,61 Similar
fibrinogen levels were found in patients treated surgically and in
those who achieved remission with somatostatin analogue ther-
apy.60 When compared with healthy controls, however, patients
with biochemical disease control continued to have significantly
elevated fibrinogen concentrations.60,61 A positive correlation
between serum IGF-I and plasma fibrinogen levels has been
reported.60
With regards to other markers of coagulation and fibrinolysis,
data are scarce and often conflicting. Erem et al., in a cohort of
22 patients with active acromegaly, found elevated levels of AT-
III, t-PA and PAI-1, along with reduced TFPI concentrations.
The authors also reported a negative correlation between IGF-I
and PAI-1 concentrations and between GH levels and TFPI.59
Increased PAI-1 and t-PA levels have also been reported by
Wildbrett et al.,62 which in contrast to the previous study corre-
lated positively with GH and IGF-I, respectively. The latter obser-
vations are supported by in vitro studies demonstrating increased
PAI-1 production by hepatoma cells when grown in the presence
of IGF-1.63 In a third study, Landin-Wilhelmsen et al.60 failed to
demonstrate a significant difference in the PAI-1 levels between
patients with active acromegaly and healthy controls.
Overall, currently available data, although limited, suggest a
degree of hypofibrinolysis and increased thrombogenic potential
in acromegalic patients (Table 2). The haemostatic abnormalities
seen in these patients appear to be at least partially reversible
after biochemical disease control (both with medical and/or sur-
gical treatment60,62) and may contribute to the increased cardio-
vascular risk associated with acromegaly.
Hyperprolactinaemia
There is evidence in the literature that elevated prolactin levels
can predispose to a hypercoagulable state, increasing the risk of
venous and arterial thromboembolic events.
Wallaschofski et al. showed that hyperprolactinaemia potenti-
ates the ADP-induced platelet activation via expression of the
adhesion molecule P-selectin. This was observed both in a group
of pregnant women and in a group of patients with pituitary
© 2015 John Wiley & Sons Ltd
Clinical Endocrinology (2016), 84, 473–484
Hormones & Clotting 481
tumours, indicating that prolactin is an independent cofactor for
platelet aggregation.64 Additionally, the presence of the short
isoform of prolactin receptors has been identified on platelets, in
keeping with the previous hypothesis.65 Finally, increased inci-
dence of VTE in patients with prolactinoma has been
reported.66
Contrary to the previous results, Reuwer et al. failed to dem-
onstrate in vitro prolactin-induced platelet activation. Western
blot and flow cytometry did not reveal the presence of prolactin
receptors on the platelet membrane, with the authors concluding
that prolactin does not have a direct effect on platelet func-
tion.67 In a more recent study, although no significant change in
platelet activity was observed by addition of recombinant prolac-
tin in vitro, P-selectin expression was significantly reduced after
analysing platelet function in a group of 13 hyperprolactinaemic
females, suggesting that prolactin may have a protective action
against hypercoagulability.68
With regards to additional effects of hyperprolactinaemia on
haemostasis, Erem et al. demonstrated elevated platelet count,
fibrinogen, PAI-1 levels, PAI-1/t-PA ratio and reduced TFPI lev-
els in patients with prolactinoma, suggestive of a hypercoagula-
ble and hypofibrinolytic state.66 Against the previously described
hypofibrinolytic state are the recently published results from
in vitro and in vivo studies by Bajou et al.,69 which demonstrate
that the N-terminal fragment of prolactin binds PAI-1 and pot-
entiates the action of t-PA, thus enhancing the fibrinolytic
potential in a mouse restoration blood flow model.
In summary, data regarding the effects of hyperprolactinaemia
on platelet activity and haemostatic mechanisms remain conflict-
ing (Table 2). Although a significant proportion of the current
data suggest that hyperprolactinaemia in associated with hyper-
coagulability and increased thromboembolic risk, further studies
are required to support this hypothesis.
Hypogonadotrophic hypogonadism
Data in the literature about the effects of Hypogonadotrophic
hypogonadism (HH) on parameters of coagulation and fibrinoly-
sis remain very sparse. Male hypogonadism has been associated
with increased BMI, unfavourable metabolic profile and increased
cardiovascular risk.70 Patients with hypopituitarism have
increased mortality, with cardiovascular, respiratory and cerebro-
vascular diseases being the leading causes. Excess mortality in this
patient group is associated with untreated hypogonadism.71
The presence of hypercoagulability has been shown in a case–
control study of 17 patients with idiopathic HH, who were
found to have increased platelets, FV and FX activity and
reduced ATIII levels.72 Moreover, low testosterone has been
found to be associated with elevated PAI-1 levels73 and low TFPI
antigen concentrations,74 in keeping with an overall thrombotic
predisposition.
Standard mortality rates among hypopituitary patients have
been found to be higher in women compared with men.75
Female gender has been described as an independent risk factor
of increased mortality in hypopituitary patients.71 The reason
for this remains unknown and may be related, at least in part,
482 N. Kyriakakis et al.
to gender differences in coagulation parameters, which we have
previously documented.76 Traditionally, oral sex hormone
replacement in healthy postmenopausal women has been associ-
ated with increased risk of cardiovascular disease and thrombo-
embolism.77 However, a study by Zegura et al. showed
improvement in the lipid profile and fibrinolytic parameters
(reduction in the euglobulin clot lysis time, tPA antigen, fibrino-
gen and PAI-1 levels) after 28 weeks of oestrogen replacement
therapy, in 43 healthy women who had surgically-induced men-
opause.78 Additionally, an in vitro study by Garand et al.79 has
shown that TAFI protein levels produced by human hepatocellu-
lar carcinoma cells were reduced, when these were cultured in
the presence of female sex hormones, suggesting that female ste-
roid hormones may improve the fibrinolytic capacity.
Overall, despite the lack of studies designed specifically to
assess the haemostatic balance in patients with HH, existing data
suggest that sex hormone deficiency is associated with a
hypercoagulable and hypofibrinolytic state, which may augment
the risk of cardiovascular complications in these individuals
(Table 2).
Conclusions
There is increasing evidence that almost all endocrinopathies alter
the haemostatic balance to some extent. These changes vary from
mildly abnormal laboratory findings of uncertain clinical impor-
tance, to clinically significant thrombotic or bleeding episodes.
Occasionally, studies have produced contradictory results in rela-
tion to the haemostatic changes observed. The reason for this may
be due to the relatively small number of samples analysed, thus
failing to take into account the effects of confounding factors.
Although validated assays have been used in most studies, subtle
differences in the methodologies cannot be ruled out, which may
have also accounted for some of the observed differences.
Although data remain less uniform for some endocrine disorders
(i.e. prolactinomas), the thrombotic or bleeding risk has been
more clearly elucidated for others. There is strong evidence that
endogenous hyperthyroxinaemia and hypercortisolaemia predis-
pose to hypercoagulable states. Additionally, the VTE risk is par-
ticularly pronounced for patients with glucocorticoid excess.
Hypothyroidism, on the contrary, appears to influence haemosta-
sis in a more complex way, with subclinical hypothyroidism dis-
playing a thrombotic potential, while severe hypothyroidism is
associated with a bleeding tendency. Current data for acromegaly,
GHD and HH are relatively limited, although existing evidence
suggests alterations that predispose to hypercoagulability. Clearly,
further studies are important to fully characterize the degree of
abnormality endocrine disease imparts on the coagulation and
fibrinolytic system, and the mechanism by which this occurs.
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