Anabolic Androgenic Steroid Abuse: The Effects on

Thrombosis Risk, Coagulation, and Fibrinolysis

Simon Chang, MD1 Anna-Marie B. Münster, MD, PhD1 Jørgen Gram, MD, DSc1
Johannes J. Sidelmann, PhD1

1 Unit for Thrombosis Research, Department of Regional Health Address for correspondence Simon Chang, MD, Unit for Thrombosis
Research, University of Southern Denmark and Department of Research, Finsensgade 35, DK – 6700 Esbjerg, Denmark
Clinical Biochemistry, Hospital of South West Jutland, Esbjerg, (e-mail: simon.chang@rsyd.dk).
Denmark

Semin Thromb Hemost

Abstract Anabolic androgenic steroid (AAS) abuse surged during the 1980s and is seen in
approximately 1 in 20 of all males today. A wide spectrum of AAS compounds and abuse
regimens are applied and AAS abuse has been associated with an unfavorable

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cardiovascular profile. The aim of this review is to critique the collected data concerning
effects of AAS abuse on thrombosis risk through presentation of condensed evidence
from studies investigating AAS-induced changes in coagulation, fibrinolysis, and
cardiovascular risk markers. AAS abuse inflicts a procoagulant distribution of cardio-
vascular risk markers including dyslipidemia and atherosclerosis proneness. AAS abuse
overall stimulates synthesis of coagulation factors, inhibitors, and fibrinolytic proteins
Keywords resulting in both increased global coagulation and stimulation of fibrinolysis. Overall,
► anabolic androgenic supported by many case reports and some epidemiological studies, AAS abuse is
steroids associated with an increased risk of thrombosis. However, to provide clear evidence for
► coagulation a causal relationship between AAS abuse and thrombosis risk, future studies need to
► fibrinolysis address a range of potential biases, insufficient methodology, and other shortcomings
► thrombosis risk of the current literature as highlighted in this review.

Reference to performance-enhancing substances has existed
in Chinese medicine for at least 5,000 years. The Incas chewed
coca leaves, the ancient Greeks consumed fungi, and Roman
gladiators used different substances to withstand the physical
challenges. The first commercially available performance-
enhancing agent, a widely popular mixture of Bordeaux
wine and coca leaves called “Vin Mariani,” was introduced in
the middle of the 19th century. At the same time, the term
“doping” arose, stemming from the Dutch word “doop,” mean-
ing sauce. Modern doping evolved in 1935 when testosterone
was for the first time isolated from bull testes and further
chemically synthesized. Testosterone administration imme-
diately became popular among bodybuilders and weightlif-
ters1 due to its capability to increase muscle mass and strength
during exercise.2–4 Since then synthetic testosterone has been
among the most popular doping agents, and more recently also
among endurance athletes to allow a more intensive training
pattern with faster recovery.5 These substances, collectively
known as anabolic androgenic steroids (AASs), come in a
variety of formulations that can be administered orally, as
intramuscular or subcutaneous injections, or topical gels, with
some varieties (e.g., Boldenone) only approved for use in
animals. Also, slow release preparations (e.g., Nebido), for
which abuse is more complicated to detect, are gaining
popularity.6 Treatment with androgenic compounds is indi-
cated in a variety of clinical conditions (e.g., testicular failure or
female-to-male transgenderism). AAS abuse is defined as the
predominantly illicit use of androgenic compounds for recrea-
tional or competition purposes, in particular with the aim of
gaining muscle mass or increasing the oxygen-bearing capa-
city of the blood.
The word “doping” traditionally refers to professional
athletes seeking a shortcut to victory. It is, however, impor-
tant to acknowledge that the majority of AAS abusers are not

Issue Theme Hemostasis in Exercise and Copyright © by Thieme Medical DOI https://doi.org/
the Athlete; Guest Editors: Murray Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0038-1670639.
Adams, BSc(Hons), PhD, MAIMS, FFSc New York, NY 10001, USA. ISSN 0094-6176.
(RCPA), and James Fell, BEd, MPhil, PhD. Tel: +1(212) 584-4662.
Anabolic Androgenic Steroid Abuse and Hemostasis Chang et al.
professional athletes, but rather individuals striving for a
certain body image7 and that the term “AAS abuse” in fact
describes a variety of clinical presentations. The (self)med-
ication pattern in AAS abuse is erratic and completely
different from other types of medications associated with
thrombotic disorders (e.g., oral contraceptives8 or antipsy-
chotic drugs9). A recent Danish study found that AAS abusers
involved in recreational training on average had experience
with four to nine different AAS compounds and 50% of AAS
abusers also regularly used human chorionic gonadotropin
preparations and aromatase inhibitors.10 Other medications
taken concomitantly with AAS commonly include erythro-
poietin, growth hormone, insulin-like growth factor 1, insu-
lin, diuretics, thyroid hormones, and in particular, opioids to
numb the pain of an (over)strenuous workout.5 AAS abuse
regimens and availability of individual AAS compounds
change over time and studies on AAS abuse are prone to
bias related to truthful disclosure of abuse and recollection of
previous abuse.
Current AAS abuse is associated with cardiovascular,
neuroendocrine, psychiatric, and hepatic side effects with
approximately one in four of AAS abusers suffering from AAS
dependency.5 Furthermore, the prevalence of AAS abuse
surged during the 1980s and emerging morbidity among
former AAS abusers could represent long-term side effects to
AAS abuse.
It is challenging to disclose the extent of AAS abuse, as
data concerning prevalence of AAS abuse mostly come from
surveys. In a 2010 report entitled “Strategy for Stopping
Steroids” prepared in collaboration between antidoping
authorities in Denmark, Sweden, The Netherlands, Poland,
and Cyprus, the life-time prevalence of AAS abuse was
estimated to be approximately 1.5% in the population, with
large variations within subgroups.7 In fitness centers, the
prevalence was estimated to be approximately 5%. AAS abuse
was found to be more prevalent among men compared with
women with a clustering in younger individuals. The pre-
valence of AAS abuse is estimated to be as high as 20% in
bodybuilding environments among younger men.7 A Dutch
study found the typical user of performance-enhancing
drugs to be 28 years of age and that the abuse most
commonly begun at 18 years of age.11 In a Polish study, 1
to 3% of adolescents aged 15 and 16 years reported abusing
AAS.7 More recently, the global prevalence of AAS abuse
among men was estimated in a meta-analysis to be 6.4% (95%
confidence interval [CI], 5.3–7.7) and among females 1.6%
(95% CI, 1.3–1.9).12 Likewise, a contemporary American
study estimated that between 2.9 and 4.0 million Americans
have been abusing AAS.13 Today, AAS are easily available for
purchase over the internet14 and therefore we might not yet
have seen the peak in AAS abuse.
The aim of the current review is to give an up-to-date
overview of the available literature regarding AAS abuse and
thrombosis risk with special attention to the changes
inflicted by AAS on coagulation and fibrinolysis. Studies on
actual AAS abuse are primarily considered, but given that
only a few such studies have been published, studies of AAS
compounds in nonabuse settings and in vitro studies are also
Seminars in Thrombosis & Hemostasis
included. Animal studies are considered only when relevant
regarding topics with no, or very little, available human data.
AAS Abuse, Thrombosis, and Cardiovascular
Risk Markers
Anabolic androgenic steroids abuse has been repeatedly
associated with an increased risk of thrombosis. However,
the association has primarily been based on case reports and
a few small epidemiological and cross-sectional studies, as
described later.
Since the first case report of cardiac death in a young man
abusing AAS was presented in 1988,15 numerous cases with
thrombotic outcome have been described. Myocardial infarc-
tion has been identified in several cases,16–24 and also case
reports documenting stroke,25,26 renal infarction,17,27 multi-
ple abdominal arterial infarctions,28 as well as intraventri-
cular thrombus with systemic embolization to the arteries of
the extremities29,30 have been presented. In addition, AAS
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abuse has been reported in a few cases of cerebral venous
thrombosis,31–34 deep venous thrombosis, and/or pulmon-
ary embolism.35–38 Regardless of the clinical presentation of
the thrombotic event in these case reports, patients are
commonly characterized as intensively exercising young
men with no other risk factors for cardiovascular disease
(CVD) or thrombosis.
Although there is an absence of large epidemiological
studies on AAS abuse, it is the predominant conception that
AAS abuse is detrimental to cardiovascular health. In a 12-
year retrospective follow-up study, a 4.6 times higher risk of
death was demonstrated among 62 Finnish competitive
powerlifters compared with 1,094 male controls.39 The
powerlifters were assumed to be abusing AAS, as this was
the practice among Finnish competitive weightlifters during
the period studied. Of the powerlifters, 12.9% died compared
with 3.4% in the control group. Among assumed AAS abusers,
three deaths due to coronary heart disease were accompa-
nied by ventricular hypertrophy, dyslipidemia, and hyper-
tension.39 However, this study did not objectively determine
AAS abuse status in neither powerlifting nor healthy con-
trols, leaving the possibility that powerlifting per se affects
mortality. Such methodological scarcity was solved in an
elegant Swedish national population-based cohort study
with a mean follow-up period of 4 years.40 The study
population was recruited over a period of 8 years and
included 2,013 individuals who had been tested for AAS
abuse, of which 409 had been tested positive at least once.
The standard mortality rate was 8.3 (95% CI, 6.1–11.0) in
subjects tested negative and 19.3 (95% CI, 12.4–30.0) in
subjects tested positive. It is of particular importance that
AAS abusers had a hazard risk of 2.0 (95% CI, 1.2–3.3) for
cardiovascular events, although the number of events was
low in all diagnostic categories, and therefore the trend
toward increased risk of cerebrovascular disease and
ischemic heart diseases should be carefully interpreted.
Epidemiological studies relating testosterone treatment
and thrombosis risk have not been able to demonstrate
any clear association.41 However, a well-conducted
 Anabolic Androgenic Steroid Abuse and Hemostasis
population-based case–control study demonstrated a two-
fold increased incidence rate ratio for venous thromboem-
bolism during the first 6 months after treatment with
testosterone.42
The background for a possible excess of cardiovascular
morbidity in AAS abuse is uncertain. Some cross-sectional
studies have reported that steroid abuse causes left ventri-
cular hypertrophy, while other studies fail to find such an
association.43–45 Echocardiographic studies lend some sup-
port to the hypothesis that AAS abuse is associated with
cardiac changes such as septal hypertrophy, increased heart
chamber diameters, and alterations in diastolic function.45 A
recent well-designed study on 140 weightlifters supported
that AAS abuse of 2 years or longer is associated with
impaired systolic function and in addition a decreased left
ventricular ejection fraction.46 Animal studies in rats and
dogs as well as human cases and autopsy studies have shown
structural alterations to the heart with extensive fibrosis,
necrosis, and coronary artery ectasia and cardiac hypertro-
phy.20,30,47–52 It is not known to which extent such structural
cardiac abnormalities could cause or contribute to an
increasing thrombosis risk.
There is also some evidence that long-term AAS abuse
accelerates premature arteriosclerosis. Increased coronary
artery calcium scores have been reported among profes-
sional bodybuilders aged 28 to 55 years with AAS abuse53
compared with data from healthy individuals.54 Older stu-
dies applying coronary angiograms in the acute phase after
myocardial infarction in AAS abusers have found that the
coronary arteries were without atherosclerotic pla-
ques.15,16,22,55 In contrast, cases undergoing autopsy have
demonstrated diffuse coronary atherosclerosis in long-term
AAS abusers.30,56,57 More recently, it was reported that
current and former AAS abusers have increased aortic stiff-
ness compared with healthy controls. Of particular impor-
tance was that AAS abusers demonstrated more coronary
arteriosclerosis and higher coronary plaque volumes than
nonabusers.46
Studies on association between AAS and blood pressure
are difficult to interpret due to potential biases such as the
size of blood pressure cuff, variability in dosing, duration of
abuse, and a lack of objective measures. However, the pre-
vailing opinion is that AAS abuse in general causes a dose-
dependent increase in blood pressure that returns to base-
line levels months after discontinuing drug use.43,45,58,59
Increasing low-density lipoprotein (LDL) and decreasing
high-density lipoprotein (HDL) are widely accepted to be
associated with an increased cardiovascular risk. The associa-
tion between AAS abuse and lipids has also been thoroughly
studied and it has been persistently reported that AAS abuse is
associated with slightly elevated levels of LDL cholesterol and
decreased levels of HDL cholesterol.43–45,60,61 In particular,
intake of compounds that do not undergo aromatization into
estrogen (e.g., stanozolol) seems to be associated with a
marked decrease in HDL levels.43
Although low-grade inflammation has been widely stu-
died in the context of CVD, there is only limited information
regarding inflammatory biomarkers and AAS abuse. Small
Chang et al.
studies reported a slight to moderate increase in concentra-
tion of C-reactive protein (CRP) in AAS abusers compared
with nonabusers and sedentary controls.61,62 Increased CRP
was also demonstrated in 37 current AAS abusers compared
with both former abusers and nonabusers.60
Endothelial dysfunction is another core issue in relation to
cardiovascular health. Two small studies used flow-mediated
vasodilatation as a measure of endothelial function. Both
studies reported a suppressed flow-mediated vasodilatation
in AAS abusers compared with nonabusers.62,63 Endothelial
dysfunction could also affect platelet adhesion and activa-
tion. Increased platelet aggregation has been demonstrated
in AAS abusers,64 in healthy men after injections of 200 mg
testosterone cypionate,65 and in human in vitro and animal
studies performed in the 1970s and 1980s.43 It has also been
suggested that AAS could increase contractility of the cor-
onary arteries by decreasing nitric oxide release and indu-
cing vasospasms.66,67
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The Effect of AAS on Coagulation and
Fibrinolysis
The effect of AAS on the plasma concentration and function
of proteins involved in coagulation and fibrinolysis has been
addressed in several clinical intervention studies employing
a single androgenic steroid drug, while cross-sectional stu-
dies have focused on comparing AAS abusers, in most cases
taking a combination of drugs, with control subjects. Many
studies were performed decades ago, when AAS were con-
sidered as drugs with potential use in treatment of patients
suffering from coagulation factor deficiencies or deficiencies
in the regulatory mechanisms of coagulation or fibrinolysis.
Some of the data are case reports, and most studies lack
power due to a modest number of subjects included. Type II
errors (i.e., failing to observe a difference when in truth there
is one) cannot be excluded and the interpretation of the
results obtained is not straightforward. The dose, formula-
tion, and route of administration may affect the impact of
AAS on the hemostatic system, and it should be noticed that
the hemostatic effects of AAS recorded in controlled clinical
trials with well-defined AAS administration may be mark-
edly different from those obtained in AAS abusers who
administer a high-dose cocktail of AAS compounds in com-
bination with other drugs that could also potentially affect
hemostasis. It should also be noted that short-term inter-
vention studies have addressed the effect of AAS on hemos-
tasis and that follow-up studies are warranted. AAS
potentiates both the activation and the regulation of hemos-
tasis, but the long-term effect of AAS, which potentially may
translate into clinical outcomes (i.e., thrombosis or bleeding),
has not been studied in sufficient detail to date.
Despite methodological shortcomings, the aim is to com-
bine and discuss the current knowledge regarding the effect
of AAS on the plasma concentration and function of proteins
involved in the hemostatic processes. A detailed description
of the hemostatic system is beyond the scope of this review
with the reader referred to a previous publication in this
journal.68
Seminars in Thrombosis & Hemostasis
Anabolic Androgenic Steroid Abuse and Hemostasis Chang et al.
Surface-Induced Activation of Coagulation
The effect of AAS on the factors involved in contact activation
has been addressed in few studies (►Table 1). A significant
increase in coagulation factor XII (FXII)69,70 and significant
decrease in prekallikrein and high-molecular-weight kinino-
gen (HMWK) were observed in healthy individuals after
administration of stanozolol (5 mg, twice a day and
600 mg/day of the structurally closely related danazol).69
The effect of AAS on plasma levels of coagulation factor XI has
yet to be addressed.
Further downstream of the surface-induced coagulation
pathway, the effect of AAS on plasma concentrations of
coagulation factors VIII (FVIII) and IX (FIX) has been studied
in patients with hemophilia. Administration of danazol
(600 mg/day) to such patients is reported to increase the
concentration of both FVIII and FIX.71–73 The number of
patients included in the studies is low, and treatment of
hemophiliacs with stanozolol, in contrast, did not affect the
plasma concentration of FVIII and FIX.74 Moreover, inter-
vention studies on administering stanozolol or oxandrolone
(10 mg, twice daily) to healthy volunteers75,76 or patients
suffering from protein C deficiency,77 as well as cross-sec-
tional studies of bodybuilders with AAS abuse,78 support the
notion that AAS does not affect the plasma concentration of
FVIII. Stanozolol (5 mg, twice daily), administered to healthy
individuals and patients with protein C deficiency, is shown
to increase the plasma levels of FIX significantly.79,80 The
effect could not be confirmed in another intervention study
on protein C–deficient patients treated with identical doses
of stanozolol.77 Taken together, the studies indicate that the
effect of AAS on the plasma levels of FVIII and FIX depends on
the formulation of AAS.
Tissue Factor–Induced Activation of Coagulation
The plasma concentration of tissue factor is elevated in
women with altered plasma testosterone levels due to poly-
cystic ovary syndrome. This suggests a potential effect of AAS
on tissue factor expression,81 but studies of any direct effect
of administered AAS on the plasma concentration of tissue
factor have not yet been reported. Interventional and cross-
sectional studies on various AAS compounds all support that
AAS is without effect on the plasma concentration of coagu-
lation factor VII (►Table 1).69,77–80,82
Studies of healthy men and women receiving stanozolol
(5 mg, twice daily) have demonstrated significant increases
in the plasma concentrations of coagulation factor X (FX), V
(FV), and prothrombin.69,77,79,80 A newer intervention study
employing oxandrolone (10 mg, twice daily)75 confirmed
the potentiating effect of AAS, which increased FV by
approximately 70%, and prothrombin by more than 30%.
The concentration of FX also increased, but was not statis-
tically significant. Of particular notice, the study demon-
strated a persistent increase in prothrombin 4 weeks after
discontinuation of oxandrolone. In line with this finding, a
recent cross-sectional study has demonstrated increased
concentrations of both FX and prothrombin in current as
well as former AAS abusers compared with nonusers.82
Former AAS abusers included in the study had refrained
Seminars in Thrombosis & Hemostasis
from AAS abuse for average of 2.5 years, indicating that the
effect of AAS abuse on these central coagulation factors may
persist years after cessation. However, the subjects included
in the study used high-dose AAS in combination with other
drugs which may affect hemostasis different from controlled
doses of a single AAS. This may also explain why Chang et al82
observed an AAS-induced increase in the plasma concentra-
tion of fibrinogen, in contrast to controlled intervention
trials reporting either a reduction in plasma fibrino-
gen69,76,77,83–86 or no effect of AAS on fibrinogen
levels.61,73,75,87 However, it has also been demonstrated
that the effect of AAS on plasma fibrinogen is dependent
on the formulation of the drugs applied.88
The influence of AAS on turnover of prothrombin has been
addressed in few studies. In a cross-sectional setup, it was
demonstrated that significantly more AAS abusers presented
elevated plasma levels of prothrombin fragment 1 þ 2 and
thrombin–antithrombin complexes than nonusers89 and
similarly a case report has indicated that AAS increases the
turnover of prothrombin.90 These findings are in close agree-
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ment with the results obtained by Chang et al demonstrating
a significant increase in thrombin generation measured as
the endogenous thrombin potential (ETP) in both current
and former AAS abusers.82 In combination with the persis-
tent AAS-induced increase in FX and prothrombin men-
tioned earlier, this finding suggests that AAS abuse has a
persistent effect on the turnover of prothrombin.
The potential effect of AAS on coagulation factor XIII
(FXIII) has only been investigated in few studies demonstrat-
ing no effect on the plasma protein concentration of FXIII.69
The function of FXIII as a fibrin stabilizing factor, however,
increases due to AAS abuse, indicating that the enzymatic
properties of FXIII are altered by the action of AAS abuse
(Chang S et al., unpublished data, March 2018).
Regulation of Coagulation
Several studies have focused on the effect of AAS on the
regulation of coagulation (►Table 2). Many studies are case
reports, but also cross-sectional and intervention studies are
reported, involving a modest number of patients or healthy
individuals. A fair number of studies have focused on the
effect of AAS on antithrombin, protein C, and free protein S,
whereas the other coagulation inhibitors are addressed in
only few studies.
Complement C1-esterase inhibitor (C1-inh) is the major
regulator of the contact system inhibiting activated FXII and
kallikrein.91 Inherited deficiency of C1-inh leads to heredi-
tary angioedema.92 Danazol administration has been shown
to induce a more than 80% increase in the plasma concen-
tration of C1-inh,69,93 and AAS are used for treatment of
hereditary angioedema to prevent the swelling attacks char-
acterizing this disease.94 Also, the plasma concentration of
α-1-antitrypsin, the major inhibitor of activated FXI,95 is
increased by AAS.88,96 The concentration of α-2-macroglo-
bulin, which inhibits a variety of proteases including
enzymes of the contact pathway and fibrinolysis, is signifi-
cantly reduced by some AAS,96 but unaffected by others.76,96
Taken together, these studies may indicate that the initiation
 Table 1 The effect of anabolic androgenic steroids on the plasma concentration of coagulation factors

Subjects Fibrinogen Factor II Factor V Factor VII Factor VIII Factor IX Factor X Factor XII Factor XIII
Anderson et al 99 Healthy, n ¼ 33 Decrease
Intervention
Jarrett et al85 Patients, n ¼ 50 Decrease
Intervention Controls, n ¼ 48
Burnand et al 86 Patients, n ¼ 23 Decrease
Intervention
Ansell et al 78 AAS abusers, n ¼ 16 NS NS NS
Cross-sectional
Barbosa et al 88 Patients, n ¼ 80 NS/Decreasea
Intervention Controls, n ¼ 65
Gralnick et al 71,72 Hemophiliacs, n ¼ 571, Increase Increase
Intervention n ¼ 772
Greer et al74 Hemophiliacs, n ¼ 15 NS NS
Intervention
Glueck et al 83 Patients, n ¼ 5 Decrease
Intervention
Kahn et al 75 Healthy, n ¼ 14 NS Increase Increase NS NS NS
Intervention
Kluft et al 79 Patients, n ¼ 32 Increase NS Increase Increase
Intervention Controls, n ¼ 14
Kluft et al 69 Healthy, n ¼ 16 Decrease Increase NS Increase Increase NS
Intervention
Preston et al 80 Healthy, n ¼ 14 Increase NS Increase Increase
Intervention
Severo et al)61 AAS abusers, n ¼ 10 NS
Case–control Controls, n ¼ 12
Broekmans et al 77 Patients, n ¼ 5 Decrease Increase Increase NS NS NS Increase
Intervention
Small et al 76 Healthy, n ¼ 12 NS NS
Intervention
Thorisdottir et al70 Patients, n ¼ 4 Increase
Intervention
Anabolic Androgenic Steroid Abuse and Hemostasis

Chang et al 82 Current abusers, n ¼ 37 Increase Increase NS Increase

Cross-sectional Former abusers, n ¼ 33
Controls, n ¼ 30

Abbreviation: NS, nonsignificant.

Note: Blank cells indicate no data reported in that study for the given factor.

Seminars in Thrombosis & Hemostasis

Chang et al.

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 Table 2 The effect of anabolic androgenic steroids on the plasma concentration of coagulation inhibitors and markers of thrombin activation

Subjects Antithrombin Protein C Protein S Protein S C4b-BP TFPI Heparin cofactor II TAT Prothrombin
Total Free fragment 1 þ 2
Anderson et al99 Healthy, n ¼ 33 Increase Decrease NS Decrease Decrease Increase
Intervention
Ansell et al78 AAS abusers, n ¼ 16 NS Increase NS Increase
Cross-sectional

Seminars in Thrombosis & Hemostasis

Broekmans et al77 Patients, n ¼ 5 Increase Increase NS Increase Increase
Intervention
Chang et al82 Current abusers, n ¼ 37 Increase Increase Increase Increase
Cross-sectional Former abusers, n ¼ 33
Controls, n ¼ 30
Ferenchick et al89 Abusers, n ¼ 32 Increase Increase Increase NS NS
Cross-sectional Controls, n ¼ 17
Gonzalez et al97 Patients, n ¼ 2 Increase
Intervention
Jespersen et al130 Patient, n ¼ 1 Increase
Anabolic Androgenic Steroid Abuse and Hemostasis

Case
Kluft et al79 Patients, n ¼ 16 Increase
Intervention Controls, n ¼ 14
Kluft et al69 Healthy, n ¼ 14 Increase Increase
Intervention
Chang et al.

Ledford et al90 Patient, n ¼ 1 Increase Increase NS Increase NS Increase Increase

Case
Mannucci et al98 Patient, n ¼ 1 Increase
Case
Preston et al80 Healthy, n ¼ 14 Increase Increase
Intervention
Small et al76 Healthy, n ¼ 12 NS
Intervention
Thorisdottir et al70 Patients, n ¼ 4 Increase Increase Increase NS Increase
Intervention
Walker et al96 Patients, n ¼ 20 Increase
Intervention
Winter et al131 Patients, n ¼ 2 Increase
Case

Abbreviations: C4b-BP, C4b-binding protein; NS, nonsignificant; TAT, thrombin–antithrombin complex; TFPI, tissue factor pathway inhibitor.
Note: Blank cells indicate no data reported in that study for the given factor.

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 Anabolic Androgenic Steroid Abuse and Hemostasis
and propagation of contact activation are dampened by the
effect of AAS on the major inhibitors of the pathway; how-
ever, further studies are required to verify this hypothesis.
Patients with protein C or antithrombin deficiency have
been treated with AAS, utilizing the promoting effect of
androgen on the synthesis of both these coagulation inhibi-
tors.77,79,80,97,98 Numerous interventional and cross-sec-
tional studies have consistently demonstrated that the
plasma protein concentrations and functional levels of pro-
tein C, antithrombin, heparin cofactor II, and protein S are
increased by AAS,69,70,77–80,82,89,90,97,98 indicating that the
liver synthesis of these proteins is enhanced by AAS. Total
protein S, in contrast, is in most reports lowered by
AAS.77,78,90,99 However, one study of four subjects treated
with danazol (600 mg/day) demonstrated a significant and
persistent increase in total protein S and a parallel increase in
free protein S,70 suggesting a drug-dependent association
between AAS and the plasma levels of protein S. Another
study that used supraphysiological intramuscular doses of
AAS in healthy males observed a decrease in protein C
activity and free protein S during AAS treatment.99 Notably,
however, more than half of plasma protein S circulates in
complex with C4b binding protein, and studies have indi-
cated that AAS reduce the concentration of this plasma
protein.70,99 Thus, the balance between free and total protein
S may be altered by AAS.
In contrast to antithrombin, protein C, and protein S,
which are synthesized by the liver, tissue factor pathway
inhibitor (TFPI) is produced by vascular endothelial cells.100
In cell culture studies, synthesis of TFPI is demonstrated to
increase upon stimulation with testosterone101,102 and total
and free testosterone reported as predictors of plasma
TFPI.103 Low plasma levels of testosterone, as observed
among elderly men, are associated with reduced concentra-
tion of TFPI, but supplementation with intramuscular tes-
tosterone injections does not increase TFPI,104 questioning a
direct association between testosterone and TFPI blood
levels. High-dose AAS, however, as administered in AAS
abuse, increases plasma TFPI significantly,82 supporting a
significant dose response association between AAS and TFPI.
Binding of TFPI to phospholipid surfaces is facilitated by
protein S ensuring the interaction between TFPI and acti-
vated FX.105,106 Thus, the upregulation of both protein S and
TFPI by AAS may significantly impact coagulation. This is
underscored by the observation that the prolonged lag time
and time to peak recorded during thrombin generation in
AAS abusers are significantly associated with increased TFPI
levels.82
AAS therefore have significant impact on the regulation of
coagulation by increasing the plasma concentration of
antithrombin, protein C, free protein S, heparin cofactor II,
and TFPI.
The Integrated Effect of AAS Abuse on Coagulation
Conflicting results are published regarding the effect of AAS
on global coagulation assays such as the APTT and PT,72,77,78
but studies using thromboelastography suggest that AAS
may affect coagulation in a prothrombotic direction. Studies
Chang et al.
on AAS-treated rats and calves revealed significantly
reduced clotting times but increased clot strength in treated
animals compared with controls, both when the coagulation
process was activated by surface contact or tissue factor,
suggesting that AAS induces a general pro-coagulant
state.107,108
The integrated effect of AAS abuse on coagulation eval-
uated by measures of thrombin generation has demon-
strated that AAS abuse prolongs plasma clotting time and
time to peak thrombin concentration, and that this effect is
related to the increased inhibition of coagulation associated
with AAS abuse.82 The effect of the elevated levels of coagu-
lations inhibitors, however, seems overwhelmed by the
effect of AAS on the plasma concentration of coagulation
factors resulting in a pronounced increase in the ETP, an
integrated measure of plasma coagulation potential. This
effect is apparently persistent, because the plasma concen-
trations of prothrombin and FX as well as ETP are elevated in
individuals refraining from AAS abuse for more than 2 years,
Downloaded by: University of Connecticut. Copyrighted material.
indicating a chronic effect of AAS abuse on the hemostatic
system.82
Fibrinolysis
The first observation of enhancement of fibrinolysis by
AAS was published in 1962 by Fearnley and Chakrabarti
demonstrating reduced clot lysis time in 16 patients
and healthy individuals treated with testosterone109 and
has been subsequently confirmed in other clinical studies
(►Table 3).78,85,86,110,111 The effect of AAS on fibrinolysis was
initially addressed in animal studies112 and in several human
studies using euglobulin lysis time assays.76,78,84,110,111,113
Euglobulin fractionation of plasma facilitates the precipita-
tion of plasminogen activators, whereas very low concentra-
tions of fibrinolytic inhibitors are present.114 Thus, the effect
of AAS on fibrinolysis determined by euglobulin clot lysis
time assays favors the effect of AAS on plasminogen activa-
tors without taking the effect on fibrinolytic inhibitors into
account. This apparent profibrinolytic effect of AAS is, how-
ever, challenged by preliminary results from our group,
indicating that the fibrinolytic susceptibility of fibrin is
impaired in individuals abusing AAS (Chang S et al., unpub-
lished data, March 2018). Whether the effect of AAS on fibrin
is related to the action of FXIII, plasmin inhibitor, binding of
plasminogen or other proteins to fibrin, or whether the effect
of AAS is genuinely related to the structure of the fibrin clot
must be addressed in future studies.
The effects of AAS on the specific fibrinolytic components
plasminogen, tissue-type plasminogen activator (t-PA), and
plasminogen activator inhibitor 1 (PAI-1), the major inhibitor
of t-PA, were later investigated. Plasminogen is consistently
reported as increased following AAS intake.69,75–77,88,110
Approximately 50% of plasma plasminogen circulates in com-
plex with histidine-rich glycoprotein (HRG) linked through
lysine binding sites on the HRG molecule.115,116 The plasma
concentration of HRG is significantly reduced by AAS resulting
in increased plasma levels of free plasminogen available for
binding to fibrin.69,77 AAS may therefore stimulate fibrinolysis
via this action.
Seminars in Thrombosis & Hemostasis
 Table 3 The effect of anabolic androgenic steroids on the plasma concentration of fibrinolytic proteins

Subjects Plasminogen HRG t-PA antigen t-PA activity Euglobulin Clot lysis PAI-1 antigen PAI-1 activity Plasmin inhibitor
99
Anderson et al Healthy, n ¼ 32 NS Decrease
Intervention
Ansell et al78 AAS abusers, n ¼ 16 NS NS Profibrinolytic No
Cross-sectional
Barbosa et al88 Patients, n ¼ 80 Increase

Seminars in Thrombosis & Hemostasis

Intervention Controls, n ¼ 65
Blamey et al113 Patients, n ¼ 27 Profibrinolytic
Intervention Controls, n ¼ 13
Broekmans et al77 Patients, n ¼ 5 Increase Decrease Increase Decrease
Intervention
Burnand et al86 Patients, n ¼ 23 Profibrinolytic
Intervention
Davidson et al110 Patients, n ¼ 34 Increase Profibrinolytic
Intervention
Anabolic Androgenic Steroid Abuse and Hemostasis

Ferenchick et al89 AAS abusers, n ¼ 32 Decrease Decrease

Cross-sectional Controls, n ¼ 17
Glueck et al83 Patients, n ¼ 5 NS Increase Decrease Increase
Intervention
Jarrett et al85 Patients, n ¼ 50 Profibrinolytic
Intervention
Chang et al.

Controls, n ¼ 48
Kahn et al75 Healthy, n ¼ 14 Increase Decrease
Intervention
Kluft et al69 Healthy, n ¼ 16 Increase Decrease Increase
Intervention
Ledford et al90 Patients, n ¼ 1 Increase Decrease No
Case
Small et al76 Healthy, n ¼ 12 Increase Profibrinolytic Increase
Intervention
Thorisdottir et al70 Patients, n ¼ 4 No
Intervention
Verheijen et al117 Healthy, n ¼ 9 Decrease Increase Decrease
Intervention
Walker et al111 Patients, n ¼ 20 Profibrinolytic
Intervention

Abbreviations: HRG, histidine rich glycoprotein; NS, nonsignificant; PAI-1, plasminogen activator inhibitor I; t-PA, tissue plasminogen activator.
Note: Blank cells indicate no data reported in that study for the given factor.

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 Anabolic Androgenic Steroid Abuse and Hemostasis
Plasma t-PA activity is increased, and correspondingly PAI-1
activity is decreased in individuals receiving
AAS,69,75,77,83,89,90,99,117 suggesting a profibrinolytic effect
of AAS (►Table 3). Treatment with supraphysiological con-
centrations of AAS, however, does not affect t-PA activity,99
indicating a dose dependency in the effect of AAS on t-PA
activity.
The frequently reported reduction in PAI-1 activity may
indicate that AAS abuse could be related to bleeding ten-
dency because reduced or deficient PAI-1 activity is asso-
ciated with bleeding.118,119 Only a few case reports, however,
have demonstrated bleeding episodes in individuals abusing
AAS,120–122 and the bleeding incidences in these individuals
were not related to the effect of AAS on the plasma levels of
PAI-1.
Conflicting results are recorded when studying the effect
of AAS on the protein concentration of t-PA (i.e., t-PA anti-
gen). Some studies demonstrate no effect,78,117 other reports
disclose an AAS-induced increase in t-PA antigen,83,90
whereas reduced t-PA antigen was observed in another study
among AAS abusers compared with controls.89 Thus, the
reported effect of AAS on t-PA may appear somewhat puz-
zling. Here, the methods used for determination of t-PA and
PAI-1 must be considered. Activity assays reveal the free and
active forms of t-PA and PAI-1, whereas antigen methods
determine the plasma concentration of the proteins. The
plasma protein concentrations of t-PA and PAI-1 are closely
related, as the major part of t-PA circulates in plasma bound
to PAI-1. Moreover, plasma PAI-1 consists of free active PAI-1,
PAI-1 in complex with t-PA, and latent PAI-1 without inhi-
bitory capacity.123 The specificity of the various antigen
methods toward the various forms of t-PA and PAI-1 differs,
making it difficult to compare results obtained by different
methods.124,125 This may to some extent explain the differ-
ent results obtained regarding the effect of AAS on t-PA, with
respect to the activity and the protein concentrations
reported.
The effect of AAS on PAI-1 antigen has been addressed
only in one published clinical study where no effect of AAS on
the protein concentration of PAI-1 antigen was observed.83
Studies with human umbilical vein endothelial cells, how-
ever, demonstrate a significant reduction in PAI-1 protein
concentration and mRNA expression following exposure to
testosterone at physiological concentrations.101 Considering
these methodological issues, the reported effects of AAS on
the plasma concentrations of t-PA and PAI-1 antigen should
be interpreted with caution.
Only one study has dealt with the effect of AAS on
urokinase-type plasminogen activator (u-PA), which demon-
strated no effect of AAS on plasma u-PA activity.69 In con-
trast, conflicting results regarding the effect of AAS on
plasmin inhibitor are evident with increased76,83 as well as
no effect69,70,90 reported.
The Integrated Effect of AAS Abuse on Fibrinolysis
The combined data on the function of fibrinolytic activators
and inhibitors suggest a profibrinolytic effect of AAS abuse,
while the effect of AAS abuse on plasma concentration of
Chang et al.
fibrinolytic proteins remains unsolved. Studies focusing
specifically on AAS-induced protein expression of fibrinoly-
tic proteins in liver cells, vascular endothelial cells, and
adipocytes are warranted and may clarify the effect of AAS
on synthesis of fibrinolytic proteins. The potential effect of
AAS on the half-life and clearance of t-PA-PAI-1 complexes
may also be of interest and could provide insight to the
pharmacokinetics of AAS. Consistent findings regarding the
effect of AAS on plasmin inhibitor and urokinase are also
needed before firm conclusions can be drawn.
Linkage between AAS Abuse and
Thrombosis
The relationship between AAS abuse and thrombosis has not
been adequately answered by available studies of which only
a few report actual thrombotic outcomes. Few high-quality
studies on actual AAS abuse have been performed and the
literature on AAS compounds in controlled settings is com-
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posed of heterogeneous studies of varying quality covering a
wide spectrum of different compounds, dosages, and parti-
cipants. AAS abuse is often undisclosed and not system-
atically recorded in any registries, complicating large-scale
studies. Also, it would be unethical to randomize to a regi-
men of AAS abuse, and identifying and including a large
number of subjects starting AAS abuse on their own for
completing a prospective study seems utopic. Nonetheless,
such studies are needed to explore and/or confirm mechan-
isms leading to increased thrombotic risk.
The evidence from case reports, autopsy studies, and
epidemiological studies collectively point to AAS abuse
being associated with an increased risk for thrombosis. There
are several case reports of unwarranted thrombosis in young
healthy individuals with AAS abuse.44 Due to the undisclosed
nature of AAS abuse and lack of routine testing for AAS abuse,
it is highly likely that AAS abuse–related thrombotic events
are under-reported.
The potential starter effect of AAS abuse on thrombotic
risk, as acknowledged with oral contraception in females, has
not been thoroughly addressed. Prospective studies investi-
gating AAS abuse are small and have a short follow-up when
considering that often study participants are young healthy
males with a low risk for thrombosis. To our knowledge, no
study has evaluated the duration of AAS abuse as a predictor
for thrombosis risk and in particular the potential conse-
quences of former AAS abuse have not been thoroughly
investigated. AAS became widely popular in bodybuilding
environments among younger individuals during the 1980s
and 1990s who have now crossed into the ages associated
with increased risk of thrombosis. Notably, men with former
AAS abuse could be more prone to develop hypogonadism
later in life due to testicular failure and reduced testosterone
levels following AAS cessation. Male hypogonadism has been
associated with an increased risk of CVD126 and male AAS
abusers could thus be double exposed during the course of
life. Moreover, a recent comprehensive series of studies on
current and former AAS abusers10,60,127,128 and another
recent published study on weightlifters on and off AAS46
Seminars in Thrombosis & Hemostasis
Anabolic Androgenic Steroid Abuse and Hemostasis
together described an unfavorable cardiovascular phenotype
associated with AAS abuse that may persist even years after
cessation. Long-term effects of former AAS abuse could in
fact be the most pressing issue as we have no knowledge of
how an often relative short exposure to AAS during the
younger years affects health during the rest of adulthood
and old age.
The collected evidence from mainly cross-sectional and a
few prospective studies indicate that AAS abuse induces an
unfavorable distribution of cardiovascular risk markers,
mainly dyslipidemia, proneness to arteriosclerosis, cardiac
abnormalities, and hemostasis. Moreover, nonassociation
studies performed 30 to 40 years ago likely suffer from the
insufficient diagnostic methods available at that time, espe-
cially regarding in vivo arteriosclerosis. Also, although not
directly associated with thrombosis, the development of
cardiac hypertrophy47,129 and other structural cardiac
abnormalities in AAS abusers5 could have an impact on
recovery from cardiovascular events. To our knowledge, no
study has investigated if recovery or rehabilitation is altered
among AAS abusers following CVD.
Conclusion
Available clinical evidence relating AAS abuse and thrombo-
sis risk suffers from methodological limitations, but overall it
seems probable that AAS abuse is affecting hemostasis and
altering distribution of cardiovascular risk markers in a
procoagulant direction. However, future clinical and epide-
miological studies with direct thrombosis outcomes are
needed to clarify if these effects translate into a clinical
proneness for thrombosis.
Conflicts of Interest
The authors have no financial or other conflicts of interest.
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