American Journal of Hematology 81:95–100 (2006)

Effects of Oxandrolone, an Anabolic Steroid,

on Hemostasis

Nighat N. Kahn,1,2* Asru K. Sinha,1,2 Ann M. Spungen,1,2 and William A. Bauman1,2

1
Department of Medicine, Mount Sinai School of Medicine, New York, New York
2
Veterans Affairs Medical Center, Bronx, New York

This study evaluated the short-term effects of oxandrolone, an anabolic androgenic

synthetic steroid, on blood coagulation and the hemostatic/fibrinolytic system in healthy
individuals. Subjects (n = 14) were administered oxandrolone (10 mg twice daily) for 14
days. Blood was obtained on days 0, 1, 3, 7, 9, 14, and then at day 42 (28 days after
discontinuation of the drug). Samples were analyzed for the plasma plasminogen, plas-
minogen activator inhibitor (PAI-1), fibrinogen, and coagulation factors (II, V, VII, VIII, and
X). After 7 days of administration of oxandrolone, the plasma plasminogen level signifi-
cantly increased [100% ± 21% to 174% ± 21% (P < 0.0001)]. PAI-1 was significantly
decreased at day 3 [16 ± 9 to 7 ± 4 mg/dL (P < 0.01)]. Coagulation factors II and V
significantly increased at day 14 [88 ± 15 to 122 ± 11 (P < 0.005) and 105 ± 21 to 179 ±
36% (P < 0.0001)], respectively. Factor VII level decreased by day 3 [91% ± 26% to 83% ±
18%, NS], but after 14 days factor VII level returned to baseline (91% ± 26% to 93% ± 19%,
NS). The increase of factor VIII level was not significant (111% ± 64% to 125% ± 55%, NS).
Factor X increased steadily over 14 days of drug treatment [96% ± 11% to 107% ± 25%,
NS] and after discontinuation, decreased and returned to baseline by day 42 [107% ± 25%
to 89% ± 25%, NS]. Fibrinogen decreased by 22% ± 12%, (NS). Administration of oxan-
drolone, to healthy young men was associated with a significant increase in select blood
coagulation factors and plasminogen. These changes create a state of potential hyper-
coagulability that appears to be counterbalanced by increased fibrinolytic activity to
maintain homeostasis. Am. J. Hematol. 81:95–100, 2006. ª 2006 Wiley-Liss, Inc.

Key words: oxandrolone; blood coagulation; fibrinolytic system; fibrinogen; plasmino-

gen

INTRODUCTION However, studies in animals have shown that

Biochemical markers for hypercoagulability and
associated increased risk for cardiovascular disease
(CVD) include elevated levels of fibrinogen, tissue
factor–factor VII, or von Willebrand factor (vWF),
or decreased fibrinolytic system, including elevated
levels of plasminogen activator inhibitor-1 (PAI-1)
antigen and decreased tissue plasminogen activator
(t-PA) [1–11]. Sex hormone deficiency (e.g., estrogen
in women and testosterone in men) has been asso-
ciated with an increased risk of CVD [12–19]. Hypo-
gonadal men have been shown to have low levels of
basal fibrinolytic activity. This may be due to
increased fibrinolytic inhibition because of increased
PAI-1 levels [16].
ª 2006 Wiley-Liss, Inc.
androgens at physiological concentrations had signif-
icant effects on the extracellular matrix, nitric oxide
production, and the arachidonic metabolism in
endothelial cells and platelets [20–22], which in-
Contract grant sponsor: Bio-Technology General Corporation
*Correspondence to: Nighat N. Kahn, Ph.D., Veterans Affairs
Medical Center, Bronx, New York 10468.
E-mail: nighat.kahn@med.va.gov
Received for publication 18 December 2004; Accepted 11 August
2005
Published online in Wiley InterScience (www.interscience.wiley.
com). DOI: 10.1002/ajh.20532

96 Kahn et al.
directly effect hemostatic function by increasing
blood pressure, platelet aggregation, and vascular
tone. In men, testosterone replacement treatment
has been associated with a significant increase in
platelet aggregation due to increased expression of
the platelet thromboxane (TX) A2 receptors. These
androgen effects would be expected to translate into
unfavorable prothrombotic effects [23–25]. However,
it has also been reported that androgens have a salu-
tary effect by reducing PAI-1 and increasing fibrino-
lytic activity (i.e., increased t-PA and lower PAI-1).
Fibrinolytic activity is regulated by the release of t-
PA from the endothelial cells into the circulation and
by the amount of t-PA inhibitor (PAI-1) present in
the circulation [8,25]. Lower levels of PAI-1 increase
fibrinolytic activity and hence reduce the risk of
potential vascular thrombosis. However, in male abu-
sers of anabolic steroids, the net effect on the hemo-
static system may change from anti- to prothrombotic
[18,19,29].
In general, at the prescribed pharmacological
doses, oral anabolic steroids, such as stanozolol and
danazol, have been reported to increase fibrinolytic
activity by decreasing PAI-1 levels [30–32]. Danazol
has been shown to increase plasma levels of factor
VIII and IX in hemophilia A or Christmas disease
[29]. Other investigators have reported that the pro-
gestational and anabolic–androgenic synthetic ster-
oids, norethindrone acetate and oxandrolone, have
reduced coagulation factors [33]. These observations
suggest a differential effect of anabolic agents on the
hemostatic/fibrinolytic systems that may be dose-
dependent or drug-dependent.
Oxandrolone is an anabolic androgenic steroid
(AAS), which has been used in various clinical situa-
tions for over 30 years, such as HIV- and AIDS-
related muscle wasting, severe burn injury, trauma
following major surgery, neuromuscular disorders,
and alcoholic hepatitis [34]. In the U.S., oxandrolone
is the only AAS that is FDA approved for restoration
of weight loss after severe trauma, major surgery or
infections, malnutrition due to alcoholic cirrhosis,
and Duchenne or Becker muscular dystrophy [34].
To date, there have not been adequate studies address-
ing the effects of oxandrolone on blood coagulation.
The present study evaluated the short-term adminis-
tration of oxandrolone therapy on hemostasis.
MATERIALS AND METHODS
Subjects
Fourteen healthy, able-bodied subjects, who were
non-smokers, between the ages of 21 and 55 years
[ages 35 ± 11 (mean ± SD] were recruited for the
study. The mean height and weight were 68 ± 3 cm
10968652, 2006, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.20532, Wiley Online Library on [08/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
and 180 ± 27 lbs, respectively. Individuals with
hypertension, diabetes mellitus, liver disease, lipid
disorder, or any chronic illness were excluded. The
study was performed in a hospital setting, but the
subjects were performing their daily activities when
not engaged in the investigation. The Institutional
Review Board, Veterans Affairs Medical Center,
Bronx, NY, approved the protocol prior to the initia-
tion of the study.
Oxandrolone Treatment
After baseline (day 0) blood values were obtained,
subjects were administered oxandrolone, 10 mg twice
daily (maximum FDA-recommended dose), for 14
days. Blood was then obtained from subjects on
days 1, 3, 7, 9, and 14 for measurement of the plasma
plasminogen, PAI-1, and coagulation factors (II, V,
VII, VIII, and X). Platelet aggregation studies were
performed at baseline and at the end of the 14-day
treatment period. Coagulation studies were repeated
at days 21, 28, and 42 (after discontinuation of the
drug for an additional 28 days).
Collection of blood and preparation of platelet-rich
plasma (PRP). Blood samples were collected using
siliconized needles in sodium citrate (9 vol of blood
to 1 vol of 0.013 M sodium citrate) in plastic tubes.
Platelet-rich plasma (PRP) was be prepared by cen-
trifuging the blood samples at 200g for 15 min at
23 C. Platelet-poor plasma (PPP) was prepared by
centrifuging PRP at 10,000g for 15 min at 23 C
[35–37].
Platelet aggregation. Platelet aggregation was
determined by placing 0.5 mL of platelet-rich plasma
in a silicon-coated cylindrical cuvette (8 mm in dia-
meter) containing a Teflon-coated magnetic stirring
bar. Aggregation of platelets was initiated by adding
ADP [35,36] as an aggregating agent in an aggreg-
ometer (Chronolog, Broomall, PA) and stirring the
PRP at 37 C at 1200 rpm. The aggregometer was
calibrated so that the difference in light transmission
between PRP and PPP was defined as 100%.
Determination of coagulation factors (II, V, VII,
VIII, and X) plasminogen and PAI-1 activity in
plasma. Hemostatic factor analysis was performed in
blood anti-coagulated with sodium citrate (13 mM
final concentration) and kept on ice until centrifuga-
tion and separation of plasma at 3,000g for 20 min at
4 C. Plasma was separated from the red blood cells
and aliquots were frozen and stored at 70 C for
subsequent analysis. Enzyme-linked immunosorbent
assay was used to measure PAI-1 antigens and plas-
minogen. A STAGO STA Compact instrument and
reagents were used. Briefly, assay calibration was
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Effects of Oxandrolone on Hemostasis 97

carried out with the reagents as described by the transaminase (SGOT), glutamate pyruvate transami-
manufacturers. nase (SGPT), and g-glutamyltransferase (GGT) were
The percent activity of a coagulation factor in the performed in the general chemistry laboratory, by a
experimental plasma was compared with normal colorimetric assay, on an autoanalyzer (Beckman, LX
plasma. This was done by running a single-factor 20).
assay. A calibration curve was created with each
run, using the calibration plasma (Instrument Lab- Statistical Analysis
oratory Company).
Descriptive statistics were performed for the demo-
Screening for the determination of factor VIII was
graphic variables. Values are reported as mean ± SD.
run on the ACL for the intrinsic pathway (activated
A single-factor repeated-measures analysis of var-
partial thromboplastin time or APPT) factor assay.
iance was used to test for significant changes over
The extrinsic pathway (prothrombin time or PT) fac-
time for the dependent variables. A Scheffe post-hoc
tor assay tested for factor VII (the only factor unique
analysis was performed to determine pairwise com-
to this pathway) plus factors found in the common
parisons for values within the time factor. Signifi-
pathway (II, V, X). When all the reagents were
cance was accepted at P < 0.05.
assembled in the test tube, the time it took to form
a clot was counted in seconds. One of the basic dif-
ferences between the intrinsic and extrinsic pathways RESULTS
is the activating substance. The extrinsic pathway was
Effect of Oxandrolone on Plasminogen and PAI-1
tested by adding tissue factor and Ca2+. The extrinsic
Plasminogen. After 7 days of oral administration of
pathway was initiated by adding a substance that
oxandrolone, there was a progressive increase in the
mimics platelet factor (micro-silica glass beads and
plasma plasminogen from the baseline value of 100%
cephalin) and Ca2+ was added.
± 21% to 174% ± 21% (P < 0.0001), and plasma
Quantitative determination of PAI-1 and plasmino-
plasminogen continued to increase by the end of 14
gen was by the synthetic chromogenic substrate
days of therapy to 192% ± 60% (P < 0.0001). After
method [34]. Determination of PAI-1 was performed
discontinuing oxandrolone administration for 7 days,
by a new venom based assay. For PAI-1, plasma (25
the plasma plasminogen level decreased to 121% ±
mL) was mixed with reagent 1 (urokinase, 100 mL) and
20% (P<0.0001), and after 28 days decreased further
incubated at 4 C for 4 min. Then, 100 mL of reagent 2
to near the baseline level (108% ± 21%, P < 0.0001;
(purified plasminogen with added inhibitors of a2-
Fig. 1).
antiplasmin and a2-macroglobulin) was added,
PAI-1. After 1 day of administration of oxandro-
mixed, and incubated for 4 min. Reagent 3 (chromo-
lone, a non-significant decrease in PAI-1 level was
genic substrate, 100 mL) prewarmed at 37 C was
observed. After 3 days of oxandrolone therapy,
added and mixed, and the absorbance was measured
there was a significant decrease in PAI-1 from the
at 405 nm. The reagents were reconstituted with the
recommended water and filled in the 0.5-mL sample
cups. Patient specimens and controls were placed in
the sample tray, and analyses were started.
Determination of fibrinogen. Fibrinogen, the pre-
cursor to fibrin, is also referred to as factor I. This
test on the ACL system (Automated Coagulation
Laboratory) is incorporated into the PT assay.
Plasma aliquots that were frozen and stored at
70 C were used for analysis. The samples and
reagent were dispensed into the cuvette. The ACL
uses the principle of light scatter to detect the forma-
tion of a clot. The time of initial fibrin strand forma-
tion is reported as PT result. The reaction continues
to be monitored and the clot continues to form until
all the fibrinogen is used up. Calibration plasma
(AssessTM) was used for the calibration of the system. Fig. 1. Effect of oxandrolone on plasminogen. An enzyme-
Determination of liver function tests (LFTs). LFTs linked immunosorbent assay method was used to measure
PAI-1 antigens and plasminogen (details in Materials and
alkaline phosphate (ALP), lactate dehydrogenase Methods). Error bars represent standard deviations. *P <
(LDH), aspartate aminotransferase (AST), alanine 0.0001 for BL versus treatment day; .P < 0.0001 for
aminotransferase (ALT), glutamate oxaloacetate treatment day 14 versus washout day.
 10968652, 2006, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.20532, Wiley Online Library on [08/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
98 Kahn et al.

basal level of 16 ± 9 to 7 ± 4 U/mL (P < 0.01). The
level of PAI-1 remained suppressed during the 14-day
course of oxandrolone administration. After 7 days of
discontinuing oxandrolone, the PAI-1 levels increased
to the baseline level (16 ± 8 U/mL, P < 0.01; Fig. 2).
Effect of oxandrolone on fibrinogen. Various hemo-
static and fibrinolytic factors have been identified as
independent cardiovascular risk factors in prospective
studies. However, the largest evidence exists for fibri-
nogen [38–40]. After 14 days of oxandrolone admin-
istration, the fibrinogen level had decreased 22% ±
12% (from 223 ± 112 to 187 ± 49 mg/dL, NS).
Within 7 days after discontinuing oxandrolone
administration, the fibrinogen level returned to the
baseline level.
26%, P ¼ 0.05; factor V, 179% ± 36% to 110% ±
18%, P < 0.0001), but these levels remained elevated
over baseline levels. By 28 days after discontinuing
oxandrolone, the levels had returned to near baseline
levels (Fig. 3A, B).
Factor VII. Oxandrolone administration had a
variable, non-significant effect on the plasma level
of factor VII. After 3 days of oxandrolone therapy
the factor VII level decreased slightly from 91% ±
26% to 83% ± 18%. After 14 days, the level was
similar to the basal level (93% ± 19% from 91% ±
26%). After 14 days of discontinuing oxandrolone
therapy, factor VII level progressively increased over
the baseline level to 102 ± 19, and 28 days after

Effect of Oxandrolone on Coagulation Factors

Before the administration of oxandrolone, the
basal plasma levels of factors II, V, VII, VIII, and X
were determined to be 88% ± 15%, 105% ± 21%,
91% ± 26%, 111% ± 64%, and 96% ± 11%,
respectively.
Factors II and V. After 3 days of oxandrolone
administration, increases of factors II and V were
apparent (88% ± 15% to 100% ± 17% and 105%
± 21% to 167% ± 28% basal levels, respectively).
These factors continued to increase during the course
of administration of the drug, and after 14 days the
increases were 122% ± 11% (P < 0.005) and 179%
± 36% (P < 0.0001), respectively. After discontinu-
ing of oxandrolone (day 42), these peak levels
decreased: factor II, 122% ± 11% to 106% ±

Fig. 3. Determination of coagulation factors (II, V). Factors

Fig. 2. Effect of oxandrolone on plasminogen activator
inhibitor-1 (PAI-1). Quantitative determination of PAI-1 and
plasminogen was by the synthetic chromogenic substrate
method [34]. Determination of PAI-1 by a new venom-based
assay (details in Materials and Methods). Error bars
represent standard deviations. *P < 0.01 for BL versus
treatment day; .P < 0.01 for treatment day 14 versus
washout day.
II (A) and V (B) were determined on the ACL system by
running a single-factor assay (see Materials and Methods).
The % activity of each factor, after oxandrolone
administration, was compared to a normal control plasma.
Error bars in the figure represent standard deviations. In
(A), *P < 0.005 for BL versus treatment day; .P = 0.05 for
treatment day 14 versus washout day; in (B), *P < 0.0001 for
BL versus treatment day; .P < 0.0001 for treatment day 14
versus washout day.

discontinuing oxandrolone administration, factor VII
returned to near-baseline level.
Factor VIII. The effect of oxandrolone therapy on
factor VIII levels was not statistically significant.
Three days after the administration of oxandrolone
the basal level of factor VIII increased slightly over
the basal level (111% ± 64% to 125% ± 55%, NS).
Factor X. Following 14 days of administration of
oxandrolone, the basal level of factor X increased
steadily from 96% ± 11% to 107% ± 25% (NS).
After discontinuing oxandrolone, factor X level
decreased from the peak treatment level to 89% ±
25% (NS).
There was no correlation between the subject’s age
or body weight with baseline or treatment response to
oxandrolone for any of the coagulation factors.
The effect of 14 days of oxandrolone administra-
tion on ADP-induced platelet aggregation was not
significant.
Liver function tests were monitored during oxan-
drolone administration and after discontinuation of
the drug. In one subject, the ALP was elevated at
baseline and remained elevated during drug treatment
and the washout periods. In five additional subjects,
ALT and AST became elevated (<2-fold) during the
14 days of administration of oxandrolone. In two
subjects, LFTs returned to within normal limits dur-
ing drug treatment. In three subjects, LFTs returned
to within normal limits during the washout period.
DISCUSSION
The results presented herein demonstrate that
administration of oxandrolone, a synthetic anabolic
steroid, to healthy young men was associated with a
significant increase of both blood coagulation factors
and fibrinolysis. Oxandrolone activated two separate
pathways: the intrinsic pathway and the extrinsic
pathway, both of which contain factor VII. As a
consequence of activating these two pathways, the
common pathway, which contains factors X, V, II
(prothrombin), and fibrinogen (factor I), was also
activated. Discontinuation of oxandrolone adminis-
tration reversed this effect on the coagulation cas-
cade.
Oxandrolone administration appears to activate
the prothrombinase complex (PTC). There was the
increase of the vitamin K-dependent factors (II, X),
suggesting that oxandrolone directly influenced the
hepatic production of these factors. Because oxandro-
lone administration increased prothrombin (factor
II), and prothrombin is essential for the clotting of
blood, an increase in factor II may lead to increased
coagulation in the presence of PTC through the for-
mation of thrombin. Oxandrolone administration
10968652, 2006, 2, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.20532, Wiley Online Library on [08/07/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Effects of Oxandrolone on Hemostasis 99
also resulted in a significant increase in factor V
levels. Factor V has been associated with venous
thrombosis, and its structure has a 40% homology
to factor VIII. Factor VIII appeared to be unchanged
by oxandrolone administration.
Increased factor VII (tissue factor) has been asso-
ciated with coronary heart disease [7] and plays a vital
role in the initial activation of the coagulation cas-
cade (extrinsic pathway) when it complexes with tis-
sue factor. Present evidence suggests that the extrinsic
pathway is critical to the initiation of fibrin forma-
tion. Platelet activation and subsequent hyperaggre-
gation have been linked to CVD and acute ischemic
events [39,40]. Oxandrolone administration had a
variable but not significant effect on factor VII levels.
Oxandrolone administration had no significant
effect on ADP-induced platelet aggregation because
oxandrolone administration resulted in a significant
increase of factor V and a non-significant increase of
factor X (10%). Previously, we have shown that even
a 2% increase in factor X during the activation of
both the intrinsic and extrinsic pathways of the blood
coagulation pathways inhibits thromboxane A2
synthesis in platelets, and this inhibition requires fac-
tor V [40].
Anabolic steroids are potent stimulants of protein
synthesis in tissues [41]. Due to the brief duration of
oxandrolone administration, it was improbable that
hemoglobin and hematocrit values were affected
because the hematopoietic effect of androgens does
not peak for 5 months [42]. It is possible that admin-
istration of oxandrolone induced specific factor VII
inhibitors, resulting in an apparent reduction in the
level of this clotting factor. Although the administra-
tion of oxandrolone increased the plasma level of
factor V, there was no concomitant increase of coa-
gulant factor VIII (VIIIC), indicating that the
increase of factor V alone may not favor the develop-
ment of disseminated intravascular coagulation
(DIC) [43]. The simultaneous increase of plasminogen
and decrease of PAI-1 after the administration of
oxandrolone would result in an increased plasmin
level in the circulation that would provide a coun-
ter-regulatory mechanism for the dissolution of fibrin
deposition to maintain homeostasis. Furthermore,
although DIC has been related to liver diseases and
factors II, V, VII, and X have been reported to
decrease in DIC, in this study administration of oxan-
drolone increased select coagulation factors (factors
II and V), suggesting that the administration of oxan-
drolone did not result in the increase of plasma coa-
gulation. Administration of oxandrolone 20 mg/day
for 14 days resulted in simultaneously stimulating
both pro-coagulatory and fibrinolytic activity, result-
ing in a balanced effect on the hemostatic system.

100 Kahn et al.
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