ORIGINAL CONTRIBUTION
Lower-Extremity Functional Electrical Stimulation
Decreases Platelet Aggregation and Blood Coagulation in
Persons With Chronic Spinal Cord Injury: A Pilot Study#6

Nighat N. Kahn, PhD1,2; Susan P. Feldman, PhD2; William A. Bauman, MD1,2
1James J. Peters VA Medical Center, Bronx, New York; 2Mount Sinai School of Medicine, New York, New York

Received October 28, 2008; accepted November 17, 2009
Abstract
Background: Individuals with spinal cord injury (SCI) develop premature cardiovascular disease. Regularexercise reduces the incidence and symptoms of cardiovascular disease in able-bodied individuals; thesesalutary effects of exercise have not been documented in persons with SCI.
Objective: To evaluate the effects of functional electrical stimulation leg cycle ergometry (FES-LCE) exercise
training on platelet aggregation and blood coagulation in persons with SCI.
Participants: Subjects (n 5 14) with stable chronic (.1 year) paraplegia (T1–T10) or tetraplegia (C4–C8).
Methods: Blood samples were collected before and after the first and eighth sessions (2 sessions per week
for 4 weeks) of FES exercise.
Results: Platelet aggregation was inhibited by 20% after the first session and by 40% (P , 0.001) after theeighth session. Thrombin activity was unchanged after the first session (10.7 ± 0.85 s to 10.43 ± 0.56 s)
and decreased after the eighth session (12.5 ± 1.98 s to 11.1 ± 1.7 s; P , 0.0003). Antithrombin III activity
increased after the first (103.8% ± 8.9% to 110% ± 6.9%; P , 0.0008) and eighth sessions (107.8% ±12.1% to 120.4% ± 13.1%; P , 0.0001). Cyclic adenosine monophosphate increased after the first (9.9% ±
2.5% to 15.8% ± 3%; P , 0.001) and eighth sessions (17.8% ± 4.2% to 36.5% ± 7.6%; P , 0.0001). Afterthe eighth session, factors V and X increased significantly (88% ± 27% to 103% ± 23%, P , 0.0001; 100%
± 40% to 105% ± 7%, P , 0.01, respectively); factors VII and VIII and fibrinogen did not change
significantly. A significant reduction in platelet activation/aggregation was demonstrated in response to FESLCE. The decrease in thrombin level was caused by the simultaneous increase in antithrombin activity.
Conclusion: These findings provide new insight into the potential protective effects of FES-LCE against therisk of cardiovascular disease.
J Spinal Cord Med. Apr 2010;33(2):150–158
Key Words: Spinal cord injuries; Functional electrical stimulation; Leg cycle ergometry; Cardiovasculardisease; Tetraplegia; Paraplegia; Paralysis; Exercise regimen; Hypercoagulability; Blood coagulation;
Thrombin; Antithrombin
INTRODUCTION
In the United States, 13.6% (31.3 million) of the total
noninstitutionalized population report some limitation inphysical activity as a result of chronic health conditions;
3.8% (8.8 million) are unable to perform any major
activity, ,6% (13.6 million) have restricted major
activity, and 4.4% (10.1 million) have some limitationof activity (1). Immobilization or prolonged inactivity as a
Please address correspondence to Nighat Kahn, PhD, RR&D
Center of Excellence, James J. Peters VA Medical Center, 130 W.
Kingsbridge Road, Bronx, NY 10468; p: 718 584 9000, ext.
6074; f: 718 741 4675 (e-mail: nighat.kahn@va.gov).
G 2010 by the American Paraplegia Society

150

result of any condition, including spinal cord injury (SCI),
is associated with hyperinsulinemia and impaired glucose
tolerance; both factors are associated with increased
cardiovascular risk (2,3).
In cross-sectional studies, persons with SCI have beenplaced at the lowest end of the fitness range. Persons
with paraplegia have been shown to be poorly conditioned and are only marginally more fit than those withtetraplegia. Nearly 25% of otherwise healthy young
subjects with paraplegia fail to achieve a fitness level(peak oxygen consumption after arm ergometry) that is
sufficient for independent living (4–7). It is highly unlikelythat this level of fitness can improve without some formof exercise regimen (8). Of the 179,000 persons with SCI
in the United States, 40% are at least 45 years old and 1

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2010in 4 has lived 20 or more years after injury. SCI is nolonger a static medical condition but a medical condition
associated with constantly changing needs, abilities, andlimitations (9–12).
A clustering of risk factors associated with cardiovascular disease (CVD) has been demonstrated in individuals
with SCI, including dyslipidemia (low levels of highdensity lipoprotein and high triglyceride levels), hypertension, diabetes mellitus, and hyperinsulinemia. Additional risk factors include a high prevalence of cigarettesmoking and physical inactivity and the fact that the
majority of the people with SCI are men. However, theserisk factors account for only half of the observed risk for
CVD. The emerging role of acute thrombosis in the
etiology of CVD suggests additional novel risk factors that
could mediate risk associated with SCI (3). The deleterious effects of SCI-induced paralysis might be reducedby the introduction of well-designed exercise programs
at an appropriate interval after injury.
Able-bodied individuals exercise for many reasons.
Exercise is performed to increase muscle mass, strength,and endurance to recondition and reduce the risk of CVD
by decreasing blood coagulation factors (13), loweringbody fat, reversing insulin resistance, and reducing
physical stress. In the short term, exercise has beenshown to reduce blood coagulation and platelet aggregation (14–16). Persons with SCI have limited options forexercise that may be attributed not only to external
factors but also lack of desire. Therefore, it is imperativethat the selected exercise activities effectively reduce therisks of physical dysfunction without increasing the risksof physical injury (whether muscular or skeletal).
Although many forms of exercise have been shown
to be beneficial in persons with SCI, for those unable toperform voluntary motor movement exercise, functional
electrical stimulation (FES) exercise induced by electrically stimulated contraction has been used to train
individual body segments and/or invoke cycling movements, with or without arm movement (17,18). Electricalstimulation of local muscle sites increases muscle massand circulation and favorably alters muscle fiber composition (19). In tetraplegia, electrically stimulated cycling
improves fitness and lower-extremity circulation, associated with reversal of cardiac muscle atrophy (20,21). Arm
and wheelchair ergometry have been shown to increasearm endurance, decrease CVD risks associated withhyperlipidemia, improve body composition with increased lean mass and decreased fat mass, and improve
whole-body uptake of insulin-stimulated glucose transport in the quadriceps muscles (22,23). In addition, there
are reports of increased expression of GLUT 4, a muscle/
adipose tissue–specific glucose transport protein, anddecreased platelet aggregation (5,14,15,23).
Individuals with SCI have been reported to havepremature and accelerated CVD (2,24). An epidemiologic study showed that CVD was the leading cause ofdeath more than 30 years after injury (46% of all deaths)

and among those above 60 years of age (35% of alldeaths) (3,25–27). Currently, the knowledge is very
limited regarding the effect of exercise on hemostatic
factors and fibrinolysis in subjects with chronic SCI.
Biochemical markers for hypercoagulability are associated with increased risk for CVD among able-bodied
populations (28). Hypercoagulability may result fromelevated levels of fibrinogen, Factor VII, or von Willebrand factor or a decreased fibrinolytic system, including elevated levels of plasminogen activator inhibitor-1
antigen and decreased tissue plasminogen activator(15,29). Hypercoagulability may partially explain theincreased risk of CVD in people with SCI.
As in able-bodied individuals, regular physical exercise of moderate intensity decreases platelet aggregability by increasing levels of tissue plasminogen activatorand decreasing plasminogen activator inhibitor-1 activity(15,29). In addition, the exercise-associated improvement in the lipid profile and the reduction in fat mass
may improve glucose utilization, increase sensitivity ofplatelets, which decreases platelet aggregability andblood coagulation, and increase fibrinolysis (13–15).
Thus, it can be hypothesized that physical exercise hasa beneficial impact on blood coagulation and fibrinolysis.
Because prolonged inactivity following SCI has beenshown to be associated with an increased prevalence of
cardiovascular risk factors (3), the purpose of the present
study was to determine the effects of functional electricalstimulation leg cycle ergometry (FES-LCE) on blood
coagulation factors in persons with SCI (1,24).
MATERIALS AND METHODS
Subject Selection
Subjects (n 5 14) with stable chronic (.1 year)
paraplegia (T1–T10) or tetraplegia (C4–C8) enrolled in
an FES-LCE training program (electrically induced lowerextremity ergometer manufactured by Therapeutic Alliance Inc, New York, NY) were recruited for study
participation. Two subjects were terminated from thestudy; one subject fractured her femur, and anotherdeveloped a pressure ulcer (neither event was related to
the FES-LCE program).
The subjects were asked to abstain from aspirin andother medications known to affect platelet aggregationfor 2 weeks prior to blood donation. None of the subjects
were prescribed oral anticoagulants.
FES-LCE was performed for 8 sessions. Before andafter exercise (sessions 1 and 8), blood samples werecollected in sodium citrate (13 mM final concentration).
The study was approved by the Institutional Review
Boards for Clinical Research, Mount Sinai School of
Medicine, and the James J. Peters Veterans Affairs Medical
Center, Bronx, New York.
Exercise Prescription
Computerized FES allowed active LCE exercise of limbs
paralyzed by upper motor neuron lesions. Previously

Effects of FES Exercise in SCI

151

untrained subjects with SCI who required FES for leg
movement were recruited for this study. Individuals with
SCI participated in an FES-LCE exercise program for 2
sessions per week for 4 weeks. The lower-extremity
ergometer used in the study employs 6 channels ofelectrical stimulation delivered to 12 carbon surface
electrodes. The stimulation was applied to the quadriceps, hamstrings, and gluteal muscle groups bilaterallywith a constant current of 0 to 132 mA at a sequential
frequency of 30 Hz and a pulse width of 350 microseconds, resulting in stationary bicycling.
The initial workload was zero and resistance wasincreased in increments up to 0.0125 kilopond based on
the subject’s tolerance. Each exercise session consisted ofmultiple exercise bouts of discontinuous training, terminating in a total exercise time of up to 30 minutes, with a
5-minute rest period between bouts. Each exercise bout
was preceded by a 2-minute warm-up and followed by a2-minute cool-down. During the warm-up and cooldown, the legs were passively pedaled while receiving
low-level electrical stimulation. Fatigue was defined as
the point at which the subjects could no longer maintaina minimum pedaling speed of 35 rpm.
Blood samples were obtained at baseline (firstsession) and at the completion of training (eighth
session), before and after each training session. Futurestudies will address the duration of the effects of FES-LCE
exercise after termination of exercise training.
Collection of Blood
Blood (20 mL) was drawn from each subject andanticoagulated by mixing 9 volumes of blood with 1
volume of 0.13 M sodium citrate. Platelet-rich plasma(PRP) was prepared by centrifuging blood at 200g for
15 minutes at 23uC. Platelet-poor plasma was preparedby centrifuging PRP at 3,000g for 15 minutes at 23uC
(30).
Platelet Aggregation
Platelet aggregation was determined by placing 0.5 mL
PRP in a silicon-coated cylindric curette containing a
Teflon-coated magnetic stirring bar. Aggregation ofplatelets was initiated by adding adenosine diphosphate(2 to 4 mM) as an aggregating agent in an aggregometer(Chronolog, Broomall, PA) and stirring the PRP at 37uC at
1,200 rpm (31,32).
Determination of Coagulation Factors, Thrombin,
Antithrombin III, and Fibrinogen Activity
in Plasma
Hemostatic factor analysis was performed in blood
anticoagulated with sodium citrate (13 mM final concentration) and kept on ice until centrifugation andseparation of plasma at 3,000g for 20 minutes at 4uC.
Plasma was separated from the red blood cells andaliquots were frozen and stored at 270uC for subsequent
analysis (32).

152

Screens for factors V, VII, VII, X, thrombin, antithrombin III (AT III), and fibrinogen were run on an
automated IL ACL Advance #2 instrument. Factors (V, VII,
VII, X) in the coagulation cascade (intrinsic and extrinsic
pathway) were tested. Prothrombin time (PT) measuresthe extrinsic pathway and was tested by adding tissue
factor (TF; here, thromboplastin was used) and Ca2+,
whereas the intrinsic pathway (or activated partial
thromboplastin time (APTT)) was initiated with asubstance that mimics platelet factor (microsilica glass
beads and cephalin) and Ca2+ was added. This test
activates Factor VII, which starts the common pathway;
the instrument detects the start of fibrin formation. When
all reagents were assembled in the test tube, the time toform a clot was recorded in seconds.
The percent activity of a coagulation factor in theexperimental plasma was compared with normal plasma.
This was performed by running a single factor assay. A
calibration curve was created with each run, using theCalibration Plasma tool (Instrument Laboratory Company, Lexington, MA).
To assay thrombin and fibrinogen, the reagents werereconstituted with the recommended water and placed
into 0.5-mL sample cups. The specimens were placed in
the sample tray and analysis was started.
Assay of Cyclic Adenosine Monophosphate
Washed platelets (2 3 109) in Tyrode’s buffer (pH 7.5)
containing 5.0 mM magnesium chloride (MgCl2) wereincubated with 10 mM theophylline for 2 minutes, in a
total volume of 200 mL, at 23uC. Prostaglandin E1(1.0 mM) then was added to the cell suspension. Afterincubation for an additional 1 minute, ice-cold trichloroacetic acid (5%) and 1.0 N hydrochloric acid wereadded to the mixture. The concentration of cyclic
adenosine monophosphate (cAMP) in the extract wasdetermined (30).
Statistical Analysis
Results are reported as means ± SDs. The statistical analysis
for normally distributed data was performed with paired
Student t test with Bonferroni correction for multiple
comparisons to test differences between the groups.
Differences were considered significant at P , 0.0125.
RESULTS
Effect of FES-LCE Exercise on Thrombin andAntithrombin III
Thrombin. After the first session of FES-LCE exercise,plasma thrombin level decreased marginally from baseline value of 10.7 ± 0.85 s to 10.43 s ± 0.56 s (notsignificant). The basal level of thrombin was within thenormal range. Pre-exercise plasma thrombin activity
increased by 20% from session 1 to session 8 (Figure 1).
After the eighth session, thrombin activity decreased
significantly, from 12.5 ± 1.98 s to 11.1 ± 1.7 s (P ,0.001) (Table 1, Figure 1).

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Figure 1. Effect of FES exercise training on thrombin.
Blood samples for thrombin levels were collected before andafter the first and eighth FES exercise sessions. Results are
expressed as means ± SDs.

Antithrombin III. The basal level of AT was within thenormal range (80%–130%). Following FES-LCE exercise,in parallel with the aforementioned decrease in thrombin
activity, there was a concomitant increase in AT. After the
first session of FES-LCE exercise training, AT activity
increased from 103.8% ± 8.9% to 110% ± 6.9% (P ,0.001); AT activity increased after the eighth session,from 107.8% ± 12.1% to 120.4% ± 13.1% (P , 0.001)(Table 1, Figure 2). There was no significant change inthe pre-exercise values. AT activity was significantly
increased after the eighth session compared with after
the first session.
Effect of FES-LCE Exercise on Fibrinogen
Fibrinogen was assayed because it has been identified as
an independent cardiovascular risk factor. Fibrinogenlevels did not increase significantly after FES-LCE exercise
training. After the first session of FES-LCE training, theFigure 2. Effect of FES exercise on AT activity. The percent
activity of AT III was determined before and after the firstand eighth FES exercise sessions for comparison. AT activity
post–FES exercise was compared after the first and eighth
sessions. Results are expressed as means ± SDs.
fibrinogen level increased slightly from the basal level of
410 ± 78 mg/dL to 425 ± 97 mg/dL (change notsignificant). Normal levels of fibrinogen vary from 150 to
400 mg/dL. After the eighth session of FES-LCE exercise,the fibrinogen level had decreased slightly from 439 ±104 mg/dL to 427 ± 65 mg/dL (change not significant)(Tables 1 and 2).
Effect of FES-LCE Exercise Training on Blood
Coagulation Factors
Before the initiation of FES-LCE exercise training, basal
plasma levels of factors V, VII, VIII, and X were
determined to be 96% ± 19%, 109% ± 23%, 140% ±24%, and 97% ± 5%, respectively (Table 2, Figures 3
and 4). (The normal plasma levels of factors V, VII, VIII,
and X range from 60% to 150%).

Table 1. The Effect of FES-LCE Exercise on the Various Thrombogenic Factors and Platelet Function in Subjects
Trained Twice a Week for 30 Minutes for 4 Weeks (8 Sessions)First Session

Eighth Session

Tests Performed

Before Exercise

After Exercise

Before Exercise

After Exercise

After Eighth Session

Thrombin
AntithrombincAMP
Plt Agg
Factor V
Factor X
Factor VII
Factor VIII
Fibrinogen

+
+
+
+
+
+
+
+
+

NC
q
q
Q
q
q
NC
+
NC

+
+
+
+
+
+
+
+
+

Q
q
q
Q
q
q
NC
NC
NC

P , 0.0003
P , 0.0001
P , 0.0001
P , 0.001
P , 0.0001
P , 0.01
NS
NS
NS

Q, decrease; q, increase; NC, no change; NS, not significant; cAMP, cyclic adenosine monophosphate; and Plt Agg, platelet
aggregation.

Effects of FES Exercise in SCI

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Table 2. Effect of FES-LCE Exercise Training on Blood Coagulation Factors VII, VIII, and Fibrinogen

Test Performed

First Session
Before Exercise

First Session
After Exercise

Eighth Session
Before Exercise

Eighth Session
After Exercise

Factor VII (%)
Factor VIII (%)
Fibrinogen (mg/dL)

109 ± 27
149 ± 25410 ± 78109 ± 26
137 ± 10425 ± 97112 ± 24
136 ± 7439 ± 104113 ± 27
137 ± 10427 ± 65

After the first session of FES-LCE exercise, plasma
levels of factors, V, VII, VIII, and X were determined to be
99% ± 18%, 109% ± 27%, 149% ± 25%, and 98% ± 6%,
respectively (changes not significant) (Table 2, Figures 3
and 4). After the eighth FES-LCE exercise session, factor V
and factor X increased significantly from 88% ± 27% to103% ± 23% (P , 0.0001) and 100% ± 40% to 105% ±7% (P , 0.01), respectively (Figures 3 and 4). The activityof plasma factors VII and VIII did not change significantly
after the eighth session of FES-LCE exercise and were

determined to vary from 112% ± 24% to 113% ± 27%
and 136% ± 7% to 137% ± 10%, respectively (Table 2).
Effect of FES-LCE Exercise Training on cAMP
After the first session of FES exercise, the cAMP level inplatelets increased, from 9.9% ± 2.5% to 15.8% ± 3% (P, 0.001). Basal cAMP levels vary from 2 to 4 picomol/
108 platelets. After the eighth session of FES-LCE exercise,the cAMP levels in platelets were significantly increased,from 17.8% ± 4.2% to 36.5% ± 7.6% (P , 0.001)(Figure 5). Pre-exercise and postexercise levels of plateletcAMP were significantly higher at the eighth session
compared with the first session (Figure 5).
Effect of FES-LCE Exercise Training on
Platelet Aggregation
Platelet aggregation after the first session of FES-LCE
exercise was not significantly inhibited. However, adenosine diphosphate–induced aggregation of platelets was
significantly inhibited by 40% (P , 0.001) after theeighth session of FES-LCE exercise.

Figures 3 and 4. Determination of activity of coagulation
factors V and X. Results are expressed as means ± SDs.

154

Figure 5. Effect of FES exercise on cAMP. The formation ofcAMP was determined by adding 100 nM PGI2 to platelet
suspensions. All comparisons (eg, before vs after exercise,after the first and eighth sessions, before exercise at eachtime point, and after exercise at each time point) weresignificant. Results are expressed as means ± SDs.

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DISCUSSION
The results presented herein demonstrate that subjects
with SCI had a significant reduction in platelet activation
after their first session of FES-LCE exercise. Platelet
hyperactivity, among other factors, stimulates atherosclerosis and may lead to CVD in persons with SCI (30).
Previously, it had been demonstrated that the platelets
from subjects with SCI developed resistance to theinhibitory effect of prostaglandin I2 (PGI2) in controlling
platelet-stimulated thrombin generation, thereby increasing excess thrombin production and the release ofplatelet-derived growth factor (PDGF, a cytokine) (33–37). Thrombin and PDGF are atherogenic mitogens andshould be controlled, because if they are not inhibited by
the normal counterregulatory mechanism(s), atherosclerosis would be expected to be accelerated (35).
Thrombin is the most potent agonist of platelet
aggregation; it promotes platelet activation, via activation of the dual protease-activated receptors (PAR) PAR 1
and PAR 4, on the platelet, proceeding through theactions of Gi-proteins that are inhibitory to cAMP
(38,39). Thrombin has an essential role in blood
coagulation by activating factor XI, factor V, and factor
VIII; positive feedback of the end products of thispathway accelerates the production of thrombin. Additionally, thrombin converts fibrinogen to fibrin and playsa critical role in the development of arterial thrombosis.
However, there are no therapeutic strategies that
effectively target PAR 1 and PAR 4 receptors (39).
Thrombin is also a potent mitogenic agent for arterialsmooth muscle cells, inducing the proliferation of humanmesangial cells that encodes the mRNA synthesis of
PDGF, and it has been implicated in atherosclerotic
plaque formation (33,34). The effects of thrombin are
mediated through thrombin’s interaction with platelets
and inhibited by PGI2 binding to specific receptors on theplatelet surface, which activates membrane adenylate
cyclase and increases cAMP, leading to the inhibition ofplatelet function (30,39). Intraplatelet cAMP was shown
to be significantly increased after the first and eighth FESLCE exercise sessions. These values were also higher preand postexercise at the eighth session compared to thoseat the first session.
Basal levels of PDGF in SCI plasma have previously
been shown to be 3 times higher than normal levels;
release of platelet-stimulated thrombin and PDGF from
SCI platelets was not inhibited by the PGI2-stimulated
increase of cAMP formation, suggesting that in nonexercising individuals with SCI, the potential for thrombin generation was significant and not directly counterbalanced by normal regulatory mechanisms (36).
Physical training has been shown to reverse endothelium
dysfunction by releasing arachidonic acid metabolites,
especially PGI2, from contracting muscles; it also produces increased levels of the vasodilators PGE2 and PGI2
while reducing the vasoconstrictor thromboxane A2 in
the interstitial fluid of the muscles in non-SCI individuals(37,38,40,41). The increase in platelets cAMP (preexercise vs postexercise training) after the first andeighth sessions of FES-LCE exercise training in subjects
with SCI was presumably caused by increases in PGI2
production, which would inhibit thrombin generation.
Exercise training has been reported to improve glucose
utilization and enhance insulin action in individuals withSCI (29), and insulin has been shown to increase the levelof platelet PGI2 and inhibit thrombin generation (35,36).
Furthermore, FES-LCE exercise induced a significant
decrease in thrombin activity with a concomitant
increase in AT activity. AT III inhibits thrombin and otherenzymes involved in the clotting cascade. AT remarkably
reduces infarction volume in mice (41). The physiologic
target proteases of AT are those of the intrinsic
coagulation system, namely the activated forms of factor
X (Xa), factor IX (IXa), factor VII (VIIa), factor XI (XIa),
factor XII (XIIa), and factor II (thrombin) (IIa). AT III has apotent inhibitory effect on the proinflammatory andprocoagulant processes (42–44). After FES-LCE exercise,the increase in AT generation diminished the potential
for activation of blood coagulation factors VII, VIII, X, andthrombin, as well as reducing fibrin formation that would
enhance blood clot dissolution, thereby further diminishing the outcomes of thrombosis.
AT exerts anti-inflammatory activity by promoting
endothelial release of PGI2 (45), a potent vasodilator andinhibitor of platelet aggregation (31,45,46). In individuals with SCI, 8 sessions of FES-LCE exercise training
inhibited platelet aggregation by 40% through anincrease in platelet cAMP activity, without a concomitant
activation of blood coagulation. FES-LCE exercise, therefore, may be beneficial in controlling an enhancement inplatelet activation that may lead to a thrombotic episode.
Although after the eighth session, and before thebout of exercise, the thrombin level was increased byabout 20% over the baseline value; this was expected
because exercise training is associated with modest
increases in thrombin levels (14–16). However, it should
be appreciated that despite the modest increase, thethrombin levels remained within the normal range.
Although it may not be intuitive, especially if one isfocused on the absolute values for thrombin, that
coagulation had been favorably modified after FES
exercise training; this is strongly suggested from thehighly favorable response of platelet aggregation, which
was significantly reduced at the eighth session before
exercise, regardless of previous AT III levels.
Factor V has a dual function in procoagulation andanticoagulation pathways (47). In individuals with SCI,
after the eighth session of FES-LCE exercise training,
Factor V activity increased significantly, acting as a
cofactor to reduce Factor VIII activity and thrombin
generation. In addition, a significant increase in Factor V
and Factor X after FES-LCE exercise may suggest that, on
the platelet surface, a Factor Va-Xa complex was formed
and resulted in increased prostaglandin (PGI2) synthesis,

Effects of FES Exercise in SCI

155

inhibiting platelet aggregation. As previously shown, a
2% increase in Factor X inhibits thromboxane A2
synthesis in platelets, and this inhibition requires Factor
V (47).
Factor VII (tissue factor) has been associated withcoronary heart disease and plays a vital role in the initialactivation of the coagulation cascade (extrinsic pathway)when it complexes with TF from a leaking or ruptured
atherosclerotic plaque. The present evidence suggeststhat the extrinsic pathway is critical to the initiation offibrin formation (40,42). In one report, in persons with
SCI, the plasma procoagulant activities of Factor VII andfibrinogen concentrations were significantly increased,
demonstrating the increased activity of the extrinsic andcommon pathways at baseline (48). These data suggestthat SCI may, via as-yet unknown mechanisms, lead tothe alteration of the extrinsic and common coagulation
pathways and several factors of the hemostatic andfibrinolytic systems (16,49–51). The effects of physicalexercise in 56 patients after myocardial infarction before
and after 4 weeks of training showed that the levels of
Factor VII before treadmill test had decreased significantly (by 10.6%) (50). However, Factor VII levels were
unchanged and remained normal after 8 sessions of FESLCE exercise training. Although Factor VII levels were notsignificantly reduced by FES-LCE exercise training,perhaps its activation may have been diminished byelevated levels of AT.
Increased plasma levels of fibrinogen are associatedwith a risk of various CVDs that is roughly double that ofnormal (51). Fibrinogen is the final substrate of thecoagulation system, is converted to fibrin throughthrombin generation, and promotes platelet aggregation, thrombosis, and early atherogenesis (49,51). Also,
fibrinogen and Factor VII appear to be as effective as totalcholesterol in predicting future risk of coronary heartdisease (40). In individuals with SCI after FES-LCE
exercise training, fibrinogen activity remained unchanged. Because Factor VII and fibrinogen are associated with CVD, and because these factors did not increase,this indicates that the common blood coagulation
pathway was not activated.
Compared with able-bodied individuals, SCI subjects
with injuries above the level of T1 have been shown tohave lower circulating catecholamine levels at rest, andlevels may increase only slightly with exercise. Catecholamines are known to affect platelet function and blood
coagulation. In the present article, there was nodifference in the inhibition of platelet aggregation or of
coagulation factors after FES exercise.

changes in 3 parameters (fibrinogen, factors VII and VIII);
however, favorable changes were observed for the 6other determinations. Our findings for thrombin, AT III,fibrinogen, and FVII are consistent with previous observations in sedentary men evaluated for changes in blood
coagulation before and after exercise on a treadmill.
This is the first study to demonstrate that FES-LCE
exercise training may suppress platelet aggregation. It
appeared that this effect was caused by greater activity inthe platelets’ intracellular cAMP. Cyclic AMP production
is known to be stimulated by PGI2 and to cause theinhibition of platelet aggregation in individuals with SCI.
In individuals with SCI, FES-LCE exercise training did not
activate the 2 separate blood coagulation pathways: theintrinsic pathway and the extrinsic pathway, both ofwhich contain Factor VII, Factor VIII, thrombin, andfibrinogen. Factor X, Factor V, and AT were activatedafter FES-LCE exercise. These results indicate an additional possible protective effect against cardiovasculardisease of FES-LCE exercise training, independent of the
known favorable changes in lipoprotein concentrations
associated with exercise. FES-LCE exercise training,
compared to alternative treatments, such as surgery or
pharmacotherapy, is not only cost effective but also may
have a beneficial impact on the quality-adjusted life
expectancy of persons with SCI. Thus, FES-LCE exercise
training should be considered as an essential componentof the medical management of persons with SCI to
improve their hemostatic profile and reduce the risk of
CVD.
ACKNOWLEDGMENT
The authors are indebted to Dr Kristjan Ragnarsson,
Professor and Chairman of the Department of Rehabilitation Medicine of Mount Sinai, School of Medicine forallowing us to conduct the study in the Department of
Rehabilitation.
REFERENCES

CONCLUSION
In conclusion, 8 sessions of FES-LCE exercise training
induced favorable hemostatic changes in individuals with
SCI. Nine parameters were analyzed (thrombin, AT,
cAMP, platelet aggregation, fibrinogen, and coagulation
factors V, VII, VIII, and X). There were no significant

156

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The Journal of Spinal Cord Medicine

Volume 33

Number 2

2010