Research Article

Elevated Heparin-Induced Antibodies Are More Common in

Diabetic Patients with Vascular Disease
Joseph J. Naoum,
1,2
Nibal R. Chamoun,
1
Mitul S. Patel,
2
Tiffany K. Street,
2
Mazen Haydar,
1
Jean Bismuth,
2
HosamF. El-Sayed,
2
Mark G. Davies,
2
Alan B. Lumsden,
2
and Eric K. Peden
2
1
Lebanese American University and University Medical Center Rizk Hospital, P.O. Box 11-3288, Zahar Street,
Achrafeh, Beirut, Lebanon
2
Houston Methodist and DeBakey Heart and Vascular Center, Houston, TX, USA
Correspondence should be addressed to Joseph J. Naoum; jjnaoum@tmhs.org
Received 31 October 2013; Accepted 30 December 2013; Published 6 February 2014
Academic Editor: Louis M. Aledort
Copyright 2014 Joseph J. Naoum et al. Tis is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Background. Hypercoagulable disorders can lead to deep vein thrombosis (DVT), arterial thrombosis or embolization, and early
or recurrent bypass graf failure. Te purpose of this study was to identify whether diabetes increased the likelihood of heparin-
induced platelet factor 4 antibodies in at risk vascular patients. Methods. We reviewed clinical data on 300 consecutive patients.
A hypercoagulable workup was performed if patients presented with (1) early bypass/graf thrombosis (<30 days), (2) multiple
bypass/graf thrombosis, and (3) a history of DVT, pulmonary embolus (PE), or native vessel thrombosis. Relevant clinical variables
were analyzed and compared between patients with diabetes (DM) and without diabetes (nDM). Results. 85 patients (47 women; age
53 16 years, range 1682 years) had one of the defned conditions and underwent a hypercoagulable evaluation. Screening was done
in 4.7%of patients with early bypass grafthrombosis, 60%of patients were screened because of multiple bypass or grafthrombosis,
and 35.3% had a previous history of DVT, PE, or native vessel thrombosis. Of the 43 patients with DM and 42 nDM evaluated, 59
patients (69%) had an abnormal hypercoagulable profle. An elevated heparin antibody level was present in 30% of DM and 12% of
nDMpatients (chi-squared test < 0.04). Additionally, DMwas associated with a higher likelihood of arterial complications while
nDM was associated with a higher rate of venous adverse events (chi-squared test < 0.003). Conclusions. Diabetes is associated
with a higher likelihood of developing heparin-induced antibodies and an increased combined incidence of arterial complications
that include early or multiple bypass/graf thrombosis. Tis fnding may infuence the choice of anticoagulation in diabetic patients
at risk with vascular disease.
1. Introduction
Inherited or acquired hypercoagulable states represent a
cause of morbidity in patients with vascular disease. Hyper-
coagulable disorders can lead to deep vein thrombosis
(DVT), arterial thrombosis or embolization, and early or
recurrent bypass graf failure [1, 2]. Te latter have usually
been attributed to a failure of surgical technique rather
than a hypercoagulable-mediated event. Patients are usually
considered to have a hypercoagulable state when they have a
laboratory or a clinical picture associated with an increased
thrombotic risk. Patients with diabetes mellitus (DM) are at
an increased risk of cardiovascular complications as a result
of cerebrovascular, cardiac, or peripheral arterial disease [2].
Diabetic patients exhibit a heightened activation of platelets
and clotting factors [3] which is also enhanced by the
presence of hypertension (HTN) [4]. Platelet hyperactivity
in DM can be demonstrated by the presence of increased
circulating platelet aggregates and the presence of higher
plasma levels of platelet release products such as platelet
factor 4 (PF4) [5]. Tese fndings support the concept that
DM can be associated with a hypercoagulable state which
can be potentially exacerbated in patients with overt arterial
disease or those who have undergone vascular intervention.
Heparin-induced thrombocytopenia (HIT) is an immune
mediated reaction that results from the exposure to heparin
Hindawi Publishing Corporation
rombosis
Volume 2014, Article ID 649652, 5 pages
http://dx.doi.org/10.1155/2014/649652
2 Trombosis
products. Antibodies against epitopes within PF4 form when
this proteininteracts with heparinand binds to mucopolysac-
charides or glycosaminoglycans. Tese antibodies bind the
heparin-PF4 (HPF4) complex and cause platelet activation
[6, 7]. Te frequency of clinical thrombocytopenia is variable
but has been reported to be between 0.5 and 6.5% [8, 9].
Even with exposure to heparin, there exists a majority of
patients who do not develop HIT but have HPF4 antibodies
present that has been reported to vary between 13% and
50% [8, 10]. Yet, some healthy individuals who have not
been previously exposed to unfractionated heparin may
demonstrate antibodies for HPF4 with a frequency of 1.4%
[11]. Te presence of HPF4 antibodies has been shown to
independently increase the risk of adverse cardiovascular
events even without the evidence of clinically signifcant
thrombocytopenia [10, 12, 13]. Te purpose of this study
was to identify whether diabetes increased the likelihood of
developing HPF4 antibodies in at risk vascular patients.
2. Materials and Methods
2.1. Study Design. We retrospectively reviewed clinical data
on 300 consecutive patients over the age of 18 years. A
hypercoagulable workup was performed if patients presented
with (1) early bypass/graf thrombosis (<30 days) using either
autologous vein or synthetic graf, (2) multiple bypass/graf
thrombosis, and (3) a history of DVT, pulmonary embolus
(PE), or native vessel thrombosis. Relevant clinical variables
were analyzed and compared for patients with diabetes (DM)
and without diabetes (nDM). Study data was obtained via
a review of the patients medical records as part of an
institutional review board-approved protocol.
2.2. Study Setting. Te study was performed at the Houston
Methodist Hospital that is an academic medical center with
1000 beds in a catchment area of 5 million people. It is a
tertiary and quaternary referral facility.
2.3. Technique. Specifcally, HPF4 antibody measurements
were performed centrally at the Houston Methodist Hospital
clinical chemistry laboratory. Total antibodies were mea-
sured by enzyme-linked immunosorbent assay (ELISA) (GTI
Diagnostics, Waukesha, WI) and results were obtained as
optical density (OD) and reported as positive when above the
reference laboratory standard (OD > 0.4).
2.4. Statistics. Te chi-squared test was used to compare
categorical variables. Calculations were performed using
Excel sofware.
3. Results
We reviewed clinical data on 300 consecutive patients. A
hypercoagulable workup was performed if patients presented
with (1) early bypass/graf thrombosis (<30 days), (2) mul-
tiple bypass/graf thrombosis, and (3) a history of DVT,
pulmonary embolus (PE), or native vessel thrombosis. Eighty
fve patients (47 women; age 53 16 years, range 1682
Table 1: Comparison of patient characteristics for both diabetics
(DM) and nondiabetics (nDM). CAD: Coronary artery disease,
PVD: peripheral vascular disease, A-fb: atrial fbrillation, COPD:
chronic obstructive pulmonary disease, CKD: chronic Kidney Dis-
ease, ESRD: end-stage renal disease, Chol: hypercholesterolemia,
and AAA: abdominal aortic aneurysm.
Demographics
Number of patients
DM nDM
Men 21 17
Women 22 25
Average age (yrs) 54 13 54 18
CAD 22 9

Hypertension 43 32

PVD 16 6

A-fb 2 8

COPD 8 8
Varicose veins 0 3
CKD 3-4 2 3
ESRD 32 22

Chol 20 9

AAA 0 4

Chi-squared < 0.05.

years) had one of the defned conditions and underwent a
hypercoagulable evaluation. Screening was done in 4.7% of
patients with early bypass graf thrombosis, 60% of patients
were screened because of multiple bypass or graf thrombo-
sis, and 35.3% had a previous history of DVT, pulmonary
embolus (PE), or native vessel thrombosis. All DM patients
in the group had hypertension and were more likely to have
coronary artery disease, peripheral arterial disease, end-stage
renal disease (ESRD), and hypercholesterolemia than the
nDM group (chi-squared test < 0.05) (Table 1). Of the 43
patients with DM and 42 nDM evaluated, 59 patients (69%)
had an abnormal hypercoagulable profle with an elevated
HPF4 antibody present in 30% of DM and 12% of nDM (chi-
squared test < 0.04) (Table 2). All DM patients were in a
stable treated phase and none were newly diagnosed. Briefy,
we also found that lupus anticoagulant was present in 35% of
DM and 33% of nDM, functional protein S defciency in 19%
and 21%, antithrombin III defciency in 16% and 14%, func-
tional proteinCdefciency in14%and 7%, and anticardiolipin
antibodies in 9% and 7%, respectively. Yet, none of these
reached statistical signifcant diference between the two
groups.
Group analysis showed that DM was associated with a
higher combined likelihood of arterial complications that
includedearly bypass/grafthrombosis (<30 days) or multiple
bypass/graf thrombosis (chi-squared test < 0.003). On the
other hand, nDMwas associated with a higher combined rate
of venous adverse events such as DVT, PE, or superfcial vein
thrombosis (chi-squared test < 0.003). Additionally, when
comparing DMpatients with ESRDon hemodialysis ( = 31)
and DM without ESRD not undergoing dialysis ( = 12),
Trombosis 3
we found no diference in the presence of HPF4 antibodies
between these two subgroups (chi-square-test = 0.8).
4. Discussion
A study by Diaz and colleagues showed no increase in the
presence of HPF4 antibodies in healthy DM patients when
compared with a healthy control population. As in our study,
antibody titers were measured by ELISA and reported as
OD readings [8]. In contrast to that report, our fndings
show that DM patients at risk with vascular disease were
signifcantly more likely to develop HPF4 antibodies than
nDM patients. All patients in our series had presented with
either early bypass/graf thrombosis (<30 days), multiple
bypass/graf thrombosis, or a history of DVT, PE, or native
vessel thrombosis. All had been previously exposed to hep-
arin and 64% of the patients were on dialysis receiving
scheduled heparin during treatments three times a week.
In this at risk population, an elevated HPF4 antibody was
present in 30% of DM and 12% of nDM (chi-squared test <
0.04) without evidence of thrombocytopenia. Te presence
of HPF4 antibodies without clinical evidence of HIT is not
uncommon and our series shows a range consistent with
previous reports [10, 12, 14].
Patients on hemodialysis receive heparin regularly during
their scheduledtreatments andmany also developHPF4 anti-
bodies without a clinical manifestation of thrombocytopenia
or HIT [9]. Krane and associates investigated the presence
of HPF4 antibodies in hemodialysis patients with DM and
found that HPF4 antibodies were present in 18.7% of the
patients [15]. Zhao and associates found the presence of HPF4
antibodies in maintenance hemodialysis patients to be lower
at 5.6% and demonstrated that DM patients were more likely
than nDM patients to develop antibodies [16]. In our study,
29%of DMpatients with ESRDundergoing hemodialysis had
HPF4 antibodies compared to 25% of DM patients without
ESRD not undergoing hemodialysis. Tere was no diference
between the two groups. Tis may suggest that with DM
the routine or frequent exposure to heparin is not necessary
for the development of HPF4 antibodies, but rather that a
nonfrequent exposure may be all that is needed to stimulate
antibody formation. Borsey and colleagues showed that PF4
concentration was elevated in both DM with and without
retinopathy compared to nDM controls [17]. Additionally,
Roy and associates have shown similar results in DMpatients
[18]. A possible explanation for the risk of HPF4 formation
that extends beyond the duration or frequency of heparin
exposure in DM is that persistent heparin exposure may not
be necessary for antibody formation to occur against the
excess PF4 that exists surface bound to mucopolysaccharides
or glycosaminoglycans on the platelet surface [13, 19].
Blank and associates support the concept that endothelial
cells (EC) derived from diferent vascular beds have diferent
characteristic features and can respond diferently to inju-
rious agents. According to this concept, EC can integrate
diferent extracellular signals and respond diferently to the
same injurious agent in distinct regions of the vascular
system, whether arterial or venous. As such, the authors
Table 2: Patients with diabetes (DM) and without diabetes (nDM)
presenting with acquired heparin platelet factor 4 (HPF4) antibod-
ies.
HPF4 antibodies DM (%) nDM (%) Total (%)
Present 13 (30)

5 (12) 18 (21)
Not present 30 (70) 37 (88) 67 (79)
Total 43 (51) 42 (49) 85 (100)

Chi-squared test < 0.04.

demonstrated that activation of microvascular EC by HPF4
antibodies was direct, while activation of large vessel EC
occurs indirectly and is associated with platelet activation
or the release of cytokines [7]. Diabetes is associated with
the development of ECdysfunction, enhanced platelet aggre-
gation and activation [20], increased circulating platelet
aggregates, anda higher level of platelet release products, such
as beta-thromboglobulin, thromboxane B
2
, and PF4 [3, 5].
Additionally, nicotinamide adenine dinucleotide hydroge-
nase (NADH) levels are increased with DM and can generate
reactive oxygen species which have been known to induce
activationof endothelial growthfactors responsible for vascu-
lar dysfunction [21]. NADH has been shown to signifcantly
stimulate the dose-dependent release of IL-6 and modulate
the efects of cytokines on peripheral blood cells [22]. In
our study, subgroup analysis showed that DM was associated
with a higher combined likelihood of arterial complications
that included early or multiple bypass/graf thrombosis (chi-
squared test < 0.003). Tus, patients with DM may have
experienced both direct activation of microvascular EC by
HPF4 antibodies and activation of large vessel EC as a result
of the enhanced state of platelet aggregation and cytokine
activation postulated above in addition to the associated
higher likelihood of developing peripheral arterial disease
and vascular complications [2].
Cacciapuoti discussed that antiphospholipid syndrome,
polycythemia vera, atrial fbrillation, acquired hyperhomo-
cysteinemia, myeloproliferative disease, and DMare the most
frequent causes of an acquired hypercoagulable state respon-
sible for DVT [23]. In a report by Adams and colleagues,
no signifcant increased risk of deep venous thrombosis was
found in patients with DM compared with patients nDM
in a study population who underwent elective total knee
arthroplasty [24]. However, in a recent report by Wang
and Zhao, the risk of DVT in patients afer total knee
arthroplasty with DM was 2.76 times the risk in nDM
patients using logistic regression modeling [25]. In a study
of 2488 venous thromboembolism patients in which 476
had a clinical history of DM, the latter was associated with
a signifcant increase in the risk of recurrent deep vein
thrombosis [26]. In contrast to these reports, our study
showed that at risk vascular nDM patients were associated
with a higher combined rate of venous adverse events such
as DVT, PE, or superfcial vein thrombosis (chi-squared test
< 0.003) when compared to patients with DM. Heit and
colleagues studied 1922 patients over a 25-year period and
found that DM was also not an independent risk factor for
4 Trombosis
incident venous thromboembolismin the population studied
[27].
All DM patients in our study had hypertension and
were more likely to have coronary artery disease, periph-
eral arterial disease, end-stage renal disease (ESRD), and
hypercholesterolemia than nDM. Te presence of DM was
associated with an increased cardiovascular morbidity and
has important implications especially when associated with
the presence of HPF4 antibodies. Mattioli and colleagues
studied 124 consecutive patients with unstable angina who at
baseline did not have HPF4 antibodies and were treated with
unfractionated heparin. Te combined incidence of death,
myocardial infarction, recurrent angina, urgent revascular-
ization, and stroke was 66% in patients with antibodies and
44% in patients without antibodies during a 1-year followup
[12]. In an observational study, Kress and associates detected
the incidence of preoperative HPF4 antibodies and assessed
the associated risk of postoperative adverse events in a nonse-
lected group of patients undergoing cardiac surgery. Of those
screened, 5.4%hadHPF4 antibodies preoperatively. Te pres-
ence of HPF4 antibodies was associated with a longer hospital
length of stay, higher incidence of prolonged mechanical
ventilation, acute limb ischemia, and gastrointestinal and
renal complications including the need for hemodialysis. Te
authors showed that HPF4 antibodies before surgical heparin
administration was an independent and clinically signifcant
risk factor for postoperative events following cardiac surgery
and recommend that a risk profle of patients should include
HPF4 antibody status [28]. In addition, patients who had
been previously treated with unfractionated heparin as part
of cardiac surgery management and had developed HPF4
antibodies were more likely to die or develop myocardial
infarction, pulmonary embolism, or stroke than patients who
were antibody negative. Tese patients retained a higher
thrombotic event rate up to a 1-year followup [14].
Te present report has several limitations. Te scope
of this retrospective study focused on measuring HPF4
antibodies in patients who had already presented with
complications related to their vascular disease. At the time
of screening, all patients had been exposed at least once
to unfractionated heparin as part of the management of
their vascular disease or complications. However, except for
the population on hemodialysis who had scheduled weekly
exposure to unfractionated heparin during treatment, we
did not collect additional data on the timing or frequency
of heparin exposure in the remainder of patients not on
hemodialysis. Tis may be relevant for Mattioli and col-
leagues have shown that within 6 days of heparin exposure
30% of patients can develop HPF4 antibodies [12]. We did
not ascertain whether alternative therapies or modes of
anticoagulation in these patients may have had an efect
on outcome. Stribling and associates propose to treat the
presence HPF4 antibodies in high-risk clinical scenarios with
nonheparin anticoagulants or direct thrombin inhibitors
[13]. However, limited evidence is available to guide on the
optimal nonheparin anticoagulant to be used during vascular
surgery with suspected or documented HIT [29, 30]. Te
ELISAimmunoassay is a quantitative test capable of detecting
HPF4 antibodies [31]. It is a sensitive antigen-based assay
with high negative predictive value but a variable specifcity
between 50% and 89%. Tis results in the detection of both
nonpathogenic and pathogenic antibodies in patients with
and without clinical HIT. Te utility of this test is ruling out
the presence of HPF4 antibodies during the HIT workup.
Te 14C-Serotonin release assay (SRA) is a functional test
to detect antibodies capable of activating platelets which
has a specifcity and sensitivity of more than 95%. Despite
being one of the reference standard tests for the detection
of HPF4 antibodies, this test is not readily available in all
laboratories [3133]. We did not utilize the functional SRA
tests to determine if the associated thrombotic events were
due to immunogenic heparin-induced antibodies capable of
activating platelets. We believe that our observations may
contribute to the understanding of the relation between
DM and HPF4 antibodies in at risk vascular patients. We
intend that the data generated in this work be validated by
prospective studies in the future.
5. Conclusions
Diabetes is associated with a higher likelihood of developing
heparin-induced antibodies and an increased combined inci-
dence of arterial complications that include early or multiple
bypass/graf thrombosis. Te routine or frequent exposure to
heparin as observed in ESRD patients on hemodialysis did
not increase the risk for HPF4 antibody formation in DM
patients. Our fndings may help stratify patients at risk for
vascular complications and potentially infuence the choice
of anticoagulation especially in DM patients who are at risk
with vascular disease.
Conflict of Interests
Te authors declare that there is no confict of interests
regarding the publication of this paper.
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Oncology
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Hindawi Publishing Corporation
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Oxidative Medicine and
Cellular Longevity
Hindawi Publishing Corporation
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PPAR Research
The Scientifc
World Journal
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Immunology Research
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Journal of
Obesity
Journal of
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Hindawi Publishing Corporation
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Computational and
Mathematical Methods
in Medicine
Ophthalmology
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Diabetes Research
Journal of
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Hindawi Publishing Corporation
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Research and Treatment
AIDS
Hindawi Publishing Corporation
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Gastroenterology
Research and Practice
Hindawi Publishing Corporation
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Parkinsons
Disease
Evidence-Based
Complementary and
Alternative Medicine
Volume 2014
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