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32]

Original Article

Access this article online Markers of Coagulation Activation in

Quick Response Code:

Patients With Hemoglobinopathy in

Western Saudi Arabia
Soheir Adam, Galila Zaher

Website: Abstract:
www.jahjournal.org
DOI: OBJECTIVE: This study aims to examine markers of coagulation activation and their possible clinical
10.4103/1658-5127.204426 associations in sickle cell disease (SCD) and thalassemia.
MATERIALS AND METHODS: This study was conducted on patients with hemoglobinopathy
followed up at King Abdulaziz University Hospital between October 2010 and November 2011.
Demographic and clinical data were collected for all participants. The independent t-test was used to
compare two group means, while the one-way analysis of variance test was used to compare more
than two group means.
RESULTS: The study included 122 hemoglobinopathy cases and 34 controls. Protein C,
protein S, antithrombin, and activated protein C resistance (APCR) were significantly lower in
patients with hemoglobinopathy than in the control group, while D-dimer levels were significantly
higher (P < 0.001 for all comparisons). Patients with SCD had significantly higher protein C and
D-dimer levels than those who had thalassemia (P < 0.01 for both). Arterial and venous
thromboses were more prevalent in patients with SCD (12.5 and 18.7%), compared to
patients with thalassemia (9.3 and 2.3%, respectively). Cases had significantly lower protein
C, protein S, antithrombin, and APCR values (P < 0.001 for each), and higher D-dimer levels
(P = 0.016) than male controls. There was no significant difference in markers of coagulation
activation between patients who had undergone splenectomy compared with those who had
intact spleens.
CONCLUSION: Natural anticoagulants were significantly lower, and D-dimer levels were higher in
Saudi patients with SCD and thalassemia compared to healthy controls. The procoagulant phenotype
was more pronounced in patients with SCD and was associated with a higher prevalence of clinical
thrombosis, compared to patients with thalassemia in this population.

Keywords:
Coagulation activation, sickle cell disease, thalassemia

[4]
Introduction factor, and chronic platelet activation.
Previous studies have reported compli-

S ickle cell disease (SCD) and thalassemia

are considered as hypercoagulable
[1,2]
cations due to hypercoagulability in
patients with hemoglobinopathies.
[5,6]
Evi-
disorders. Available evidence for hyper- dence of thrombophilia ranges from
coagulability in SCD includes abnormal subclinical disturbances in the levels of
Department of levels of prothrombin fragment 1.2 and D- hemostatic factors to an increased incidence
[3] [1]
Hematology, King dimer, accelerated Factor VII turnover, of a variety of thromboembolic events, such as
Abdulaziz University, increased levels of thrombin–antithrombin pulmonary embolism and deep venous
[6]
Jeddah, Saudi Arabia complexes, abnormal expression of tissue thrombosis. Furthermore, pulmonary
Address for hypertension (PHT) is common in patients
correspondence: with SCD, with an estimated prevalence rate
Dr. Soheir Adam, MBBCh,
This is an open access article distributed under the terms
FRCPath, Department of
of the Creative Commons Attribution-NonCommercial-
Hematology, King
ShareAlike 3.0 License, which allows others to remix,
Abdulaziz University, PO How to cite this article: Adam S, Zaher G. Markers
tweak, and build upon the work noncommercially, as
Box 80215, Jeddah 21589, of coagulation activation in patients with hemoglo-
long as the author is credited and the new creations
Saudi Arabia.
are licensed under the identical terms. binopathy in Western Saudi Arabia. J Appl Hematol
E-mail:
2017;8:1-6.
sadam@kau.edu.sa For reprints contact: reprints@medknow.com

© 2017 Journal of Applied Hematology | Published by Wolters Kluwer - Medknow 1

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Adam and Zaher: Coagulation activation in hemoglobinopathies
[7,8]
of 30%. Chronic intravascular hemolysis has been
reported to play a pivotal role in the pathogenesis of
[8-10]
PHT. Other investigators have found that PHT in
SCD may be caused by a variety of different factors,
including continuous endothelial activation, in situ
thrombosis, and thromboembolism of the pulmonary
[11]
artery.
Saudi patients with SCD were found to have
higher levels of markers of thrombin generation and
inflammatory cytokines during painful crisis compared
to those in steady state in a previous study, indicating
that the painful vaso-occlusive crisis increases the
[12]
inflammatory state in SCD.
While hemoglobinopathies are described as hyper-
coagulable states, little is known about the clinical
associations of markers of hypercoagulability in the
Saudi population. In this paper, we examine markers
of coagulation activation and their possible association
with the clinical complications seen in SCD and
thalassemia.
Materials and Methods
This study was conducted between October 2010
and November 2011 at King Abdulaziz University
Hospital (KAUH) and included 122 patients with
hemoglobinopathy and 34 controls. The Research
Ethics Committee at King Abdulaziz University
approved this research study.
Patients with hemoglobinopathy attending hematology
clinics at KAUH were approached consecutively to
participate in the study. Patients were enrolled in the
study after signing in an informed consent. Blood
samples were collected for laboratory studies, and
data were collected by interview and review of
medical records. Citrated plasma was collected, and
0preparation was completed in accordance with the
manufacturers’ instructions. Functional assays for
antithrombin, protein C, protein S, and activated
protein C resistance ratio (APCR ratio) were
estimated using the commercial kit (Dade Behring,
Marburg, Germany). D-dimer was estimated using
Advanced D-dimer (Dade Behring, Marburg,
Germany). All the previous laboratory tests were
performed routinely in the hematology laboratory at
KAUH, where samples were run in batches and
assayed on Blood Coagulation System (BCS®XS)
analyzer. Non-routine measurements of plasma
concentration of Fibrinopeptide A (FPA) and
Fibrinopeptide B (FPB) were performed by Enzyme
Linked Immunosorbent Assay (ELISA) technique
using the commercial kit IMUCLONE by
BioMEDICA.
2 Journal of Applied Hematology | Vol 8, Issue 1, January-March 2017
Study inclusion criteria were:
• Patients able and willing to participate in the study
after signing in their informed consent.
• Patients with a diagnosis of SCD or thalassemia
receiving care at KAUH.
• Patients with SCD, thalassemia intermedia (TI), and
thalassemia major (TM).
Study exclusion criteria were:
• Pregnant patients.
• Patients with SCD in acute vaso-occlusive crisis.
• Patients transfused within one month from sample
acquisition.
• Patients on anticoagulant medications.
A data collection tool was designed to assist with
the collection and collation of demographic and
clinical data. This instrument was used to collect
information from the study patients’ electronic
medical records including age, gender, clinical
signs and symptoms, as well as results of
laboratory investigations.
Statistical analysis
The Statistical Package for the Social Sciences
(SPSS Inc., IBM, New York, US), version 22, was
used to analyze the data. Demographic and
coagulation factor data are described in absolute
numbers and percentages; and continuous vari-
ables are presented as means and standard
deviations (SDs). The independent t-test was used
to compare two group means, while the one-way
analysis of variance (ANOVA) test with the least
significant difference (LSD) was used to compare
more than two group means. These tests were
done with the assumption of normal distribution.
Otherwise, Welch’s t-test for two group means and
Games Howell method for multiple groups
were used instead of the LSD test. To correlate
variables which were represented by means,
Pearson’s correlation coefficient was used. Lastly, a
conventional P-value of <0.05 was the criterion for
rejecting the null hypothesis.
Results
The study included 122 hemoglobinopathy cases
and 34 controls, of whom 83 (53.2%) were males. The
mean age was 26.7 (8.9) years (range, 13–48 years).
Patients with TM comprised the majority of the
hemoglobinopathy cases (86 patients, 70.5%), followed
by those with SCD (32 patients, 26%) and TI (4 patients,
3.3%). A total of 20 cases of venous thrombosis and 26
arterial events were present. Venous thromboembolism
(VTE) was clinically suspected in 12 patients (9.8%)
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Adam and Zaher: Coagulation activation in hemoglobinopathies

and a radiological diagnosis of VTE was confirmed in
eight patients (6.5%) whereas there was no evidence of
VTE in 102 of the cases (82.9%). Embolic stroke was
present in 26 patients. The prevalence of VTE was
higher among patients with SCD compared to patients
with thalassemia, with frequencies of arterial and venous
thrombosis of 12.5 and 18.7%, respectively, in patients
with SCD, and 9.3 and 2.3%, respectively, in patients with
thalassemia.
On ultrasound examination, approximately 39.3% of
the cohort had splenomegaly, while 34.4% were found
to have an absent spleen, either due to autosplenectomy
or a history of surgical removal of the spleen. In
approximately one-third of the patients (26.2%),
spleen size was normal.
Protein C, protein S, antithrombin, and APCR were
significantly lower in patients with hemoglobinopathy
than in the control group [Figure 1], while D-dimer
levels were significantly higher (P < 0.001 for all
comparisons). On the other hand, values for
fibrinopeptide A and lupus anticoagulant did not differ
significantly between cases and controls.
When compared with patients who had thalassemia,
those with SCD had significantly higher protein C and
D-dimer levels [P < 0.01 for both; Figure 2]. Although
patients with SCD had higher protein S, antithrombin,
fibrinogen, and platelet levels, these differences did not
reach statistical significance. Similarly, patients with
SCD and thalassemia did not differ in terms of
hemoglobin, and white blood cells (WBC) values or

Figure 1: Comparison of laboratory markers of coagulation activation in patients with hemoglobinopathy and controls

Figure 2: Markers of coagulation activation in patients with sickle cell disease and patients with thalassemia

Journal of Applied Hematology | Vol 8, Issue 1, January-March 2017 3

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Adam and Zaher: Coagulation activation in hemoglobinopathies

the prevalence of lupus anticoagulant and APCR.
Differences in coagulation markers were present both
overall and when stratified by gender. Among males,
cases had significantly lower protein C, protein S,
antithrombin, and APCR values (P < 0.001 for each),
and higher D-dimer levels (P = 0.016), than male controls.
Values were similar between female cases and controls
(differing only in the actual P-value for the D-dimer level
comparison, which was P = 0.006 for the females).
Markers of coagulation activation did not differ
significantly between patients who had a history of
venous thrombosis, and those who did not [Table 1].
Similarly, results of laboratory investigations did not
differ between patients with hemoglobinopathy with
and without a history arterial thrombosis.
Using the one-way ANOVA test, we found a
significantly higher mean platelet count (P < 0.001)
and mean WBC count (P = 0.003) among patients
who had undergone auto- or surgical splenectomy
compared with those who had intact spleens
[Table 2]. However, the levels of the other markers of
coagulation activation did not differ significantly
between the two groups.
Discussion
There is substantial evidence in the literature that SCD and
other chronic hemolytic anemias such as beta-thalassemia
represent hypercoagulable states. This is reflected in the
increased incidence of thrombotic complications seen
in these patients, including VTE, in situ pulmonary
[13]
thrombosis, and stroke. Both disorders have been
associated with specific laboratory findings consistent
with increased platelet and coagulation activation, and
[14]
decreased levels of natural anticoagulants. For example,
in one previous study of patients with SCD, markers of

Table 1: Comparison of laboratory values between patients with a history of arteriovenous thrombosis and those with
no history of thrombosis
Variable Total N = 122 Mean ± SD Venous thrombosis P-value
Thrombosis N = 46 Mean ± SD No thrombosis N = 76 Mean ± SD

PC (%) 67.89 ± 28.0 63.50 ± 13.4 68.52 ± 29.8 0.822

PS (%) 60.99 ± 22.5 38.75 ± 23.7 64.17 ± 21.3 0.140
AT (%) 88.72 ± 18.0 100.00 ± 15.6 87.11 ± 18.2 0.360
LA (seconds) 34.16 ± 5.3 36.00 ± 7.1 33.89 ± 5.3 0.618
DD (μg/ml) 2.41 ± 2.6 2.62 ± 2.7 0.87 ± 0.0 0.383
APCR (ratio) 0.86 ± 0.1 0.90 ± 0.1 0.86 ± 0.1 0.445
FIB (mg/dl) 264.31 ± 53.8 239.50 ± 19.1 268.82 ± 57.4 0.502
HB (g/dl) 8.45 ± 1.4 8.40 ± 0.8 8.46 ± 1.5 0.957
WBC (×109/L) 13.86 ± 6.0 10.20 ± 1.3 14.35 ± 6.3 0.378
Plt (×109/L) 337.71 ± 170.5 477.50 ± 78.5 319.07 ± 172.1 0.228
Abbreviations: APCR, activated protein C resistance; AT, antithrombin; DD, D-dimer; FA1, fibrinopeptide A; FIB, fibrinogen; LA, lupus anticoagulant; PC, Protein
C; PS, protein S; SD, standard deviation; WBC, white blood cells.

Table 2: Comparison of laboratory parameters between patients with intact spleens and those with a history of
splenectomy
Variable N Total=122 Abdomen US P-value
Intact spleen N = 80 Mean ± SD Splenectomy/autosplenectomy N = 42 Mean ± SD

FA1 (ng/ml) 6.19 ± 5.3 8.92 ± 8.3 0.248

FB1 (ng/ml) 2.99 ± 3.2 3.98 ± 7.2 0.115
FPS (IU/dl) 902.98 ± 176.4 901.99 ± 191.2 0.105
PC (%) 55.20 ± 22.6 51.88 ± 18.7 0.716
PS (%) 56.00 ± 15.0 55.17 ± 18.8 0.788
AT (%) 84.48 ± 15.3 84.14 ± 17.6 0.432
LA (seconds) 37.87 ± 5.7 35.61 ± 6.2 0.223
DD (μg/ml) 0.97 ± 1.4 1.45 ± 1.4 0.181
APCR (ratio) 0.84 ± 0.1 0.83 ± 0.1 0.510
FIB (mg/dl) 254.38 ± 57.1 291.70 ± 98.3 0.102
HB (g/dl) 7.81 ± 1.4 8.38 ± 1.5 0.147
WBC (×109/L) 11.17 ± 8.0 18.08 ± 11.5 0.003a
Platelet (×109/L) 302.93 ± 213.3 517.26 ± 233.8 <0.001a
a
Significant using Independent t-test @<0.05 level. APCR, activated protein C resistance; AT, antithrombin; DD, D-dimer; FA1, fibrinopeptide A; FB1,
Fibrinogen B; FIB, fibrinogen; FPS, Free Protein S; HB, Hemoglobin; LA, lupus anticoagulant; PC, Protein C; PS, protein S; SD, standard deviation; WBC, white
blood cells.

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Adam and Zaher: Coagulation activation in hemoglobinopathies
coagulation including plasma thrombin–antithrombin
complex, prothrombin fragment 1.2, and D-dimer levels
were shown to be increased at steady state (i.e.,
[1]
during asymptomatic periods). The same study
reported increased levels of these markers during acute
pain episodes and found that the frequency of pain
episodes in the subsequent year correlated with D-
dimer plasma levels. These findings suggest that vaso-
occlusive events may be triggered by coagulation
[1,15]
activation. The authors have previously found that
D-dimer levels were increased in a sample of 40 Saudi
patients with SCD, and protein C and S levels were lower,
[16]
compared to sickle cell trait and unaffected controls. In
this study, we explored a possible relationship between
laboratory coagulation markers and thromboembolic
manifestations, stroke, and splenectomy in a sample of
Saudi patients with SCD and thalassemia. Studies
in patients with thalassemia also point toward an
underlying hypercoagulability related to platelet
activation, increased erythrocyte endothelial adherence,
decreased protein C and S levels, and increased thrombin
generation. Furthermore, thrombophilic propensity in
hemolytic anemias overall was found to be increased
[17]
following splenectomy.
In this study, we explored a possible relationship
between laboratory coagulation markers and
clinical complications (including VTE, stroke, and
splenectomy) in a sample of Saudi patients with SCD
and thalassemia. We found significantly lower levels of
the natural anticoagulants protein S, protein C, and
antithrombin in patients with hemoglobinopathies
compared with controls, both overall and when
stratified by gender. These results are consistent with
[1,15,18,19]
those from prior studies. No previous study has
specifically compared markers of coagulation activation
between patients with SCD and thalassemia. In the
current report, patients with SCD had significantly
higher D-dimer values, suggesting that SCD is
associated with a higher rate of thrombin generation.
The finding that thrombotic events were seen more
frequently in patients with SCD compared with
patients with thalassemia also reflects this. Available
clinical assays for measurement of D-dimer antigen,
detect both the terminal digestion product for fibrin
and high molecular weight soluble fibrin fragments
that are yet to enter a fibrin gel or that have already
[20]
been released before plasma degradation. This may
explain why D-dimer assay was elevated in this study
population, while other plasma markers were not
significantly increased. Further, exposure of
phosphatidyl serene in sickle red cell membranes leads
to thrombin generation in whole blood. Recently, a study
of global thrombin generation in SCD concluded that
cellular contribution in SCD is pivotal in thrombin
[21]
generation. Thus, global thrombin generation assays
Journal of Applied Hematology | Vol 8, Issue 1, January-March 2017
show an increase in thrombin generation in whole blood
but not in plasma.
Loss of splenic function has more recently been
found to increase the risk for thromboembolic events,
although the actual risk is related to the underlying
[17]
disorder. The greatest risk is seen in patients with a
primary disorder associated with chronic hemolysis,
such as hemoglobinopathies. However, when we
examined patients with hemoglobinopathy who had
surgical or auto-splenectomy and compared them to
those with an intact spleen, we did not see significant
differences in the natural anticoagulant or D-dimer
[19,22,23]
levels. Thus, unlike in prior studies, we did not
find evidence that splenectomy is associated with an
increase in hypercoagulability. However, a recent
study found no evidence of increased global thrombin
generation in patients with splenectomized thalassemia
[21]
in platelet-poor plasma. Similarly, markers of
coagulation activation did not differ in patients with
splenectomized and non-splenectomized thalassemia
[24,25]
in other populations. In a study of splenectomized
Saudi SCD patients; there was evidence of
reduction in the rate of hemolysis and post-
splenectomy transfusion requirements were also
[26]
reduced. Since hemolysis was found to be closely
associated with a higher risk of coagulation activation;
thus, down-regulation of hemolysis may explain the
reduced prothrombotic markers in our population.
Interestingly, the risk for post-splenectomy
thromboembolic events in patients with thalassemia
has been found to be significantly greater in TI than in
[17]
TM. Unfortunately, the number of patients with TI in
our cohort was very low (3.3%), making it difficult for us
to draw any relevant conclusions. Not surprisingly,
however, patients without a functional spleen had
higher WBC counts and platelet levels.While
patients with SCD and thalassemia have numerous
complications, some patients experience a more
severe phenotype compared with others. This is true
in SCD when comparing the African haplotype
to the Arab-Indian haplotype. The cohort in this study
includes Saudi Arabian patients with the Arab-Indian
SCD haplotype, which is phenotypically different
from other SCD haplotypes. For example, leg ulcers
and priapism are uncommon in this population. In
addition, certain disease complications, including
pain crises and silent cerebral infarcts, generally
occur at later ages compared to African SCD
[27-29]
haplotypes. This phenotypical variance may
indicate that our results are specific for Saudi
patients with SCD and are not necessarily
generalizable to other populations with SCD. If so,
comparison of the results of coagulation studies in
Arab-Indian patients with SCD to those in other
populations could provide important insights into the
5
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Adam and Zaher: Coagulation activation in hemoglobinopathies
unique pathophysiological mechanisms underlying the
different clinical phenotypes.
In conclusion, we found significantly lower levels of
natural anticoagulants and higher levels of D-dimer in
patients with SCD and thalassemia compared to
healthy controls, supporting the theory that they
represent hypercoagulable states. Patients with SCD
had evidence of increased thrombin generation, as
reflected by elevated D-dimer values compared to
patients with thalassemia, which was paralleled by
an increase in clinical thromboembolic events. Future
research should ideally focus on the pathophysiology
behind the phenotypic variation in patients with
hemoglobinopathy in different populations.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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