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Epidemiology of Activated Protein C Resistance and
Factor V Leiden Mutation in the Mediterranean Region
Mehrez M. Jadaon
Department of Medical
Laboratory Sciences, Faculty of Allied Health Sciences, Kuwait
University, Kuwait
Correspondence
to: Mehrez
M. Jadaon. Department of Medical Laboratory Sciences, Faculty of Allied
Health Sciences, Kuwait University, Kuwait. P.O. Box 31470 –
Sulaibekaht 90805 – Kuwait. Tel.: (965) 6664 3485, Fax: (965) 2498
3835. Email: mehrez@hsc.edu.kw,
mehrezmls99@yahoo.com
Published: September 8, 2011
Received: July 11, 2011
Accepted: August 17, 2011
Mediterr J Hematol Infect Dis 2011, 3: e2011037, DOI 10.4084/MJHID.2011.037
This article is available from: http://www.mjhid.org/article/view/8811
This is an Open Access article
distributed under the terms of
the
Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited
Abstract
Venous
thromboembolic disorders (VTE) are serious disorders with high
morbidity and mortality rates. Many genetic and acquired risk factors
were identified to cause VTE. The most common genetic risk factor is
Factor V Leiden mutation (FVL). FVL was found in high percentage of
populations of Caucasian origin but was almost absent in
non-Caucasians. It was also reported in populations living in North
Africa and the Middle East. This review article briefly explains
FVL and how it causes VTE, the distribution of FVL worldwide, and then
it elaborates on the epidemiology of FVL in the Mediterranean Region
and how this brought speculations that FVL might have originated in the
Eastern Mediterranean area.
Introduction
Thrombophilia
is the term given to abnormal blood coagulation condition leading to
increased tendency towards coagulation (hypercoagulability status).
People with hypercoagulability are at risk of developing thrombosis,
especially venous thromboembolic disorders (VTE) including deep vein
thrombosis (DVT) and pulmonary embolism (PE). VTE is a significant
cause of morbidity and mortality in many countries with an annual
incidence of 1/1000.[ 1-4] Many genetic and acquired
risk factors for the
development of VTE were identified. In fact, the WHO expert group
(1996) defined thrombophilia as a tendency to develop VTE that may be
genetically determined, acquired or both.[ 5] Genetic
factors include
activated protein C resistance (APC-R) associated with Factor V Leiden
mutation (FVL), Prothrombin G20210A mutation associated with high
levels of prothrombin, genetic deficiencies of proteins C, S and
antithrombin, and others. Acquired risk factors include lupus
anticoagulants, pregnancy, use of contraceptives, major surgeries,
cancer, inflammations, and others. This review article focuses on the
epidemiology of APC-R/FVL in the Mediterranean area. For a better
understanding of the pathophysiology involved in causing
hypercoagulability by APC-R/FVL, it may be helpful to start by a quick
revision of the process of coagulation and its associated natural
anticoagulants.
Blood Coagulation
Normally, blood loss through injured vessels is prevented by a normal
physiological process called “Hemostasis”. Normal human hemostasis is a
balanced system which, on one hand, prevents excessive bleeding from
any injured site, while on the other hand maintains blood circulation
inside intact blood vessels by inhibiting intravascular coagulation. An
efficient hemostatic process possesses intrinsic well-balanced
regulatory systems, involving a number of dynamic mechanisms and
chemical and physical reactions. It usually includes platelets, blood
vessels and the coagulation system. In blood coagulation, a prominent
response to an injury is recruited in the form of series of stepwise
(cascade) chemical interactions leading to fibrin formation. This
complex system involves certain proteins called the plasma clotting
factors (enzymes). These enzymes circulate in the blood in an inactive
form, and get activated in case of vessel injury. In summary, when a
blood vessel is injured, the coagulation cascade is initiated by the
release of tissue factor (thromboplastin) and the exposure of
intravascular collagen, which activates clotting factors VII and XII,
respectively. These clotting factors activate other clotting factors in
a stepwise procedure ending up with the formation of a fibrin clot. A
fibrin clot, in association with platelets, form a plug that blocks the
injured blood vessel, preventing bleeding and allowing for wound
healing. After healing, the fibrin clot is dissolved by the enzyme
plasmin in a process called fibrinolysis. The whole process is under
careful supervision by three main proteins that circulate normally in
the blood; namely protein C (and its active form activated protein C;
APC), protein S (PS) and antithrombin (AT). These so-called “natural
anticoagulants” monitor the processes of coagulation and fibrinolysis
in order to prevent excessive clotting.[ 6-8]
Abnormalities in clotting
factors may lead to bleeding problems (hemophilia), while abnormalities
in the natural anticoagulants may lead to hypercoagulability and
thrombosis, with certain exceptions in both. Figure 1 gives an
illustrative drawing of the process of coagulation and its associated
fibrinolysis process and natural anticoagulants.
Activated Protein C Resistance
and Factor V Leiden Mutation
In 1993, a Swedish research team led by B. Dahlbäck recognized an
unusual phenomenon affecting the coagulation system. They were studying
the effect of addition of external APC to plasma of patients with VTE.
Normally, APC should inactivate clotting Factor V (FV) ( Figure 1) and
therefore slow down the coagulation process. However, in certain
patients studied by Dahlbäck and his team, this slowing down did not
occur. They called this phenomenon “APC resistance”, and they
originally though this could be due a deficiency in a yet unknown
protein that co-helps APC in inactivating FV.[ 9] One
year later, another
group of researchers from Holland, led by R. M. Bertina, discovered a
missense point mutation in the FV gene, where adenine (A) replaced
guanine (G) at nucleotide position 1691 of exon 10 of the FV gene, only
eleven nucleotides upstream of the beginning of intron 10. They called
this mutation as FV Leiden mutation (FVL) after the Dutch city where
they made their discovery in.[ 10] This nucleotide
replacement happened to
be in the codon for the amino acid residue arginine 506 (CGA) normally
present in the factor V molecule, creating a new codon (CAA) which is
translated as glutamine. In order to inactivate FV, APC needs to
recognize arginine at position 506 of the FV molecule ( Figure 2).
Because of the amino acid change in FVL, APC can no longer inactivate
FV efficiently, but FV retains its coagulation capabilities and
therefore carriers of FVL develop hypercoagulability which may
clinically manifest as VTE episodes. Later studies showed that people
with FVL were at higher risk of developing VTE (10-fold in heterozygous
carriers and 30 to 140-fold in homozygous carriers).[ 9-16]
In addition,
most homozygotes for FVL were reported to get at least one VTE event in
their life time.[ 17,18] This explains the great
clinical and scientific
consideration this mutation had appealed and the hundreds of studies
conducted on its prevalence and risk for developing VTE in almost every
part of the world.
Figure 1. The
processes of coagulation and fibrinolysis as a series of chemical
reactions leading to the formation of a clot to stop bleeding from the
site of injury, and then removing the clot afterwards. Solid lines
indicate activation process, while dashed lines indicate inactivation
process. Abbreviations: antithrombin (AT), protein C (PC), activated
protein C (APC), protein S (PS), phospholipids (PL), lupus
anticoagulants (LA), tissue plasminogen activator (tPA), tPA inhibitor
(tPAI), α2 antiplasmin (α2AP), thrombin activatable fibrinolysis
inhibitor (TAFI).
Figure 2. FV molecule
showing arginine 506 as a main point of action for APC which is
negatively affected by FVL.
World Distribution of Factor V
Leiden
Since its discovery, several studies were conducted to determine the
prevalence of FVL mutation in normal subjects and in patients with VTE,
as well as to measure the risk value of this mutation in developing
VTE. First reports appeared in Europe, which concentrated on
populations of Caucasian origin. They found FVL to be present in a
quite high percentage of patients with VTE (15-65%) and healthy
subjects (1-15%). Similar results were obtained when Caucasians where
studied in non-European countries like USA, Australia and Israel. Table
1 gives examples of studies on FVL in European and non-European
Caucasians.[ 2, 3, 10, 12, 14-16, 19-64]
However, when studies where extended
to other ethnic groups, FVL was surprisingly found to be very rare in
Africans, South-East Asians, Chinese, Japanese, American Indians,
Greenland Eskimos and Aboriginals of Australia ( Table 2).[ 21, 58, 61, 65-78]
These findings suggested that FVL might have occurred as a single event
sometime in the distant past in a common European Caucasian ancestor,
whose offspring are the present time Caucasian carriers of this
mutation living in Europe and other countries. This assumption was
later strengthened by molecular studies that reported FVL to be always
associated with one haplotype of single nucleotides polymorphisms
(SNPs), as will be discussed later. Later on, studies were conducted on
Arabs and populations living in the Middle East and North Africa (The
MENA region), as summarized in Table 3.[ 31, 63, 79-133] These
studies
showed a high prevalence of FVL in these populations, who are not
usually classified as Caucasians. However, the MENA region is
geographically very close to Europe and had witnessed a lot of human
movement from and to Europe, and hence such populations are expected to
have some Caucasian genes in their DNA. Therefore, the presence of FVL
in Arabs and North African populations should not be a surprising
upshot.
Table 1. Prevalence
of FVL in Caucasian patients with VTE and normal subjects living in
European and non-European countries. European countries on the
Mediterranean Sea are shown.
Table 2. Prevalence of
FVL in non-Caucasian patients with VTE and normal subjects in different
parts of the world.
Table 3. Prevalence of
FVL in patients with VTE and normal subjects in Arabs and non-Arabs
living in different Middle-Eastern and North African countries.
Countries on the Mediterranean Sea are shown.
Factor V Leiden in the
Mediterranean Region
Currently, there are 20 countries that have seacoasts on the
Mediterranean Sea and therefore are called the Mediterranean countries;
5 are in North Africa, 4 in West Asia and 11 in South Europe. Figure 3
gives a map of the Mediterranean Sea and its countries, showing the
prevalence of FVL in these countries which are based on the studies
listed in tables 1 and 3. No
data could be retrieved from the
literature on prevalence of FVL in Libya, Malta, Bosnia or Montenegro.
However, one study reported FVL in Yugoslav people which included
patients and healthy subjects from all over the former Yugoslavia, and
possibly some of their subjects were from Bosnia and Montenegro.[ 48]
There were no reports from Albania itself, but one study was conducted
in Kosovo, the people of which are considered as Albanians.[ 53] In table
1, the prevalence of FVL in the people of the Basques was put
separately, although not being a separate country, because of the
unique rarity of FVL in these people.[ 42,43] This has
an important issue
which will be discussed later. In Israel, the population consists of a
mixture of Palestinian Arabs and other immigrants from different parts
of the world, largely being of European Caucasian origin. Therefore,
the results there were split between tables
1 and 3 according to the
origin of the studied populations.
One may notice that the prevalence of FVL is present in its maximum
peak in this part of the World. In addition, there is generally an
Eas-to-West decline in prevalence of FVL in these countries. This
observation was also noticed by Lucotte et al (2001) who also observed
a South-to-North decline of these values in Europe, only when
southwestern populations were excluded.[ 134] These
observations raised
discussions in the literature on the exact place where FVL has first
appeared.
Figure 3. Map of the Mediterranean
Sea and its countries showing the prevalence of FVL in healthy
populations living there.
Has Factor V Leiden originated
in the Eastern Mediterranean?
As was mentioned before, the first reports on the prevalence of FVL
found high prevalence of FVL in European Caucasians, while the
prevalence was almost zero in other ethnic groups. In addition, studies
showed an association of FVL with one haplotype in all carriers of the
mutation. Therefore, scientists got a perception that FVL has occurred
once in the past time in one European Caucasian person. Anthropology
proposes that Caucasoid populations who settled in Europe were diverted
from Mongoloid populations (who moved to East Asia) around 32 thousands
of years ago; therefore FVL should have appeared sometime earlier than
32,000 years ago.[ 2, 4, 11, 135-137] It was suggested that the mutation
occurred in Europe first, and then spread to other parts of the world.
However, the observed highest prevalence of FVL in Eastern
Mediterranean countries have raised speculations that FVL might have
occurred somewhere there and then spread to
Europe.[ 43, 99, 100, 134, 138, 139] The
author of this paper has found FVL to
be associated with one haplotype in 67 Arabs from Eastern Mediterranean
region, which was the same haplotype found in European carriers of the
mutation, giving another confirmation that FVL occurred as a single
event in the past even in Arabs. [ 140] Castoldi et
al (1997) suggested
that FVL probably occurred outside Europe.[ 138] The
rarity of FVL in the
French and Spanish Basque populations, which are thought to be the
oldest ethnic groups in Europe of Paleolithic origin, has also
suggested FVL to occur outside Europe first.[ 42,43]
Lucotte et al (2001)
proposed that FVL expanded in Europe during the Neolithic period, from
a probable Anatolian center of origin in Turkey, which has occurred
around 10,000 years ago.[ 134] This may explain the
highest prevalence of
FVL in East Mediterranean countries, and that the prevalence decreases
when radiating away from this region towards Europe or other parts of
the world. Still, more genetic and molecular studies may be needed to
detect certain genetic loci or markers that may help in following the
movement of carriers of FVL in the Mediterranean region to definitely
determine the exact location where FVL might have occurred first.
Conclusions
Molecular and epidemiological studies provide evidences that FVL should
have occurred as a single event in the past. The Mediterranean region
has the highest prevalence of FVL in the world. This suggests it as the
area where this mutation has arisen, possibly 10,000 years ago, and
then it was spread to other parts of the world.
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