Prothrombin G20210A Mutation in the Mediterranean Region
Medical Laboratory Sciences, Faculty of Allied Health Sciences, Kuwait
Mehrez M. Jadaon. Department of Medical Laboratory Sciences, Faculty of
Allied Health Sciences, Kuwait University, P.O. Box 31470 – Sulaibekaht
90805 – Kuwait. Tel.: (965) 6664 3485 Fax: (965) 2498 3835. Email: firstname.lastname@example.org email@example.com
Published: November 28, 2011
Received: October 1, 2011
Accepted: October 7, 2011
Mediterr J Hematol Infect Dis 2011, 3(1): e2011054, DOI 10.4084/MJHID.2011.054
This article is available from: http://www.mjhid.org/article/view/9310
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provided the original work is properly cited
are many genetic and acquired risk factors that are known to cause
venous thromboembolic disorders (VTE). One of these is the Prothrombin
G20210A mutation, which has been identified in 1996. Prothrombin
G20210A mutation causes higher levels of the clotting factor
prothrombin in the blood of carriers, which creates a higher tendency
towards blood clotting (hypercoagulability), and therefore the carriers
become at higher risk of developing VTE. High prevalence of Prothrombin
G20210A mutation was reported in Caucasian populations, but the
prevalence was almost absent in non-Caucasians. That was most obvious
in countries of South Europe and the Mediterranean region. This review
article discusses Prothrombin G20210A mutation, how it causes VTE, the
origin of the mutation, and its distribution worldwide with special
concentration on the Mediterranean area.
thromboembolic disorders (VTE) are serious disorders accounting for
high morbidity and mortality rates with an annual incidence of
Many genetic and acquired risk factors
were identified to
cause VTE including Factor V Leiden mutation, genetic deficiencies of
proteins C, S and antithrombin, lupus anticoagulants, pregnancy, use of
contraceptives, major surgeries, cancer, inflammations, and Prothrombin
G20210A mutation. This review article focuses on Prothrombin G20210A
mutation, its pathophysiology, prevalence and origin, with a special
concentration on this mutation in the Mediterranean region.
Role of Prothrombin in the
In case of blood vessel injury, blood coagulation is
a cascade of chemical reactions to form a blood clot to block the
injured blood vessel and prevent blood loss. Several enzymes and
proteins, generally known as blood clotting factors, are involved in
blood coagulation, a very important one is thrombin (clotting factor
II). Thrombin is usually produced in the liver in an inactive form
called prothrombin, which circulates in the blood until being activated
in case of injury. Potrhombin gets activated into thrombin by another
clotting factor called activated factor X. The main function of
thrombin is to convert fibrinogen (clotting factor I) into a fibrin
clot that blocks the injured blood vessel. In fact, thrombin is a very
robust enzyme that plays a major role in the coagulation system by
activating many clotting factors and other elements of the coagulation
system like the blood platelets. Thrombin is usually under careful
monitoring by an inhibitor called antithrombin (AT), which
down-regulates thrombin after clot formation and prevents accidental
formation of thrombin in sites away from injured vessels.[5,6]
very crucial to prevent the formation of unnecessary clots inside
intact blood vessels. The formation of such intravascular clots
predisposes to the development of VTE.
Prothrombin G20210A Mutation
Because of the importance of thrombin in the coagulation
genetic or acquired deficiency of prothrombin usually causes impaired
clotting and therefore bleeding problems (hemophilia). On the contrary,
if prothrombin is produced in higher quantities in the blood, this is
expected to cause an increased tendency towards blood clotting, a
condition known as “hypercoagulability”, which usually manifests
clinically as VTE. It has been demonstrated that prothrombin levels
more than 115% of the normal level have 2-fold increased risk of
] Poort et al (1996) performed an
sequencing on the prothrombin gene (on chromosome 11) for patients with
] They found a single
missense mutation (guanine to
adenine; GA) at nucleotide position 20210, which is present in the 3′
untranslated region of the prothrombin gene. This Prothrombin G20210A
mutation is present outside the coding region for prothrombin, and
hence it does not affect the actual structure of the prothrombin
molecule and it does not affect its function as a strong clotting
factor when activated into thrombin. However, Prothrombin G20210A
mutation was found to cause elevated levels of blood prothrombin (by
one-third above normal; 133%), which is more than the extra 15% needed
to develop VTE. Also, it has been proven that Prothrombin G20210A
mutation leads to increased mRNA and protein expression for
Moreover, increased prothrombin levels may lead to an increase in a
protein called thrombin-activatable fibrinolysis inhibitor (TAFI),
which is an inhibitor of the fibrinolysis process. Fibrinolysis is the
process by which the blood removes clots. Therefore, an increase in
TAFI may disturb the fibrinolysis process and therefore allow for
accumulation of clots leading to VTE.[9,10]
pathophysiological pathway of causing VTE in cases having Prothrombin
G20210A mutation with elevated TAFI. All these findings may explain why
Prothrombin G20210A mutation may cause hypercoagulability and an
increased risk of developing VTE. Such increased risk was reported to
be 2 to 4-fold.[7,11-15]
Prevalence of Prothrombin
The prevalence of Prothrombin G20210A mutation in European
was found to be roughly 3-17% in patients with VTE and 1-8% in healthy
controls. That was also true in Caucasians living outside Europe like
in the USA, Australia, Brazil and Israel (Table 1
). It may be noticed
here that the prevalence of Prothrombin G20210A mutation is higher in
the Southern European countries than in the Northern countries, in
spite of presence of overlapping between the North and South. On the
other hand, Prothrombin G20210A mutation was found to be very rare or
even absent in Asian and African populations, and in native populations
of America (Amerindians) and Australia (Table
). This was also true
when these populations were studied in countries outside their origin
like African Americans and Asians living in the USA. The only exception
to the above observations is the high prevalence reported in Hispanics
and Mexican Mestizos; the latter are descendants of mixed marriages
between Europeans and Amerindians. The presence of European genes in
such populations may explain the high prevalence of Prothrombin G20210A
mutation in these.
High prevalence of Prothrombin G20210A mutation was also reported in
populations living close to Europe, namely countries of the Middle East
and North Africa. In fact, the prevalence in these countries was very
comparable with the prevalence reported in Southern European countries.
Therefore, the countries present on the coasts of the Mediterranean
Sea, including Southern Europe, may be grouped together sharing the
same prevalence of Prothrombin G20210A mutation (Table 2
countries, 20 in total, have a prevalence of 3-24% in patients with VTE
and 1-12% in the general population. No reports could be found in
Malta, Syria, Bosnia, Albania and Macedonia. The highest prevalence was
found by a study in Egypt in patients with VTE, but the highest among
the general populations (healthy controls) was in Palestinians living
in Israel (Israeli Arabs). Unfortunately, there were no reports on the
prevalence in Palestinian patients with VTE, which kight be higher than
the one reported in Egypt, noting that Egypt and Palestine are
Prevalence of Prothrombin G20210A mutation in different
populations and countries worldwide.
Prevalence of Prothrombin G20210A mutation in the
Origin of Prothrombin G20210A
The highest prevalence of Prothrombin G20210A mutation in European
Caucasians brought up speculations that Prothrombin G20210A mutation
might have occurred as a single event in a single Caucasian ancestor
and that the current Caucasian carriers of the mutation should have
descended from that proposed grandparent. This assumption was supported
by a molecular study that found a haplotype to be associated with more
than two third of carriers of the mutation compared to one third of
non-carriers. This suggests a founder effect, and the mutation was
estimated to occur around 24 thousand years ago after the divergence of
Africans from Non-Africans and Caucasoids from Mongoloids.[110
] It is
tempting to explore this founder haplotype in non-Caucasian carriers of
the Prothrombin G20210A mutation in the Middle East and North Africa to
see if this founder effect occurred there too. In addition, it may be
interesting to study this mutation in the Basque population (in France
and Spain), who is thought to be the oldest ethnic group living in
Europe. Finding or not finding the mutation in this population may give
a hint on the origin of the mutation and to know if it occurred inside
or outside Europe. Also, if a future study can prove that Palestinian
patients with VTE have the highest prevalence of Prothrombin G20210A
mutation (like the general Palestinian population), then this region
(Palestine/Israel) may be the place where the mutation has occurred and
then spread to Europe and other parts of the Mediterranean region. This
region has witnessed a lot of mankind movements since the old ages,
since the Neolithic period, and then the Phoenicians who appeared in
Lebanon and then cruised to many cities on the Mediterranean coast,
followed by the Roman and Greek civilizations, and more recently the
Crusaders and Ottomans. Therefore, it is encouraging to try to find
certain genetic or chromosomal markers that can help in following the
migratory history of manhood in the Mediterranean region which may give
a final approach towards determining exactly where the mutation has
occurred first and how it spread all over the Mediterranean region.
prevalence of Prothrombin G20210A mutation differs in different
countries and ethnic groups, being highest in Caucasians, especially
those in the Southern Europe, and in the Mediterranean region. Further
studies are needed to verify where exactly has the mutation occurred
first and how it was carried to other parts of the world.
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