Factor XI Coagulation Defficiency
by Marilynn Seman
Factor XI, or Plasma Thromboplastin Antecedent (PTA for short) is a clotting
factor that functions in the very early stages of the blood coagulation
pathway. It is a precursor to Plasma Thromboplastin, which is one of the
proteins that alters the shape of blood platelets. allowing for the normally
of blood clots as a response to tissue damage.
Factor I deficiency is an extremely rare affliction that occurs in one out
of one million individuals in most populations throughout the world. However,
there is a race of people. the Ashkenazi Jews, that develop this disease
at a relatively alarming ratio of 1 in every 190 individuals (Asakai et
al, 1991). This frequency of affliction in the Ashkenazi race has allowed
for the perpetuation of the deficiency and for much of the current knowledge
about the mode of expression of Factor XI deficiency. The potential reasoning
behind the isolation of the disease within the Ashkenazi race will be discussed
Factor XI deficiency is an autosomal, recessive trait. This means that the
mutation is not linked to the sex determining X chromosome as is the more
common Hemophilia A (Asakai, et al.. 1991). Consequently. men and women
are equally susceptible to Factor XI deficiency. This also means that both
homologous chromosomes in the human genome must be affected by the mutation
leading to Factor XI efficiency.
That is to say, the disorder must be inherited from both parents in order
for it to affect an individual. A person with only one affected chromosome
may be a carrier of the disease, but will not be afflicted with the disorder.
This is because the one functioning !non-mutated) chromosome produces enough
Factor XI for normal clotting. There are three different types of mutations
1sading to factor XI deficiency that occur at the gene that encodes the
PTA protein. An individual can inherit any combination of two of these mutations,
one from each of his or her parents. and will be affected by the disorder
to some degree depending on which combination of mutation types are inherited
(Asakai et al, 1991i. It works like this: Three mutation types are Type
I, Type TI, Type III A person inherits a Type I chromosome from his mother
and a Type I· chromosome from his father - He is Type I/II. A person
inherits a Type II chromosome from his mother and a Type II chromosome from
his father - He is a Type II/II and so on...
The Type I mutation is the rarest. It is due to a mutation at an intron/exon
border in the human gene that codes for PTA (Asakai et al, 1991). This is
the area the separates the part of gene that actually codes for the manufacture
of a protein ( exon ! from the part of a gene that is "blank"(intron).
The blank portion of a gene is normally cut out before it is translated
to make a protein. Type · mutation causes cutting enzymes to cut too
much and part of the coding sequence is removed along with the blank information.
Without the right coding sequence. no PTA is manufactured and the blood
coagulation pathway cannot function. The Type II mutation is the most common
and leads to the most severe bleeding disorder. Type II is a "non-sense"
mutation caused by a misplaced "STOP" code in the transcription
of RNA from DNA (Asakai, et al, 1989). Subsequently the RNA stops adding
amino acids to the PTA protein chain prematurely. Nonfunctional protein
is formed and again, the blood coagulation pathway fails.
Type III mutation is also a missense mutation that stems from the substitution
of a single amino acid for another in the protein chain (Asakai et al..
19S9). This switch leads to the breakdown of the protein structure and once
again, the coagulation pathway breaks down.
Further study of the various mutation types have shown that of the various
possible combinations. Type II/II idividuals are nore seriosly affected
(have more blreding problems) than type II/III and type II/III individuals
are more seriously affected than type III/III. In other words, the Type
II mutation leads to more severe problems and the severity of any disorder
is proportional to the presence of the type II mutation. This is because
type II individuals make less PTA than Type III individuals. Genetic studies
show that one type II mutation leads to a production of only .6% of normal
amounts of PTA while type III leads to 5% of normal amounts. The math is
quite simple then: Type II/II = .6% + .6% or 1.2% of normal; Type II/III
= .64, + 5% or 5.6% of normal and type III/III = 5% + 5% or 10% of normal
production (Asai et al., 1991). It is easy to see why some individuals are
more severely affected depending on what mutation types they harbor. In
fact, type III/III individuals often suffer none of the ill effects normally
associated with factor XI deficiency. Since the Type I mutation is so rare,
no current information exists about its effects on PTA production.
One additional aspect of Factor XI deficiency which was alluded to earlier
deserves further examination - the relative prevalence of Factor XI deficiency
within the Ashkenazi Jewish population. Geneticists have evidence that traces
the origin of other gene mutations common in the Ashkenazi race to a tie
when Jews were ostracized from Russia by the Czars of the late 1500's and
early 1600's (Editorial. 1995). Jewish people of this era were exiled to
areas of Europe which are now Lithuania, Poland and the Ukraine. Whenever
a concentration of people or any organism is confined to a limited area,
the chance for genetic recombination in the population becomes very limited.
This is known as the "founder effect" and what results as a limited
"gene pool" (Strickberger , 1996). Mutation rates increase in
such populations and the effects of related mutations begin to show in a
much higher percentage of the population. The majority of the Ashkenazi
Jewish race now resides in Israel, with significant populations in Western
Europe and the United States. These populations suffer from an unusually
large number of genetic disorders, including Tay Sach's disease, Gauder's
disease and the Factor XI Deficiency, 11 of which can likely be attribted
to the isolation of the race and resulting founder effects.
Asakai, R. M.D, PH.D., Chung. D.W.. P.D., Davie, E.W., PH.D., Seligsohn,
M.D. (1991). Factor XI deficiency in Ashkenazi Jews in Israel. The New England
Journal of Medicine, 3253, 153-157.
Asakai, R., Chung, D.W., Ratnoff, O.D., Davie, E.W (1989). Factor XI (plasma
thromboplastin antecedent) deficiency in Ashkenazi Jews is a bleeding disorder
that can result from three types of point mutations. Proceedinqs of the
National Academy of Sciences USA, 86, 7667-7671.
Editorial (1995, February 2). Nature's sister journals in review. Where
history meets geneticst The Ashkenazi population. Nature, 373, p.455
Strickberge, M.. !1996). Evolution, 2d Ed., Jones and Bartlett Publishers,
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