Genetic causes of hemophilia and its impacts
on body functioning”


Clotting factors are proteins in the blood that control bleeding. When
a blood vessel is injured, the walls of the blood vessel contract to limit the flow
of blood to the damaged area. Then, small blood cells called platelets stick to
the site of injury and spread along the surface of the blood vessel to stop the
bleeding. At the same time, chemical signals are released from small sacs
inside the platelets that attract other cells to the area and make them clump
together to form what is called a platelet plug.On the surface of these
activated platelets, many different clotting factors work together in a series
of complex chemical reactions to form a fi brin clot.. Coagulation factors are identifi
ed with Roman numerals.(1)

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Factor VIII an essential blood coagulation protein, is a key
component of the fluid phase blood coagulation system. Human factor VIII is a
single chain of about 300 kDa consisting of domains described as A1-A2-B-A3-C1-
C2. In patients with haemophilia  the
long-term consequences of repeated haemarthrosis include cartilage damage and
irreversible arthropathy, resulting in severe impairments in locomotion.
Quantifying the extent of joint damage is therefore important in order to
prevent disease progression and compare the efficacy of treatment strategies.

challenges confront adult hemophilia patients with inhibitors, including
difficulty in controlling bleeding episodes, deterioration of joints, arthritic
pain, physical dis­ability, emotional turmoil, and social issues.


Hemophilia A is an X-linked bleeding disorder affecting
approximately 1 in 5,000 males, and is caused by deficiency of factor VIII, a
cofactor in the activation of factor X by factor Ixa(36)

Clotting factors are proteins in the
blood that control bleeding. When a blood vessel is injured, the walls of the
blood vessel contract to limit the flow of blood to the damaged area

The clot acts like a mesh to stop
the bleeding. Coagulation factors circulate in the blood in an inactive form.
When a blood vessel is injured, the coagulation cascade is initiated and each
coagulation factor is activated in a specifi c orderto lead to the formation of
the blood clot.

The protein undergoes processing prior
to secre­tion into blood resulting in a heavy chain of 200 kDa (A1-A2-B) and a
light chain of 80 kDa (A3-C1-C2) linked by metal ions. The role of factor VIII
is to increase the catalytic efficiency of factor IX a in the activation of
factor X. Variants of these factors lead frequently also to severe bleeding

The human factor VIII procoagulant protein(VIUC) was purified from
the VIUC-factor VIII-related antigen complex in commercial factor VIII
concentrate by immunoadsorbent chromatography with a monoclonal anti-VIURAg antibody
bound to Sepharose.


Combined factor V and factor VIII deficiency is an inherited bleeding
disorder that is caused by low levels of factors V and VIII. Because the amount
of these factors in the body is lower than normal, the clotting reaction is
blocked prematurely and the blood clot does not form. The combined defi ciency
is completely separate from factor V deficiency and factor VIII deficiency.

Combined factor V and factor VIII deficiency is an autosomal recessive
disorder, which means that both parents must carry the defective gene in order
to pass it on to their child. It also means that the disorder affects both
males and females. The defi ciency is very rare, but like all autosomal
recessive disorders, it is found more frequently in areas of the world where
marriage between close relatives is common.


Most cases are found around the Mediterranean Sea, especially in
Israel, Iran, and Italy. Normally the disorder is caused by a single gene
defect that affects the body’s ability to transport factor V and factor VIII
outside the cell and into the bloodstream, and not by a problem with the gene for
either factor. Deficiencies of factor VIII and factor IX are known as
hemophilia A and B, respectively. Rare clotting factor defi ciencies are
bleeding disorders in which one or more of the other clotting factors (i.e.
factors I, II, V, V,VIII,VII, X, XI, or XIII) is missing or not working

While bypassing agents can achieve an effective level
of control for most bleeding episodes in hemophilia patients with inhibitors,
their hemostatic efficacy is not equiva­lent to that of factor replacement in
patients without inhibitors and bleeding is harder to control.(2) Patients with
inhibitors have worse treatment-related outcomes, including greater incidence
of joint abnormalities, more rapid progression of arthropathy, more chronic
joint pain,(3-6) and an increased incidence of intracranial hemorrhage than
patients without inhibitors.(7)

factor VIII is a glycoprotein synthesized mainly in hepatocytes, but also in
kidneys, endothelial cells and lymphatic tissue. It is one of the largest
coagulation factors  present in the blood­stream
in association with von Willebrand factor  in a non-covalent complex (8). The vWF
protects factor VIII from premature proteolysis and transfers it to sites of
endothelial injury. The half-life of coagulation factor VIII is about 12 hours.
The active form of factor VIII is a non-enzymatic cofactor for the prothrom­binase
and tenase complex in the intrinsic coagulation pathway that accelerates factor
X activation induced by activated factor IX in the presence of phospho­lipids
and calcium ions.


The gene for
factor VIII is located on the X chromo­some. A mutation in this gene that codes
for co­agulation factor VIII results in congenital bleeding disorder, i.e.
hemophilia A. This mutation almost exclusively occurs in male germ cells. The
effect of the mutation is absent or decreased synthesis of factor VIII or
synthesis of abnormal protein (9).

Hemophilia A is
diagnosed in 1 of 5000 male new­borns. In Poland, frequency of hemophilia is
estimated at 1 : 12 300 inhabitants. In approximately 30–50% of af­fected
patients mutation occurs spontaneously and their family history is negative.

Treatment of
bleedings in course of hemophilia and related disorders consists of
supplementation of miss­ing coagulation factor i.e. its substitution (10).


The first lyophilized
factor VIII concentrates appeared on the market in the late 1960s and since
that time they have been the basis of hemophilia A treatment. Unfor­tunately,
quite quickly, substitutive therapy was found to be also associated with some
very serious side effects for patients. The concentrates produced from pooled
plas­ma received from thousands of donors were sources of hepatitis B virus,
and since 1989 also of hepatitis C vi­rus. In the early 1980s, in a very short
time, 60–80% of hemophilia patients became infected by human immuno­deficiency
virus that was contained in lyophilized concentrates. There are several types of Haemophilia: haemophilia A, haemophilia B, haemophilia C, parahaemophilia,
and acquired haemophilia A.(47-50).

Haemophilia A affects about 1 in 5,000–10,000, while
haemophilia B affects about 1 in 40,000, males at birth.(47-50)


breakthrough in hemophilia treatment start­ed with the discovery of human
factor IX and factor VIII genes in 1982 and 1984, respectively (11). Soon after
these discoveries some research groups proved that mammalian cells transfected
with human factor VIII cDNA were able to synthesize that factor. Recombinant
factor VIII manufactured using genetic en­gineering technology became available
in the early 1990s (12).

In the 1990s,
when recombinant factor VIII became available for patients, it was predicted to
replace human plasma derived concentrates. Unfortunately, at present only in
some countries, for example Canada and Ireland, 100% of affected patients
receive recombinant factor VIII. In The United States that percentage is about
65% and in many rich and highly developed countries of the European Union this
ratio is significantly lower.

In Poland, only
coagulation factor concentrates manu­factured from human plasma are used. The
reason for that is very high production cost of recombinant factor VIII (13).

So far, all available recombinant factor VIII formula­tions have
been produced in mammalian cells:

Common symptoms

nosebleeds (epistaxis)

easy bruising

heavy or prolonged menstrual bleeding (menorrhagia)

bleeding in the mouth, particularly after

dental surgery or tooth extraction

bleeding in the head (newborns)

heavy bleeding at circumcision

Other reported symptoms

bleeding in the gut (gastrointestinal bleeding)(1)


Human coagulation factor
VIII is a glycoprotein en­coded by a gen of 186 000 base-pairs (bp) comprising
26 exons. It is synthesized as a single polypeptide chain containing 19
signaling peptides. Factor VIII consists of 2332 amino acids forming six
domains described as A1-A2-B-A3-C1-C2 .

Although brain haemorrhage and bleeding into internal organs
represent major threats to the life of PWH, approximately 80%–90% of bleeding
episodes occur in the musculoskeletal system, especially in the large synovial joints,
aswell as in themuscles, thus constituting the principal health problem. This
induces progressive cartilage damage,leading to joint destruction and
subsequent severe functional limitation.


Treatment and, ideally, the prevention of musculoskeletal  are the main challenges in PWH. The adequate
prevention of musculoskeletal system  complications
requires the early detection of the first signs of joint impairment in
relatively asymptomatic patients as well as the efficient followup of musculoskeletal
system complications already present. Appropriate treatment, whether
haemostatic or orthopedic, is only possible if we have reliable assessment tools
at our disposal which can make it possible to quantify the benefits of such


The musculoskeletal system  assessment
has traditionally been evaluated using both radiological and clinical joint
scoring systems(14-17). Information obtained from these scores is regularly used
in clinical practice to evaluate the effects of different  treatments on the progression of arthropathy,

clotting factor prophylaxis, physical therapy, and surgical procedures(18).

There are two C domains within the FVIII struc­ture —
C1 and C2. The C1 and C2 domain comprise 153 and 160 amino acids, respectively.
Crystal structure of the C2 domain consists of ?-sandwich forming the internal
domain structure, and attached ?-hairpins and loops forming a hydrophobic


Coagulation factor VIII is proteolytically activated by
thrombin. Activation results from cleavage of the heavy chain in: Arg372 (A1 —
A2 domain linkage) and Arg740 (A2 — B domain linkage) amino acid sites and
cleav­age of the light chain in amino acid site(28-31)

Catastrophizing is a coping strategy used by hemophilia
patients who lack a personal sense of psychosocial well-being, and strong
positive correlations have been described between the use of this coping
mechanism and pain and dis­ability in these patients.(19) A
serious consequence of progressive joint disease that can­not be surgically
corrected in all patients with hemophilia is chronic pain; often, this pain
persists despite the patient’s and medical team’s best efforts to control joint
bleeding and dis­ease progression.(20,21)

Gene mutations re­sult in absent or decreased factor
VIII synthesis or ab­normal protein expression (33-35).


The medication desmopressin may
be used in those with mild haemophilia A.(41) Studies of gene therapy are
in early human trials.(42). In 2017 a
gene therapy trial on nine people with haemophilia A reported that high doses
did better than low doses. 43,44) Haemophilic arthropathy is
characterized by chronic proliferative synovitis and cartilage destruction.(46)

A healthy diet and regular exercise keep the body healthy and strong.
Exercise can also help reduce stress, anxiety and depression,and reduce the
frequency and severity of joint bleeds.People who are overweight place
additional stress on the joints such as particularly the knees and ankles,
leaving them increasingly susceptible to bleeds.

Several strategies are important in the management of
evolving joint disease in patients with inhibitors, including exercise,
physical therapy, orthopedic interventions, and pain management.(22) In
addition, recent studies(23-25).suggest that the prevention of joint bleeding
may be possible with the regular use of secondary prophylaxis with bypassing
agents, a therapeutic modality that could be helpful in interrupting the
progression of joint disease if started early in patients who are experiencing
repeated bleeding in a particular joint.

Discussion and Conclusion

factors are proteins in the blood that control bleeding. When a blood vessel is
injured, the walls of the blood vessel contract to limit the flow of blood to
the damaged area. Then, small blood cells called platelets stick to the site of
injury and spread along the surface of the blood vessel to stop the bleeding.
At the same time, chemical signals are released from small sacs inside the
platelets that attract other cells to the area and make them clump together to
form what is called a platelet plug.

Haemophilia is an inherited bleeding disorder where blood doesn’t
clot properly. It is caused when blood does not have enough clotting factor.
A clotting factor is a protein in blood that controls bleeding.There are two
types of haemophilia .Both have the same symptoms.Haemophilia A is the most
common form and is caused by having reduced

levels of clotting factor VIII Haemophilia B, also known as
Christmas Disease, is caused by having reduced levels of clotting factor IX..Haemophilia
is not contagious.


factor VIII is a protein involved in the blood coagulation process. Its absence
or low blood ac­tivity causes haemophilia A. The treatment of haemo­philia-related
bleedings and related bleeding disorders consists of coagulation factor VIII
substitution. Nowa­days few types of substitutes are used worldwide. The most
commonly used therapeutics are plasma-derived products. Even though no patient
infections have been observed lately, it cannot be excluded that they are com­pletely
free of any infectious particles. The latest re­searche is directed at
development of coagulation factor that can effectively overcome immunological
response or has increased half-time but it is still not free from viral
transmission risk. The next step in haemophilia treatment development would be
obtaining recombinant coagulation factor VIII by less expensive prokaryotic
expression system. That would allow significant lowering of production costs,
shortening of production time, better product availabil­ity, and — first of all
— elimination of the risk of infec­tion.


 Musculoskeletal impairments
in PWH may stem from structural and functional abnormalities, which have
traditionally been evaluated radiologically or clinically




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