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Indian J. Pharm. Biol. Res. 2014; 2(4):68-76
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ISSN: 2320-9267
Indian Journal of Pharmaceutical and Biological Research (IJPBR)
Journal homepage: www.ijpbr.in
Review Article
Recent trends and advances in hemophilia – its management and new therapeutic outcomes
Jiguru Prasant*
Flat no: 7, 4th Floor, Sonaappartments, 50 sebastain road, Rezimental Bazar, Secunderabad, India
ARTICLE INFO:
Article history:
Received: 23 October 2014
Received in revised form:
5 November 2014
Accepted: 15 November 2014
Available online: 31 December
2014
Keywords:
Hemophilia, Factor VIII, factor IX,
Hemostasis, Thrombin.
ABSTRACT
Hemophilia unfortunately a less attracted disease for researchers compared to other life
threatening diseases. The prevalence of hemophilia is estimated to be about 1:10,000 birth
and that of the severe form of the disease to be about 6% per 1,00,000 population. The most
pathetic part of this disease is that even medical personnel are sometimes not familiar with its
diagnosis and management. There is obviously a need to establish facilities and treatment
options that will help the patient with hemophilia to manage their life with ease. As this is a
genetic disorder no complete cure is possible as of now. The only available treatment option
is the infusion of factors and some adjuvant therapies depending upon the bleeding conditions
.The initiative for the development of new dosage forms, new delivery systems of the existing
therapies or new treatment options has to be driven by pharmacy professionals. This article
present an overview of hemophilia, in order to drag the attention of medical as well as
pharmacy professionals for the benefit of millions of hemophilic patients .
Introduction
Hemophilia is a group of inherited blood disorders in which
the blood does not clot properly. Hemophilia is the standard
international spelling, also known as haemophilia in the UK,
other translations include: hémophilie, hemofilie, hemofili,
hemofilia, hämophilie, emofilia. We will use the standard
international spelling for the purpose of this section[1].
Bleeding disorders are due to defects in the blood vessels, the
coagulation mechanism, or the blood platelets[2]. An affected
individual may bleed spontaneously or for longer than a
healthy person after injury or surgery.
The blood coagulation mechanism is a process which
transforms the blood from a liquid into a solid, and involves
several different clotting factors. The mechanism generates
fibrin when it is activated, which together with the platelet
plug, stops the bleeding.
When coagulation factors are missing or deficient the blood
does not clot properly and bleeding continues.
Patients with Hemophilia A or B have a genetic defect which
results in a deficiency in one of the blood clotting factors.
*
Types of Hemophilia / Haemophilia
Hemophilia A and Hemophilia B[3]
There are two main types of hemophilia - Hemophilia A (due
to factor VIII deficiency) and Hemophilia B (due to factor IX
deficiency). They are clinically almost identical and are
associated with spontaneous bleeding into joints and muscles
and internal or external bleeding after injury or surgery.
After repeated bleeding episodes permanent damage may be
caused to the joints and muscles that have been affected,
particularly the ankles, knees and elbows[4].
Approximately 1 in 5,000 males is born with Hemophilia A,
and 1 in 30,000 males is born with Hemophilia B. Hemophilia
affects people of all races and ethnic origins globally. The
conditions are both X-linked and virtually all sufferers of
hemophilia are males. Female carriers may also bleed
abnormally, because some have low levels of the relevant
clotting factor.
People with hemophilia have a genetic mutation in the
affected gene on the X chromosome, which results in reduced
production of Factor VIII or IX and creates a bleeding
Corresponding Author: Jiguru Prasant, Flat no: 7, 4th Floor, Sonaappartments, 50 sebastain road, Rezimental Bazar,
Secunderabad, India. E-Mail: [email protected]
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Prasant et al. / Indian J. Pharm. Biol. Res., 2014; 2(4):68-76
tendency, because coagulation takes much longer than normal,
thus making the clot weak and unstable[5]. Approximately one
third of patients with hemophilia have no family history of the
disease, either because of new genetic mutations, or because
previous affected generations either had daughters (who were
carriers) or sons who died in early childhood from hemophilia
or any other cause or who were not affected[6,7]
[6,7].
Acquired hemophilia
This is very rare. The patient develops the condition during
his/her lifetime and it does not have a genetic or heritable
cause. It occurs when the bodyy forms antibodies that attack
one or more blood clotting factors, (usually factor VIII), thus
preventing the blood clotting mechanism from working
properly. Patients may be male or female and the pattern of
bleeding is rather different from that of classical
classi
hemophilia,
the joints being rarely affected. The disorder is particularly
associated with old age and occasionally complicates
pregnancy[8].
Causes Hemophilia[9]
People with hemophilia are born with it. It is caused by a fault
in one of the genes thatt determine how the body makes blood
clotting factor VIII or IX. These genes are located on the X
chromosome.
To understand how hemophilia is inherited, it is important to
learn about chromosomes.
Female (X + Xfaulty) is a carrier, but does not have
hemophilia. The “good” X chromosome allows the production
of enough clotting factor to prevent serious bleeding problems.
Male (Y + Xfaulty) will develop hemophilia and can pass it
on.
If the father has hemophilia and the mother has no faulty gene
(is not a carrier):
Father (Y + Xfaulty). Mother (X + X).
Review Article
What are chromosomes? Chromosomes are blocks of DNA
(deoxyribonucleic
ibonucleic acid). They contain very detailed and
specific instructions that determine:
How the cells in a baby's body develop.
What features the baby will have, including, for example, hair
and eye color.
Whether the baby is male or female.
In humans there are 23 pairs of chromosomes, including the
sex chromosome pair.
There are two types of sex chromosome:
The X chromosome
The Y chromosome
All humans have a pair of sex chromosomes: [10]
Males have an X + Y pair
Females have an X + X pair
NB Females do not have any Y chromosomes.
What chromosomes do we inherit from our parents?
A Male inherits his
X chromosome from his mother
Y chromosome from his father
A Female inherits
One X chromosome from her mother
One X chromosome from her father
She does not inherit
erit both X chromosomes from her mother.
She has no Y chromosomes.
[11,12]How can we calculate the risk of hemophilia in
offspring? x-linked
linked recessive, carrier mother (Before reading
on, remember that the faulty gene is never on the Y
chromosome. If it is present, it will be on the X chromosome.)
There is no risk of inherited hemophilia in their sons because
becaus
boys will inherit their X chromosome from the mother, not the
father (they inherit the father's Y chromosome only, which
does not have the faulty gene).
All the daughters will be carriers but will not develop
hemophilia although they will inherit the father's
fat
X
chromosome, which has the faulty gene. However, their
maternal X chromosome, which does not have the faulty gene,
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Prasant et al. / Indian J. Pharm. Biol. Res., 2014; 2(4):68-76
usually allows the production of enough clotting factor to
prevent serious bleeding problems.
If the father does not have hemophilia and the mother has a
faulty gene:
Father (Y + X). Mother (X + Xfaulty).
There is a 50% chance that sons will develop hemophilia
because: There is a 50% risk that a son will inherit his
mother's Xfaulty chromosome, plus his father's Y
chromosome - he will have hemophilia. There is a 50% chance
he will inherit his mother's "good" X chromosome, plus his
father's Y chromosome - he will not have hemophilia. There is
a 50% chance that daughters will be carriers, (but no chance of
developing hemophilia), because: There is a 50% chance she
will inherit her mother's Xfaulty chromosome, making her a
carrier. There is a 50% chance she will inherit her mother's
"good" X chromosome, which would mean she would not be a
carrier. Approximately one third of patients with hemophilia
have no family history of the disease, either because of new
genetic mutations, or because previous affected generations
either had daughters (who were carriers) or sons who died in
early childhood from hemophilia or any other cause or who
were not affected.
Pathophysiology[13-15]
Factor VIII production, processing, and structure
Primary sites of factor VIII (FVIII) production are thought to
be the liver and the reticuloendothelial system. Liver
transplantation corrects FVIII deficiency in persons with
hemophilia, and persons with mild hemophilia with
progressive liver disease have a rise in FVIII levels, thus
establishing the liver as the major site of FVIII synthesis.
FVIII messenger RNA has been detected in the liver, spleen,
and other tissues.[3] Studies of FVIII production in transfected
cell lines have shown that following synthesis, FVIII moves to
the lumen of the endoplasmic reticulum, where it is bound to
several proteins that regulate secretion, particularly
immunoglobulin binding protein, from which it has to
dissociate in an energy-dependent process.
Cleavage of FVIII's signal peptide and the addition of
oligosaccharides also occur in the endoplasmic reticulum. The
chaperone proteins, calnexin and calreticulin, enhance both
FVIII secretion and degradation.
A part of the factor FVIII protein in the endoplasmic reticulum
is degraded within the cell. The other part enters the Golgi
apparatus, where several changes occur to produce the heavy
and light chains and to modify the carbohydrates. The addition
of sulfates to tyrosine residues of the heavy and light chains is
necessary for full procoagulant activity, with the sulfated
region playing a role in thrombin interaction. This
posttranslational sulfation of tyrosine residues impacts the
procoagulant activity of factor VIII and its interaction with
von Willebrand factor (vWF).
vonWillebrand factor[16]
FVIII circulates in plasma in a noncovalently bound complex
with vWF, which plays significant roles in the function,
production, stabilization, conformation, and immunogenicity
of FVIII.[4] VWF has been termed FVIII-related antigen
(FVIII-R); related terminology for FVIII is FVIII-coagulant
(FVIII-C).
VWF appears to promote assembly of the heavy and light
chains of FVIII and more efficient secretion of FVIII from the
endoplasmic reticulum. It also directs FVIII into the WeibelPalade bodies, which are the intracellular storage sites for
vWF.
In plasma, vWF stabilizes FVIII and protects it from
degradation. In the presence of normal vWF protein, the halflife of FVIII is approximately 12 hours, whereas in the
absence of vWF, the half-life of FVIII-C is reduced to 2
hours.[5, 6, 7]
The clotting cascade
[17]The role of the coagulation system is to produce a stable
fibrin clot at sites of injury. The clotting mechanism has 2
pathways: intrinsic and extrinsic. See the image below.
Coagulation pathway
The intrinsic system is initiated when factor XII is activated
by contact with damaged endothelium.[18] The activation of
factor XII can also initiate the extrinsic pathway, fibrinolysis,
kinin generation, and complement activation.
Review Article
In conjunction with high-molecular-weight kininogen
(HMWK), factor XIIa converts prekallikrein (PK) to kallikrein
and activates factor XI. Activated factor XI, in turn, activates
factor IX in a calcium-dependent reaction. Factor IXa can bind
phospholipids. Then, factor X is activated on the cell surface;
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activation of factor X involves a complex (tenase complex) of
factor IXa, thrombin-activated FVIII, calcium ions, and
phospholipid.
In the extrinsic system, [19]. The conversion of factor X to
factor Xa involves tissue factor (TF), or thromboplastin; factor
VII; and calcium ions. TF is released from the damaged cells
and is thought to be a lipoprotein complex that acts as a cell
surface receptor for factor VII, with its resultant activation. TF
also adsorbs factor X to enhance the reaction between factor
VIIa, factor X, and calcium ions. Factor IXa and factor XII
fragments can also activate factor VII.
In the common pathway, factor Xa (generated through the
intrinsic or extrinsic pathways) forms a prothrombinase
complex with phospholipids, calcium ions, and thrombin-
activated factor Va. The complex cleaves prothrombin into
thrombin andprothrombin fragments 1 and 2.
Thrombin converts fibrinogen into fibrin and activates FVIII,
factor V, and factor XIII. Fibrinopeptides A and B, the results
of the cleavage of peptides A and B by thrombin, cause fibrin
monomers to form and then polymerize into a meshwork of
fibrin; the resultant clot is stabilized by factor XIIIa and the
cross-linking of adjacent fibrin strands.
Because of the complex interactions of the intrinsic and
extrinsic pathways (factor IXa activates factor VII), the
existence of only one in vivo pathway with different
mechanisms of activation has been suggetdSee the image
below.
The hemostatic pathway. APC = activated protein C
The hemostatic pathway. APC = activated protein C (APC);
AT-III = antithrombin III; FDP = fibrin degradation products;
HC-II = heparin cofactor II; HMWK = high-molecular-weight
kininogen; PAI = plasminogen activator inhibitor; sc-uPA =
single-chain urokinase plasminogen activator; tc-uPA = twochain urokinase plasminogen activator; TFPI = tissue factor
pathway inhibitor; tPA = tissue plasminogen activator
[20]FVIII and factor IX circulate in an inactive form. When
activated, these 2 factors cooperate to cleave and activate
factor X, a key enzyme that controls the conversion of
fibrinogen to fibrin. Therefore, the lack of FVIII may
significantly alter clot formation and, as a consequence, result
in clinical bleeding.
Three levels of hemophilia are recognized, according to the
level of clotting factor amounts in the blood. These are often
expressed as percentages of normal:
Above 5% - mild hemophilia
1% to 5% - moderate hemophilia
Less than 1% - severe hemophilia
Hemophilia Symptoms and Diagnosis[21,22]
Hemophilia symptoms vary, depending on the degree of blood
clotting factor (coagulation factor) deficiency and they also
depend on the nature of any injury.
Moderate hemophilia
Those with inherited moderate hemophilia will be noticeable
early on. The child will bruise easily and may also experience
internal bleeding symptoms, especially around the joints, and
after a blow or a fall. Bleeding that occurs inside a joint is
usually referred to as a joint bleed.
Review Article
Mild hemophilia
People with inherited mild hemophilia may not have any
symptoms until an event occurs which wounds the skin or
tissue, such as a dental procedure or surgery, and results in
prolonged bleeding. In societies where male circumcision is
carried out soon after birth, mild hemophilia will be detected
earlier. Joint bleeding is uncommon.
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Symptoms of a joint bleed
Tingling sensation in the joint, Pain in the joint, Irritation in
the joint, If left untreated, the patient may eventually
experience:
More severe pain in the joint, Joint stiffness, The affected area
becomes swollen, tender and hot Joint bleeds most commonly
affect the: Ankles, Knees, Elbows and may less commonly
affect the shoulders, hips or other joints.
Any surgical intervention, circumcision, dental procedure or
injury will result in prolonged bleeding in a person with
hemophilia.
Symptoms are similar to those found in moderate hemophilia,
but occur more frequently and are usually more severe.
A child with severe hemophilia will often bleed for no
apparent reason, often referred to as spontaneous bleeding.
Most commonly, in early childhood from about 18 months of
age, the nose or mouth start to bleed or apparently
spontaneous bruises appear, particularly on the legs. Parents
are sometimes suspected of causing non-accidental injury
(deliberate harm) to their children.
Symptoms
of
hemophilia
type
bleeding
may
include:[23,34,25]
Several large or deep bruises, Joint pain or swelling,
Unexplained bleeding or bruising, Blood in feces (stools),
Blood in urine, Unexplained nosebleeds, Unexplained gum
bleeding, Tightness in the joints
Intracranial hemorrhage (bleeding inside the skull)
About 1 in every 30 patients with hemophilia will have
intracranial hemorrhage at least once during their lives. This
should be treated as a medical emergency. Spontaneous
intracranial hemorrhage is rare and in many cases bleeding
inside the skull will be the result of a blow to the head.
Symptoms of intracranial hemorrhage include:
A bad headache, Vomiting, Confusion, Fitting (Convulsion),
Loss of balance, Slurred speech, or other speaking difficulties,
Stiff neck, Vision problems, Loss of coordination, Some of the
facial muscles do not work (sometimes all of them)
How is hemophilia diagnosed?
Prenatal testing - if a pregnant woman has a history of
hemophilia, a hemophilia gene test can be done during
pregnancy. A sample of placenta is removed from the uterus
and tested. This test is known as a CVS (chorionic villus
sampling) test.
Blood test - if a doctor suspects a child may have hemophilia a
blood test can determine whether the patient has hemophilia A
or B, and how severe it is. Blood tests can be performed from
the time of birth onwards.
Treatment for Hemophilia / Haemophilia[26,27]
Up to a few decades ago a considerable proportion of patients
with hemophilia died prematurely because of hemophilia.
Tragically, many deaths were the result of childhood injury or
Review Article
surgery. Over the last forty years treatment has advanced so
much that the vast majority of patients today are expected to
live long and active lives.
The main breakthrough in treatment occurred when
coagulation factor deficiencies linked to hemophilia could be
identified and then replaced, using products derived from
human blood.
In the past patients used to receive whole blood or plasma
infusions to control episodes of bleeding. Even though this
helped, levels of clotting factors, especially factors VIII and
IX, never reached the levels required for really effective blood
coagulation, nor could these levels be sustained - in other
words, serious bleeding was only partly treated.
Cryoprecipitate, made through the cold precipitation of frozen
plasma from1965 onwards, was the first really effective
treatment for hemophilia A. Freeze-dried concentrates made
from human plasma containing the right levels of Factors VIII
and IX became available in the late 1960s and early 1970s.
Being able to keep the treatment at home and use it as required
meant that patients could travel, leave the home, go to work,
and enjoy a level of independence. However, a large number
of patients subsequently became infected with blood-borne
pathogens, such as hepatitis B, hepatitis C and HIV.
From the mid 1980s rigorous donor selection and viral
inactivation procedures reduced the risk of blood-borne viral
transmission to nearly zero. During the 1990s it became
possible to prepare synthetic (recombinant) factors, using
specially prepared mammalian cells and these recombinant
concentrates are now widely used.
Hemophilia treatment will mainly depend on its severity and
for patients with Hemophilia A or B involves clotting factor
replacement therapy. There are two approaches:
• On demand - giving treatment to stop prolonged
bleeding when it occurs. This is more common in the
management of patients with mild hemophilia.
• Preventative treatment (prophylaxis) - medication to
prevent
bleeding
episodes,
and
subsequent
complications, such as joint and/or muscle damage.
More commonly used for patients with moderate or
severe hemophilia.
Clotting factor concentrates [28]
Clotting factor concentrates can be made in two different
ways:
Plasma-derived clotting factors - prepared from the plasma of
donated human blood.
Recombinant clotting factors - the first generation of
recombinant products use animal products in the culture
medium and had human albumin (a human blood product)
added as a stabiliser. Second generation products use animalderived materials in the culture medium but do not have added
albumin and instead use sucrose or other non-human derived
material as a stabiliser. Third generation clotting factors have
no albumin present at any stage of their preparation. Mouse
monoclonal antibodies have been routinely used in the
purification of coagulation factors for many years but a
recently licensed recombinant factor VIII employs a synthetic
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ligand for this step. [29]This has resulted in the production of
the first factor VIII concentrate to be free of all exogenous
human and animal protein, a goal which was reached for
hemophilia B when the first recombinant factor IX was
licensed in 1997.
Desmopressin (DDAVP)(for mild hemophilia A)[30]
This medication is a synthetic hormone which encourages the
body to produce more of its own Factor VIII. It is unsuitable
for patients with hemophilia B and those with severe
hemophilia A. In patients with milder forms of hemophilia A,
factor VIII replacement therapy may be necessary, especially
for severe bleeds, or after serious injury or major surgery.
RICE (Rest, Ice, Compression, Elevation)[31,32,33]
RICE is a treatment many health care professionals
recommend for joint bleeds. It also reduces swelling and tissue
damage when used together with clotting factor concentrates.
Administering clotting factor concentrates
The medication is injected into a vein - generally in the back
of the hand or at the crook of the elbow. Initial treatments are
usually administered by a doctor or nurse at a hospital or
clinic. Most adults can learn how to do this themselves, which
means they can stop bleeding rapidly and effectively wherever
they are.
If the patient is a child the parents or caregivers
(UK/Ireland/Australia: carers) can learn how to administer
treatment. The majority of very young patients can receive
most of their treatment at home.
If a patient is finding it hard to access a suitable vein, or if
intensive treatment is required, a port-a-cath, or an external
catheter called a Broviac or Hickman line can be placed
surgically into a vein, allowing factor replacement therapies to
be given, and blood to be drawn easily for routine emergency
tests. The use of such catheters can be complicated by
infection and blockage and they have to be used with great
care.
Treating bleeds[34]
Bleeding episodes (bleeds) are an inevitable complication for
patients with hemophilia A and B, even for patients with mild
forms. As the underlying problem is one of prolonged
bleeding, rather than rapid bleeding, they often appear not to
be medical emergencies.
If a person with hemophilia experiences any of the
following he should seek immediate skilled medical
help:[35-37]
There is an injury to the neck, mouth, tongue, face or eye.
There is a severe blow to the head. Bleeding is heavy or
persistent. There is severe pain or swelling in any part of the
body. An open wound requires stitching.
Most other bleeds, such as joint/muscle bleeds, small injuries
and cuts that do not require stitches, and nosebleeds are
generally treated at home, but patients should always seek the
advice of a healthcare professional when in doubt. Any
treatment will be more effective if it is started early.
Review Article
Storing treatment[38,39]
Factor concentrates should usually be stored in a refrigerator
but are stable at room temperature for quite long periods. They
should not be frozen as this may damage the vials or syringes.
Some may be taken out for travel but should ideally be kept in
a cool bag. Read instructions on product storage. If you are
unsure, check with a health care professional or qualified
pharmacist.
Inhibitors[40-44]
Approximately 30% of people with severe hemophilia A
develop antibodies to transfused factor VIII, usually shortly
after their first few treatments. These antibodies (also called
inhibitors) prevent the factor VIIII treatment working
properly. It is often the case that, after a while, the inhibitors
disappear and only about 10% or less of people with severe
hemophilia A will suffer from long term inhibitors. In recent
years it has become possible to prevent inhibitors becoming
persistent through immune tolerance induction therapy. Where
inhibitors do not respond to this approach alternative
treatments are available.
Inhibitors rarely develop in mild hemophilia A or in
hemophilia B of any severity.
Prevention[45-50]
The transmittance of the hemophilia to the next generation can
be prevented by the following methods.
1)Prenatal intrauterine diagnosis with termination of
pregnancy as an option
2)Pre implantation genetic diagnostic testing (PGD)
3)IVF with egg/sperm donation
therapies under investigation
Longer acting factor concentrates[51,52,53]
A longer-acting factor VIII concentrate has recently been
approved by the FDA for clinical trials. The hope is that one
infusion a week rather than three to four infusions a week will
provide prophylaxis against spontaneous bleeding.
A preparation in which recombinant factor IX is fused to a
portion of the immunoglobulin Fc protein shows prolonged
survival and efficacy in animal models.29 Clinical trials are
planned but have not yet been initiated.
Gene therapy
Scientists at The Children's Hospital of Philadelphia
conducted an experimental protocol involving dogs with a
genetic defect predisposing them to develop hemophilia B.
Functional genes capable of producing the clotting Factor IX
were attached to an adeno-associated virus vector and injected
into the leg muscles of the animals. The theory was that the
genetically modified virus would carry the missing gene to
muscle cells, which in turn would take up the gene and begin
producing the clotting factor and releasing it into the blood
stream.
Sustained therapeutic expression of factors VIII and IX has
been achieved in preclinical studies using a wide range of
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gene transfer technologies targeted at different tissues. This
achievement has led to six different phase I/II clinical trials
that resulted in limited efficacy but minimal toxicity.
Recombinant adeno-associated viral vectors appear most
promising for hemophilia gene therapy.
Attempts are being made to learn more about the immunology
of inhibitors and ways to prevent them or improve the success
rate of immune tolerance.
Future[54,55]
Gene therapy, oral delivery of factor concentrates, long acting
infusions, controlled release implants, prolonged release of
other adjuvant therapy drugs are the areas to be concentrated
for making the life of hemophilic patients easier. A schematic
representation is given in the Figure 7.
Conclusion
Hemophilia is a bleeding disorder, very hard to live with. As
the number of patients reported with hemophilia is
comparatively less than other major diseases like cancer,
cardiac diseases, and diabetics it seems to be less concentrated
area by researchers. As technologies develop, the days are not
far away when hemophilia is treated with ease and even
complete cure possible.
Conflict of interest statement
We declare that we have no conflict of interest.
Acknowledgement
I would like to acknowledge the people who mean world to
me, my parents, & my sister. I extend my respect to my
parents and all elders to me in the family. I don’t imagine a
life without their love and blessings. Thank you mom, dad, for
showing faith in me and giving me liberty to choose what I
desired. I consider myself the luckiest in the world to have
such a supportive family, standing behind me with their love
and support.
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Cite this article as: Jiguru Prasant.Recent trends and advances in hemophilia – its management and new therapeutic outcomes.
Indian J. Pharm. Biol. Res.2014; 2(4):68-76.
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