Int. J. Pharm. Sci. Rev. Res., 26(1), May – Jun 2014; Article No.

47, Pages: 277-283 ISSN 0976 – 044X

Review Article

Hemophilia and Its Treatment: Brief Review

1* 2
Nikisha G. N. , Menezes G. A.
1 2
CRRI, Scientist, Sree Balaji Medical College & Hospital (Bharath University), Chromepet, Chennai, Tamil Nadu, India.
*Corresponding author’s E-mail: [email protected]

Accepted on: 18-03-2014; Finalized on: 30-04-2014.

ABSTRACT
Hemophilia is a genetic bleeding disorder. Hemophilia A or B is treated by recombinant clotting factor VIII or factor IX and
immunosuppressives to prevent formation of alloantibodies and inhibitors. Formation of inhibitors to these factors poses a
challenge in treating hemophila. Plasma derived activated prothrombin complex concentrate and activated recombinant factor VII
are used to treat patients with inhibitors. Treatment also varies with situations such as, pregnancy, surgery, and malignancy, as
these trigger increased risk of bleeding. This review illustrates the various etiologies of hemophilia, methods of diagnosis, newer
treatment options available for hemophilia, treatment in special circumstances and the future of hemophilia treatment. In the
present times, long lasting and permanent cure for hemophilia is not available. Replacement by factors provides a temporary cure
for hemophilia. Permanent cure may lie in the direction of gene therapy or stem cell therapy which is under development. Few
successes are achieved by gene therapy in previous studies providing cure lasting for many months without need for recombinant
factor replacement. Further modifications of therapy are required to achieve long lasting and permanent cure for hemophilia.
Keywords: Hemophilia, Bleeding disorders, Treatment of Hemophilia.

INTRODUCTION CAUSES OF HEMOPHILIA

H emophilia derived from the Greek haima (Blood)

and philia (Love), is a genetic bleeding disorder
caused by the deficiency of clotting factor-VIII
(Hemophilia-A) or factor-IX (Hemophilia-B) or factor-XI
(Hemophilia-C). Hemophilia A (also known as classic
When there is injury to the blood vessel, the platelets are
activated at the site of injury which leads to activation of
the clotting factors and formation of fibrin blood clot by
the ‘Intrinsic pathway’ of coagulation. Factor VIII and
factor IX are required to activate factor X which in turn
hemophilia) and B (also known as Christmas disease) are activates prothrombin activator which converts
X-linked recessive trait with defective F8 and F9 genes in prothrombin to thrombin. Thrombin helps in conversion
long arm of X chromosome with incidence of one in 5,000 of fibrinogen to fibrin which traps the platelets and forms
and one in 30,000 males respectively while Hemophilia C clot. Factor XI is needed to activate factor IX.5
(also known as plasma thromboplastin antecedent (PTA)
The factors VIII, IX or XI are genetically transferred to the
deficiency or Rosenthal syndrome) has autosomal
offspring through X chromosome (F8 and F9) and
recessive inheritance with defective gene in chromosome
chromosome 4 (F11). Any defect in these genes causes
4 and has incidence of one in 1,00,000 males and is more
absence or reduced production of these factors.
common in Jews of Ashkenazi.
Sometimes antibodies labeled as ‘inhibitors’ to these
Hemophilia can also be acquired due to the development factors may develop. Inhibitors may develop as a
of autoantibodies directed against the clotting factors. response to therapy with the clotting factors in
Acquired hemophilia is very rare with incidence of one in hemophiliacs or idiopathically in normal subjects without
1 million persons.1-3 any genetic defect. In these patients, even after therapy
with clotting factor, activated partial thromboplastin time
In Hemophilia there is internal or external bleeding which
(aPTT) and prothrombin time (PT) are prolonged.6 Various
may be spontaneous or with trivial trauma. It can lead to
mechanisms are suggested in the genesis of genetic
complications like chronic anaemia, haemarthrosis,
defect or inhibitor formation.
intracranial hemorrhage and compartment syndrome.
Early diagnosis and management is required to prevent 1. F8 gene mutation
4
the development of these complications. The
Hemophilia A is caused by mutations in the F8 gene. In
management varies in special situations such as,
hemophilia A, there are large DNA mutations like intron
pregnancy, major surgeries, and malignancy. This review
22 and intron 1 inversion and many small mutations like
aims in presenting the current advances in diagnosis and
missense mutations, nonsense mutations and frameshift
treatment of hemophilia and the recent
mutations.7 Factor 8 consists of 2332 amino acids and has
recommendations in the management of special
domains A1, A2, A3, B, C1, and C2. Severity of the disease
conditions or procedures in hemophiliacs.
is correlated with the type of mutation in these domains.8
According to Ryan et al, a point mutation causing amino
acid substitution N1922S in A3 domain of F8 gene leads to
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Int. J. Pharm. Sci. Rev. Res., 26(1), May – Jun 2014; Article No. 47, Pages: 277-283 ISSN 0976 – 044X
19
defective folding of A3 which ultimately stops the towards a diagnosis of hemophilia. Bleeding can be
production of factor VIII.9 There may also be Arg2150His spontaneous in severe cases or only as a response to
substitution in C1 domain of factor 8 which results in trauma in mild cases and these are correlated with the
reduced binding of factor 8 to Von Willebrand factor laboratory tests.
10
which leads to reduced stability of factor VIII.
b. Lab diagnosis
2. Lack of f8 mRNA
Hemophilia can be diagnosed by coagulation factor assays
In some hemophiliacs no defects were found in DNA. or activated partial thromboplastin time. Bleeding time,
There is defective mRNA or lack of mRNA in some of them prothrombin time and thrombin time are normal in
which prevents the relay of message.11-13 In these Hemophilia. Bleeding time is not affected as it shows only
patients, RT-PCR did not give any mRNA corresponding platelet function. Prothrombin time is not affected as it
product which is specific for factor 8. This can be due to depends only on extrinsic pathway of coagulation and
swift degradation of mRNA due to an unidentifiable factors I, II, V, VII and X. Thrombin time is normal
14
mutation in f8 intron. because it depends on fibrinogen.
3. F8 inhibitors Activated partial thromboplastin time
Inhibitor to factor VIII develops as a complication to This measures the integrity of intrinsic pathway and
20
therapy of hemophilia A, mostly in patients with deletion common pathway. In Hemophilia, there is prolongation
or nonsense mutation in F8 gene. Alloantibodies develop of aPTT. As factors VIII, IX and XI are part of intrinsic
against the replaced factor VIII and bind to A2 and C2 pathway of coagulation along with other factors, aPTT is
domain of F8 and inactivate F8 completely.6 The prolonged in all 3 types of Hemophilia.21
incidence of inhibitor development is directly
Coagulation factors F8/F9 assays
proportional to age of the individual. This may be due to
decline of immune regulation function in old age.15 The type of hemophilia and degree of factor activity can
According to Viel et al, mismatched factor VIII be assessed by factor assay. The normal value of factor
replacement by giving H1 and H2 types of factor VIII VIII is 50-150% and factor IX is 50-150%.22 In hemophilia
(present in white population) to black population in these values are reduced. Knowledge of the exact amount
whom H3, H4 and H5 are present increases the incidence of activity of clotting factors help in grading the severity
of developing alloantibodies to factor VIII in black of the disease and its precise management.19
population.16 These patients don’t respond or respond
Thrombin generation assay
poorly to therapy.
This measures the ability of blood to form thrombin. This
In Acquired Hemophilia, autoantibodies mostly of IgG
is valuable in assessing the response to therapy in
class are present against factor VIII in subjects who have
hemophiliacs with inhibitors as the conventional
normal factor VIII gene. It can be idiopathic or can
coagulation profiles are not useful in them.23 It shows the
accompany other conditions like autoimmune diseases,
overall assessment of hemostasis while aPTT shows only
cancer and drug ingestion.17 They bind to A2, A3 or C2
the time taken to form a clot.24 Thrombin generation (TG)
domain of factor VIII and inactivate factor VIII
maximum peak and lag-phase time are used to find the
incompletely.6 This results in reduced function of factor
severity of hemophilia.25,26 Severity determined by
VIII and increased aPTT even after therapy.
conventional methods show discrepancies as many
4. Defect in tissue factor pathway severe hemophiliacs may not have severe symptoms and
bleeding.27 This is because other pro-thrombotic factors
Tissue factor (TF) can initiate an alternate pathway of
play a role in bleeding in hemophiliacs which can be
coagulation in the absence of factor VIII, IX or XI by 28
detected by TG assay.
forming TF-factor VII complex. This becomes TF-Factor
VIIa complex which activates factor X to Xa. Absence of Thromboelastography
factors VIII, IX or XI is more significant when there is
The integrity of coagulation can be assessed by
deficient TF concentration.1,18
thromboelastography. R-time and K-time shows the
DIAGNOSIS OF HEMOPHILIA integrity of clotting factors.29 R- time shows the time
taken for onset of clotting. PT and aPTT show the integrity
Diagnosis of hemophilia is made on the basis of clinical
of coagulation till this point only. K time is the time taken
suspicion and laboratory tests. Mutation in a particular
from end of R until the clot reaches 20mm and it shows
gene may be detected which helps in development of
the speed of clot formation.30 This helps in monitoring of
newer modalities of treatment like gene therapy.
patients on therapy.
a. Clinical diagnosis
Thrombodynamics test
Clinical conditions, such as hemarthrosis, intracranial
It is also called spatial clot growth assay.31 It has clotting
bleeding, excessive bleeding in trivial trauma, prolonged
phase and elongation phase which can be activated by
bleeding after surgery and menorrhagia point strongly
intrinsic or extrinsic pathway. In hemophilia, clotting
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Int. J. Pharm. Sci. Rev. Res., 26(1), May – Jun 2014; Article No. 47, Pages: 277-283 ISSN 0976 – 044X
41
phase (initiation phase) when activated by intrinsic of embryo. Cell sample is lysed and PCR is done
pathway is delayed whereas activation by extrinsic followed by direct genotyping and mutation analysis.
pathway is normal. Elongation phase (which indicates clot
4. Chorionic villus sampling
thickening) and rate of clot growth are poorer. Thin
friable clots are formed which results in bleeding. These It is the most common method of prenatal diagnosis. It is
th 40
friable clots are formed because of weak positive done between 11 and 14 week of gestation. Chorionic
feedback mechanism involving thrombin.32 villus is taken through transcervical or transabdominal
route under direct ultrasound guidance and indirect or
c. Genetic diagnosis
direct mutation analysis or linkage analysis is done to
Genetic testing helps in confirmation of diagnosis and diagnose affected foetus.39
identification of carriers. This can increase the index of
5. Non invasive tests-digital PCR
suspicion and aid in early prenatal diagnosis of fetuses
which is crucial in management during delivery.33 Invasive tests always carry a risk of foetal loss. To prevent
that, non invasive tests are done by analyzing foetal DNA
Carrier detection 42,43
circulating in maternal plasma. Cell free foetal DNA
This is imperative in genetic counseling and in vigilant present in maternal plasma has amplified Y chromosomes
care of pregnant mother and possibly hemophilic child. (Y-PCR) which can be tested.37 Digital PCR known as
Hemophilia A carrier women have wide variation in levels relative mutation dosage approach can be used for the
of FVIII and rarely may show mild bleeding tendencies.19 detection of hemophilia.44,37
This is because of X-inactivation in women during
Genetic diagnosis in adults
embryonic life.34 Hemophilia carrier women are at risk for
post partum hemorrhage and hemophiliac child is at risk In adults with clinical signs and symptoms of bleeding
of intracranial hemorrhage. Inverse PCR (I-PCR) or inverse disorder, genetic testing is done to confirm genetic or
shifting PCR (IS-PCR) can be used to detect intron 1 and other etiology of hemophilia and its appropriate
intron 22 inversions.35,36 management. It can be done through many methods like
direct mutation detection, targeted mutation analysis or
Prenatal diagnosis
inverse PCR.19,45
Prenatal diagnosis of fetuses with hemophilia is crucial
MANAGEMENT OF HEMOPHILIA
during management of labour. It is done by assessing
chorionic villous sampling at 11-14 weeks of gestation or Initially in early 1960’s concentrates of antihemophilic
amniocentesis after 15 weeks of gestation or globulin46 and glycene precipitated factor VIII were used in
cordocentesis after 20 weeks of gestation.37 This is the treatment of hemophilia.47 Then in 1970’s and 80’s
beneficial in fetuses with a strong family history of plasma derived products and cryoprecipitate were used
moderate to severe hemophilia. In early 1980s to treat hemophilia.48 But this increased the incidence of
hemophilia was prenatally diagnosed mainly by HIV and Hepatitis A and B in hemophiliacs and increased
immunoradiometry, factor VIII:CAg and factor VIIIR:Ag the development of antibodies to factors VIII and IX.49-51
assays.38 By the beginning of 1990, recombinant- DNA derived
antihemophilic factors were used to treat hemophilia.52,53
1. Amniocentesis
Following that desmopressin and immunosuppressive
This is done between 15 to 18th week of gestation. Under therapy were used.54,55 Activated prothrombin complex
ultrasound guidance, through maternal abdominal wall, a concentrate was used to treat patients with inhibitors.56
needle is inserted into the amniotic sac and amniotic fluid In patients with liver cirrhosis or hepatitis due to
containing amniocytes (Foetal cells) is obtained. Direct transfusion, liver transplantation was done which
mutation detection or linkage analysis is used to find provided good results and cured factor VIII and factor IX
39 57-59
affected fetuses. deficiencies.
2. Cordocentesis ADVANCES IN MANAGEMENT
It is also called percutaneous umbilical blood sampling. In recent times, many advances are made in the
This is done if the results of other tests are uncertain. treatment of hemophilia. They include modification of
Umbilical cord blood is taken using ultrasound guided time old therapy or breakthrough of new drugs.
needle and factors VIII and IX in fetal blood are
a. Immunosuppressives
measured.40
Steroids alone or steroids with cyclophosphamide or
3. Preimplantation genetic diagnosis
rituximab or cyclosporine are used as first line therapy.
In this, in-vitro fertilization is done and affected male People who did not have complete remission with first
embryos are identified and only healthy embryos are line are given second line therapy with steroids,
returned to uterus. It is done by linkage analysis to detect cytotoxics and rituximab. According to Collins et al, first
F8 intron 22 inversion in blastomeres obtained by biopsy line therapy with combination of steroids and
60
cyclophosphamide gives a stable remission.
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Int. J. Pharm. Sci. Rev. Res., 26(1), May – Jun 2014; Article No. 47, Pages: 277-283 ISSN 0976 – 044X

b. Gene therapy frozen plasma are given to affected children. If

intracranial bleed is suspected, factor should be given
Gene therapy may provide complete lifelong cure for
immediately before confirming the diagnosis by cranial
hemophilia. Gene therapy for hemophilia B using adeno- 73
ultrasound or CT or MRI scan.
associated viral vector shows promising results in some
studies. It provides remission temporarily and further c. Management in acute hemarthrosis
studies are required to achieve permanent cure.61,62
In acute hemarthrosis, there is bleeding into the joint
There are some limiting factors to its use like humoral and
which results in rapid joint swelling, pain and reduced
cellular immune response, toxicity and safety issues
movements. Radiological confirmation is not indicated
which must be rectified in future.63 There is development
routinely. Therapy with recombinant factors VIII or IX is
of antibodies to recombinant proteins in hemophilia A.
the first line of treatment. It is followed by resting the
This can be prevented by giving adenoviral vector
joint, applying ice, compression bandage, leg elevation
expressing factor VIII to neonates as their immune system
64 and physiotherapy.74,75 In profuse hemarthrosis,
is immature.
arthrocentesis is done after complete correction of factor
c. Therapy under development deficit.74 In case of repeated hemarthrosis, synovectomy
or angiographic embolization is done.76
Many new treatment options are tried in the recent
times. Bone marrow transplantation and hematopoietic d. Management in minor/major surgical procedures
stem cell transplantation are being tried in mice.65,66 In
Hemorrhage is a common complication during surgery
vitro studies are done using solulin to increase clot
and postoperatively increasing the mortality and
stability in whole blood.67 Further studies are required to
morbidity. During surgical procedures in hemophiliacs,
achieve long lasting and permanent cure for hemophilia.
activated recombinant factor VII (rFVIIa) is used to
MANAGEMENT IN SPECIAL SITUATIONS achieve hemostasis.77,78 In major cardiac surgeries, rFVIIa
is used customarily during surgery and postoperatively.79
Management of hemophilia is challenging in special
Desmopressin is used prophylactically in open heart
situations like pregnancy, newborn, and surgeries. They
surgery patients with hemophilia.80
require special attention and a need to watch for and
prevent undue hemorrhage and complications. e. Management in malignancy
a. Management in pregnancy Cancer in hemophiliacs should be treated in same way as
non hemophiliacs. But the risk of bleeding is higher due to
Management in carriers of hemophilia during pregnancy
therapy induced thrombocytopenia. Replacement
requires prenatal diagnosis of hemophilia by chorionic
therapy should be given as continuous prophylaxis during
villous sampling or amniocentesis or cordocentesis and
chemotherapy and radiotherapy when accompanied by
careful watch for post partum hemorrhage (PPH).37
thrombocytopenia. If cancer surgery is done, low
According to study by Kadir et al 48% of hemophilia
molecular weight heparin should be given postoperatively
carriers had primary PPH. Pregnancy in carriers should be
to prevent thrombosis.81
managed by multidisciplinary approach in a tertiary care
center.68 In case of PPH, fibrinogen supplementation in f. Management in patients with inhibitors
the form of fresh frozen plasma, cryoprecipitate or
Development of inhibitors is a complication of treatment
fibrinogen concentrate or antifibrinolytic agents like
of hemophilia with replacement therapy. It is because of
tranexamic acid or recombinant activated factor VII can
the formation of alloantibodies to factor VIII. This reduces
be given.69
the efficacy of therapy by recombinant factors VIII or IX.82
In neonates born of carriers, there is increased risk of Patients with inhibitors need a bypassing agent to control
70
intracranial or extracranial hemorrhage during delivery. bleeding. Plasma derived activated prothrombin complex
This can be prevented by prenatal diagnosis of affected concentrate and activated recombinant factor VII are
83
foetus and carrier and taking proper precautions. The used as bypassing agent to aid in hemostasis.
best possible mode of delivery is under debate. According
CONCLUSION
to James et al, the optimal mode of delivery is planned
caesarian delivery before labor and this will reduce 85% In conclusion, early diagnosis of hemophilia and early
risk of intracranial hemorrhage.71 According to Ljung et al, management helps in improving the quality of living of
planned vaginal delivery without use of instruments like the patient and prevents early development of
vacuum or forceps is the optimal mode of delivery in complications. Replacement of factors provides effective
hemophilia carriers.72 Mode of delivery should be decided control of hemophilia for short term. Newer research
based on maternal and fetal factors and individualized. based options are required to provide long lasting and
complete cure for hemophilia which may be possible by
b. Management in neonate
gene therapy in the near future.
If hemophilia is suspected in neonate, it should be
diagnosed and confirmed by analysis of cord blood.
Recombinant factor VIII or factor IX concentrates or fresh
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Int. J. Pharm. Sci. Rev. Res., 26(1), May – Jun 2014; Article No. 47, Pages: 277-283 ISSN 0976 – 044X

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Source of Support: Nil, Conflict of Interest: None.

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