1.

The rare, recessive x-linked condition hemophilia impairs the body's coagulation
cascade. coagulation factor VIII (FVIII) or IX (FIX) deficiency or absence,
respectively. Bleeding (either spontaneously or as a result of trauma) into the main
joints, such as the ankles, knees, and elbows, which can lead to the development of
arthropathy, is the hallmark clinical characteristic, especially in untreated severe
forms. Bleeding into internal organs and intracranial bleeding can be fatal. Until the
1960s, the average life expectancy was 30 years, but with better knowledge of the
disorder and the development of effective therapy based on prophylactic replacement
of the missing factor, a paradigm shift has occurred, and today people with hemophilia
can anticipate a nearly normal life expectancy and quality of life. possible creation of
antagonistic antibodies to injected factor is still a very difficult obstacle for a sizable
majority of patients.

2. Although this disease is rare, its impact can be overestimated due to a lack of
records, the ignorance of many doctors, the difficulty of the laboratory diagnosis, and,
ultimately, the fulminant clinical presentation that frequently makes a diagnosis
impossible.Patients with hemophilia have protracted bleeding or oozing after an
injury, surgery, or tooth extraction. Continuous bleeding happens after minimal
trauma or even when there is no evident injury in severe hemophilia sufferers.

TYPES

Hemophilia A, also known as classic hemophilia or factor VIII deficiency, and

hemophilia B, also known as Christmas disease or factor IX deficiency, are the two
main kinds of this illness. The two varieties, despite having very similar signs and
symptoms, are brought on by gene abnormalities in two separate places. Hemophilia B
Leyden is a rare variant of the blood disorder that causes severe bleeding episodes in
childhood but little difficulties with bleeding after puberty.

HEMOPHILIA A

6. brought on by flaws in the gene that makes coagulation factor VIII, the F8C. There
are roughly

1:5000 males. On the basis of a normal prothrombin time, a changed activated partial
thromboplastin time, and decreased factor VIlI activity in plasma, hemophilia A is
identified. Female carriers are typically asymptomatic and can only be detected by
molecular analysis. In families lacking intron 22 or 1 inversions, molecular
identification of carrier status and prenatal diagnosis is based on scanning methods or
gene sequencing.
The molecular diagnosis is carried out by linkage analysis of numerous DNA
polymorphic markers associated to F8C, despite the fact that the sequence generating
the mutation cannot be detected.

PATHOGENESIS
3. Variants in the F8 and F9 genes cause hemophilia A and hemophilia B,
respectively.
A protein known as coagulation factor VIII is produced using instructions from the F8
gene. The F9 gene results in the production of coagulation factor IX, a similar protein.
Proteins called coagulation factors collaborate to help blood clot. Blood clots shield
the body against excessive bleeding after an injury by closing off damaged blood
vessels.Coagulation factor VIlI or coagulation factor IX are produced in an abnormal
manner or are produced in less quantity as a result of mutations in the F8 or F9 gene.

The blood clotting process cannot be successfully participated in by the changed or

absent protein. Blood clots cannot adequately develop in response to damage as a
result. Continuous bleeding that can be challenging to control results from these issues
with blood coagulation. The coagulation factor VIII or coagulation factor IX activity
is almost entirely eliminated by the variations that result in severe hemophilia. One of
these proteins' activity is decreased but not entirely eliminated by the variations linked
to mild and moderate hemophilia.

ACQUIRED HEMOPHILIA

This uncommon illness, which typically starts in maturity, is characterized by

abnormal bleeding into the skin, muscles, or other soft tissues. When the body
produces specialized proteins called autoantibodies that assault and render coagulation
factor VIII inoperable, acquired hemophilia is the result.
5. Although various circumstances, including pregnancy, allergic reactions,
autoimmune disorders, cancer, and puerperium seem prone to cause AH,
autoantibodies to FVIlI are idiopathic in more than half of the documented
instances.Subcutaneous bleeding that are spontaneous or caused by trauma, as well as
significant mucosal membrane hemorrhages (from the genitourinary and
gastrointestinal systems), characterize the clinical presentation.

4. Quick, correct diagnosis, bleeding control, and immunosuppression are the main
components of this disorder's management.Steroids alone or in conjunction with
cyclophosphamide are used to suppress the immune system, which may increase the
likelihood of remission.

7.Approximately 50% of people with diagnoses were previously healthy, while the
remaining cases may be brought on by pregnancy, autoimmune disorders, cancer,
infections, or drugs. when normal plasma is added, lower FVIlI, and Bethesda assay
(Nimegen modification)-measured evidence of FVIll inhibitor are present but the time
does not return to normal.

8. Immunoadsorption, immunosuppression, or immunological tolerance induction

(ITI) are techniques for eliminating antibodies.Activated prothrombin complex
concentrate (aPCC, FEIBA®), NovoSeven®, recombinant activated factor VIla
(rFVlla), antifibrinolytics, 1-deamino-8-D-arginine vasopressin (DDAVP), and FVIII
concentrates are some of the bypassing agents used to treat acute bleeding episodes in
patients with high titer inhibitors. When used alone or in combination, the anti-CD20
monoclonal antibody rituximab has demonstrated excellent outcomes.
HISTORY
9. Factor IX was earlier identified by Macfarlane and Rosemary Biggs as the factor
lacking in hemophilia B in 1952. The unique roles of Factor VIll and von Willebrand
factor in haemophilia A and von Willebrand's disease, respectively, were identified by
Arthur Bloom in 1973. the Nathwani group at UCL conducted the first effective trial
of gene therapy for hemophilia B in 2011.

CLINICAL PICTURE
20. It may be fatal to bleed into the central nervous system. Such bleeding is typically
only present in severe hemophiliacs, however it can also be present in both moderate
and mild hemophilia.Depending on the circumstances, bleeding may happen inside or
outside of the skull, intracranially, or into the spinal cord.Even though an injury may
seem slight, individuals are more likely to experience cerebral bleeding without an
injury—nearly 50% of cases. Bleeding into the spinal column is frequently
accompanied with headache, nausea, vomiting, and seizures.Joint bleeding increases
the likelihood that the joint will bleed in the future and causes gradual stiffness. The
target joint is the one that is now most prone to bleeding again. The knee, elbow,
ankle, shoulder, and wrist are the body parts that are most frequently affected by the
disease.

EXPRESSION AND TRANSMISSION

19. Males and females with one normal gene and two normal genes for Factor VIII,
respectively, are free of the hemophilia A phenotype and will not pass this disease to
their progeny.Males with hemophilia are affected by one defective gene, which they
pass on to all of their daughters but not to any of their sons. Asymptomatic carriers of
the faulty gene, females who have one normal and one aberrant gene pass it on to
roughly half of their sons and daughters.

18. This issue is typically sex-linked in that it is nearly exclusively expressed in males
but is only passed on by females.It is commonly known that several European royal
dynasties, particularly those descended from Great Britain's Queen Victoria, have
hemophilia.

IMPACT

16.Worldwide, hemophilia affects patients. According to a global report by the World

Federation of Hemophilia, low- and lower-middle-income nations account for 67% of
cases. The study also discovered that hemophilia can have a detrimental effect on
employment, with 12% of patients indicating that their condition caused them to work
part-time, take more time off, or lose their jobs.Most hemophiliacs feel pain, bleeding
episodes, and mobility issues.

DIAGNOSIS

15.Preimplantation genetic diagnosis (PGD) aims to broaden the range of options

available to couples who might be carrying a haemophiliac child and lessen the stress
these couples frequently experience during pregnancy. The female partner is required
to go through an in vitro fertilization cycle, after which the ovaries or uteruses are
biopsied. The uterus can then receive embrvos that are untouched by hemophilia. The
lady can avoid traditional invasive prenatal diagnostics and the challenging decision
of whether or not to terminate an affected pregnancy by using this method, which has
the obvious advantage of letting her know from the start that the fetus is not affected
by hemophilia. There are several methods for making this single cell genetic
diagnostic.These include sequencing, haplotype analysis, restriction enzyme-specific
diagnostics, fluorescence in situ hybridization, polymerase chain reaction (PCR), and
embryonic sexing.

CHALLENGES

12. Patients with hemophilia experience many changes throughout their lives, but the
transition from adolescence to adulthood is particularly difficult. The patient must
adjust his lifestyle to the demands of his condition throughout this transitional period
from paediatric to adult services, while also coping with all of the regular biological,
social, and emotional changes related to this stage of life. The interdisciplinary
approach, early planning, patient education, and adequate follow-up are crucial
components of the plan.

MANAGEMENT AND PROPHYLAXIS

10. Prophylactic treatment is superior than on-demand treatment, although being
significantly more expensive, independent of the number of joint- or life-threatening
bleeding or arthropathy, Early intervention is ideal for preventative treatment (primary
prophylaxis). Secondary prophylaxis that is initiated later in childhood or in adulthood
is advantageous but less economical.
11. In some cases, long-term prophylaxis is used when there is a significant family
history of bleeding. Pregnancy or some procedures can both benefit from brief
prophylactic intervals. The risks of side effects must be weighed against the
advantages of prophylaxis.

17. Engaging in physical activity while avoiding behaviors that could injure one.These
sports include skiing, motocross, rugby, soccer, and wrestling.getting dental work
done as part of particular care before surgery. The doctor for your child might suggest
factor replacement infusions. Before the procedures, these cause the child's clotting
levels to increase. using good oral care to prevent tooth and gum issues Immunizations
should be administered topically rather than intramuscularly to prevent muscle
hemorrhage.avoiding aspirin and other NSAIDs (nonsteroidal anti-inflammatory
medicines).medical identification should be worn in case of urgent situations.

TREATMENT

13.The most significant side effect of factor VIII (FVIII) replacement therapy in
patients with severe hemophilia A is the development of anti-drug antibodies. The
term "FVIlI inhibitor" refers to a considerable number of these antibodies that have
neutralizing action against FVIll.

Given the lack of endogenous circulating FVIII protein, alloimmunity to FVIII may be
somewhat anticipated; yet, only 30% of patients develop inhibitors. There are known
environmental and genetic risk factors that raise the possibility of inhibitor
development.

14. The accelerated launch of innovative therapies for the treatment of hemophilia is a
result of recombinant DNA technology. Recombinant clotting factors, clotting factors
with prolonged half-lives, alternative biologics to support hemostasis, and the advent
of gene therapy for hemophilia have all been made possible by this technology. The
ability to study the structure and function of natural molecules and apply logical
bioengineering to circumvent limits of current therapies is the basis of this technology.