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Hemophilia A Genetic Disorder: Diagnosis, Treatment And Prognosis

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Abstract

Hemophilia a genetic disorder with patient's inability to stop bleeding. There are two main types of hemophilia, hemophiliaA due to not enough clotting factor VIII and hemophilia B due to not enough factor IX,and acquired hemophilia A(AHA) caused by autoantibodies against clotting factor VIII(FVIII).AHA is associated with malignancy,autoimmune disorders, and pregnancy. Factor IX deficiency can cause interference of the coagulation cascade. People with more severe hemophilia usually suffer more severe and more bleeds than people with mild hemophilia. Complications of hemophilia include deep internal bleeding, joint damage, transfusion induced infection, adverse reactions to clotting factor treatment, and intracranial hemorrhage. Diagnosis of hemophilia can be confirmed by, coagulation screening test, bleeding scores and coagulation factor assay. Gold standard of treatment is rapid treatment of bleeding episodes decreases damage to the body.Prophylactic treatment although high costs, is more effective than on demand treatment. People with severe hemophilia without adequate treatment have generally shortened lifespans. Gene therapy is not currently an accepted treatment for hemophilia.
IOSR Journal of Dental and Medical Sciences (IOSR-JDMS)
e-ISSN: 2279-0853, p-ISSN: 2279-0861.Volume 15, Issue 10 Ver. VIII (October. 2016), PP 85-89
www.iosrjournals.org
DOI: 10.9790/0853-1510038589 www.iosrjournals.org 85 | Page
Hemophilia A Genetic Disorder: Diagnosis, Treatment And
Prognosis
MurtazaMustafa1,AY.Moktar2,H.Firdaus3,EL.IIIzam4, A.Nornazirah5,
AM.Sharifa6
1,3,5,Faculty Of Medicine And Health Sciences, University Malaysia Sabah,Kotakinabalu,Sabah,Malaysia.
2. ResearchAnd Publication Group FMHS,University Malaysia Sabah,Kotakinabalu,Sabah,Malysia.
4.Clinic Family Planning Association,Kotakinabalu,Sabah,Malaysia.
6.Qualityunit,Hospital Queen Elizabeth,Kota Kinabalu,Sabah,Malaysia.
Abstract:Hemophilia a genetic disorder with patient’s inability to stop bleeding. There are two main types of
hemophilia, hemophiliaA due to not enough clotting factor VIII and hemophilia B due to not enough factor
IX,and acquired hemophilia A(AHA) caused by autoantibodies against clotting factor VIII(FVIII).AHA is
associated with malignancy,autoimmune disorders, and pregnancy. Factor IX deficiency can cause interference
of the coagulation cascade. People with more severe hemophilia usually suffer more severe and more bleeds
than people with mild hemophilia. Complications of hemophilia include deep internal bleeding, joint damage,
transfusion induced infection, adverse reactions to clotting factor treatment, and intracranial hemorrhage.
Diagnosis of hemophilia can be confirmed by, coagulation screening test, bleeding scores and coagulation
factor assay. Gold standard of treatment is rapid treatment of bleeding episodes decreases damage to the
body.Prophylactic treatment although high costs, is more effective than on demand treatment. People with
severe hemophilia without adequate treatment have generally shortened lifespans. Gene therapy is not currently
an accepted treatment for hemophilia.
Keywords:Bleeding,Diagnosis,Factor VIII&F IX,Hemophlia,Treatment.
I. Introduction
Hemophilia the word is from the Greek haima meaning blood and philia meaning love[1]. Hemophilia
is a mostly inherited, genetic disorder that impairs body’s ability to make blood clots, a process needed to stop
bleeding[2].Hemophilia is rare, with only about 1 instance in every 10,000 births(or 1 in 5000 male births)for
hemophilia and 1 in 50,000 births for hemophilia B[3].About 18,000 people in the United States have
hemophilia. Each year in the U.S.400 babies are born with the disorder. Hemophilia usually occurs in males and
less often in females[4].It estimated that about 2,500 Canadians have hemophilia A and about 500 Canadians
have hemophilia B[5].In the 1800s hemophilia was common within the royal families of Europe[6]About 45
people in Sabah, Malaysia, and about 1000 people in West Malaysia have hemophilia [7].There are two main
types of hemophilia, hemophilia A due to not enough clotting factor VIII and hemophilia B due to not enough
factor IX[8].They are typically due to inheriting from one’s parents an X chromosomes with nonfunctional
gene[9].Other types include hemophilia C due to not enough factor XI and parahaemophilia due to nor enough
factor V [10].Acquired hemophilia A(AHA) is a rare bleeding disorder caused by autoantibodies against clotting
factor VIII (FVIII)[11].Acquired hemophilia is associated with cancers, autoimmune disorders, and
pregnancy[12].Clinical symptoms include bleeding longer after injury, easy bruising, and increased risk of
bleeding inside joints or brain. Bleeding into a joint can result in permanent damage while bleeding in the brain
can result in long term headaches,seizures, or a decreased level of unconsciousness[13].Diagnosis is by testing
the blood for its ability to clot and its levels of clotting factors [14].Treatment is by replacing the missing blood
clot factors. Prevention may occur by removing a woman’s egg fertilizing it, and testing the embryo before
putting it backs it in the uterus [14].The paper summarizes the current literature, diagnosis, treatment and
outcome of hemophilia.
II. History and Discovery Of Hemophilia
The first medical professional to describe the disease was Abulcasis.In the tenth century he described
families whose males died of bleeding after only minor traumas[15].In 1803,John Conrad 0tto,a Philadelphian
physician, wrote an account about “hemorrhagic disposition existing in certain families”in which he called the
affected males”bleeders”[16].He recognized that the disorder was hereditary and it affected mostly males and
was passed down by health females. His paper was the second paper to describe important characteristics of an
X-linked genetic disorder (the first paper being a description of color blindness by John Dalton who studied his
own family).0tto was able to trace the disease back to a women who settled near Plymouth, NH in 1720.The
Hemophilia A Genetic Disorder: Diagnosis, Treatment And Prognosis
DOI: 10.9790/0853-1510038589 www.iosrjournals.org 86 | Page
idea that affected males could pass the trait onto their unaffected daughters was not described until 1813 when
John F Hay, published an account in the New England Journal of Medicine [17].
In 1924, a Finish doctor discovered a hereditary bleeding disorder similar to hemophilia localized to in the
“Aland Islands”, southwest of Finland. The bleeding disorder is called “Von WillewbrandDisease”[18]. The
term “hemophilia” is derived from the term”hemorrhaphilia” which was used in a description of the condition
written by Friedrich Hopff in 1828,while he was a student at the University of Zurich[16].In 1937,Patek and
Taylor, two doctors from Harvard, discovered anti-hemophilic globulin [19].
Hemophilia has featured prominently in European royalty and this is sometimes known as “the royal disease”.
Queen Victoria passed the mutation for hemophilia to her son Leopold and, through two of her daughters, Alice
and Beatrice, to various royals across the continent, including the royal families of Spain, Germany, andRussia
[20].
Contaminated blood transfusion
Prior to 1985there were no laws enacted within the U.S.to screen blood. As a result may people with
hemophilia that received untested and unscreened clotting factor prior to 1992 were at extreme risk for
contracting HIV and hepatitis C via blood products. It is estimated that more than 50% of the hemophilia
population, i.e. over 10,000 people, contracted HIV from the tainted blood supply in the United States alone
[21].As a direct result of the contamination of the blood supply in the 1970s and early/mid 1980s with viruses
such as hepatitis and HIV, new methods were developed in the production of clotting factor product. The initial
response was to heat-treat(pasteurize)plasma-derived factor concentrate, followed by the development of
monoclonal factor concentrates, which us a combination of heat treatment and affinity chromatography to
inactivate any viral agents in the pooled plasma from which the factor concentrate is derived. The Lindsay
Tribunal in Ireland investigated, among other things, the slow adoption of new methods [21].
III. Genetic Factors
Hemophilia A is inherited as an X-linked recessive trait, and occurs in males and homozygous females
(only possible in the offspring of a carrier female and a hemophilic male[22].However, mild hemophilia A is
known to occur in heterozygous females due to X-inactivation, so it is recommended that levels of factor VIII
and IX be measured in all known potential carriers prior to surgery and in the event of clinically significant
bleeding[23].
Hemophilia B the factor IX gene is located on X chromosome(Xq27.1-q27-2).It is an X-linked
recessive trait, which explains why, as in hemophilia A, usually only males are affected[24].In 1990,George
Brownlee and Merlin Crossley showed that two sets of genetic mutations were preventing two key proteins from
attaching to the DNA of the people with a rare and unusual form of hemophilia B hemophilia B Leyeden-where
sufferers experience episodes of excessive bleeding in childhood but have few bleeding problems after
puberty[25.This lack of protein attachment to the DNA was hereby was turning off the gene that produces
clotting factor IX,which prevents excessive bleeding[25].
Hemophilia and its severity
There are numerous different mutations which cause each type of hemophilia. Due to differences in
changes to the genes involved; people with hemophilia often have some level of active clotting factor.
Individuals with less than 1% active factor are classified as having severe hemophilia, those with 1-5% active
factor have moderate hemophilia, and those with mild hemophilia have between 5-40% of normal levels [26].
IV. Pathophysiology
In terms of mechanism, factor IX deficiency leads to an increased propensity for hemorrhage. This is in
response to mild trauma or even spontaneously, such as in joints (hemomarthrosis)ormuscles. Factor IX
deficiency can cause interference of the coagulation cascade, therapy causing hemorrhage when there is trauma.
Factor IX when activated activates factor X which helps fibrinogen to fibrin conversion[27].Factor IX becomes
active eventually in coagulation, by cofactor factor VIII(especially IXa).Platelets provide a binding site for both
cofactors. Thiscomplex (in the coagulation pathway) will eventually activate factor X [28].
V. Clinical Manifestations
Characteristic symptoms vary with severity. In general symptoms are internal or external bleeding
episodes, which are called “bleeds”. People with more severe hemophilia suffer more severe and more frequent
bleeds, while people with mild hemophilia usually suffer minor symptoms except after surgery or serious
trauma. In cases of moderate hemophilia symptoms are variable which manifest along a spectrum between
severe and mild forms [29].
Hemophilia A Genetic Disorder: Diagnosis, Treatment And Prognosis
DOI: 10.9790/0853-1510038589 www.iosrjournals.org 87 | Page
In both hemophilia A and B,there is spontaneous bleeding but a normal bleeding time, normal
prothrombin time, normal thrombin time, but prolonged partial thromboplastin time. Internal bleeding is
common in people with severe hemophilia and some individuals with moderate hemophilia. The most
characteristic type of internal bleed is a joint bleed where blood enters into the joint spaces [30].This is most
common with severe hemophilia and can occur spontaneously (without evident trauma).If not treated promptly,
joint bleeds can lead to permanent joint damage and disfigurement. Bleeding into soft tissues such as muscles
and subcutaneous tissues is less severe but can lead to damage and requires treatment [30].
Children with mild to moderate hemophilia may not have any signs or symptoms at birth especially if
they do not undergo circumcision. Their first symptoms are often frequent and large bruises and hematomas
from frequent bumps and falls as they learn to walk. Swelling and bruising from bleeding in joints, soft tissue,
and muscles may also occur. Children with mild hemophilia may not have noticeable symptoms for many years.
Often, the first sign in very mild hemophiliacs is heavy bleeding from a dental procedure, an accident, or
surgery. Females who are carriers usually have enough clotting factors from their one normal gene to prevent
serious bleeding problems, though some may present as mild hemophiliacs [30].
Hemophilia and its complications
Severe complications are much more common in cases of severe and moderate hemophilia. Complications may
arise from the disease itself or from its treatment [31].Frequent complications include:
a) Deep internal bleeding, e.g. Deep muscle bleeding, leading to swelling, numbness or pain of a limb.
b) Joint damage from hemarthrosis(hemophilic arthropathy),potentially with severe pain, disfigurement, and
even destruction of joint and development of debilitating arthritis.
c) Transfusion transmitted infection from blood transfusions that are given as treatment.
d) Adverse reactions to clotting factor treatment, including the development of an immune inhibitors which
renders factors replacement less effective.
e) Intracranial hemorrhage is serious medical emergency caused by the buildup of pressure inside the skull. It
can cause disorientation, nausea, loss of consciousness, brain damage, and death.
Hemophiliaarthropathy is characterized by chronic proliferative synovitis and cartilage destruction [32].If an
intra-articular bleed is not drained early, it may cause apoptosis of chondrocytes and affect the synthesis of
proteoglycans. The hypertrophied and fragile synovial lining while attempting to eliminate excessive blood may
me more likely to easily re-bleed, leading to a vicious cycle of hemarthrosis-synovitis-hemarthrosis.In
addition,iron deposition in synovium may induce an inflammatory response activating the immune system and
stimulating angiogenesis, resulting in cartilage and bone destruction [33].
Hemophilia C, also known as plasma thromboplastin antecedent(PTA) deficiency or Rosenthal
syndrome, is a mild form of hemophilia[34].In terms of signs and symptoms of hemophilia C, unlike individuals
with hemophilia A and people affected by it are not the one to bleed spontaneously. In these cases, hemorrhages
tend to happen after a major surgery or injury [35].However, people affected with hemophilia C might
experience symptoms closely related to those of other forms of hemophilia that includes: oral bleeding, nose
bleeds, and blood in the urine [36].
VI. Diagnosis
The diagnosis for hemophilia B can be done by the diagnostic tests include:[37].
i) Coagulation screening test. ii) Bleeding scores. iii) Coagulation factor assay.
Differential diagnosis for this inherited condition is the following hemophilia A, factor XI deficiency,
vonWillenbranddisease, fibrinogen disorders and Bernard-Soulier syndrome [25].
The diagnosis of hemophilia A may be suspected as coagulation testing reveals increased PTT in the context of
a normal PT and bleeding time.PTT tests are the first blood test done when hemophilia is indicated
[24].However diagnosis is made in the presence of low levels of Factor VIII.A family history is frequently
present, although not essential. Recently, genetic testing has been made available to determine individual’s risk
of attaining or passing on hemophilia. Diagnosis of hemophilia A also includes a severity level which can range
from mild to severe based on the amount of active and functioning factor VIII detected in the blood. Factor VIII
levels do not typically change throughout an individual’s life. Severe hemophilia A is the most common form
occurring in the majority of the affected people. Individuals with mild hemophilia often experience often
experience few or no bleeding episodes except in the case of serious trauma (i.e.tooth extraction and
surgery)[23].
Two of the most common differential diagnosis are hemophilia B which is deficiency in Factor IX and
von Willebrand Disease which is a deficiency in von Willebrand factor (needed for proper function of Factor
VIII)[38],hemophilia is also a possible, differential diagnosis[39].
VII. Treatment
Hemophilia A Genetic Disorder: Diagnosis, Treatment And Prognosis
DOI: 10.9790/0853-1510038589 www.iosrjournals.org 88 | Page
Clotting factors are usually not needed in mild hemophilia[40].In moderate hemophilia clotting factors
are typically only needed when bleeding occurs or prevent bleeding with certain events[40].In severe
hemophilia preventive use is often recommended two or three times a week and may continue for life[40].Rapid
treatment of bleeding episodes decreases damage to the body[40].Factor VIII is used in hemophilia A and Factor
IX in hemophilia BFactor replacement can be either isolated from human blood serum,recombinant, or a
combination of the two. Some people develop antibodies (inhibitors) against the replacement factors given to
them, so the amount of factor has to be increased or non-human replacement products must be given, such as
porcine factor VIII[40].If a person becomes refractory to replacement coagulation factor as a result of
circulating inhibitors, this may be partially overcome with recombinant human factor VII[40].In early 2008,US
Food and Drug Administration (FDA) approved anti-hemophilic factor, genetically engineered from the genes
of Chinese hamster ovary cells[40].
Clotting factors are either given preventively or on-demand. Preventive use involves the infusion of
clotting factor on a regular schedule in order to keep clotting levels sufficiently high to prevent spontaneously
bleeding episodes. On-demand (or episode) treatment involves treating bleeding episodes of boys (< 30 moths)
with hemophilia A with prophylactic treatment (infusion of 25IU/kg body weight of Factor VIII every other
day)in respect to its effect on the prevention of joint-diseases. When the boys reached 6 years age, 93% of those
in the prophylactic group and 55% of those in the episode-therapy group had a normal index joint-structure on
MRI[41].Prophylactic treatment, however, resulted in average costs of $300,000 per year. The editor of an
editorial published in the same issue of the NEJM supports this idea that prophylactic treatment is more
effective than on demand treatment but also suggest that starting after the first serious joint-related hemorrhage
may be more cost effective than waiting until the fixed age to begin[42].
Alternative drugs and side effect of anticoagulants
Desmopressin(DDAVP) may be used in those with mild hemophilia A[40].Tranexamic acid or epsilon
aminocaproic acid may be given along with clotting factors to prevent breakdowns of clots[40].Pain medicines,
steroids, and physical therapy may be used to reduce pain and swelling in an affected joint[40].
Anticoagulants such as heparin and warfarin are contraindicated for people with hemophilia as these can
aggravate clotting difficulties. Also contraindicated are those drugs which have “blood thinning: side effects.
For instance, medicines which contain aspirin, ibuprofen or naprexen sodium should not be taken because they
are well known to have the side effect of prolonged bleeding[43],Also are contraindicated are activities with a
high likelihood of trauma, such as motorcycling and skateboarding. Popular supports with high rates of physical
contact and injuries such as American football, hockey,boxing,wrestling,and rugby should be avoided by the
people with hemophilia[43].Other active supports like soccer ball, basketball also have high rate of injuries, but
overall less contact and should be undertaken cautiously and only in consultation with a doctor[43].
VIII. Prognosis and Future Directions
Like most aspects of the disorder, life expectancy varies with severity and adequate treatment. People
with severe hemophilia who don’t receive adequate, modern treatment have greatly shortened lifespans and
often do not reach maturity. Prior to 1960s when effective treatment became available, average life expectancy
was only 11 years [30].By the 1980s the life span of the average hemophilia receiving appropriate treatment was
50 -60 years [30].Today with appropriate treatment, males with hemophilia typically have a near normal life
with an average lifespan approximately 10 years shorter than an unaffected male[44].
Since the 1980s the primary leading cause of death of people with severe hemophilia has shifted from
hemorrhage to HIV/AIDS acquired through treatment with contaminated blood products [30].The second
leading cause of death related to severe hemophilia complications is intracranial hemorrhage which today
accounts for one third of all deaths of people with hemophilia. Two other major causes of death include hepatitis
infections causing cirrhosis and obstruction of air or blood flow due to soft tissue hemorrhage [30].
Future directions
In those with severe hemophilia, gene therapy may reduce symptoms to those that a mild or moderate
person with hemophilia might have. The best results have been found in hemophilia B.As of 2016 early stage
human research is ongoing with a few sites recruiting participants. It is not currently an accepted treatment for
hemophilia [40].
IX.Conclusion
Hemophilia is mostly an inherited genetic disorder that impairs body’s ability to make clots, a process
needed to stop bleeding. Clinical symptoms include longer bleeding after injury, and bleeding inside joints or
the brain.Diagnosis by confirming the low Factor VIII level. Treatment is by replacing the blood clot factors.
Prophylactic treatment is more effective than episode treatment
Hemophilia A Genetic Disorder: Diagnosis, Treatment And Prognosis
DOI: 10.9790/0853-1510038589 www.iosrjournals.org 89 | Page
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Effective ways to prevent arthropathy in severe hemophilia are unknown. We randomly assigned young boys with severe hemophilia A to regular infusions of recombinant factor VIII (prophylaxis) or to an enhanced episodic infusion schedule of at least three doses totaling a minimum of 80 IU of factor VIII per kilogram of body weight at the time of a joint hemorrhage. The primary outcome was the incidence of bone or cartilage damage as detected in index joints (ankles, knees, and elbows) by radiography or magnetic resonance imaging (MRI). Sixty-five boys younger than 30 months of age were randomly assigned to prophylaxis (32 boys) or enhanced episodic therapy (33 boys). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P=0.006). The relative risk of MRI-detected joint damage with episodic therapy as compared with prophylaxis was 6.1 (95% confidence interval, 1.5 to 24.4). The mean annual numbers of joint and total hemorrhages were higher at study exit in the episodic-therapy group than in the prophylaxis group (P<0.001 for both comparisons). High titers of inhibitors of factor VIII developed in two boys who received prophylaxis; three boys in the episodic-therapy group had a life-threatening hemorrhage. Hospitalizations and infections associated with central-catheter placement did not differ significantly between the two groups. Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. (ClinicalTrials.gov number, NCT00207597 [ClinicalTrials.gov].).
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Hemophilia A (HA), being an X-linked recessive disorder, females are rarely affected, although they can be carriers. To study the mutation in F8 gene in an extended family with a homozygous female HA. All the seven affected members (six males and one female) were initially screened by Conformation Sensitive Gel Electrophoresis (CSGE) and direct DNA sequencing. A homozygous missense mutation c.1315G>A (p.Gly420Ser) was identified in exon 9 of F8 gene in homozygous state in the affected female born of 1° consanguinous marriage and in all the affected male members of the family. Her factor VIII levels was found to be 5.5%, vWF:Ag 120%. In India, as consanguineous marriages are very common in certain communities (up to 30%), the likelihood of encountering female hemophilia is higher, although this is the first case of HA out of 1600 hemophilia families registered in our Comprehensive Haemophilia Care Center. Genetic diagnosis in such cases is not necessary as all the male children will be affected and daughters obligatory carriers.
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The most important clinical strategy for management of patients with hemophilia is the avoidance of recurrent hemarthroses by means of continuous, intravenous hematological prophylaxis. When only intravenous on-demand hematological treatment is available, frequent evaluations are necessary for the early diagnosis and treatment of episodes of intra-articular bleeding. The natural history of the disease in patients with poorly controlled intra-articular bleeding is the development of chronic synovitis and, later, multi-articular hemophilic arthropathy. Once arthropathy develops, the functional prognosis is poor. Treatment of these patients should be conducted through a comprehensive program by a multidisciplinary hemophilia unit. Although continuous prophylaxis can avoid the development of the orthopedic complications of hemophilia still seen in the twenty-first century, such a goal has not, so far, been achieved even in developed countries. Therefore, many different surgical procedures such as arthrocentesis, radiosynoviorthesis (radiosynovectomy) (yttrium-90, rhenium-186), tendon lengthenings, alignment osteotomies, joint arthroplasties, removal of pseudotumours, and fixation of fractures are still frequently needed in the care of these patients.
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Haemophilia is a bleeding disorder which has always attracted wide interest both among physicians and the laity--uncontrollable haemorrhage, blood that fails to coagulate and heredity with only males affected. The disease is probably best known to the public through its appearance in European royal families and in the Russian Imperial family. The oldest known description of haemophilia is to be found in the Talmud, the collection of ancient Judaic books from the early centuries of our era. The first clinical account of haemophilia was published by the American, Otto, in 1803. He described the disease as an inheritable bleeding disorder occurring only in males, and transmitted by female carriers who are not themselves affected. The disease manifests itself in early childhood, joint bleedings being its most characteristic feature. Otto called the male patients "bleeders". The term, haemophilia, originated with a German, Friedrich Hopff (1828), who coined the name "haemorrhaphilia" which was later abbreviated to haemophilia. ... As to future prospects, it is hoped that it will soon be possible to cure the disease by means of gene therapy, and to this end promising experimental work is already in progress.
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Patients with severe hemophilia number only around 400,000 worldwide, but their lifespan has increased because of improved treatment, and with that the prevalence of the disease is increasing. Despite the relatively small number of patients with severe hemophilia, the disease has an important socioeconomic effect because of its distinctive feature: a level of clotting factor (factor VIII or factor IX) so low that without replacement therapy, frequent hemorrhages occur, most often in the ankle, knee, and elbow joints. These joint hemorrhages culminate in a severe arthropathy, with signs of inflammation (as in rheumatoid arthritis) as well as degenerative damage (as . . .
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Hemarthrosis is a common manifestation of haemophilia, and joint arthropathy remains a frequent complication. Even though the exact mechanisms related to blood-induced joint disease have not yet been fully elucidated, it is likely that iron deposition in the synovium induces an inflammatory response that causes not only immune system activation but also stimulates angiogenesis. This process ultimately results in cartilage and bone destruction. Investigating the processes that occur in the early stages of blood-induced joint disease in humans has been very limited. Therefore, the use of haemophilic animal models is critical to augment the understanding of this phenomenon. This article discusses three cellular regulators (p53, p21 and TRAIL) induced in synovial tissue that are important for iron metabolism. A cartilage remodelling programme induced by the release of cytokines and growth factors that result in articular damage is also discussed. Full elucidation of the pathogenesis of haemophilic joint disease is required to identify new avenues for prevention and therapy.
Factor XI deficiency
  • K Gomes
  • Boltonmaggsp
Gomes K,BoltonMaggsP.Factor XI deficiency.Hemophilia.2008;14(6):1183-1189.