HEMOPHILIA

By : Santri Dwizamzami Faridahanum Nasution 030 . 08 . 216

FACULTY OF MEDICINE TRISAKTI UNIVERSITY JAKARTA 2011

ABSTRACT

Hemophilia is a common inherited bleeding disorder. Based on the 2008 Global Survey of the World Federation of Hemophilia, nearly 149,000 individuals worldwide have hemophilia. This disease is caused by insufficiency of coagulation factor, FVIII (hemophilia A) and FIX (hemophilia B). The diagnosis of hemophilia is made on the basic of family history, bleeding symptoms, and findings on physical examination and laboratory examination. Prenatal diagnosis is an important aspect of reproductive choices for women in families with hemophilia. Treatment of hemophilia requires factor VIII or factor IX intravenous replacement therapy. In addition, it is also beneficial for appropriate obstetric management during labor and delivery because prolonged labor, invasive monitoring techniques, and instrumental deliveries should be avoided in affected fetuses to minimize potential fetal and neonatal hemorrhagic complications. Currently, children with hemophilia look forward to a normal life expectancy and excellent health-related quality of life.

INTRODUCTION

Hemophilia is a common inherited bleeding disorder. The first modern description of hemophilia is attributed to Dr. John Conrad Otto, a physician in Philadelphia, who in 1803 published a treatise entitled "An account of an hemorrhagic disposition existing in certain families." Hemophilia is sometimes referred to as the royal disease because several members of noble families in Europe were affected by it. Queen Victoria had no ancestors with the condition but soon after the birth of her eighth child, Leopold, in 1853, it became evident that he had hemophilia. Leopold died at the age of 31 from an intracerebral haemorrhage after a fall. Two of Queen Victoria"s own daughters, Alice and Beatrice, were also carriers of hemophilia. The condition was transmitted through them to several royal families in Europe, including Spain and Russia. Perhaps the most famous affected individual was the son of Tsar Nicholas II of Russia, Tsarevich Alexis, who was born in 1904.

Based on the 2008 Global Survey of the World Federation of Hemophilia, nearly 149,000 individuals worldwide have hemophilia and hemophilia A is the more common factor deficiency. In the United States, the number of individuals with hemophilia is estimated at approximately 16,000, with an annual incidence of 1 in 5,000 male births for hemophilia A and 1 in 25,000 male births for hemophilia B. Hemophilia affects people from all racial and ethnic groups.

DISCUSSION

HEMOPHILIA

Definition and Etiology

Hemophilia is a genetic blood disease, which is characterized by the inability of blood to clot, or coagulate even from minor injuries. This disease is caused by insufficiency of coagulation factor. There are two types of hemophilia, hemophilia A and hemophilia B. Hemophilia A ( classic hemophilia ) is caused by the lack of factor VIII. Hemophilia B, (Christmas disease ) is caused by the lack of factor IX.

Hemophilia is an inherited disorder that results from mutations, deletions, or inversions affecting a factor VIII or factor IX gene. Because these genes are located on the X chromosome, hemophilia affects males almost exclusively. Daughters of men with hemophilia are obligate carriers, but sons are normal. Each son of a carrier has a 50% chance of having hemophilia, and each daughter has a 50% chance of being a carrier.

Patophysiology

Factor VIII and IX participate in a complete required for the activation of factor X. Together with phospholipid and calcium, they form the tenase or factor X-activating. The clotting process as it occurs in the test tube, with factor X being activated by either the complex of factor VIII an IX or the complex of tissue factor and factor VII. In vivo, the complex of factor VIIa and tissue factor activates factor IX to initiate clotting. In the laboratory, prothrombine time (PT) measure the activation of factor X by factor VII and is therefore normal in patients with factor VIII or factor IX deficiency.(1) After injury, the initial hemostatic event is formation of the platelet plug, together with the generation of the fibrin clot that prevents further hemorrhage. In hemophilia A or B, clot formation is delayed and is not robust. Inadequate thrombin generation leads to failure to form a tightly cross-linked fibrin clot to support the platelet plug. Patients with hemophilia slowly form a soft, friable clot. When untreated bleeding occurs in a closed space, such as a joint, cessation of bleeding may be the result of tamponade. With open wounds, in which tamponade cannot occur, profuse bleeding may result in significant blood loss. The clot that is formed may be friable, and rebleeding occurs during the phisiologic lysis of clot or with minimal trauma.(1)

Diagnosis

The diagnosis of hemophilia is made on the basic of family history, bleeding symptoms, and findings on physical examination and laboratory examination.

Hemophilia can be severe, moderate, or mild, depending on the degree of factor deficiency. Patients with severe factor deficiency (<1% of normal) experience spontaneous bleeding without apparent trauma. Those with moderate deficiency (1% to 5% of normal) usually do not bleed spontaneously, but may bleed excessively after minor trauma, surgery, or other invasive

procedures. Patients with mild deficiency (5% to 40% of normal) experience abnormal bleeding only after significant trauma.

Age at diagnosis is related to the severity of factor deficiency. The median age for diagnosis of severe hemophilia is about 1 month. Those with moderate hemophilia are usually diagnosed within the first few years of life but mild hemophilia may be diagnosed much later. More than 95% of individuals with hemophilia will be diagnosed by the time they are 15 years of age with approximately 50% having a severe factor deficiency.

The laboratory screening test that is affected by a reduced level of factor VIII or factor IX is PTT. In severe hemophilia, PTT is usually 2-3 times the upper limit of normal. Result of the other screening tests of the hemostatic mechanism (platelet count, bleeding time, prothrombine time, and thrombin time) are normal. Unless the patients has an inhibitor to factor VIII or IX, the mixing of normal plasma with patient plasma result in corection of PTT. The specific assay for factor VIII and IX will confirm the diagnosis if hemophilia. If correction does not occur on mixing, an inhibitor may be present. In 25-35% of patients with hemophilia who receive infusions of factor VIII or factor IX, a factor-specific antobody may develop. These antibodies are directed againts the active clotting site and are termed inhibitors. In such patients, the quantitative Bethesda assay for inhibitor should be performed to measure the antibody titer.(1)

Prenatal Diagnosis

Prenatal diagnosis is an important aspect of reproductive choices for women in families with hemophilia. In addition, it is also beneficial for appropriate obstetric management during labor and delivery because prolonged labor, invasive monitoring techniques, and instrumental

deliveries should be avoided in affected fetuses to minimize potential fetal and neonatal hemorrhagic complications.(2)

Ultrasound

Some couples find out the sex of the baby by ultrasound and then make a decision about invasive testing only if the ultrasound predicts the baby to be a male. The sex can generally be predicted by ultrasound at 16 weeks gestation.

Chorionic villus sampling (CVS)

CVS can be carried out after 11 weeks gestation to obtain DNA for analysis. The sample may be taken either by the vaginal or abdominal route, depending on where the placenta is located. CVS is avoided before 11 weeks because of reports of limb abnormalities occurring when carried out earlier. The miscarriage rate associated with this procedure is approximately 1%. Amniocentesis

Amniocentesis is done after 15.5 weeks. An ultrasound is performed to locate the placenta and to select a pocket of amniotic fluid. This fluid contains cells that the fetus has shed. In some circumstances, the cells need to grow before the DNA from them can be extracted. The risk for complications with the procedure is 0.5.

Fetal blood sampling

Fetal blood sampling may be carried out at 18 weeks or more gestation. A sample is taken from the umbilical vein, under ultrasound guidance, through a needle inserted into the

abdomen. Blood is taken, and the factor level can be assayed immediately. It is important to ensure that the sample in the tube is truly foetal blood and not maternal. A difficult procedure, the risk of miscarriage is as high as 5%.

Noninvansive

Current prenatal diagnosis for hemophilia largely relies on invasive procedures such as chorionic villus sampling, which poses a finite risk to the fetuses. Consequently, many pregnant women from at-risk families do not consent to invasive testing because of the associated risks. The discovery of cell-free fetal DNA in maternal plasma has offered new opportunities for noninvasive prenatal diagnosis. Digital polymerase chain reaction (PCR) offers a highly sensitive and precise method for quantifying cell-free DNA in maternal plasma. Digital relative mutation dosage (RMD, one of PCR- based methods) can be applied for the noninvasive prenatal diagnosis of sex-linked disorders. (2)

Differential Diagnosis

Consideration in the differential diagnosis of hemophilia include congenital bleeding disorders such as von Willebrand disease, platelet disorders, and deficiency of various other coagulation factors such as factor V, VII, X, or IX or fibrinogen. In addition are autoimmune syndrome in which antibodies to factor VIII may spontaneously develop, leading to acquired hemophilia.(3)

Treatment
Treatment of hemophilia requires factor VIII or factor IX intravenous replacement therapy. The exception is that hemostasis in some patients with mild hemophilia A may be managed using

desmopressin acetate (DDAVP) if they have been demonstrated to respond to this agent. Purified concentrates of factor VIII and IX can be obtained either from human plasma or by recombinant techniques and are considered to be safe and effective. (1) The dosing of factors VIII and IX is different for 2 main reasons: first, factor VIII has a biological half life of about 8 to 12 hours, whereas factor IX has a half life in plasma ranging from 18 to 24 hours. Second, only about 50% of factor IX that is infused intravenously is recovered, probably because the factor binds to collagen IV, which can be found in the vascular tree. The physiologic purpose of the binding of factor IX to collagen is not known, but from experiments on animal models, the lack of the factor IX-collagen interaction is associated with a mild bleeding disorder. In general, about 50 units of factor VIII per kg of body weight are required to raise the plasma factor VIII level to 100% of normal. About 100 units/kg of plasma-derived factor IX and up to 130-150 units/kg of recombinant factor IX are required to achieve 100% correction. (3) The best form of treatment, however, for severe factor VIII or IX deficiency, or for patients with mild/moderate deficiency who have demonstrated recurrent joint bleeding, is prophylactic therapy. For factor VIII deficiency, 25-50 units of factor VIII per kg body weight are given IV 3 days weekly or every other day. For factor IX deficiency, about 50-100 units of factor IX are given twice weekly. The advantage of prophylactic therapy is that most bleeding, but especially joint hemorrhage, is prevented, and the most ravaging consequences of hemophilic arthropathy are avoided.

Complication (1485)

A common long-term complication of hemophilia is permanent damage to the joints (hemarthropathy) caused by repeated bleeding episodes. Once in the joint, blood can trigger an inflammatory response within the synovial tissue, resulting in tissue damage. Articular cartilage

and subchondral bone also are negatively affected by exposure to blood. Damage to the joint tissues can be seen after even short periods of exposure to small amounts of blood. Repeated bleeding into the muscle can also have long-term effects, with muscle and nerve damage potentially leading to contractures. (1,3)

In addition to frequent bleeds, hemophiliacs suffer from debilitating and progressive musculosceletal lesions, deformites, neurologic deficiences following intracranial hemorrhage and soft tissue compression, limited lifestyle and productivity, low self-esteem, poverty, drug dependency, and depression. (1,3) Initial use of plasma-derived factor concentrates resulted in a high incidence of transfusion-transmitted viruses such as hepatitis and human immunodeficiency virus. Identification of pathogens, improvements in purification methods, and subsequent development of recombinant clotting factor concentrates have virtually eliminated this complication. Currently, the most serious complication of hemophilia is the development of inhibitor antibodies, predominantly against factor VIII, which occurs frequently in response to infusion of factor VIII concentrates in those with severe hemophilia and rarely in those with mild hemophilia A.(4) The prevalence of factor VIII inhibitors is approximately 6%, with an annual incidence of 3.5 per 1000 patients with severe hemophilia A. Studies of predictors of development of inhibitors point to a genetic predisposition, with up to 30% of patients with the factor VIII inversion mutation and large deletions developing factor VIII inhibitors. Inhibitor antibodies against factor IX occur in some patients with severe hemophilia B in response to infusion of factor IX concentrates. More recently, it was recognized that patients with deletions of the factor IX gene are at high risk of developing inhibitors and anaphylactic responses to infusions of factor IX concentrates. (4)

Mortality

An increase in the mortality rate and reduced life expectancy have been a characteristic of hemophilia as the disease was first recognized. As early as 1855, reported an 80% mortality rate with a life expectancy of 14 years for severe and moderate cases. The first report on the use of plasma for replacement therapy in 1923 resulted in an increase in the life expectancy of patients. Between 1943 and 1957, patients with severe disease lived to 23.2 years and for those with mild disease to 50 years. During the 50 years of observation, the mean age at death increased from 7.8 years in 193039 to 25.5 years in 197079. The cause of death in 56% of cases was because of various forms of hemorrhage including one-third of cases because of intracranial hemorrhage but 36% of deaths were unrelated to hemophilia(i.e. non-bleeding death). Among the patients with severe hemophilia , the incidence of inhibitory antibodies was 16.7% and 4.2% for the entire group. Trauma contributed to bleeding in 23% of deaths between 1957 and 1968 but only 7% during the 12 year interval from 19691980. Spontaneous bleeding accounted for 42% and 41% of deaths, respectively. (5)

Currently, children with hemophilia look forward to a normal life expectancy and excellent health-related quality of life. Importantly, although severity of hemophilia, arthropathy and age increased the risk of disability, home treatment was associated with a 50% reduction in this risk.(5)

The two major factors impacting upon the improved quality of life, reduced morbidity and increased life expectancy are: the availability of high-quality antihemophilic factor concentrates (AHFC) for replacement therapy and comprehensive care.(5)

CONCLUSION

Hemophilia is genetic disoder resulting from a deficiency in circulating levels of plasma factors VIII and IX. These disorders have an X-linked pattern of inheritance (genes are on the long arm of the X-chromosome), although one-third of cases are new mutations occuring without a previous family history. The manifestations of hemophilia A and B are similar because both factors VIII and IX function to activate factor X. The most typical presentation occurs after 6 month of age, at which time easy bruising, oral bleeding, hemarthrosis, and intramuscular bleeding become evident. The diagnosis of hemophilia is made on the basic of family history, bleeding symptoms, and findings on physical examination and laboratory examination. The laboratory screening test that is affected by a reduced level of factor VIII or factor IX is PTT. Result of the other screening tests of the hemostatic mechanism are normal. Prenatal diagnosis is an important aspect of reproductive choices for women in families with hemophilia. Prenatal diagnostic test for examples : ultarsound, CVS, amniocentesis, fetal blood sample, and noninvansive test. The mainstay of treatment is replacement of the deficient factor. In some cases, desmopressin may also be effective.

REFERENCES

1. Scott JP, Montgomery RR. Hemorrhagic and Thrombotic Disease. In: Kliegman RM, et al., editors. Nelson Textbook of Pediatrics. 18th ed. Philadelphia: Saunder; 2007. p. 2066-69. 2. Tsui, N B Y. Kadir, R A, K. Chan, C A. et al. Noninvasive prenatal diagnosis of hemophilia by microfluidics digital PCR analysis on maternal plasma DNA. Blood 2011; 117(13): 368491. 3. Ragni MV, Kessler CM, Lozier JN. Clinical aspect and theraphy of hemophilia. In : Hoffman R, Benz EJ, Shattil SJ, et al., editors. Hematology Basic Principles and Practice. 5th ed. Philadelphia : Churchill Livingstone ; 2009. p.1911-30. 4. Pruthi RK. Hemophilia: A Practical Approach to Genetic Testing. Mayo Clin Proc. 2005;80(11):1485-99. 5. Mejia-Carvajal C, Czapek EE, Valentino LA. Life expectancy in hemophilia outcome. J Thromb Haemost 2006; 4: 5079.