Hemofilia C dan Disfibrinogenemia oleh Davrina Rianda, 0906507936 Hemofilia C adalah suatu kondisi dimana faktor XI berada dalam

kadar yang rendah. Faktor XI (FXI) memegang peranan penting dalam pembentukan trombin dependen-faktor jaringan. While factor VIII and factor IX deficiencies are the best known and most common types of hemophilia, other clotting factor deficiencies also exist. Low levels of factor XI (FXI) cause hemophilia C. FXI plays an important role in tissue factor-dependent thrombin generation on the surface of activated platelets.1 The formation of the initiating complex, TF-FVIIa-FXa, results in the generation of a small amount of thrombin. This is insufficient to produce a stable fibrin clot but stimulates a number of reactions in the amplification loop, including the activation of FXI. Subsequent formation of the tenase complex (FIXa-FVIIIa), followed by the prothrombinase complex (FXa-FVa), leads to a large burst of thrombin.1 For a schematic of these processes, click here. Hemophilia C is also known as plasma thromboplastin antecedent (PTA) deficiency or Rosenthal syndrome.1-3 Like the other hemophilias, hemophilia C is associated with bleeding, but it differs from hemophilia A and B in several ways.1-5 Bleeding Tendency Unlike with hemophilia A and hemophilia B, the frequency of bleeding with hemophilia C is not determined by the patients factor level.1 An unpredictable (or inconsistent) bleeding pattern occurs in people with this disorder.1-4 The inability to predict bleeding complicates treatment. Individuals with hemophilia C do not commonly bleed spontaneously; bleeding tends to occur after surgery or injury, especially to the mucocutaneous lining of the oral or nasal cavities and the urinary tract.1-4 Procedures with an increased risk of bleeding include the following:3

dental extractions tonsillectomies surgery in the urinary and genital tracts nasal surgery

Unlike individuals with hemophilia A and hemophilia B, patients with hemophilia C do not commonly experience joint bleeds. They may, however, experience the following: bruising, nosebleeds, or blood in the urine; and for women, menorrhagia and prolonged bleeding after childbirth.1-4 Injury may cause bleeding in muscles, joints and other areas. Causes of Hemophilia C Hemophilia C is primarily an inherited disorder, but unlike hemophilia A and B, the inheritance of hemophilia C follows an autosomal recessive pattern. The gene that causes FXI deficiency is not present on a sex chromosome and the condition, therefore, affects both genders equally. The FXI gene is 23kb in length, has 15 exons, and is found on chromosome 4q32-35. Factor XI is produced by the liver and circulates in the blood in an inactive form. The plasma half-life of FXI is approximately 52 hours.1 Throughout the world, persons of Ashkenazi (European) Jewish descent and Iraqi Jews are most commonly affected by hemophilia C.1-4 However, hemophilia C may be diagnosed in

many other ethnic groups.4 In the United States, the estimated prevalence of severe hemophilia C is 1 case per 100,000 persons. In Israel, hemophilia C has been estimated to be approximately 8% among Ashkenazi Jews, making it one of the most common genetic disorders in this group.1-4 According to a national database in the United Kingdom, 1696 patients with hemophilia C, including many non-Jewish individuals, were registered in a population of approximately 60 million.5 In hemophilia C, parents tend to be asymptomatic as it is an autosomal inherited disorder. However, due to the prevalence of the gene in some populations, an affected parent may marry an individual who carries the disorder and have affected children as well.1 Diagnosis of Hemophilia C Obtaining a detailed personal and family bleeding history of a patient is very important in the diagnosis of hemophilia C. Although this condition is found in all racial and ethnic groups, it is helpful to establish the patients background, as this may give an indication of the likely disorder.4 Various screening coagulation tests are utilized to diagnose hemophilia C, the most common being the activated partial thromboplastin time (APTT) and a FXI activity assay.2,3 Treatment of Hemophilia C Patients with severe hemophilia C do not require treatment or prophylactic (preventive) therapy for daily activities. However, replacement therapy is required for dental extractions and surgery, and treatment options depend on the type of procedure.1-3 Fresh frozen plasma, the most widely available treatment for this disorder in the United States, is normally used with good results. However, since FXI is not concentrated in fresh frozen plasma, a large volume of this product may be required to raise the FXI activity to a hemostatic level.. There are no FXI concentrates licensed in the United States. Two such products are available in Europe, but their use in patients has been limited because of reports of thrombotic complications after the use of both available concentrates. The patients generally were elderly with pre-existing risk factors for thrombotic disease.1 Patients with severe factor XI deficiency may develop an inhibitor, as seen in hemophilia A or B. The development of an inhibitor generally complicates treatment options. Approximately one-third of patients with severe (<1%) FXI deficiency who use plasma product replacement therapy may develop an inhibitor. There are a few case reports describing the successful use of recombinant FVIIa in these patients; however, recombinant FVIIa should be used with caution because thrombotic complications have been reported.1 Antifibrinolytic agents such as epsilon aminocaproic acid (Amicar) or tranexamic acid may be useful for treating mucocutaneous bleeding in individuals with hemophilia C.2 Antifibrinolytic agents are generally not used concomitantly with FXI concentrate, because of an increased risk of thrombotic complications. They are also relatively contraindicated in treating bleeding from the urinary tract because of potential clot retention.1 Desmopressin may be used in some cases to produce modest rises in FXI activity in partial deficiency,6 but the evidence for efficacy is unconvincing. Complications of Hemophilia C The complications of hemophilia C are those primarily associated with the use of fresh frozen plasma. While todays blood products are much safer than those of the past,

transmission of hepatitis A, hepatitis C, and newly discovered blood-borne diseases remain a risk for people treated with plasma-derived products. Immunization against hepatitis A and B is recommended for all individuals with hemophilia. No vaccination currently exists for hepatitis C. Living with Hemophilia C Although patients with hemophilia C may experience milder symptoms than those living with other types of hemophilia, this disorder should not be overlooked. People living with hemophilia C require effective treatment to achieve optimal outcomes after surgeries or injuries. For this reason, it is critical that patients inform their physicians of their diagnosis prior to any planned procedures. Summary Table 1 summarizes the key differences between hemophilia C and the relatively more common hemophilia A and B. Table 1. Key Differences Between Hemophilia C and Hemophilia A and B Key Difference Between Hemophilia C and Hemophilia A & B Characteristic Hemophilia C is more common among persons of Ashkenazi (European) Jewish descent.1,2 Incidence Hemophilia A and B affect all racial and ethnic groups equally.

Bleeding tendency

The frequency of bleeding with hemophilia C is not determined by the patients factor level or severity of the deficiency. Hemophilia C affects men and women equally. In hemophilia C, unpredictable (or inconsistent) bleeding patterns can complicate management. Individuals with hemophilia C are not likely to bleed spontaneously (or without known injury); bleeding tends to occur after trauma or surgery. Unlike hemophilia A and B, hemophilia C is not commonly associated with bleeding into joints and muscles. Physical signs of the disorder (e.g., bruising) are rare. Hemophilia C is primarily an inherited autosomal disorder Unlike hemophilia A and hemophilia B, it is not linked to the X chromosome and affects both genders equally Individuals with hemophilia C do not require treatment or prophylactic (preventive) therapy for daily activities. Replacement therapy is required for dental extractions and surgery Treatment options depend on the type of procedure. Individuals with hemophilia C may experience milder symptoms than those living with hemophilia A or B, but they still require effective treatment to achieve optimal outcomes after surgeries or injuries

Cause

Treatment

What Can IHTC Do for You?

As Indianas only federally recognized HTC, the IHTC is committed to working with other healthcare providers throughout the state to serve Indianas bleeding disorders population. We are available to answer any questions you might have about hemophilia in general and to consult about cases of suspected hemophilia or other bleeding disorders. The IHTC will provide detailed surgery plans and postoperative management for any patient undergoing a surgical procedure. We gladly accept referrals to our center and, based on the documented benefits of receiving care at an HTC,7 we encourage providers to involve the IHTC in the care of individuals with bleeding disorders and their families. The IHTC exceeds national staffing standards and offers an extensive spectrum of care through dedicated trained professionals. In addition to the core services provided at all HTCs(e.g., hematologists, clinical nurses, social workers, physiotherapists), the IHTC staff also includes a career counselor, risk reduction specialist, registered dietitian, clinical research professionals, genetic counselor and dental hygienist. Dental care: IHTCs dental hygienists will work with individuals with bleeding disorders and their dentists to make sure required precautions are taken in preparing for dental procedures and for long-term dental care. Visit IHTCs webpage on dental care to learn more about the special considerations for dental care in persons with bleeding disorders.

1. Gomez K, Bolton-Maggs P. Factor XI deficiency. Haemophilia. 2008;14(6):11831189. 2. Mathew P, Bolton-Maggs P. Hemophilia C. Accessed March 23, 2010 3. National Hemophilia Foundation. Factor XI deficiency. Accessed March 23, 2010 4. Asakai R, Chung DW, Ratnoff OD, et al. Factor XI (plasma thromboplastin antecedent) deficiency in Ashkenazi Jews is a bleeding disorder that can result from three types of point mutations. Proc Natl Acad Sci U S A. 1989;86:7667-7671. 5. Bolton-Maggs PH, Peretz H, Butler R, et al. A common ancestral mutation (C128X) occurring in 11 non-Jewish families from the UK with factor XI deficiency. J Thromb Haemost. 2004;2(6):918-924. 6. Castaman G, Ruggeri M, Rodeghiero F. Clinical usefulness of desmopressin for prevention of surgical bleeding in patients with symptomatic heterozygous factor XI deficiency. Br J Haematol. 1996; 94:168170. 7. Soucie J, Nuss R, Evatt B, Abdelhak A, Cowan L, Hill H, et al. Mortality among males with hemophilia: relations with source of medical care. Blood 2000;96:437-42. 8.
Congenital dysfibrinogenemia is a term used to describe a relatively rare condition wherein an inherited abnormality in the fibrin molecule results in defective fibrin clot formation. The complications associated with abnormal clot formation range from asymptomatic to life threatening. Fortunately, 40% of patients with congenital dysfibrinogenemia are asymptomatic; however, 50% of patients have a bleeding disorder and the remaining 10% have a thrombotic disorder or combined thrombotic and bleeding tendencies. Acquired dysfibrinogenemias, often called dysfibrinogenemia of liver disease, are the most common causes. Up to 50% of patients with severe liver disease secondary to cirrhosis, hepatoma, or hepatitis exhibit bleeding complications.[1]

Pathophysiology
In the clotting cascade, the various blood coagulation factors function in concert to produce a balance between fibrin clot formation and its subsequent degradation. When any factor in the cascade is absent, decreased, or abnormal, the delicate balance is disrupted, possibly leading to bleeding or thrombotic

disorders. The clinical manifestations range from no symptoms to life-threatening events depending on which coagulation factor is affected and the degree to which it is affected. In normal fibrin clot formation, a fibrin monomer forms after thrombin cleaves fibrinopeptide A and B from the alpha and beta chains of the fibrinogen molecule. Factor XIIIa then catalyzes the cross-linkage between different fibrin chains, forming a stabilized fibrin polymer or clot. Eventually, plasmin lyses the fibrin clot. Acquired dysfibrinogenemia occurs most often in patients with severe liver disease. The impairment of the fibrinogen, which is manufactured in the liver, is due to a structural defect caused by an increased carbohydrate content impairing the polymerization of the fibrin, depending on the degree of abnormality of the fibrinogen molecule. Rarely, dysfibrinogenemia may also be associated with malignancies, most commonly primary or secondary liver tumors, but acquired dysfibrinogenemia has also been reported in patients with renal cell carcinoma. One of the rarer disorders of coagulation is congenital dysfibrinogenemia, a qualitative abnormality of the fibrin molecule. Multiple variations of these dysfibrinogenemias are elucidated. Each is named for the city where it was first discovered. With only rare exceptions, the congenital dysfibrinogenemias are inherited in an autosomal dominant or codominant fashion. Depending on the fibrinogen abnormality, defects may occur in one or more of the steps in fibrin clot formation, although the most common defect involves polymerization of the fibrin monomer.[2] Bleeding may ensue when a fibrin clot forms that cannot be effectively stabilized. Bleeding in patients with congenital dysfibrinogenemia tends to be relatively mild or even absent; it is only a laboratory curiosity and is not life threatening. In contrast to the bleeding experienced by approximately half of the patients with congenital dysfibrinogenemia, one subset of patients (diagnosed with fibrinogen Oslo I) has an abnormal fibrinogen that is associated with thromboembolic complications that are often relatively mild. The abnormal fibrinogen in these patients forms a fibrin clot that is resistant to fibrinolysis by plasmin.[3]

Epidemiology

Frequency
International
Only 200-300 families are reported to have congenital dysfibrinogenemia. Hereditary transmission is autosomal dominant or codominant except in a few cases that appear to be transmitted recessively. Approximately 50% of patients with severe liver disease exhibit bleeding secondary to abnormal fibrinogen molecules.

Mortality/Morbidity
While many patients with congenital dysfibrinogenemias are asymptomatic, those who experience symptoms commonly have only mild bleeding or thrombotic events, although these are extremely rare. Severe hemorrhagic episodes may characterize a few abnormal fibrinogen variants (eg, Imperate, Dettori, Detroit). Patients with dysfibrinogenemia of liver disease often have a more severe bleeding disorder than patients with an inherited disorder. The condition tends to worsen as the liver disease worsens.

Race
Prevalence is not increased in any race.

Sex

Prevalence is not increased in either sex.

Bleeding occurs in approximately 50% of patients with an inherited disorder. Usually the bleeding is mild and may not manifest until after a surgical procedure. Patients with severe liver disease may experience extreme bleeding. Bleeding may occur due to the following: o Menorrhagia o Postoperative bleeding o Epistaxis o Postoperative wound dehiscence o Defective wound healing o Bruising o Severe hemorrhage (rare) o Mild soft-tissue hemorrhage Intraoperative bleeding Thrombotic events attributable to dysfibrinogenemia occur in less than 10% of patients with hereditary dysfibrinogenemias. Thrombotic events that may occur include the following: o Venous thrombosis (usually mild) o Arterial thrombosis (rare) o Thromboembolic event o Spontaneous miscarriage Combined bleeding and thrombotic tendencies are extremely rare and associated only with congenital dysfibrinogenemias.

Physical
Although many patients with inherited dysfibrinogenemia remain asymptomatic, signs that arise tend to be associated with poor wound healing, surgical wound dehiscence, and postsurgical bleeding out of proportion to that expected.

Causes

Congenital dysfibrinogenemias are most often inherited in an autosomal dominant or codominant fashion. Several variants are inherited autosomal recessively. Acquired dysfibrinogenemias occur in severe liver disease. The fibrinogen molecule produced by the impaired liver is not functional or able to form a stable fibrin clot.