Hemophilia overview
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Hemophilia is considered a very old disease with its history dating back to the 2nd century AD. The first modern descriptions of the condition appeared during the 19th century. Extensive work has been done over the centuries regarding the classification, inheritance pattern, and treatment of hemophilia. Hemophilia may be classified into three sub-types based on the lack of functional clotting factors: hemophilia A , hemophilia B, hemophilia C. It can also be divided into different categories based on the severity of the condition. Hemophilia can also be acquired in the setting of antibodies directed against the clotting factors. Hemophilia is a genetic bleeding disorder resulting from the insufficient levels of clotting factors in the body. The clotting factors irregularity causes a lack of clumping of blood required to form a clot to plug a site of a wound. The genes involved in the pathogenesis of hemophilia include the F8 gene in hemophilia A, F9 gene in hemophilia B, and F11 gene in C. Hemophilia predominantly affects the male population but the sub-type hemophilia C, with an autosomal inheritance pattern, can affect the males as well as females. Hemophilia A, B, and C are caused by mutations in F8, F9, and F11 genes respectively. It can also occur as a result of autoantibodies directed against the clotting factors. Hemophilia must be differentiated from other diseases leading to spontaneous bleeding and bleeding following injuries or surgery such as von Willebrand disease, hepatic failure, thrombocytopenia, vitamin K deficiency, disseminated intravascular coagulation, uremia, congenital afibrinogenemia, factor V deficiency, factor X deficiency as seen in amyloid purpura, glanzmann's thrombasthenia, Bernard-Soulier syndrome, factor XII deficiency and C1-inhibitor (C1INH) deficiency. The prevalence of hemophilia is estimated to be 20,000 cases in the United States annually. The age-adjusted prevalence of hemophilia in six US states (Oklahoma, Massachusetts, Colorado, Georgia, Louisiana, and New York) in 1994 was 13.4 cases per 100, 000 males. The incidence of hemophilia is estimated to be 1 in 5,000 male births for hemophilia A and 1 in 30,000 births for hemophilia B. The most potent risk factor in the development of hemophilia is the family history of hemophilia. Other risk factors include male sex and malignancies. Initial screening blood investigations for any child with suspected bleeding disorder include platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen test. Chorionic villus sampling at 11-14 weeks of gestation can be performed for the genetic diagnosis of hemophilia. Hemophilia can present with a bleeding episode during the neonatal period that is difficult to manage or it can present with signs and symptoms of concealed bleeding into the joint or viscera. If left untreated, hemophilia can result in complications involving multiple organs and in severe bleeding episodes it can result in death. Hemophilia patients can lead an active and healthy life and life expectancy depends on the treatment response and the presence of comorbidities. Complications of hemophilia include AIDS, hepatitis, Vitamin D deficiency, osteoporosis, and renal pathologies. Coagulation tests and coagulation assays are the gold standard for the diagnosis of hemophilia. Prolonged activated partial thromboplastin time (aPTT), normal prothrombin time (PT), prolonged bleeding time (BT), and normal fibrinogen concentration are diagnostic of hemophilia. Coagulation tests should be followed by measuring the clotting factors level by coagulation assays. Once the coagulation discrepancy has been established, individual clotting factor assay can be performed to determine the deficient/absent clotting factor. Bethesda assay can be performed in the case of acquired hemophilia to detect and quantify antibodies directed against factor VIII. Patients with hemophilia can present with a history of excessive bleeding after minor injuries or spontaneous bleeding. They can also report family history of hemophilia. Hemophilia when mild, can be asymptomatic. Common symptoms, when present, include epistaxis, oral mucosal bleeding, joint pain and swelling, lethargy and fatigue, excessive bleeding after dental procedures, prolonged bleeding after circumcision and muscle hematoma after vaccination. Patients with hemophilia usually appear normal. Physical examination of patients with hemophilia is usually remarkable for tachycardia, pallor, bruising, abdominal pain and distension, hypotension, and muscle or joint swelling. Laboratory findings consistent with the diagnosis of hemophilia include normal prothrombin time (PT), prolonged activated partial thromboplastin time (aPTT), prolonged bleeding time (BT), and normal platelet count. There are no ECG findings associated with hemophilia. An x-ray of the joints in the case of hemophilic arthropathy may be helpful in the diagnosis of hemophilia. Pettersson scoring system, designed in 1980, is widely applied for the classification of osteo-chondral changes of hemophilic arthropathy in elbows, knees, and ankles. This scoring system is based on typical findings of hemophilic arthropathy on posterior-anterior and lateral x-rays. Arnold-Hilgartner classification is also a plain radiograph grading system for hemophilic arthropathy. CT scan may be helpful in the diagnosis of hemophilia. Findings on CT scan suggestive of hemophilia include muscle, intracranial, and intraabdominal hematomas, hemophilic pseudotumor, intracranial hemorrhage, muscle ossification, and pseudoaneurysm following arterial trauma. MRI may be helpful in the diagnosis of hemophilia. Findings on MRI suggestive of hemophilic arthropathy include effusion, synovial hypertrophy, erosion, subchondral cyst, cartilage loss, osteonecrosis, fibrocartilage tear, ligament tear, loose body. There are no echocardiography findings associated with hemophilia. Ultrasound may be helpful in the diagnosis and follow-up of hemophilic arthropathy and in diagnosing massive intraabdominal bleeds. Findings on an ultrasound suggestive of hemophilic arthropathy inlcude soft-tissue changes, osteo-chondral changes, joint effusion, synovial hypertrophy, hemosiderin, and osteo-chondral abnormalities. There are no other imaging findings associated with hemophilia. There are no other diagnostic studies associated with hemophilia. Clotting factor replacement is the mainstay of hemophilia treatment. Plasma-derived factor concentrates and recombinant factor concentrates are the two types used in the replacement therapy. Other products used as therapy include desmopressin acetate, antifibrinolytics, and cryoprecipitate. Gene therapy has the potential to change the course of hemophilia therapy and care. Surgery is not recommended for the treatment of hemophilia. Primary prevention of hemophilia encompasses measures taken to raise awareness regarding the genetics of the disease and the genetic transmission of the condition. Having an X-linked mode of transmission, genetic counselling in female carriers and awareness are the main focus for the primary prevention of hemophilia. Effective measures for the secondary prevention of hemophilia include avoidance of invasive fetal monitoring of a hemophilic fetus, avoidance of operative vaginal delivery, administration of vitamin K injection with care, availability of the factor concentrate at the time of delivery, infusion of factor VIII or IX concentrate at least once weekly for ≥ 45 weeks per year, and the use of e-Diaries to improve record keeping of hemophilia patients' home treatment and bleeding episodes.
Historical Perspective
Hemophilia is considered a very old disease with its history dating back to the 2nd century AD. The first modern descriptions of the condition appeared during the 19th century. Extensive work has been done over the centuries regarding the classification, inheritance pattern, and treatment of hemophilia.
Classification
Hemophilia may be classified into three sub-types based on the lack of functional clotting factors: hemophilia A , hemophilia B, hemophilia C. It can also be divided into different categories based on the severity of the condition. Hemophilia can also be acquired in the setting of antibodies directed against the clotting factors.
Pathophysiology
Hemophilia is a genetic bleeding disorder resulting from the insufficient levels of clotting factors in the body. The clotting factors irregularity causes a lack of clumping of blood required to form a clot to plug a site of a wound. The genes involved in the pathogenesis of hemophilia include the F8 gene in hemophilia A, F9 gene in hemophilia B, and F11 gene in C. Hemophilia predominantly affects the male population but the sub-type hemophilia C, with an autosomal inheritance pattern, can affect the males as well as females.
Causes
Hemophilia A, B, and C are caused by mutations in F8, F9, and F11 genes respectively. It can also occur as a result of autoantibodies directed against the clotting factors.
Differentiating Hemophilia from other diseases
Hemophilia must be differentiated from other diseases leading to spontaneous bleeding and bleeding following injuries or surgery such as von Willebrand disease, hepatic failure, thrombocytopenia, vitamin K deficiency, disseminated intravascular coagulation, uremia, congenital afibrinogenemia, factor V deficiency, factor X deficiency as seen in amyloid purpura, glanzmann's thrombasthenia, Bernard-Soulier syndrome, factor XII deficiency and C1-inhibitor (C1INH) deficiency.
Epidemiology and Demographics
The prevalence of hemophilia is estimated to be 20,000 cases in the United States annually. The age-adjusted prevalence of hemophilia in six US states (Oklahoma, Massachusetts, Colorado, Georgia, Louisiana, and New York) in 1994 was 13.4 cases per 100, 000 males. The incidence of hemophilia is estimated to be 1 in 5,000 male births for hemophilia A and 1 in 30,000 births for hemophilia B.
Risk Factors
The most potent risk factor in the development of hemophilia is the family history of hemophilia. Other risk factors include male sex and malignancies.
Screening
Initial screening blood investigations for any child with suspected bleeding disorder include platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen test. Chorionic villus sampling at 11-14 weeks of gestation can be performed for the genetic diagnosis of hemophilia.
Natural History, Complications and Prognosis
Hemophilia can present with a bleeding episode during the neonatal period that is difficult to manage or it can present with signs and symptoms of concealed bleeding into the joint or viscera. If left untreated, hemophilia can result in complications involving multiple organs and in severe bleeding episodes it can result in death. Hemophilia patients can lead an active and healthy life and life expectancy depends on the treatment response and the presence of comorbidities. Complications of hemophilia include AIDS, hepatitis, Vitamin D deficiency, osteoporosis, and renal pathologies.
Diagnosis
Diagnostic Study of Choice
Coagulation tests and coagulation assays are the gold standard for the diagnosis of hemophilia. Prolonged activated partial thromboplastin time (aPTT), normal prothrombin time (PT), prolonged bleeding time (BT), and normal fibrinogen concentration are diagnostic of hemophilia. Coagulation tests should be followed by measuring the clotting factors level by coagulation assays. Once the coagulation discrepancy has been established, individual clotting factor assay can be performed to determine the deficient/absent clotting factor. Bethesda assay can be performed in the case of acquired hemophilia to detect and quantify antibodies directed against factor VIII.
History and Symptoms
Patients with hemophilia can present with a history of excessive bleeding after minor injuries or spontaneous bleeding. They can also report family history of hemophilia. Hemophilia when mild, can be asymptomatic. Common symptoms, when present, include epistaxis, oral mucosal bleeding, joint pain and swelling, lethargy and fatigue, excessive bleeding after dental procedures, prolonged bleeding after circumcision and muscle hematoma after vaccination.
Physical Examination
Patients with hemophilia usually appear normal. Physical examination of patients with hemophilia is usually remarkable for tachycardia, pallor, bruising, abdominal pain and distension, hypotension, and muscle or joint swelling.
Laboratory Findings
Laboratory findings consistent with the diagnosis of hemophilia include normal prothrombin time (PT), prolonged activated partial thromboplastin time (aPTT), prolonged bleeding time (BT), and normal platelet count.
Electrocardiogram
There are no ECG findings associated with hemophilia.
X-ray
An x-ray of the joints in the case of hemophilic arthropathy may be helpful in the diagnosis of hemophilia. Pettersson scoring system, designed in 1980, is widely applied for the classification of osteo-chondral changes of hemophilic arthropathy in elbows, knees, and ankles. This scoring system is based on typical findings of hemophilic arthropathy on posterior-anterior and lateral x-rays. Arnold-Hilgartner classification is also a plain radiograph grading system for hemophilic arthropathy.
CT scan
CT scan may be helpful in the diagnosis of hemophilia. Findings on CT scan suggestive of hemophilia include muscle, intracranial, and intraabdominal hematomas, hemophilic pseudotumor, intracranial hemorrhage, muscle ossification, and pseudoaneurysm following arterial trauma.
MRI
MRI may be helpful in the diagnosis of hemophilia. Findings on MRI suggestive of hemophilic arthropathy include effusion, synovial hypertrophy, erosion, subchondral cyst, cartilage loss, osteonecrosis, fibrocartilage tear, ligament tear, loose body.
Echocardiography/Ultrasound
There are no echocardiography findings associated with hemophilia. Ultrasound may be helpful in the diagnosis and follow-up of hemophilic arthropathy and in diagnosing massive intraabdominal bleeds. Findings on an ultrasound suggestive of hemophilic arthropathy inlcude soft-tissue changes, osteo-chondral changes, joint effusion, synovial hypertrophy, hemosiderin, and osteo-chondral abnormalities.
Other Imaging Findings
There are no other imaging findings associated with hemophilia.
Other Diagnostic Studies
There are no other diagnostic studies associated with hemophilia.
Treatment
Medical Therapy
Clotting factor replacement is the mainstay of hemophilia treatment. Plasma-derived factor concentrates and recombinant factor concentrates are the two types used in the replacement therapy. Other products used as therapy include desmopressin acetate, antifibrinolytics, and cryoprecipitate. Gene therapy has the potential to change the course of hemophilia therapy and care.
Surgery
Surgical intervention is not recommended for the management of hemophilia.
Primary Prevention
Primary prevention of hemophilia encompasses measures taken to raise awareness regarding the genetics of the disease and the genetic transmission of the condition. Having an X-linked mode of transmission, genetic counselling in female carriers and awareness are the main focus for the primary prevention of hemophilia.
Secondary Prevention
Effective measures for the secondary prevention of hemophilia include avoidance of invasive fetal monitoring of a hemophilic fetus, avoidance of operative vaginal delivery, administration of vitamin K injection with care, availability of the factor concentrate at the time of delivery, infusion of factor VIII or IX concentrate at least once weekly for ≥ 45 weeks per year, and the use of e-Diaries to improve record keeping of hemophilia patients' home treatment and bleeding episodes.