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Current Challenges in the Management of Hemophilia
Kenneth A. Bauer, MD
Participating Faculty: Hemophilia: Managing the Cost of Care With a Focus on Patient Outcomes
Post Test: Hemophilia: Managing the Cost of Care With a Focus on Patient Outcomes

Current Challenges in the Management of Hemophilia

Kenneth A. Bauer, MD
Hemophilia is characterized by genetic mutations resulting in the deficiency of factors critical to the normal process of coagulation, sometimes resulting in spontaneous bleeding into soft tissue, joints, and internal organs. The 2 most common subtypes are hemophilia A, or factor VIII deficiency, and hemophilia B, or factor IX deficiency. Hemophilia affects an estimated 20,000 individuals in the United States. The diagnosis and management of patients with severe hemophilia is complex, and requires preventive treatment (prophylaxis) to avoid bleeding episodes and related complications and the use of replacement therapy with coagulation factors during acute bleeding episodes. To achieve optimal long-term results, the treatment of patients with hemophilia requires a comprehensive approach coordinated by a multidisciplinary team of specialists. Hemophilia imposes a substantial burden from economic, societal, and patient perspectives.

Am J Manag Care. 2015;21:S112-S122
The body’s clotting mechanism is a stepwise process that requires a number of key proteins to ensure the cessation of any type of bleeding, from bleeding due to simple superficial abrasions to deep internal hemorrhages. A group of bleeding disorders referred to as hemophilia is characterized by genetic mutations resulting in the deficiency of factors critical to the normal process of coagulation.1 Derived from the Greek root “hemo,” meaning blood, and “philia,” meaning love, these disorders can present with spontaneous bleeding into soft tissue, joints, and internal organs, and were identified in humans as early as the second century.2 This article will review the pathophysiology and clinical features of, and management strategies for hemophilia A and B.

Classification

The 2 most common hemophilia subtypes are hemophilia A, or factor VIII deficiency, and hemophilia B, or factor IX deficiency, which are due to inherited mutations in the genes for these coagulation factors. Both genes are located on the X chromosome; therefore, essentially all affected individuals are male, whereas females who inherit the affected X chromosome are carriers.1 Rarely, females can develop hemophilia A or B if both genes are defective, if there is only 1 X chromosome (eg, Turner’s syndrome), or if the normal X chromosome is excessively inactivated (eg, via lyonization).

Hemophilia affects an estimated 20,000 individuals in the United States,3 with hemophilia A accounting for approximately 80% of cases.4 Numerous different mutations in the factor VIII gene have been described. Although the majority of patients have a family history of hemophilia, spontaneous mutations account for about one-third of new diagnoses.1 An inversion mutation of the F8 gene located on the long arm of the X chromosome5 is found in about 40% of patients with severe hemophilia A. A mutation in the F9 gene in hemophilia B results in a deficiency of the coagulation protein factor IX. Hemophilia B presents phenotypically similarly to hemophilia A.

Both hemophilia A and B show varying clinical symptoms based on the level of factor produced. The classification scheme for these disorders is based on severity and corresponding factor activity levels. The most severe manifestations are associated with factor levels less than 1%, with moderate symptoms associated with factor levels between 1% and 5%, and the mildest cases occurring with factor levels greater than 5%.6 Most of the cost in caring for hemophilia is incurred by patients with severe disease, who comprise half of all patients. Forty percent of patients with hemophilia have mild disease, and ten percent have moderate disease.7-10

Pathophysiology

In humans, the liver is the predominant source of factor VIII, which is then secreted and circulated in the bloodstream in an inactive form in a complex with von Willebrand factor.1 Several other tissues produce factor VIII, including the endothelium. Factor IX is produced entirely by the liver.

The coagulation cascade is a multi-step mechanism through which the body stops bleeding. To ensure adequate hemostasis, several key proteins are activated in a sequential fashion to ultimately form a fibrin plug, or clot. The tissue factor: FVIIa complex initiates the coagulation protease cascade, activating both FIX to FIXa and FX to FXa. This results in the formation of small amounts of thrombin, activating the cofactors FV and FVIII. Factor XI undergoes feedback activation by thrombin. The tenase complex (FVIIIa:FIXa) amplifies the clotting cascade by activation of FX to FXa. The prothrombinase complex (FVa:FXa) activates prothrombin to thrombin, the central protease of the clotting cascade. Fibrinogen is cleaved into soluble fibrin monomers by thrombin, which also activates FXIII to FXIIIa, resulting in a fibrin matrix. Thrombin then activates platelets by cleaving protease-activated receptors.11

Clinical Features Hemophilia A and B are present at birth in affected male infants; however, the disease may not become clinically evident until a few weeks or months into infancy.2 Patients with mild hemophilia typically experience excessive bleeding only after serious injury, trauma, or surgery, whereas those with moderate hemophilia bleed excessively after injury but also sometimes spontaneously. Patients with severe hemophilia commonly experience spontaneous bleeding episodes.6

The first symptom may be prolonged bleeding after circumcision, which is contraindicated if the diagnosis is suspected. In severe cases, patients experience spontaneous bleeding into joints and soft tissues, which ultimately restricts mobility and promotes inflammation. This can present clinically as impaired movement, posturing, or irritability in the male infant. Other sites of bleeding include mucosal surfaces and the central nervous system, the latter carrying particularly devastating consequences. Without treatment, the disease can be fatal in early infancy.1

Patients with moderate to mild hemophilia may not present with obvious signs of bleeding as mentioned above, but may experience prolonged bleeding after surgical procedures. This bleeding often prompts laboratory investigation. The clinical course for these patients is favorable, with fewer complications and reduced need for treatment compared with patients with severe hemophilia.1

Long-Term Complications

Hemarthroses and Hemophilic Arthropathy


Chronic hemarthroses are one of the most common long-term complications of hemophilia.12 Intra-articular bleeding may resolve on its own or with treatment in an acute case. However, many patients will experience recurrent bleeding and develop single or multiple target joints that are often painful and restrict their daily activity.13 Common sites are the knee, elbow, and ankle.14 Over time, chronic synovitis and chronic hemarthroses can result in degenerative joint disease, osteoarthritis, and osteophyte formation; surgery may be required if other more conservative treatment options are not successful.12,14

Clinical deformity of the joints in chronic hemophilic arthropathy can be difficult to treat. Because of the chronic synovitis and accumulation of fluid in the joint space, the joint can hypertrophy while the attached muscles atrophy. This severely restricts range of motion and may lead to the development of contractures. The large joints are the most commonly affected; arthropathy of the elbow can be especially problematic. Destruction of the elbow joint can result in ulnar nerve compression and neurologic complications. Severe limitations in range of motion, chronic pain, and crippling disability are the ultimate outcomes for many patients who experience chronic hemophilic arthropathy.15

Hematomas

Hematomas, another complication of hemophilia, generally do not arise spontaneously. Nonetheless, they can be problematic because even slight trauma can result in a hematoma, which may potentially impinge on organs, nerves, and vessels. These can form in any location, but are of particular concern when they occur in the muscles of distal limbs, due to the potential risk of compartment syndrome. Depending on the location, hematomas can grow quite large and escape clinical detection until neurologic complications related to nerve compression appear. In some cases, persistent severe anemia is the presenting symptom.1

Complications of Treatment

The treatment of hemophilia has involved risk for patients in the past. The early therapy for hemophilia involved the transfusion of plasma, which was inefficient because of the large volumes needed to achieve an adequate level of the factor being replaced.16 Factor therapy in the form of cryoprecipitate and clotting factor concentrates was an improvement over plasma transfusion and improved the quality of life (QOL) for patients with severe hemophilia by allowing home treatment, but the use of this treatment modality was soon hampered by widespread infection by hepatitis viruses and human immunodeficiency virus (HIV) in the early 1980s.17,18 Approximately 90% of patients with hemophilia were infected with the hepatitis C virus (HCV), and more than 55% of this cohort was coinfected with HIV.19 This problem ultimately led to the development of heat-treated products that reduced the transmission rate of these viruses. With the development of genetically engineered recombinant factor therapy in the 1990s, the risk of acquiring HCV and HIV from factor replacement therapy has been virtually eliminated. Furthermore, improvements in screening of blood donors, plasma purification, and viral inactivation procedures including pasteurization and solvent-detergent treatments have made current plasma-derived factor concentrates extremely safe therapeutic options.20

Development of Inhibitor Antibodies

An inhibitor is an antibody directed against either factor VIII or IX that may be created by the body following treatment to replenish the missing factor. Inhibitor antibodies form in 20% to 33% of patients with hemophilia A and are less likely to be a clinical problem in patients with factor IX deficiency; formation of inhibitors occurs in 1% to 6% of patients with hemophilia B.21 Patients with inhibitors experience poorer clinical outcomes than those who do not develop inhibitors, including more severe bleeding episodes, intracranial hemorrhage, and accelerated disability.22 The highest incidence and greatest severity of joint disease occur in patients with inhibitors.23

Inhibitors are more likely to develop in patients with severe hemophilia, who are already prone to spontaneous and serious bleeding episodes. The development of an inhibitor is influenced by several factors.21 The risk of inhibitors is increased in younger patients receiving the first several doses of factor.21 African American and Latino patients are more likely to develop an inhibitor compared with Caucasian patients.24 This variability in inhibitor type, level, and development is likely reflective of the heterogeneity of genetic mutations in hemophilia, particularly in hemophilia A. In addition, genetic differences in an individual’s immune system apart from the F8 gene mutation may render certain patients more susceptible than others to inhibitor formation.21 It remains controversial whether the type of factor concentrate influences the risk of inhibitor development.25 To address the question of whether recombinant versus plasma-derived factor concentrates influence the risk of inhibitor development, the Survey of Inhibitors in Plasma Product Exposed Toddlers (SIPPET) study has been designed to compare inhibitor incidence in patients exposed to the different concentrates. Results of this ongoing study are awaited.

Comorbid Conditions

With advances in hemophilia care, the increased life expectancy for patients with hemophilia has resulted in older patients experiencing comorbid conditions not previously observed in this population. In a study of patients 40 years or older with hemophilia, the average number of comorbidities was between 3 and 6. The most common comorbidities were identified as chronic HCV, hypertension, HIV, chronic arthropathy, and overweight/ obesity.26

Blood-Borne Infection

 
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