Hemophilia and von Willebrand disease (VWD) are the most common congenital bleeding disorders. Bleeding disorders are a group of conditions that result when the blood cannot clot properly. In normal clotting, platelets stick together and form a plug at the site of vascular damage. Proteins in the blood called coagulation factors then interact in a series of physiological processes to form an insoluble fibrin clot that holds the platelets in place and allows healing to occur at the site of the injury while preventing blood from escaping the blood vessel. The coagulation factors are indicated by Roman numerals (e.g., VII, VIII, and IX).
HEMOPHILIA --- TYPES A, B, C
Hemophilia is a rare, typically inherited, bleeding disorder that can range from mild to severe, depending on how much clotting factor is present in the blood. Hemophilia A is considered the classic form of the disease, and is a consequence of a congenital deficiency of factor VIII. Hemophilia B, also called Christmas disease, is the result of a congenital deficiency of factor IX. Hemophilia C, a rare form of hemophilia, is the result of a congenital deficiency of factor XI. The defect results in the insufficient generation of thrombin by factor VIIIa, factor IX, or factor XI complex by means of the intrinsic pathway of the coagulation cascade. Individuals with less than 1 percent normal factor are considered to have severe hemophilia. Individuals with 1 percent to 5 percent normal factor are considered to have moderately severe hemophilia marked by spontaneous bleeding from the oral mucosa, joint bleeding, and bleeding from minor trauma. Individuals with more that 5 percent but less than 40 percent normal factor are considered to have mild hemophilia. Clinical bleeding symptom criteria have also been used for hemophilia classification when individuals have bleeding symptoms different than what would be expected from the plasma coagulant levels.
Because blood does not clot properly without enough clotting factor, any cut or injury carries the risk of excessive bleeding. The hallmark of congenital hemophilia is hemorrhage into the joints, or hemarthrosis. Synovial cells in joints synthesize high levels of tissue factor inhibitor, which predisposes hemophilic joints to bleed. This bleeding leads to progressive inflammation, deterioration, and deformities of the joint. In addition, people with hemophilia may suffer from internal bleeding that can damage organs and tissues over time.
Treatment options include fresh frozen plasma and clotting factor products that are made from human blood products such as donated plasma, or synthetic (recombinant) products. The administration of antihemophilic factor products temporarily replaces the missing clotting factor to treat or prevent bleeding episodes. Human preparations are manufactured from human plasma obtained and screened from tested United States donors for use in the treatment of bleeding episodes. Improved screening techniques and specific viral-inactivation treatments have made these products safer. A major breakthrough has enabled scientists to create synthetic blood factors, called recombinants, in the laboratory by cloning the genes responsible for specific clotting factors. Today’s factor replacement therapies are much safer, reducing the risk of viral pathogens such as hepatitis B, hepatitis C, and HIV infection.
Hemophilia A (Factor VIII Deficiency)
Some examples of the human preparations of coagulation factor VIII for the treatment of hemophilia A include, Alphanate®, Koate®DVI, Hemophil M, Humate-P®, and Wilate®. Recombinant antihemophilic factor products for use in those with hemophilia A include Advate®, Adynovate, Afstyla®, Eloctate®, Esperoct®, Jivi®, Kogenate FS®, Kovaltry®, Novoeight®, Nuwiq®, Recombinate®, and Xyntha®. Additionally, Hemlibra® is an example of a humanized monoclonal antibody. These products have various US Food and Drug Administration (FDA)--labeled indications, depending on the specific product, which may include prevention and control of bleeding episodes; short-term routine prophylactic treatment to reduce or prevent spontaneous musculoskeletal bleeding episodes and the risk of joint damage; and/or prevention or control of bleeding in surgical procedures in certain individuals with hemophilia A.
Jivi® is not indicated for use in previously untreated individuals, and it also not indicated for use in children less than 12 years of age due to a greater risk for hypersensitivity reactions.
Hemophilia B (Factor IX Deficiency)
For the treatment of hemophilia B, human preparations of coagulation factor IX includes Alphanine® SD, Mononine®, and Profilnine® SD. Recombinant antihemophilic factor IX products include Alprolix®, BeneFIX®, Idelvion®, Ixinity®, Rebinyn®, Rixubis®. These products have various US Food and Drug Administration (FDA)--labeled indications, depending on the specific product, which may include the prevention or control of bleeding during surgical procedures. In addition to those indications, Alprolix® and Rixubis® also have an FDA approval for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in individuals with hemophilia B.
Hemophilia C (Factor XI Deficiency)
For the treatment of hemophilia C, replacement therapy via factor XI concentrates are not currently available in the United States.
HEMOPHILIA WITH INHIBITORS TO FACTORS VIII OR IX
Some individuals with severe forms of hemophilia A or hemophilia B develop autoantibody inhibitors that can neutralize factor VIII or factor IX, respectively. They neutralize the coagulant effects of replacement therapy. The levels of factor inhibitors are often measured by using the Bethesda method. The Bethesda method quantitates the inhibitor titer.
Treatment of hemophilia with inhibitors to factors VIII or IX is complex and ranges from products that increase factor levels to factor-bypassing agents. Several different immune tolerance therapy regimens have been developed. For example, if attempts to lower antibody levels with immunosuppressants or corticosteroids have been unsuccessful, large doses of replacement factor VIII or factor IX can be used to try to produce inhibitor suppression, or eradication can be utilized. In addition, genetically engineered or recombinant antihemophilic factor VIII (e.g., Advate®, Kogenate FS®, Recombinate®) has the same biological effects as human factor VIII and has FDA approved indications for certain individuals with factor VIII inhibitor disorder with inhibitor titers less than 10 Bethesda units per milliliter.
Additionally, FEIBA is a human plasma-derived activated prothrombin complex concentrate (APCC) whose Factor VIII inhibitor bypassing activity controls spontaneous bleeding episodes and is also used during surgical interventions in individuals who have hemophilia A and hemophilia B with inhibitors. In December 2013, FEIBA received FDA approval for use as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A or B who have developed inhibitors.
Recombinant activated coagulation factor VIIa (e.g., NovoSevenRT®, Sevenfact®) has FDA labeled indications for use in the treatment of bleeding episodes or for the prevention or control of bleeding in surgical interventions and invasive procedures in certain individuals with hemophilia who have inhibitors to factor VIII or factor IX.
Emicizumab-kxwh (Hemlibra®) is a human monoclonal antibody that was approved by the FDA for the treatment of hemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors.
FACTOR I DEFICIENCY, CONGENITAL
Fibrinogen is a soluble protein in the bloodstream that is required to form clots. Fibrinogen is broken down to fibrin by the enzyme thrombin. Factor I (Fibrinogen) deficiency is a rare inherited bleeding disorder that is comprised of an absence of fibrinogen (afibrinogenemia), a low level of fibrinogen (hypofibrinogenemia), or fibrinogen of low quality that does not clot properly (dysfibrinogenemia).
Management of acute hemorrhage include cryoprecipitate or fresh frozen plasma. Additionally, there are FDA-approved fibrinogen concentrates (Human), Fibryga® and RiaSTAP®, indicated for the treatment of acute bleeding episodes in individuals with congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia. (NOTE: Fibryga® and RiaSTAP® are not indicated for dysfibrinogenemia.)
FACTOR VII DEFICIENCY, CONGENITAL
Factor VII is one of the vitamin K--dependent coagulation factors synthesized in the liver. Plasma factor VII predominately exists in an inactive form; however, approximately one percent circulates in the activated form as factor VIIa. In response to injury or inflammation, factor VIIa activates other clotting factors, initiating the coagulation cascade. Congenital factor VII deficiency is a rare hemorrhagic disorder. The severity of the bleeding manifestations in affected individuals varies from mild to severe.
Management of acute hemorrhage primarily consists of administration of factor VII to treat bleeding episodes. Due to the short half-life of factor VII, a treatment alternative may include recombinant-activated coagulation factor VIIa (NovoSevenRT®), which is similar to human plasma--derived factor VIIa, with FDA labeled indications that include the treatment of bleeding episodes and the prevention or control of bleeding in surgical interventions or invasive procedures in certain individuals who have a factor VII deficiency. The need for prophylaxis is determined by the individual's clinical presentation and the number of clinically significant bleeding episodes requiring intervention.
FACTOR VIII DEFICIENCY, ACQUIRED
Acquired hemophilia A is the development of factor VIII inhibitors (autoantibodies) in persons without a history of factor VIII deficiency. It develops with a frequency of one case per one million population per year. Though the disorder is rare, it is known to cause significant morbidity and mortality. It may be associated with other disease conditions (e.g., collagen vascular disease, drug reaction, lymphoproliferative malignancies), or it can be idiopathic.
Early treatment is directed toward achieving hemostasis and inhibitor eradication. Appropriate options for the treatment of bleeding episodes or for the prevention or control of bleeding in surgical procedures will depend on clinical presentation, and may include the use of immunosuppressive agents, desmopressin (1-desamino-8-D-arginine vasopressin [DDAVP]), Obizur and other factor VIII concentrates, antihemophilic factor VIII/von Willebrand factor complex (human) (Alphanate®), recombinant-activated coagulation factor VIIa (NovoSevenRT®) or FEIBA.
FACTOR VIII DEFICIENCY, CONGENITAL
See HEMOPHILIA A section (above).
FACTOR IX DEFICIENCY
See HEMOPHILIA B section (above).
FACTOR X DEFICIENCY, ACQUIRED OR CONGENITAL
Factor X is a vitamin K–dependent factor that is the first step in the common pathway to thrombus formation. Factor X can be activated by either the intrinsic or extrinsic clotting cascades. Factor X clotting deficiency may be acquired or congenital.
Treatment options include fresh frozen plasma or plasma-derived prothrombin complex concentrates (plasma products containing a combination of vitamin K-dependent proteins) to stop or prevent bleeding. Additionally, Coagadex® is the first human factor X concentrate approved by the FDA for the treatment of hereditary factor X deficiency. It is indicated for routine prophylaxis to reduce the frequency of bleeding episodes, on-demand treatment and control of bleeding episodes, and for perioperative (period extending from the time of hospitalization for surgery to the time of discharge) management of bleeding in patients with mild and moderate hereditary Factor X deficiency.
FACTOR XI DEFICIENCY, ACQUIRED OR CONGENITAL
See HEMOPHILIA C section (above).
FACTOR XIII DEFICIENCY
ACQUIRED FACTOR XIII DEFICIENCY
Acquired factor XIII deficiency has been described in association with a variety of diseases such as hepatic failure, inflammatory bowel disease, and myeloid leukemia. Deficiency of factor XIII can be corrected with infusions of fresh frozen plasma, cryoprecipitate, or factor XIII concentrates.
CONGENITAL FACTOR XIII DEFICIENCY
Factor XIII is the protein responsible for stabilizing the formation of a blood clot. Congenital factor XIII deficiency is known as fibrin-stabilizing factor deficiency. In the absence of factor XIII, a clot will still develop, but it will remain unstable. This condition, a rare autosomal disease, is perhaps the rarest of all factor deficiencies. It is a potentially life-threatening bleeding disorder in which the blood clots normally but the clots formed are unstable, leading to recurrent bleeding. It is estimated that the condition affects one in every three million to five million births. It affects men and women equally. Most individuals with factor XIII deficiency experience symptoms from birth, often bleeding from the umbilical cord stump. Symptoms such as menorrhagia, bleeding in soft tissue, abnormal bleeding during or after injury or surgery, and hemarthrosis tend to continue throughout life but may be managed prophylactically.
Treatment options for factor XIII deficiency include cryoprecipitate or fresh frozen plasma, which are made from human blood products such as donated plasma. In February 2011, Factor XIII Concentrate (Human) (Corifact®) was approved by the FDA for routine prophylactic treatment of congenital factor XIII deficiency and was later indicated for the peri-operative management of surgical bleeding in adult and pediatric patients with congenital factor XIII deficiency. Corifact® received orphan drug designation by the FDA because it is intended for use in a rare disease or condition. It was approved for marketing under the FDA's accelerated approval regulations. Additionally, in December 2013, the FDA approved the first recombinant product, Tretten®, for use in the routine prevention of bleeding in those who have congenital Factor XIII A-subunit deficiency.
GLYCOPROTEIN COMPLEX IIb/IIIa DEFICIENCY
Glanzmann’s thrombasthenia is a rare inherited bleeding disorder caused by an abnormality in the glycoprotein complex IIb/IIIa. This disorder prevents platelets from initiating clot formation.
Treatment options for Glanzmann’s thrombasthenia include blood platelet transfusions and recombinant-activated coagulation factor VIIa (NovoSevenRT®). NovoSevenRT® was approved by the FDA for the treatment of bleeding episodes and peri-operative management in adults and children with Glanzmann’s thrombasthenia with refractoriness to platelet transfusions, with or without antibodies to platelets.
VON WILLEBRAND DISEASE (VWD)
Von Willebrand disease (VWD) is a congenital condition that results when there is an abnormality, either quantitative or qualitative, of von Willebrand factor. von Willebrand factor is required for normal platelet adhesion: it functions in both primary (involving platelet adhesion) and secondary (involving factor VIII) hemostasis. In primary hemostasis, von Willebrand factor attaches onto the platelet surface and acts as an adhesive bridge between the platelets and the damaged subendothelium at the site of vascular injury. In secondary hemostasis, von Willebrand factor protects factor VIII from degradation and delivers it to the site of injury. Bleeding tendency is usually mild and is characterized by a tendency for easy bruising, frequent epistaxis, and menorrhagia. VWD is classified into three different types (Types 1, 2, and 3), based on the levels of von Willebrand factor and factor VIII activity in the blood. Type 1 is the mildest and most common form; Type 3 is the most severe and least common form.
Desmopressin (1-desamino-8-D-arginine vasopressin [DDAVP]) is a synthetic vasopressin analogue that has become a mainstay of therapy for most individuals with mild VWD. At appropriate doses, desmopressin causes a two-fold to five-fold increase in plasma von Willebrand factor and factor VIII concentrations in individuals who are healthy and responsive. Desmopressin can be used to treat bleeding complications or to prepare individuals with VWD for surgery. In a subtype of VWD (type IIB), desmopressin may cause a paradoxical drop in the platelet count and should not be used in a therapeutic setting without prior testing to see how the individual responds.
The goal of therapy is to correct the defect in platelet adhesiveness (by raising the level of effective von Willebrand factor) and to correct the defect in blood coagulation (by raising the level of factor VIII). Products such as von Willebrand factor/coagulation factor VIII complex (human) (Wilate®) and antihemophilic factor/von Willebrand factor complexes (human) (Alphanate® and Humate-P) are developed from human plasma consisting of two different proteins (factor VIII and von Willebrand factor).
Wilate® has been FDA approved for the treatment of spontaneous or trauma induced bleeding episodes in certain individuals with severe VWD, as well as individuals with mild or moderate VWD in whom desmopressin is known or suspected to be ineffective or contraindicated. This product is also indicated for the perioperative management of bleeding.
Alphanate® has been FDA approved for surgical and/or invasive procedures in individuals with VWD in whom desmopressin (DDAVP) is either ineffective or contraindicated. This product is not indicated for individuals with severe VWD (Type 3) undergoing major surgery.
Humate-P® has been approved by the FDA for the treatment of spontaneous and trauma-induced bleeding episodes and for the prevention of excessive bleeding related to surgery in adult and pediatric individuals with VWD. The FDA has also approved Humate-P® in individuals with mild and moderate VWD for whom desmopressin is known or suspected to be ineffective. In addition, Humate-P® is the first product specifically FDA approved for individuals with severe VWD who are undergoing major surgery.
Additionally, a synthetic (recombinant) product, Vonvendi, has been FDA approved for the on-demand treatment and control of bleeding episodes in adults diagnosed with von Willebrand disease. This product was later approved for the perioperative management of bleeding.
There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.