Medical Policy

Policy Num:       M5.001.017
Policy Name:     Hemophilia Antihemophilic Factor
Policy ID:          [M5.001.017] [Ac/ MA / M+ / P ][01.001.023]

Last Review:       May 10, 2024
Next Review:      May 20, 2025
 

Related Article:

A56482 Hemophilia Factor Products

Hemophilia Antihemophilic Factor

Summary

The hemophilias are a group of related bleeding disorders that most commonly are inherited. Inherited bleeding disorders include abnormalities of coagulation factors and platelet function; the most common of these disorders is von Willebrand disease. However, when the term "hemophilia" is used, it most often refers to the following two disorders:

●Factor VIII deficiency (hemophilia A)

●Factor IX deficiency (hemophilia B, also called Christmas disease)

Patients with hemophilia, particularly those with severe disease, develop bleeding episodes that are treated with replacement of the missing factor (ie, factor VIII or factor IX concentrates). A complication of hemophilia treatment is the development of an inhibitor, which usually occurs shortly after replacement therapy has been initiated. The inhibitors are antibodies (primarily IgG) directed against the specific deficient factor.

Development of inhibitors is typically assessed in relationship to the number of exposure days (ie, days on which the patient has received one or more doses of replacement factor).

OBJECTIVE

This topic reviews the pathophysiology risk factors for inhibitor development in hemophilia A and B, as well as our approach to inhibitor eradication by immune tolerance induction.

POLICY STATEMENTS

Criteria for the Management of Anti-Hemophilic Factors

1. The prescription must be written by a hematologist.

2. Anti-hemophiliac factors will be covered for indications approved by the FDA (refer to Table 1).

3. Prophylactic Therapy.

a. Therapy. prophylactic with anti-hemophiliac factors may be considered in the following situations:

▪ Patient with severe hemophilia A or B defined by a level of coagulation factor <1%.

▪ Patients with repeated episodes of bleeding, mainly in the joints. Secondary prophylaxis can be considered for 4-8 weeks.

▪ Previous prophylactic therapy and after surgery or invasive procedure for up to 14 days.

4. Anti-hemophilic factors will be available for the management of the following cases

a. Suspected bleeding in joints or muscles

b. Any injury to the head, neck, mouth or eyes or evidence of bleeding in some of these areas.

c. Unusual headache, particularly if it is followed by trauma

d. Severe pain or swelling somewhere in the body  and. Any open wound that requires closure by surgical or adhesive means

f. History of an accident or trauma that may result in internal bleeding

g. Any procedure or invasive surgery

h. Persistent or profuse bleeding

i. Gastrointestinal bleeding

j. Fractures, dislocations or sprains

Refer to Table 3 for plasma factor levels and duration of replacement therapy recommended by the World Federation of Hemophilia.

Note: The calculated dose should be adjusted to the unit of the available vial and to the patient's response

Recommendations of plasma level of factor and duration of administration1

POLICY GUIDELINES

Medication will be covered as per indications above.

BACKGROUND

Hemophilia A and B are recessive diseases linked to the X chromosome that occur in male children of female carriers. However, sometimes hemophilia must

be differentiated from other coagulation disorders when the family history is negative or unknown. The differentiation between hemophilia and other disorders,

such as some types of von Willebrand disease or acquired factor inhibitors, and the distinction between hemophilia A and B are crucial for proper management.

Hemophilia typically refers to a hereditary bleeding disorder caused by deficiency of coagulation factor VIII (hemophilia A), factor IX (hemophilia B), or factor XI

(hemophilia C)

·     Hemophilia A- Inherits factor VIII deficiency (factor 8 [F8]), an X-aligned recessive disorder.

•     Hemophilia B- inherits factor IX deficiency (factor 9 [F9]), also called Christmas Disease, a recessive disorder linked to the X chromosome.

•     Hemophilia C-Inherits factor XI deficiency (factor II); also called Rosenthl syndrome; an autosomal recessive disorder Rarely, heterozygotes may

      have bled (caused by, autosomal dominant transmission, due to heterodimer binding). Hemophilia C is especially common in Ashkenazi Jews (Jews

      from Eastern Europe).

•   Acquired factor deficiencies- Deficiencies of acquired clotting factors caused by an autoantibody (often with factor VIII) is sometimes referred to as

    acquired hemophilia. The terms "acquired factor inhibitors" or "acquired factor deficiency" are preferable to avoid classifying the patient as having

    hemophilia A or B.

•  Inhibitors- In hemophilia, inhibitor refers to an autoantibody that it is usually formed in response to the infused factor. Inhibitors are more common in

   people with very low baseline factor levels.

•  Gravity- Hemophilia is characterized as mild, moderate or severe, based on the activity level of the residual factor or baseline (also referred to as "factor

   level"); this is expressed as a percentage of normal or in international units (IU) / ml. Levels of factor normally correlate with the degree of bleeding and

   symptoms present.

•  Severe hemophilia- Severe hemophilia is defined as factor activity of <1 percent, which corresponds to <0.01 IU / ml /

•  Modern hemophilia - Moderate hemophilia is defined as a level of factor activity> 1 percent of normal and <5 percent of normal, corresponding to> 0.1

   and <0.05 IU / ml.

•  Mild hemophilia - Mild hemophilia is defined as a factor activity level> 5 percent of normal and <40 percent normal (> 0.05 and <0.40 IU / ml.

Epidemiology

Hemophilia A is more common than hemophilia B. Hemophilia A is also more likely to be serious.

• Hemophilia A- Hemophilia A occurs in approximately 1 in 5,000 live-born males. Approximately two   thirds have severe disease (ie, factor IX activity <1

  percent of normal).

Severe hemophilia is almost exclusively a disease of men, although women may be affected in some rare cases (eg, compound heterozygosity, skewed

lionization, loss of X chromosome). In contrast, mild hemophilia has been described in up to a quarter of the carrier women who are heterozygous.

Hemophilia occurs in all ethnic groups and throughout the world. A publication of the World Hemophilia Foundation estimates that 43 percent of the population

with hemophilia in the world lives in India, Bangladesh, Indonesia, and China, of which only 12 percent have been diagnosed [4].

Clinical manifestations

The clinical manifestations of hemophilia are related to bleeding, problems with haemostasis, sequelae of hemorrhage, or complications of coagulation factor

infusion.

Bleeding sites

Intracranial hemorrhage - intracranial hemorrhage (ICH) is relatively rare compared to other sites of bleeding, but it is one of the most dangerous and life-

threatening events in people with hemophilia [24].

The joints and muscles. Hemarthrosis (ie, bleeding in a joint) is the most common site of bleeding in outpatients, accounting for up to 80 percent of bleeding

[29,30]. Spontaneous hemarthrosis are characteristic of severe disease. Bleeding in the joint cavity originates in the synovial vessels.

Epistaxis, oral bleeding, gastrointestinal. Bleeding can occur from numerous sites of the pharynx gold, such as the nose, oral mucosa, and gum; Sometimes

this type of bleeding follows minor trauma or dental procedures. In addition, coughing or vomiting can produce hemorrhage in the posterior pharynx, which can

lead to compromising air life or airway obstruction.

Genitourinary tract. Hematuria is a frequent manifestation of severe hemophilia; It is usually benign and is not associated with progressive loss of kidney f

unction. Bleeding can come from the kidneys or the bladder and may persist for days or weeks. Urethral obstruction with colic may occur when clots form.

Other etiologies should be excluded if a particular episode is associated with pain or is not sensitive to therapeutic intervention.

Development of inhibitors

An important complication in patients with severe hemophilia A is the development of autoantibodies that block the activity of the relevant factor (ie, inhibitors).

These inhibitory antibodies develop in response to the exogenous factor; occur in approximately 25 percent of patients with severe hemophilia A and 3 to 5

percent with severe hemophilia B. Inhibitors are much less common in patients with mild or moderate disease, presumably because the infusion factor is not as

likely to be recognized as a foreign protein in these individuals. Inhibitors complicate episodes of bleeding, since they diminish the response capacity to factor

infusions; In addition, anaphylactic reactions can occur with factor IX inhibitors.

REGULATORY STATUS

N/A

RATIONALE

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.
 

Population Reference No. 1 Policy Statement

For individuals with treatment of classic type A hemophilia, including perioperative management. Interventions of interest: Antihemophilic factor derived from human plasma, Monoclate-P, Koate-DVI. Comparators of interest are: Standard treatment without management of antihemophilic factors. Relevant outcome includes: Overall survival, Change in disease status, Quality of life, Treatment related morbidity. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

Population Reference No. 2 Policy Statement

For Individuals with Control and prevention of hemorrhagic episodes in classic hemophilia A.  Interventions of interest: Antihemophilic factor derived from human plasma and Hemofil M. Comparators of interest are:Standard treatment without management of antihemophilic factors. Relevant outcome includes: Overall survival, Change in disease status, Quality of life and Treatment related morbidity. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

Population Reference No. 3 Policy Statement

For individuals with Control and prevention of bleeding in adults and children with hemophilia A. Perioperative management of hemophilia A and Prophylaxis to reduce bleeding episodes and reduce joint damage in patients with hemophilia A and no previous damage. Interventions of interest are Antihemophilic facto, Recombinant, Helixate FS and Kogenate FS. Comparators of interest are standard treatment without management of antihemophilic factors. Relevant outcome includes Overall survival, Change in disease status, Quality of life and treatment related morbidity. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

Population Reference No. 4 Policy Statement

For individuals with control and prevention of bleeding in adults and children with hemophilia A, Perioperative management of hemophilia A and can be used to control bleeding in the presence of low levels of factor VIII inhibitors (<10 BU / mL) in hemophilia A. Interventions of interest: antihemophilic factor, recombinantand recombinate. Comparators of interest are standard treatment without management of antihemophilic factors. Relevant outcome includes: overall survival, change in disease status, quality of life and treatment related morbidity. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

Population Reference No. 5 Policy Statement

For Individuals with Control and prevention of bleeding in adults and children with hemophilia A, perioperative management of hemophilia A and routine prophylaxis to prevent / reduce episodes of bleeding in hemophilia A. Interventions of interest: Antihemophilic factor, Recombinant and advate. Comparators of interest are standard treatment without management of antihemophilic factors. Relevant outcome includes overall survival, change in disease status, quality of life and treatment related morbidity. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

Population Reference No. 6 Policy Statement

For individuals with control and prevention of hemorrhagic episodes and for surgical prophylaxis in patients with hemophilia A (congenital factor VIII deficiency or classic hemophilia).  Interventions of interest: antihemophilic factor, recombinant and refacto. Comparators of interest are standard treatment without management of antihemophilic factors. Relevant outcome includes: overall survival, change in disease status, quality of life and treatment related morbidity. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 7 Policy Statement

For individuals with control and prevention of bleeding in adults and children with hemophilia A and surgical prophylaxis for hemophilia A. Interventions of interest: Anti-hemophilic factor, recombinant (Removal of Domain B) and Xyntha. Comparators of interest are: standard treatment without management of antihemophilic factors.  Relevant outcome includes: overall survival, change in disease status, quality of life and treatment related morbidity. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 8 Policy Statement

For individuals with control and prevention of bleeding in adults and children with hemophilia B, including peri-operative management. Interventions of interest: Factor IX, recombinant and BeneFIX.  Comparators of interest are:standard treatment without management of antihemophilic factors. Relevant outcome includes: overall survival, change in disease status, quality of life and treatment related morbidity. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 9 Policy Statement

For individuals with Control and prevention of bleeding episodes in adults with hemophilia B, perioperative management in adults with hemophilia B.and routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults with hemophilia B. Interventions of interest: Factor IX, recombinant and
 Rixubis. Comparators of interest are: standard treatment without management of antihemophilic factors.  Relevant outcome includes: overall survival, change in disease status, quality of life and treatment related morbidity.  The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 10 Policy Statement

For individuals with Prevention and control of bleeding in patients with hemophilia B.  Interventions of interest are Factor IX, derived from human plasma, Mononine and AlphaNine SD. Comparators of interest are standard treatment without management of antihemophilic factors.  Relevant outcome includes: overall survival, change in disease status, quality of life and treatment related morbidity.  The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 11 Policy Statement

For individuals with prevention and control of bleeding episodes in patients with hemophilia B. The interventions of interest: Factor IX complex derived from human plasma, Bebulin, Bebulin VH and Profilnine SD.  The comparators of interest are standard treatment without management of antihemophilic factors.  The relevant outcome includes: overall survival, change in disease status, quality of life and treatment related morbidity. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 12 Policy Statement

For individuals with control of spontaneous bleeding or for perioperative management of patients with hemophilia A or B and inhibitors. Interventions of interest:
Anti-coagulant inhibitor complex, plasma derivatives, FEIBA NF and FEIBA VH. Comparators of interest are standard treatment without management of antihemophilic factors. Relevant outcome includes overall survival, change in disease status, quality of life and treatment related morbidity. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 13 Policy Statement

For individuals with treatment of hemorrhagic episodes and perioperative management in patients with hemophilia A or B and inhibitors or with acquired hemophilia and treatment of bleeding episodes and peri-operative management in patients with congenital factor VII. Interventions of interest are Factor VIIa, recombinant and NovoSeven RT. Comparators of interest are: standard treatment without management of antihemophilic factors. Relevant outcome includes: overall survival, change in disease status, quality of life and treatment related morbidity.  The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

Population Reference No. 14 Policy Statement

For individuals with treatment and prevention of bleeding in patients with hemophilia A, treatment of bleeding in adults and children with von Willebrand disease, including spontaneous episodes or trauma-induced episodes, prevention of excessive bleeding during and after surgery where desmopressin is not effective or contraindicated, alphanate is not indicated for severe von Willebrand disease.  Interventions of interest are complex antihemophilic factor derived from human plasma / von Willebrand factor, Humate-P and Alphanate.  Comparators of interest are standard treatment without management of antihemophilic factors. The relevant outcome includes overall survival, change in disease status, quality of life are treatment related morbidity. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 15 Policy Statement

For individuals with treatment of spontaneous hemorrhagic episodes or trauma induced in patients with severe or mild / moderate von Willebrand disease, where desmopressin is not effective or contraindicated. Interventions of interest are Factor VII complex derived from human plasma with von Willebrand factor and Wilate. Comparators of interest are standard treatment without management of antihemophilic factors. Relevant outcome includes overall survival, change in disease status, quality of life and treatment related morbidity. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

Medicare Coverage

Medicare Article A56482

Indications and Limitations of Coverage 

Anti-inhibitor coagulant complex, AICC, is a drug used to treat hemophilia in patients with factor VIII inhibitor antibodies. AICC has been shown to be safe and effective and has Medicare coverage when furnished to patients with hemophilia A and inhibitor antibodies to factor VIII who have major bleeding episodes and who fail to respond to other, less expensive therapies.

References

. National Hemophilia Foundation. Guidelines for emergency department management of individuals with hemophilia. MASAC Document #175. October 15, 2006. Disponible en www.hemophilia.org. Accedido 10 de noviembre de 2007.

2. Abshire TC, Manco MJ, Shapiro AD. Prophylaxis versus Episodic Treatment to Prevent Joint Disease in Boys with Severe Hemophilia. N Engl Med 2007; 357: 535-44.

3. National Hemophilia Foundation. Types of Bleeding Disorders. http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=179&contentid=45&rptname=bleeding. Accedido 14 de noviembre de 2012

4. Srivastava A, Brewer AK, Mauser-Bunshocten EP, et al. Guidelines for the management of hemophilia. Haemophilia. 2012. DOI: 10.1111/j.1365-2516.2012.02909.x.

5. National Hemophilia Foundation. MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders. MASAC Document #210. http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=57&contentid=693. Accedido 14 de noviembre de 2012

6. Hemophilia of Georgia. Protocols for the treatment of hemophilia and von Willebrand disease. Third edition. World Federation of Hemophilia. http://www.wfh.org/en/page.aspx?pid=1270. Accedido 14 de noviembre de 2012

7. National Hemophilia Foundation. Factor XIII Deficiency. http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=190&contentid=58&rptname=bleeding. Accedido 14 de noviembre de 2012

8. National Hemophilia Foundation. Factor VII Deficiency. http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=187&contentid=50&rptname=bleeding. Accedido 14 de noviembre de 2012

9. Hemofil M [package insert]. Westlake Village, CA: Baxter Healthcare; 2010.

10. Koate-DVI [package insert]. Research Triangle Park, NC: Talecris Biotherapeutics; 2011.

11. Monoclate-P [package insert]. Kankakee, IL: CSL Behring, LCC; 2010.

12. Advate [package insert]. Westlake Village, CA: Baxter Healthcare; 2012.

13. Helixate FS [package insert]. Kankakee, IL: CSL Behring, LCC; 2011.

14. Kogenate FS [package insert]. Tarrytown, NY: Bayer Healthcare; 2012.

15. Recombinate [package insert]. Westlake Village, CA: Baxter Healthcare; 2010.

16. Xyntha [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals; 2012.

17. BeneFIX [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals; 2011.

18. AlphaNine SD [package insert]. Los Angeles, CA: Grifols Biologicals, Inc; 2011.

19. Mononine [package insert]. Kankakee, IL: CSL Behring, LCC; 2011.

20. Bebulin [package insert]. Westlake Village, CA: Baxter Healthcare; 2011.

21. Profilnine SD [package insert]. Los Angeles, CA: Grifols Biologicals, Inc; 2011.

22. FEIBA NF [package insert]. Westlake Village, CA: Baxter Healthcare; 2011.

23. NovoSeven RT [package insert]. Princeton, NJ: Novo Nordisk Inc.; 2012.

24. Simpson E, Lin Y, Stanworth S, Birchall J, Doree C, Hyde C. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev. 2012;3:CD005011.

25. Micromedex Healthcare Series [database online]. Greenwood Village, CO: Thomson Reuters (Healthcare), Inc; 2012. http://www.thomsonhc.com/hcs/librarian. Accedido 14 de noviembre de 2012

26. Alphanate [package insert]. Los Angeles, CA: Grifols Biologicals, Inc; 2008.

27. Humate-P [package insert]. Kankakee, IL: CSL Behring, LCC; 2010.

28. Wilate [package insert]. Hoboken, NJ: Octapharma USA Inc.; 2010.

29. Corifact [package insert]. Kankakee, IL: CSL Behring, LCC; 2011.

30. ReFacto [package insert]. Wyeth Pharmaceuticals, Philadelphia, PA 19101.

31. Brooker M. Registry of clotting factor concentrates. Ninth edition, 2012. World Federation of Hemophilia. http://www.wfh.org/en/page.aspx?pid=1270. Accedido 14 de noviembre de 2012

32. Rixubis [package insert]. Baxter Healthcare Corporation, Westlake Village, CA 06-2013

33.Kempton CL, White GC 2nd. How we treat a hemophilia A patient with a factor VIII inhibitor. Blood 2009; 113:11.

34. https://www.novo-pi.com/rebinyn.pdf

35. https://www.novomedlink.com/rare-bleeding-disorders/products/treatments/rebinyn.html

36. Medicare Article  A56482

Codes

Applicable Modifiers

N/A

Policy History