The Basics

Clotting factors are proteins present in plasma that work together to stop bleeding. Hemophilia is an inherited bleeding disorder caused by low levels or a complete lack of certain clotting factors. Individuals with hemophilia A, the more common type of hemophilia, do not have enough clotting factor VIII (FVIII) in their plasma. Those with hemophilia B are deficient in clotting factor IX (FIX).2


Von Willebrand disease (VWD) is a genetic bleeding disorder caused by missing or defective von Willebrand factor (VWF).2

 

Hemophilia A occurs in 1 in 5000 male births and is about 4 times as common as hemophilia B. The number of people with hemophilia in the US is estimated to be approximately 20,000.1

VWD is the most common bleeding disorder in the US, affecting 1-3% of the population.7

The worldwide incidence of hemophilia is not well known, but IS estimated at more than 400,000 people.2

What is hemophilia?

Hemophilia is a bleeding disorder that affects the way blood clots.1 People born with hemophilia are missing some or all of a type of protein called clotting factor. The 2 main types of hemophilia are hemophilia A and hemophilia B. People with hemophilia A are missing some or all of clotting factor VIII. People with hemophilia B are missing some or all of a different clotting factor called factor IX.2

Clotting factors are important because they help in the clotting process. When a blood vessel is cut or injured, clotting factors help platelets (which are disc-shaped blood cell fragments made in your bone marrow) form a plug in the wound that stops the bleeding.1,2

Why do mostly males have hemophilia A?

Hemophilia A is caused by a defective gene located on the X chromosome. Females have 2 X chromosomes, and males have 1 X chromosome and 1 Y chromosome. The defective gene is passed down from a mother, who carries it (but is unaffected by the gene), to her son. Females are unaffected because they have 2 copies of the X chromosome, so if the factor VIII gene on an X chromosome is defective, the gene on the other X chromosome can make enough factor VIII. Because males have only 1 X chromosome and 1 Y chromosome, if their only copy of factor VIII gene on the X chromosome is defective, they will have hemophilia A.3,4

Because females get 1 X chromosome from their mother, and 1 X chromosome from their father, a father who has hemophilia will pass the defective X chromosome to his daughters, and his daughters will be carriers. Because males get their X chromosome from their mother, they will not inherit the defective X chromosome, and therefore males born to a father with hemophilia and a mother who is not a carrier will not be affected.

What are inhibitors to FVIII?

The development of inhibitors is one of the most serious complications of FVIII replacement. Inhibitors greatly reduce the ability of FVIII to stop bleeding.3,4

In many patients with inhibitors, treatment goals can be met using a plasma-based product that contains both FVIII and VWF.

Up to 3 in 10 patients with hemophilia A who take FVIII replacement therapy will develop inhibitors.3,5

What is von Willebrand disease?

Von Willebrand disease (VWD) is an inherited bleeding disorder.1 People with VWD have a deficiency in a protein called von Willebrand factor (VWF). VWF is a glue-like protein that helps cells in your blood, called platelets, clump together and form a plug that prevents blood loss following an injury. People with VWD cannot make this plug because their body does not make enough VWF. VWD is the most common bleeding disorder.7 It is estimated that 1 in 1000 people have VWD.8

What causes von Willebrand disease?

VWD is caused by a problem in one of the genes that tells the body to make VWF.9 VWD affects men and women equally, regardless of race. A man or woman with VWD has a 50% chance of passing the disease on to their child.1,7

What are the types of von Willebrand disease?

There are 3 main types of VWD and several subtypes. The 3 main types are:7,9,10

  • VWD type 1: The most common form. A person with type 1 has about 20% to 50% of normal levels of VWF. Levels of the blood clotting factor VIII might also be reduced
  • VWD type 2: People with type 2 produce enough VWF, but the protein is defective and affects the way that platelets clump together
  • VWD type 3: The least common but the most severe form of VWD. People with type 3 might have a total absence of VWF, and factor VIII levels are often less than 10%

In people with VWD types 2 and 3, bleeding episodes may be severe and potentially life threatening.9

What are signs and symptoms of von Willebrand disease?7

  • Bruising easily
  • Bleeding gums
  • Frequent nosebleeds
  • Excessive bleeding after losing a tooth or oral surgery
  • Women can have increased menstrual bleeding
  • Severe internal or joint bleeding (with type 3 VWD)

How is von Willebrand disease diagnosed?7

  • Appearance of the above symptoms
  • Diagnosing VWD can be difficult. Laboratory blood tests can be performed to determine the amount, structure, and function of VWF
  • A family history of VWD. Because VWD is an inherited condition, a child of people who have the VWD gene needs to be tested

What happens in von Willebrand disease blood clotting?

  1. The blood vessel constricts, reducing blood flow through the wounded area
  2. The body does not produce enough VWF, so platelets don't stick together and the platelet plug does not form as effectively. Bleeding continues7
  3. People with VWD often do not produce enough clotting factor VIII either. Factor VIII is crucial in forming the mesh that holds the platelet plug in place. Without enough factor VIII, the mesh does not as effectively1,7,11
  4. When a person with VWD uses plasma-derived FVIII/VWD complex, enough VWF and factor VIII are temporarily added to the blood, allowing platelets to effectively form a platelet plug and blood to form the mesh that holds the platelet plug together; bleeding can be stopped or prevented6

What is Plasma?

Plasma is a clear, straw-colored liquid component of blood comprised mostly of Water, salts, and proteins. Plasma contains proteins needed for blood clotting and defending the body against infection. These proteins include FVIII, FIX, and VWF.

Plasma Collection Process

PLASMA DONATIONS NEEDED TO TREAT 1 HEMOPHILIA PATIENT FOR 1 YEAR

Purity and Safety

A look inside Grifols state-of-the-art facilities

 

For more than 70 years, Grifols has pioneered many of the methods used to collect human plasma and transform it into medicines for people who have rare, life-threatening diseases, such as immune deficiencies, hemophilia and genetic emphysema.

Unlike traditional pharmaceuticals, plasma medicines require a lengthy and complex manufacturing process.

Manufacturing consistency is achieved not only through testing the final product, but also by carefully controlling

the starting material and the manufacturing process. The process begins with fractionation to extract the therapeutic proteins from plasma, followed by purification and virus inactivation to safeguard the products for patient use.

ALPHANATE is made from human plasma. Plasma products carry a risk of transmitting infectious agents, such as viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, despite steps designed to reduce this risk.6

For more than 70 years, Grifols has pioneered many of the methods used to collect human plasma and transform it into medicines for people who have rare, life-threatening diseases, such as immune deficiencies, hemophilia and genetic emphysema.

Unlike traditional pharmaceuticals, plasma medicines require a lengthy and complex manufacturing process.

Manufacturing consistency is achieved not only through testing the final product, but also by carefully controlling the starting material and the manufacturing process. The process begins with fractionation to extract the therapeutic proteins from plasma, followed by purification and virus inactivation to safeguard the products for patient use.

ALPHANATE is made from human plasma. Plasma products carry a risk of transmitting infectious agents, such as viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, despite steps designed to reduce this risk.6

  •  

    History of Grifols

    Founded in 1940, Grifols is one of the world leaders in the production of plasma derivatives. The company has affiliates in the United States, Europe, Latin America, Southeast Asia and Japan; industrial plants in Spain and the United States; and more than 13,000 employees worldwide.

     
     
  •  

    Manufacturing

    The manufacturing process includes several process steps for maximum safety of the final product. Specific pathogen-elimination steps are deliberately introduced into the manufacturing process as an additional safety measure.

     
     
  •  

    Donor Process

    All Grifols plasma donors undergo a thorough medical examination, and their plasma is rigorously tested using FDA-approved methods to help ensure that it meets stringent qualifications for use in our therapeutic products.

     
     
  •  

    Future of Grifols

    Grifols scientists are constantly studying new therapeutic indications and applications in other disease states. Grifols promotes projects to contribute to social progress including bioethics, improving health of disadvantaged groups and supporting plasma donors.

     
     

Indications

ALPHANATE® (antihemophilic factor/von Willebrand factor complex [human]) is indicated for:

  • Control and prevention of bleeding episodes and perioperative management in adult and pediatric patients with factor VIII (FVIII) deficiency due to hemophilia A
  • Surgical and/or invasive procedures in adult and pediatric patients with von Willebrand disease (VWD) in whom desmopressin (DDAVP) is either ineffective or contraindicated. It is not indicated for patients with severe VWD (type 3) undergoing major surgery

ALPHANATE is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components.

Anaphylaxis and severe hypersensitivity reactions are possible with ALPHANATE. Discontinue use of ALPHANATE if hypersensitivity symptoms occur, and initiate appropriate treatment.

Development of procoagulant activity-neutralizing antibodies (inhibitors) has been detected in patients receiving FVIII-containing products. Carefully monitor patients treated with AHF products for the development of FVIII inhibitors by appropriate clinical observations and laboratory tests.  

Thromboembolic events have been reported with AHF/VWF complex (human) in VWD patients, especially in the setting of known risk factors.

Intravascular hemolysis may occur with infusion of large doses of AHF/VWF complex (human).

Rapid administration of a FVIII concentrate may result in vasomotor reactions.

Because ALPHANATE is made from human plasma, it may carry a risk of transmitting infectious agents, eg, viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, despite steps designed to reduce this risk.

Monitor for development of FVIII and VWF inhibitors. Perform appropriate assays to determine if FVIII and/or VWF inhibitor(s) are present if bleeding is not controlled with expected dose of ALPHANATE.

The most frequent adverse drug reactions reported with ALPHANATE in >1% of infusions were pruritus, headache, back pain, paresthesia, respiratory distress, facial edema, pain, rash, and chills.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1.800.FDA.1088.

Please see full Prescribing Information for ALPHANATE.

 


Reference

  1. Triplett DA. Coagulation and bleeding disorders: review and update. Clin Chem. 2000;46(8 Part 2):1260-1269.
  2. Hemophilia A (factor VIII deficiency). National Hemophilia Foundation Website. http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=179&contentid=45&rptname=bleeding. Accessed April 29, 2013.
  3. Kempton CL, White GC II. How we treat a hemophilia A patient with a factor VIII inhibitor. Blood. 2009;113(1):11-17.
  4. Leissinger CA. Prevention of bleeds in hemophilia patients with inhibitors: emerging data and clinical direction. Am J Hematol. 2004;77:187-193.
  5. Scharrer I, Bray GL, Neutzling O. Incidence of inhibitors in haemophilia A patients—a review of recent studies of recombinant and plasma-derived factor VIII concentrates. Hemophilia. 1999;5:145-154.
  6. ALPHANATE® (antihemophilic factor/von Willebrand factor complex [human]) Prescribing Information. Grifols.
  7. What is von Willebrand disease? National Heart, Lung and Blood Institute Website. http://www.nhlbi.nih.gov/health/health-topics/topics/vwd/. Updated June 1, 2011. Accessed July 30, 2013.
  8. Mannucci PM, Tuddenham EGD. Hemophilias–from royal genes to gene therapy. N Eng J Med. 2001;344(23):1773-1780.
  9. Rodeghiero F, Castaman G, Tosetto A. Optimizing treatment of von Willebrand disease by using phenotypic and molecular data. Hematology. 2009; 2009: 113-123.doi:10.1182/asheducation-2009.1.113.
  10. Pollak ES. von Willebrand Disease. Medscape Reference Drugs, Diseases & Procedures. http://emedicine.medscape.com/article/206996-overview. Updated February 11, 2013. Accessed April 16, 2013.
  11. Tortora GJ, Derrickson B. The cardiovascular system: the blood. In: Principles of Anatomy and Physiology. 12th ed. Hoboken, NJ: John Wiley & Sons,Inc. 2009: 689-716.