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Types of Bleeding Disorders

von Willebrand Disease
Hemophilia
Factor XI
Other Factor Deficiencies

von Willebrand Disease

von Willebrand disease or vWD is thought to be the most common bleeding disorder among the general population. The National Hemophilia Foundation (NHF) estimates that 1 – 2 in 100 people have vWD. Both men and women are affected. vWD is an under–recognized and under–diagnosed disorder, in that many people with the disorder are unaware of their condition. The knowledge of having vWD is vitally important, as it leads to:

1. A decreased risk of complications such as excessive bleeding with injury or medical interventions; and
2. Better control of bleeding symptoms with decreased risk for prolonged or complicated bleeding events.

vWD Defined
von Willebrand disease is an inherited blood clotting disorder. In 1926, Finnish internist Dr. Erik von Willebrand first described vWD after evaluating a large family from the Aland Islands (located in the Baltic Sea between Sweden and Finland) whose bleeding disorder inheritance pattern was dominant and not related to sex unlike classical hemophilia (factor VIII deficiency). The family’s bleeding symptoms ranged from mild to severe, and males and females were equally affected. The bleeding symptoms were also distinct from hemophilia, with abnormal bleeding from the skin and mucous membranes. The first identified person in the family died at 14 years of age from bleeding during her fourth menstrual cycle.

von Willebrand protein or factor (vWF) is part of the blood clotting mechanism. vWF is a large protein made of building blocks called multimers. Multimers are assembled and stored in cells lining the blood vessels. vWF is released into the circulation where it binds to factor VIII, the clotting factor that, when deficient, is associated with hemophilia. For many years it was difficult to study or recognize patients with vWD because of this close association between the von Willebrand factor and factor VIII. Factor VIII needs to be bound to vWF to protect it from being degraded in the blood.

Besides binding and protecting factor VIII, another important role of vWF in coagulation is helping platelets (cells in the body that are important in forming the primary plug to stop bleeding, called a hemostatic plug) bind to an injured area. Therefore, defects in vWF may lead to what is commonly called “platelet–like” bleeding such as bleeding from mucosal surfaces (the mouth, gastrointestinal tract and urogenital tract), development of easy bruising and petechiae (small red dots caused by the rupture of small blood vessels).

In affected people, the von Willebrand factor isn’t normal, either in amount (i.e., an insufficient quantity) or structure. Either mechanism may lead to impaired function and therefore an increased risk of bleeding. vWD is classified into subtypes. Affected individuals with the same subtype may manifest a variable range of severity, from mild to moderate to severe.

Levels of severity are categorized as:

• Type 1 = mild
• Types 2A and 2B = moderate
• Type 3 = severe

Rarer forms of vWD exist, such as 2M and 2N. (Type 2M vWD is a rare subtype of vWD type 2. Type 2M affects approximately 0.5–2% of people with vWD.)

The majority of persons with vWD fall in the mild to moderate range (approximately 80% of all cases). Yet even those who are mildly affected should become knowledgeable about their bleeding disorder, as surgery or an injury may lead to excessive bleeding without appropriate therapeutic interventions. Type 3, the most severe form of vWD, is also the least common form, affecting 1 or 2 people per million. Persons with type 3 vWD have an almost complete lack of von Willebrand factor, as well as decreased factor VIII and ristocetin cofactor activity levels.

Similar to hemophilia patients, individuals affected with vWD do not bleed faster than normal, but rather, take longer to stop bleeding. It should be noted that bleeding may occur without injury or trauma in people with vWD, especially internal bleeding. This is usually seen in patients with moderate to severe von Willebrand disease, and may be associated with other medical problems such as ulcers.

Symptoms of vWD
The symptoms of von Willebrand disease include:

• Menorrhagia – unusually heavy or prolonged menstrual bleeding
• Metrorrhagia – increased and abnormal bleeding between menstrual cycles
• Epistaxis – excessive nose bleeds
• Easy bruising
• Abnormal bleeding in the mouth and gums
• Abnormal bleeding following surgery, particularly surgery involving mucous membranes (e.g., tonsillectomy), childbirth or dental procedures

Diagnosis of vWD
vWD is most often diagnosed by hematologists, physicians specializing in blood disorders. As a federally recognized comprehensive hemophilia treatment center (HTC), the IHTC is the leading medical facility in Indiana in the diagnosis and treatment of vWD. If you need to locate a hemophilia treatment center outside of Indiana, please refer to the listing of federally recognized HTCs at the Centers for Disease Control and Prevention’s (CDC) National Center for Infectious Diseases web site, www.ncid.cdc.gov, or call the National Hemophilia Foundation at (800) 42–HANDI.

Laboratory testing for vWD requires a specialized laboratory skilled in this area. To accurately diagnose vWD, a panel of tests must be performed. These tests may include:

• Factor VIII activity
• Ristocetin cofactor – performed to evaluate von Willebrand factor activity
• von Willebrand factor antigen – evaluates the amount of vWF present (it does not indicate how well the factor works)
• Multimer analysis – looks at the structure of the protein
• Platelet function

Other testing may be performed as necessary, such as blood typing. Some uncommon testing may be performed in specific clinical situations.

Diagnosing vWD can be challenging. A host of factors can confound vWD testing results, making the tests difficult to interpret and leading to misdiagnosis. These include but are not limited to physical/emotional stress, exercise just prior to the patient’s blood being drawn for testing, and hormone changes including pregnancy and taking oral contraceptives. Testing may need to be repeated to reach a conclusive diagnosis.

Inheritance of vWD
If you are diagnosed with vWD, it is recommended that your family be evaluated for the disease, as vWD is an inherited disorder. The abnormal gene present in vWD parents is known as an autosomal chromosome or autosome, which is not a sex–linked chromosome. As a result, both men and women can pass the defective vWD gene onto their children. Affected parents have a 50% chance of passing the defective gene to each of their children.

vWD can also occur as the result of a spontaneous genetic mutation. As in those affected with vWD by birth, individuals who are affected by a mutation can pass the defective gene onto their children.

Treatment of vWD
There is no cure for von Willebrand disease. However, the disorder can often be successfully managed. The patient’s age, symptoms and the subtype and severity of the vWD will determine the proper treatment regimen. Treatment includes the use of:

Clotting factor concentrate that contains and replaces the abnormal vWF such as Humate–P®, which may be utilized in managing type 2A, 2B and type 3 vWD as well as used for severe bleeding in other types.

• Stimate® nasal spray, which causes the release of stores of vWF into the circulation. Stimate® is usually used in type 1 patients. Stimate® is a medication, not a blood product. It may be associated with some symptoms and these should be discussed in detail with your physician before it is used as a therapeutic agent.
• Oral birth control pills in women whose primary symptom is menorrhagia or metrorrhagia and who are not responsive to other therapies.
• Adjunctive therapies such as local fibrin glue, microfibular collagen and antifibrinolytic therapies are commonly employed to control bleeding episodes in this patient population.

Healthy Advice
If you have been diagnosed with a bleeding disorder, it is critical that you become well educated about the disease. Your local hemophilia treatment center is the best educational resource to provide you all the information you need to know about von Willebrand disease.

It is also very important that you inform all your healthcare providers that you have vWD, especially your primary care physician and dentist (and, if you are female, be sure to notify your obstetrician/gynecologist). Your healthcare providers are encouraged to contact your HTC to provide them the proper medical guidance in delivering optimal medical management. For Indiana patients, the IHTC is happy to provide educational seminars on bleeding disorders to your primary care and other medical and dental providers. For more information on arranging such a session, contact the IHTC toll free at (877) CLOTTER.

To manage vWD, patients should:
Be seen regularly by a hematologist who specializes in the diagnosis and treatment of vWD; optimum treatment by a team of multidisciplinary medical care providers is available at your local federally recognized HTC

• Adhere to the treatment regimen provided by your hematologist
• Exercise and/or engage in regular physical activity
• Become an advocate for your own healthcare and wellness
• Contact your HTC prior to having any type of surgery or other invasive procedure; this includes dental work involving heavy gingival manipulation and/or block injections (numbed cheeks)

References
What You Should Know About Bleeding Disorders, National Hemophilia Foundation, 1997 For You and Your Doctor, National Hemophilia Foundation, 2001 von Willebrand Disease (vWD): A Patient’s Guide to Understanding, Aventis Behring L.L.C., 2000
Indiana Hemophilia & Thrombosis Center Inc. 2001

Hemophilia

Hemophilia is a bleeding disorder that affects the body’s blood clotting (or coagulation) system.  Normal blood clotting involves as many as 20 blood proteins, or clotting factors.  Individuals with hemophilia lack one of these factors, resulting in an abnormal bleeding tendency.  People with hemophilia tend to experience bleeding—either spontaneously or after an injury—into their joints, muscles, and soft tissues.  Bleeding into the abdomen, kidneys, and intestines may also occur.  Superficial cuts are generally not a problem for those with hemophilia:  bleeding is longer, not faster, compared to those with a normal clotting system.

The two main forms are hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency).

Quick Facts about Hemophilia

• Approximately 18,000 people (mainly males) in the United States have hemophilia.
• Approximately one in 5,000 males born in the United States has hemophilia.
• All races and economic groups are affected equally.
• Factor VIII deficiency is the most common type of hemophilia.

Classification
Hemophilia is classified by the amount of the clotting factor present in the blood.  The normal range of clotting factors VIII and IX is between 50% - 150%, yet people with hemophilia have much lower levels.  Patients with reduced levels of clotting factor have mild or moderate hemophilia, while patients with the lowest levels of clotting factors have severe hemophilia.

Those with mild hemophilia tend to have few bleeding episodes, which usually occur with an injury, trauma, or surgery.  People with moderate hemophilia bleed approximately 4 to 6 times a year, while those affected with severe hemophilia experience more frequent bleeding events.  These bleeds may occur weekly and without known injury (spontaneously).

Risk Factors & Causes of Hemophilia
Hemophilia is caused by an inherited X-linked recessive trait, meaning that the gene that causes the disorder is located on the X (sex) chromosome.  A person’s gender is determined by the combination of two possible sex chromosomes (X and Y) that are inherited from his or her parents.  A female (XX) inherits one X chromosome from her mother and one X chromosome from her father; whereas, a male (XY) inherits one X chromosome from his mother and one Y chromosome from his father.
Females carry two copies of the X chromosome, so if the factor (VIII or IX) gene on one chromosome is defective, the other gene can compensate.  Males, however, carry only one X chromosome; so, if the factor (VIII or IX) gene on that chromosome is defective, they will have hemophilia.  For this reason, the disorder primarily occurs in males.  Females with one defective factor (VIII or IX) gene are called carriers of the trait, and are capable of passing the trait on to their children.

Risk factors for hemophilia include:

• Male gender
• Family history of bleeding

Treatment of Hemophilia
While there is currently no cure for hemophilia, this condition can be successfully managed.  Concentrates or medications are given to patients to make up for a low clotting factor level.  This replacement (or infusion) therapy stops or prevents bleeding by increasing the patient’s factor level for a certain period of time.  The amount of factor and the frequency of administration depend upon the severity of bleeding, the site of the bleeding, and the size of the patient.  Factor concentrates are administered by placing a needle in the patient’s vein (venipuncture) or through a surgically implanted device called a Port-a-Cath.  There are two main factor replacement therapy schedules:

Prophylaxis Infusion Therapy
Some people with severe hemophilia are treated in a replacement therapy program called prophylaxis.  These patients are infused on a regular basis in order to prevent bleeding episodes.  Prophylactic infusion programs use a considerable amount of factor to minimize the number of bleeding episodes.

Episodic Infusion Therapy
Patients on an episodic therapy program are infused after a bleed has occurred.  Those with mild and moderate hemophilia—who tend to bleed less frequently—may infuse episodically.

Some factor products are made from human blood products (such as donated plasma, called plasma-derived products), while others (called recombinant factor) are made in a laboratory and do not use human blood components.  Recombinant products offer a safer alternative and prevent blood-borne transmission of infectious diseases to the hemophilic population.

Availability & Cost of Hemophilia Therapy
Clotting factor is an expensive therapy, with the average annual cost of factor products ranging from $50,000-$100,000 for an individual with severe hemophilia.  The costs of prophylactic therapy may easily exceed this range.  There are several reasons for the high cost of treatments:

Hemophilia requires lifelong replacement therapy

Prophylaxis regimens may call for large doses of factorInhibitors limit treatment options

Factor replacement products are typically provided to patients through home healthcare companies or hemophilia treatment center (HTC) pharmacy programs.

Complications of Hemophilia
The most common complication of hemophilia is joint damage, or hemophilic arthropathy, which may occur over time with bleeding into the joints.  The complications of untreated hemophilia can be debilitating, as chronic pain, swelling, and permanent joint damage lead to limited range of motion and decreased quality of life.
In some patients with hemophilia, the immune system develops antibodies that inactivate (or inhibit) the factor replacement product.  These inhibitors prevent clot formation by destroying the factor product before it can stop the bleeding.  Inhibitors not only complicate the treatment of bleeding episodes, but require that patients use infusion products that are different than the normal clotting factor concentrates.

The development of inhibitors is more common in patients with severe deficiencies than mild or moderate disease; and is more likely in patients with factor VIII deficiency compared to factor IX.  Inhibitors tend to develop in severe patients during childhood and often within the first 30 days of infusion therapy; however, in patients with moderate or mild deficiency (who infuse less frequently), inhibitors may occur later on.

Today’s blood products are much safer than those of the past.  Yet, transmission of hepatitis A, hepatitis C, and newly discovered blood-borne diseases remain a risk for people treated with plasma-derived products.  While no vaccination currently exists for hepatitis C, immunization against hepatitis A and B is recommended for all hemophilia patients, regardless of their type of factor product.

The good news is that many complications can be prevented.  People with hemophilia should be sure to:

• Stay up-to-date on vaccinations
• Attend annual comprehensive clinic evaluations
• Avoid situations that may cause bleeding
• Maintain good oral hygiene (to prevent extensive dental procedures)
• Identify and treat bleeding events promptly, as directed by hematologist

Living with Hemophilia
Comprehensive hemophilia treatments centers (HTCs), in providing specialized patient care, and modern medical technology, in the development of safer products, are giving people with hemophilia the opportunity to live longer, more productive lives.  Significant advancements have been made over the last 20 years, and the future continues to hold the promise of increasingly better therapies and improved outcomes for those with hemophilia.

Background on Carriers of Hemophilia
Generally, carriers are individuals who have or “carry” a gene for a condition but do not have the condition themselves. In hemophilia, women are carriers because the gene causing the condition is on the X chromosome. If a woman has a gene for hemophilia, she usually is not affected because women have two X chromosomes; therefore, they have a gene on their second X that compensates for the hemophilia gene. Men, however, only have one X chromosome, so if they have the gene causing hemophilia they will be affected. Carriers can pass the hemophilia gene they carry onto their children, resulting in sons with hemophilia and daughters who are also carriers.

Men who have hemophilia will pass their X chromosome to all of their daughters; therefore, they will all be carriers (also known as obligate carriers). Sons receive a Y chromosome from their fathers, rather than an X, and therefore will not be affected or carry the gene. A woman is an obligate carrier of hemophilia if any of the following apply:

1. she is the biological daughter of a man who has hemophilia,
2. she is the biological mother of more than one son with hemophilia, or
3. she is the biological mother of at least one son with hemophilia and has at least one other blood relative with the disorder.

For a woman who is at risk to be a carrier, the most accurate method of carrier testing is to compare her DNA to that of a male family member with hemophilia. If she has the same change in her gene for hemophilia as her affected family member, she is a carrier for hemophilia. It is possible for boys with hemophilia to be born to women who are not carriers. This occurs when there is a new genetic change during the development of one or more of the mother’s eggs, which is then passed onto the child. More commonly, however, in cases where there is not a family history of hemophilia, the mother is a new carrier.

The gene causing hemophilia normally contains the instructions for the body to make clotting factor. When women are carriers, they have one gene that functions properly and one that does not. Therefore, they are expected to have half the amount of clotting factor as other women. Occasionally, carriers can have less clotting factor than expected and experience bleeding symptoms. It is recommended that women who are carriers or are at risk to be carriers have their clotting factor levels evaluated. This evaluation is available at your local comprehensive hemophilia treatment center.

Important Information for Carriers of Hemophilia
If you are pregnant or planning a pregnancy and there is hemophilia in your family, there are some important facts you should know:

1. Knowing your chance to have a child with hemophilia is important medical information for you, your child and your physician.
2. There is testing available to better define your chance of having a child with hemophilia.
3. Prenatal testing may be available to test the baby during your pregnancy.

Hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) are bleeding disorders caused by an abnormality in one of the clotting factors. Both types of hemophilia are inherited as X–linked recessive conditions. They are called “X–linked” because the genes for factor VIII and IX are located on the X chromosome. Chromosomes are in each of our cells and contain all of our genetic information. Chromosomes are very similar between males and females, except females have two X chromosomes while males have an X and a Y. Thus, females normally have two copies of clotting factor VIII and IX genes and males have only one copy. When there is an alteration or change in the factor VIII or factor IX gene, a male will have hemophilia. A female with an alteration will be a carrier of hemophilia.

Testing is available to find out whether a female who has hemophilia in her family is a carrier. Genetic testing is the most accurate method of carrier testing. It involves obtaining a blood sample to look for the specific gene alteration causing hemophilia in a family. Testing for carrier status with factor levels does not rule out carrier status. If you were tested by factor levels, you may have received inaccurate information. Finding out if you are a carrier provides important medical information for you and your children. Carrier testing may help you make family planning decisions, allows for prenatal diagnosis if desired, and may indicate precautions to be taken when your child is born for both you and your baby. Therefore, if you are currently pregnant or planning to have children, it is important to find out more about your risks and the availability of testing.

Steps you should take to find out about carrier testing:

1. Talk with your physician and arrange to meet with a genetic counselor to discuss carrier testing and your options.
2. Contact the Indiana Hemophilia & Thrombosis Center Inc. (IHTC) at (317) 871–0000 or toll–free at (877) 256-8837 to speak to the center’s genetic counselor.
3. Talk with your family to find out what type of hemophilia (factor VIII or factor IX) is present, the severity (mild, moderate or severe) and whether anyone has had genetic testing done.
4. If you are found to be a carrier for hemophilia or there is a chance you are a carrier, difficult delivery (notably, suction apparatus or use of high forceps) should be avoided and a male baby should be tested for hemophilia at birth through cord blood testing. Cord blood testing instructions and kits are available through the center. Circumcision should be delayed until the baby boy’s results are known.

Factor XI Deficiency: A Unique Bleeding Disorder

While Factor VIII and Factor IX deficiencies are the best known types of hemophilia—and the most common—other clotting factor deficiencies also exist.  Low levels of Factor XI (another blood protein required for clot formation) cause Hemophilia C, which is also known as Plasma Thromboplastin Antecedent (PTA) Deficiency or Rosenthal Syndrome.

Quick Facts about Factor XI Deficiency

• The disorder was first described in 1953.
• Factor XI deficiency is a rare disorder, but is more common among persons of Ashkenazi (European) Jewish descent.
• Hemophilia C is an inherited disorder, which affects men and women equally.
• Physical signs of the disorder are rare (e.g. bruising is uncommon).

Bleeding Tendancy
Hemophilia C is different from Hemophilia A and Hemophilia B in that the frequency of bleeding (with Hemophilia C) is not determined by the patient’s factor level.  Unpredictable (or inconsistent) bleeding patterns occur in people with this disorder.  Individuals with Hemophilia C are not likely to bleed spontaneously (or without known injury) and bleeding tends to occur following trauma or surgery.

Procedures with an increased risk of bleeding include the following:

• dental extractions
• tonsillectomies
• surgery in the urinary & genital tracts
• nasal surgery

Unlike those with Hemophilia A and Hemophilia B, patients with Hemophilia C are not likely to experience joint bleeds.  They may, however, experience the following:  bruising, nosebleeds, or blood in the urine; and for women, menorrhagia and prolonged bleeding after childbirth.

Risk Factors & Causes of Factor XI Deficiency
Throughout the world, persons of Ashkenazi (European) Jewish descent are most commonly affected by Hemophilia C, with an estimated 8% of this group affected. This disorder occurs in other groups, as well.  Approximately one person of non-Jewish heritage has Hemophilia C per every million people living in the United States.  An estimated 5% of persons with bleeding disorders in the United Kingdom have Factor XI deficiency, and most of these patients are of non-Jewish descent.

Hemophilia C is primarily an inherited disorder.  Yet, unlike Hemophilia A and Hemophilia (which are sex-linked disorders and are inherited with the X-sex chromosome), Hemophilia C is an autosomal disorder.  This means that the gene that causes Factor XI deficiency is present on a non-sex chromosome and the condition, therefore, affects both genders equally. 

Treatment of Factor XI Deficiency
Again, unlike those with Hemophilia A and Hemophilia B, patients with Hemophilia C do not require treatment or prophylactic (preventive) therapy for daily activities.  However, replacement therapy is required for dental extractions and surgery, and treatment options depend on the type of procedure.

Fresh frozen plasma—the most widely available treatment for this disorder—is normally used with good results.  However, since Factor XI is not concentrated in fresh frozen plasma, a large volume of this product may be needed.  (There are no Factor XI concentrate products available in the U.S., and while two of these treatments are produced in Europe, they have had limited patient use.)  Further, the development of an inhibitor, which occurs in approximately one-third of patients with severe (<1%) Factor XI deficiency using plasma product replacement therapy, largely complicates treatment options.

Complications of Factor XI Deficiency
The complications of Hemophilia C are those associated with the use of fresh frozen plasma.  While today’s blood products are much safer than those of the past, transmission of hepatitis A, hepatitis C, and newly discovered blood-borne diseases remain a risk for people treated with these plasma-derived products.

No vaccination currently exists for hepatitis C; however, immunization against hepatitis A and B is recommended for all hemophilia patients.

Living with Factor XI Deficiency
Patients with Factor XI deficiency may experience milder symptoms than those living with other types of hemophilia, yet this disorder should not be overlooked.  People living with Hemophilia C require adequate treatment in order to achieve positive outcomes from surgeries or traumatic events.  For this reason, it is critical that patients inform their physicians of their diagnosis prior to any planned procedures.

Other Factor Deficiencies:  A Look at Rare Bleeding Disorders

There are several other factor deficiencies which cause hemophilia, besides the commonly known Factor VIII and IX disorders.  Bleeding disorders also result from low levels of the following clotting factors:  I, II, V, VII, X, XII, and XIII.  Each disorder is described below.

Factor I Deficiency
The term Factor I deficiency is used to describe a group of three conditions, in which fibrinogen—a blood protein that is involved in the beginning of the clotting process—is either:

• Present in normal quantities, but defective (called dysfibrinogenemia),
• Present in very low levels (called hypofibrinogenemia), or
• Absent altogether (called afibrinogenemia).

Since fibrinogen is required for platelets to stick together at the site of injury, Factor I deficiency is considered a combined bleeding disorder, as both the platelets and clotting factor are abnormal.

Factor II Deficiency
Clotting Factor II (called prothrombin) is also involved in the beginning of the clot formation process.  Factor II deficiency describes conditions in which prothrombin is either:

• Present in normal quantities, but defective (called dysprothrombinemia), or
• Present in very low levels (called hypoprothrombinemia)

This disorder can be either inherited (in an autosomal recessive pattern) or acquired (with severe liver disease or vitamin K deficiency), and is very rare.

* affects men and women equally

Unlike other factor deficiencies (which are due to low levels of a specific blood protein), Factor II deficiency is usually due to a defective blood protein (prothrombin).