Glanzmann's Thrombasthenia

What is Glanzmann's Thrombasthenia?

Your blood contains small, sticky cells called platelets. When you cut or injure a blood vessel and begin to bleed, platelets rush to the site of injury. There, they stick to the blood vessel and try to stop the leak. They also send out a chemical signal that attracts other platelets. Then, those platelets stick to the platelets at the injury site to form a plug that stops the bleed.

Platelet Adhesion, Activation, and Aggregation

Numerous proteins on the surface of platelets help platelets work properly. One type of these proteins is called glycoprotein. Various glycoproteins are found on the platelet surface and work together like a bridge to connect platelets with each other and to the wall of the injured blood vessel (Table below). Each glycoprotein has a specific target, either another platelet or a target in the vessel wall, and a specific role to play in forming the platelet plug.

This is the first part of making a blood clot. If this step doesn’t happen correctly, then it becomes harder for the clotting factors to work in making a stable clot of fibrin strands.

Types of glycoproteins and their functions

Glycoprotein Alternate Name Binding Target Platelet Activity Disorder
Ia-IIa integrin α2β1 Collagen Adhesion N/A
Ib Ib-IX;V vWF Adhesion Bernard-Soulier Syndrome 
IIb-IIIa integrin αIIbβ3 Fibrinogen Aggregation Glanzmann's Thrombasthenia
IIIb IV Collagen Activation Adhesion N/A

Platelets and their glycoprotein receptors

 

Some of the reasons that platelets do not work as they should are:

  • There may not be enough platelets
  • You may have a normal amount of platelets but they might not be functioning
  • Platelets may not be able to stick to the blood vessel or to each other
  • Platelets are sometimes not able to send or receive the chemical signals

When any of these happen, a person has a platelet disorder.

Glanzmann’s Thrombasthenia (GT) is a type of platelet function disorder, meaning the platelets aren’t working right. Specifically, patients with GT have a missing or defective glycoprotein (called Glycoprotein IIb/IIIa or “GP 2B-3A”), which is in charge of making the platelets stick together through binding to fibrinogen (clotting factor 1). This means platelets cannot aggregate or clump together to make a plug.

 

Glanzmann’s Thrombasthenia was first identified in children from a village in the Swiss Alps called Le Valais in 1918 by a pediatrician from Berne, Switzerland, Dr. Eduard Glanzmann. Since then, Glanzmann’s thrombasthenia has been identified in many other populations all over the world.

What causes it?

Humans have 22 pairs of chromosomes (autosomes) plus the sex chromosomes (X and Y). Glanzmann’s Thrombasthenia is an “autosomal recessive” disorder that impacts both males and females. The “recessive” part means you need to inherit one abnormal gene from each of your parents to have the disease. Parents may either have GT (2 abnormal genes) or be “carriers” (one normal and one abnormal gene). The illustrations below show the potential inheritance patterns of an autosomal recessive disorder.

These risks apply to each pregnancy, so if for example both parents are carriers, then each pregnancy has a 1 in 4 chance the child will be affected.

It’s a little more complicated than this in Glanzmann’s Thrombasthenia since there are actually 2 genes, one for the “2A” part and one for the “3B” part. Both of these are on chromosome 17, one of your 22 pairs of chromosomes. Either one can be abnormal and passed on to result in GT.

About one in 1,000,000 people worldwide have the disease. Men and women are affected equally. Children are often diagnosed early in life and usually before the age of five due to serious bleeding episodes. For example, infants with Glanzmann’s Thrombasthenia have more frequent bleeding from gums during teething or losing baby teeth. In some cases, infants will bleed longer than normal after vaccinations. Children with GT also experience frequent nosebleeds and gum bleeding from normal tooth brushing. Women with GT can experience severe bleeding during menstruation (often worse for their first period) and during childbirth. Minor procedures such as dental work can be a major problem, as can major surgery, and may result in bleeding prompting a diagnostic evaluation.

What are the symptoms?

The most common types of bleeding seen in patients with Glanzmann’s Thrombasthenia include:

  • Easy bruising
  • Petechiae - small red or purple spots on the skin caused by a minor broken capillary
  • Bleeding from the nose or gums
  • Heavy menstruation (in women)
  • Excessive bleeding after surgery or injury
  • Excessive bleeding after child birth

Less common types of bleeding seen in patients with Glanzmann’s Thrombasthenia include:

  • Bleeding into head and brain (headache, neck ache, drowsiness, loss of consciousness)
  • Bleeding into gastrointestinal tract (vomiting blood, bloody or black bowel movements)
  • Joint bleeds

In contrast to patients with more common bleeding disorders like congenital hemophilia A or B, patients with Glanzmann’s Thrombasthenia tend to have more mucocutaneous bleeding, or bleeding involving mucous membranes (nose, mouth, stomach) and skin, but do not tend to experience joint or muscle bleeding. This is illustrated in the figure below.

How is it diagnosed?

Two of the standardized tests for clotting are: prothrombin time (PT) and activated partial thromboplasin time (aPTT). Both of these tests look at the time it takes for the liquid portion (plasma) in your blood to clot. They do not measure platelet function, and as a result are not effective in diagnosing patients with Glanzmann’s Thrombasthenia.

Platelet counts and platelet shape are sometimes measured. These don’t measure platelet function, and therefore are both normal in patients with Glanzmann’s Thrombasthenia.

Platelet functional assays describe a general set of tests that look at platelet function, and would likely be abnormal in patients with Glanzmann’s Thrombasthenia.

Platelet aggregation studies look at how platelets effectively clump together in response to chemical exposure similar to what might prompt clotting at the site of blood vessel injury. As you know from the discussion above, Glanzmann’s Thrombasthenia involves a defect in how platelets clump together. Thus, platelet aggregation (clumping) studies are abnormal in patients with GT. Specifically, platelet clumping is absent with all stimuli except one chemical called ristocetin. This is the key test for GT. It is only performed in some specialized laboratories and requires a newly drawn blood sample, so you may need to go to a special lab center to have the test done.

The test used to confirm Glanzmann’s Thrombasthenia is flow cytometry, which is able to test the platelets binding to antibodies that recognize glycoproteins “2A” or “3B” mentioned above. This quantifies the amount of GP 2A-3B activity present and the “type” of GT.

Routine and specialized diagnostic tests

Tests Values
Routine  
PT Normal
aPTT Normal
Platelet count Normal
Specialized  
Platelet aggregation Absent or severely diminished except ristocetin
Flow cytometry for GP 2B-3A  Diminished

The flow cytometry results are used to categorize the level of GP IIb/IIIa complexes on the platelets. Though there are differences in the GPIIb/IIIa receptor levels, this does not predict the severity of bleeding in Glanzmann’s Thrombasthenia.

  • Type I: < 5% of normal GP IIb/IIIa levels
  • Type II: 5%–20% of normal GP IIb/IIIa levels
  • Variant-type: the level of GP IIb/IIIa is >20%, but the proteins are dysfunctional

How is it treated?

Treatment can depend on what type of bleed you may have or what type of procedure you may be undergoing. Your health care professional or treatment center team will make specific recommendations on the best approaches for each situation.

For minor injuries or nose/gum bleeds, your health care professional may suggest you use pressure or topical treatments that you can apply when you call their office or the treatment center for further instructions.

In situations where bleeding does not stop quickly or more serious bleeds or trauma, additional topical agents that stop bleeding (e.g. fibrin glue, nasal packing, nasal cauterization), oral agents (e.g. antifibrinolytic medications), intravenous drugs that help you clot, or transfusions of platelets may be recommended to get your bleed under control.

For abnormal/excess bleeding associated with monthly periods, use of hormonal treatment may be recommended.

Often even seemingly simple bleeds like nose bleeds or monthly periods may result in significant blood loss or iron deficiency and become life-threatening. It is important with every bleed to contact your health care professional or treatment center. At some point if you lose enough blood at one time or over many bleeds you may need to receive blood transfusions, or be hospitalized to control bleeding and monitor your condition.        

Surgery and dental procedures require some planning for patients with Glanzmann’s Thrombasthenia. Your healthcare professional or treatment center team will help decide on a strategy for preventing unwanted bleeding during the procedure, and decide on a post-operative course to make sure that you heal properly. A combination of local strategies, medications, and/or platelet transfusions may be recommended. They will also coordinate with the dentist, surgeon, and anesthesiologist.

People with inherited platelet function disorders should not take Aspirin®, nonsteroidal anti-inflammatory drugs (such as ibuprofen and naproxen), and blood thinners, and should avoid certain herbal supplements which result in decreased platelet function and thus can make bleeding symptoms worse (see Document Downloads). Contact your health care professional or treatment center team before starting any medications.

There have been some patients with Glanzmann’s Thrombasthenia that have undergone bone marrow transplants with cells from HLA (human leukocyte antigen) matched siblings or other HLA matched donors. After the transplant, they are once again able to make normal platelets and are ‘cured’ of the disease. They do need to remain on treatment to suppress their immune system after this type of transplant, and it is not without risks. Your health care professional or treatment center team will let you know if this is a treatment option for you.

Complications of treatment

Platelet transfusion may be given when other measures are not working to stop bleeding in patients with Glanzmann’s Thrombasthenia. Platelets are derived from one or more blood donors, and as such have a very low but possible risk of transmitting infectious agents (e.g. viruses) between donors and recipients. Patients can also have transfusion reactions when receiving any blood products.

Antibodies

Because your platelets do not have the normal Glycoprotein/GP 2B/3A on the surface, your body might not recognize the GP 2B/3A of the platelets you receive as being a normal part of yourself. As such, you might develop antibodies to the new platelets thinking these are foreign. How often these antibodies occur, how many platelet transfusions somebody normally receives before they occur, and if antibodies are only temporary or permanent once you get them are all not really well known.

In addition, when you receive platelets they are either are either “pooled” from multiple donors or from a single donor (“apheresis” platelets). These platelets might not have exactly the same friendly proteins on the surface. We call these surface markers antigens, and code them using the term “HLA”. Just like your body may think the GP 2B/3A on the “normal platelets” is foreign, it might also think the HLA on the surface is foreign. So, your body could also develop antibodies to HLA markers that are not identical to yours. If enough time permits or if there is time for planning (e.g. before elective surgery), HLA matched platelets can be obtained to try to reduce the risk of developing antibodies.

Refractoriness

At some point in time, platelet transfusions may not work as well as expected or at all in treating a bleeding episode or preventing bleeding during a procedure. This is known as refractoriness, and is based upon the healthcare professional’s observations, not a laboratory test. Refractoriness typically comes after using platelets for some period of time for bleeding episodes, but just how many patients become refractory to platelets, how long that refractoriness lasts, and if platelets would work again in the future are not well understood. Many patients with refractoriness have antibodies to GP 2B/3A, but some do not.

Tips for staying healthy

Manage anemia

Iron deficiency can occur with even the smallest of bleeds, and is a significant complication for patients with Glanzmann’s Thrombasthenia with severe or frequent bleeding. If you are losing as little as 5 milliliters (about 1 teaspoon) of blood per day, you are also losing 2.5 milligrams of iron in your blood and you may become anemic. It is important that you manage your bleeds and tell your health care professional how frequently you are bleeding. Iron replacement therapy may be recommended.

Develop a comprehensive care plan

Be sure to follow any maintenance or preventive measures your health care professional has planned for you. Glanzmann’s Thrombasthenia can be a severe condition, but with the right care and support it can be properly managed.

  • Maintain good dental hygiene to avoid gum disease that could lead to bleeding.
  • Maintain healthy blood iron levels through appropriate diet.
  • Avoid anti-inflammatory drugs (e.g., aspirin, ibuprofen, naproxen) or herbal supplements that affect platelets, unless your health care professional directs you to use them (see resources page).
  • Women - Discuss your menstrual bleeding and any issues with planned pregnancy/childbirth with your hematologist and obstetrician/gynecology.
  • Discuss your desired activities and sports participation with your healthcare professional to determine which activities are most appropriate for you. At different ages, certain activities become more contact-intense and pose higher risk of bleeding. Discuss with a health care professional before starting a new exercise routine or a new activity, or if you are having bruising or bleeding with current activities.
  • Don’t limit your discussions with your treatment center staff or hematologist to treating bleeds or just you.
    • Speak about how your disorder affects you emotionally, physically and socially. A comprehensive plan should address your emotional and social well-being as well as dealing with issues that might come up at school/work.
    • Frequent bleeding in Glanzmann’s Thrombasthenia can impact caregivers and siblings too, and they may also need to understand how to navigate issues with missed work/school or how to cope with emotional issues or stress/anxiety issues dealing with a family member with GT.
    • Discuss with your health care professional or social worker (if available) at your treatment center what community resources may be available in your community to help cope with emotional or stress/anxiety issues.

Medical Alert

Patients with Glanzmann’s Thrombasthenia should always have their medic alert ID with them, whether it’s a bracelet, necklace, seat belt attachment, or wallet identification card. It is important to know that EMT’s are not trained to look into wallets for medical information cards. When they do look there it is usually too late. Wearing a medic alert is the best way to alert anyone in the case of an emergency when the patient cannot speak for themselves. Also it is important to let GT patients know that they should always carry a picture ID, and their medical insurance if applicable.  Another helpful tip is to put an “ICE” (In Case Of Emergency) contact in your phone. This contact should have the information of a person to call in case of an emergency.

Share your Glanzmann’s Thrombasthenia experience

Because it is rare, Glanzmann’s Thrombasthenia often goes undiagnosed. And, unlike other rare bleeding disorders, there is not a lot of information available to help people with GT understand their condition. The diagnosis of GT may make you feel isolated, since there may not be others in your community or associated with your treatment center that have the disease. You may find others with GT affiliated with a local or state hemophilia chapter, or involved with an online or national platelet disorders support organization.  Once you have a greater understanding and gain experience, you have an opportunity to become an advocate and speak up for yourself and others.

If you know family members, friends, or families with Glanzmann’s Thrombasthenia in your community who are having similar bleeding issues, it is important that you share what you know with them as well as your local HTC, hematologist, or health care professional. Doing so may help build a stronger GT community.