Introduction

Before we discuss complications of Glanzmann Thrombasthenia (GT), let’s understand what it actually means. GT is a condition when a person fails to produce a protein called platelet integrin alpha IIb beta 3, a platelet fibrinogen receptor.¹

Platelet fibrinogen receptor is a special protein on platelets that helps them stick together by binding to fibrinogen, a protein in the blood.¹ This sticking of platelets is crucial for forming clots that stop bleeding when you're injured.¹ So, without these receptor proteins, platelets can't clump together properly, making it difficult for the body to stop bleeding.

Therefore, people with GT often have prolonged bleeding episodes from a minor cut or from an injury that could lead to significant blood loss, needing a transfusion.¹ 

What causes glanzmann thrombasthenia?

In 1918, Swiss doctor Eduard Glanzmann described a condition where people had normal numbers and sizes of platelets (the cells that help blood clot) but had trouble forming clots, leading to longer bleeding times.² These patients also had what looked like red or purple spots beneath the skin caused by the breakage and leakage of blood vessels.²

In the modern day,  it is established that the ITGA2B and ITGB3 genes are found close to each other on chromosome 17, but are controlled separately.² GT occurs when both copies of either of these genes (ITGA2B or ITGB3) have harmful mutations. Therefore, GT is an autosomal recessive disease with two inherited mutated copies of the genes.² Having one mutation in each of the two genes (instead of both mutations in the same gene) does not cause GT.²

As of 2020, studies found that GT was more common in groups of people that had consanguineous lineages (parents are related). Despite this, GT is still an extremely rare disease.² 

However, we still have to answer the question, ‘How does a platelet integrin alpha IIb beta 3 deficiency arise from mutated genes?’ Well, there is evidence of a missense mutation or a mutation that results in an incorrect amino acid (protein building blocks) in the sequence, as the genetic code is slightly off. The missense mutation causes the megakaryocyte (the cell that makes the platelet in question) to make abnormal platelets that cannot work properly.² Therefore, the individual is deficient in functional platelets as megakaryocytes fail to produce normal platelets.²

Additionally, a missense mutation can block the movement of important protein complexes (pro-αIIbβ3) from inside the cell (where they are made) to the surface of the cell (where they are needed) for proper function, leading to the characteristic deficiency seen in GT.^2,3

How does GT cause bleeding problems? 

The alpha IIb beta 3 integrin is a key protein on platelets that acts as a binding site for fibrinogen, a protein essential for helping platelets stick together to form clots.² When platelets are triggered, usually due to injury, this integrin receptor changes its form, allowing fibrinogen to attach.¹ This connection helps platelets clump together (aggregation) to create a clot, which stops the bleeding a process known as primary haemostasis.¹

If these fibrinogen receptors don’t work well or there aren’t enough of them (due to GT mutation), the body can’t effectively form clots, leading to either spontaneous bleeding or excessive bleeding with injuries (a characteristic symptom of GT).¹

Additionally, in GT, platelets are less capable of producing thrombin, which plays a crucial role in turning fibrinogen into fibrin.¹ Fibrin is important for reinforcing the clot, a process called secondary haemostasis. As a result, both stages of blood clotting are impaired in GT, leading to more serious bleeding.¹

Symptomatic complications of GT

Purpura (bruising)

This is caused by the rupture of small vessels under the skin, and as the blood struggles to clot, it presents red or purple spots or patches.²

Epistaxis (nosebleeds)

Epistaxis is when a blood vessel in the nasal mucosa breaks, which for someone with GT could be prolonged and result in serious blood loss due to their inability to clot.³ This is one of the most common GT symptoms, as it affects 60-80% of patients.² However, the chance of epistaxis reduces with age.² 

Gingival bleeding

Gingival bleeding is the bleeding of the gums, which normally occurs in people with poor oral hygiene as their gums have not been cleaned properly, meaning they will bleed when probed. However, someone with GT may have no signs of periodontitis and still have excessive bleeding from the gingival area.⁴ Additionally, this can be seen in 20-60% of individuals with GT, most often when having routine dental treatment.²

Menorrhagia (heavy menstrual bleeding)

Women without GT may suffer from heavy bleeding. However, studies have shown that menorrhagia affects 60-90% of women with the condition.² Menorrhagia can be especially common during the first period for a woman with GT.⁵ This is because, during early cycles without ovulation, the hormone oestrogen causes the lining of the uterus to grow thicker. This leads to a higher risk of severe bleeding, as there is more lining (which turns into blood) that has to leave the body.² 

Gastrointestinal bleeding

Gastrointestinal bleeding is seen in approximately 10-20% of individuals with GT.² However, there are two types of gastrointestinal bleeding. Firstly, melena, which refers to black, tarry stools. Melena happens when bleeding occurs higher up in the digestive system, like in the stomach or small intestines, and the blood turns dark as it moves through the digestive tract.⁶ 

Secondly, hematochezia, which refers to red or fresh blood in the stool, usually comes from bleeding lower in the digestive system, such as the colon or rectum.⁶ 

Mucocutaneous bleeding

Mucocutaneous regions are where the tissue is connected with the skin, so it usually means the mouth, rectum, nose, throat, or any orifices.⁷ Bleeding from these areas can occur randomly or with minor trauma.²

Epistaxis in children

Nosebleeds are the most frequent cause of severe bleeding, particularly in children.² The likelihood of severe nosebleeds tends to decrease as children get older, as the blood vessels in the nasal septum become less fragile, and kids stop habits like nose-picking.²

Complications of treatment for GT patients

Dental procedures

Dentists should make considerations for someone with GT, which before treatment would be a pre-procedural plan, perhaps discussed as a multidisciplinary team (dentists and haematologists), such that blood and platelets needed for transfusions are available around dental treatment.

In a dental setting, controlling bleeding for a patient with GT typically involves a combination of treatments.⁸ Platelet transfusions are often used to replace the patient's non-functioning platelets, helping them form clots during the procedure. However, sometimes alloimmunisation (a reaction against the platelet proteins IIb and/or IIIa) can occur.⁹

Another option is recombinant factor VIIa (rFVIIa). The rFVIIa works by attaching to the surface of activated platelets and helps produce more thrombin.¹⁰ Thrombin boosts the sticking together (adhesion) and clumping (aggregation) of platelets that are missing the integrin alpha IIb beta 3, thereby stimulating the clotting process without needing fully functional platelets. The rFVIIa are particularly helpful if the patient has developed antibodies against transfused platelets.¹⁰

Antifibrinolytic agents like tranexamic acid (taken orally or as a mouth rinse) are used to slow the breakdown of clots to ensure that the clots remain stable until after the procedure.¹¹ 

Additionally, local measures such as applying pressure, using gauze, or placing topical agents like fibrin sealants or collagen sponges on the bleeding area help physically stop bleeding and promote clotting. Together, these treatments help control bleeding and support clot formation in GT patients undergoing dental procedures.⁸ 

Menstruation (periods)

The risk of heavy menstrual bleeding (menorrhagia) requires monitoring, as it can lead to severe blood loss and a trip to the emergency room. However, oral contraceptives can be prescribed to reduce the bleeding. One option is the use of high-dose oral contraceptives, such as norgestimate-ethinyl estradiol, to stabilise hormone levels and reduce bleeding.¹² If the bleeding becomes severe, leading to acute blood loss anemia.¹²

Summary

Individuals with Glanzmann thrombasthenia face a range of bleeding complications, including frequent and severe nosebleeds (epistaxis), heavy menstrual bleeding (menorrhagia), easy bruising (purpura), gum bleeding, and gastrointestinal bleeding (melena or hematochezia). Spontaneous bleeding from mucous membranes like the mouth and nose is common. During dental procedures, there is a heightened risk of excessive bleeding, often requiring platelet transfusions or medications like recombinant factor VIIa and antifibrinolytic agents to control bleeding. Careful planning and coordination with healthcare providers are essential to manage these complications and prevent severe blood loss.