Introduction

Have you ever cut yourself? Normally, many of us will have had a cut or bruise at some point in our lives during our youth or later in life, but the question is, what happens next? Our bodies internally adjust to our needs and therefore have an intricate system that allows us to cater for damage, such as when we cut ourselves. This is called the clotting cascade.

It prevents us from bleeding too much, from harmful bacteria entering our bodies, and from clots forming when they shouldn’t, like in blood vessels, which can lead to strokes and heart attacks. Although it is a little complex, it is designed to amplify the body’s response quickly using only a small amount of energy, and has a couple of fail-safes too that let the body work well without one or two things functioning properly.

However, when something important stops functioning well, the balance in our blood can go awry, which leads to various issues. One of these is Glanzmann Thrombasthenia, a condition characterised by restricted clotting capacity leading to heavy blood loss when blood vessels are injured. With limited treatments available for this condition, we will explore it in more detail in the article, as well as ways to treat it and minimise its effects on patients' lives.¹ 

What is Glanzmann's Thrombasthenia?

Glanzmann's Thrombasthenia (GT) is a rare inherited bleeding disorder that affects the blood's ability to form clots. Normally, when we get a cut or injury, tiny cells called platelets in our blood stick together to form a clot that acts like a plaster and helps plug the bleeding.¹ In people with Glanzmann's Thrombasthenia, these platelets don't work properly because they are missing or have a defective sugar-protein called GPIIb/IIIa, which is crucial for the platelets to stick together.¹

As a result, people with GT often experience excessive bleeding, even from small injuries. The condition is usually diagnosed in childhood and is inherited in an autosomal recessive manner, meaning both parents pass on the faulty gene to the child. However, as much as 0.5% of the world’s 7.4 billion people may be carriers for this disease, meaning that although they don’t have the disease, they carry a faulty gene that they can pass on to their children. 

As such, it is important to be able to spot the symptoms, such as nosebleeds, heavy periods in girls, bleeding gums, easy bruising, and intestinal bleeding at times. Surgery and childbirth can also result in heavy blood loss, which can be fatal if not treated properly. One-third of women with GT also experience postpartum bleeds within 24 hours of birth, and one-fourth of GT patients do so within the first 3 months of giving birth.³

Treatments for GT

There is no cure for GT, but treatment focuses on managing bleeding episodes. This might include blood transfusions, platelet transfusions, or medications that help control bleeding.

Insignificant cases of bleeding or conservative forms of treatment for GT patients both involve doses of medication that prevent clots from being dissolved, called antifibrinolytics.³ As the body constantly forms clots, it also breaks them down to maintain homeostasis and prevent excessive clot formation that can block arteries and cause strokes.

Preventing this breakdown can enable more clots to form in GT patients who otherwise may not form many clots at all. Thus, this can help the body bleed slowly during moderate bleeding events. However, in significantly large bleeds, this may not be sufficient, and other forms of treatment may be necessary.

Platelet transfusions

Platelet transfusions are one form of treatment for GT patients with excessive bleeding, for example, after surgery or injury.⁶ This helps compensate for the defective platelets and replenishes them with healthy ones, allowing the right pathways to be naturally activated for normal clotting. This works because the transfused platelets contain the GPIIb/IIIa protein, which is missing or defective in people with GT.

Risks associated with platelet transfusions

However, it’s important to note that repeated platelet transfusions can sometimes develop antibodies against donor platelets in patients, making the treatment less effective over time as the platelets are attacked by the patient’s immune system.²

Enlarged spleen

Another reason why platelet transfusions may not work is an enlarged spleen, which destroys all platelets too quickly, regardless of whether they belong to the GT or came from a transfusion.²

Bacterial infections

Fever and widespread infections can also destroy platelets and make them ineffective in excessive bleeding treatments, especially in cases of sepsis. Furthermore, competitiveness between the patient’s and the donor’s platelets may lead to the donor platelets being ineffective, as many may not act at the site of the bleed.⁶

In all these cases of insufficient platelet survival, the transfused platelets may not be able to aid the patient's clotting adequately, thus leading to complications and even possibly death. 

Pregnancy

Blood-borne bacterial infections may also be transmitted to the patients following platelet transfusion, and there is also a greater risk to pregnant GT women as the foetus may be affected. Although a large proportion of GT patients suffer bleeds during pregnancy, this is normally mild and doesn’t lead to complications. 

Platelet transfusions in pregnancy can lead to the foetus developing a low platelet count (thrombocytopaenia) as it doesn’t make as much of its own to have sufficient levels in its bloodstream. The foetus may recognise the platelets as foreign and react accordingly. This occurred in 75% of pregnant GT cases reviewed, leading to 4 miscarriages, too.

Others

Another factor to consider with platelet transfusion as a remedy for excessive bleeding is that immune-matched donor platelets may not be available at the time of the emergency. Currently, it is the main form of treatment for GT patients during massive bleeds.

Activated factor VII transfusions (FVIIa)

Another possible treatment for GT patients is activated factor VII transfusions (FVIIa). This is the activated form of the inactive factor VII found in the body, which is naturally activated by tissue factor exposure. 

In 2004, activated factor VII (VIIa) became commercially available thanks to a company in Denmark; thereafter, it became a form of treatment for GT patients.⁵ Instead of activating the intrinsic pathway via Von Willebrand factor exposure in activated platelets, this instead activates the extrinsic pathway and thus also allows an amplified response, leading to fibrin clots forming.

In cases where GT patients have rejected or become refractory to platelet transfusions, physicians have used FVIIa transfusions to remedy the situation successfully.²

In a study, 159 admissions of various ages were treated; FVIIa transfusions were efficient in 88%.² Only 4 admissions were over 65, and treatment in these cases was successful and uncomplicated. Therefore, FVIIa transfusions may be used to treat GT patient haemorrhagic emergencies instead of platelet transfusions due to their high efficacy.² 

Nevertheless, because they are manufactured commercially, they are quite an expensive form of treatment. However, there is neither a risk of blood-borne bacterial infection transmission from FVIIa, nor is there a risk to neonates, which makes it safer for use in GT pregnancies than platelet transfusions. In another study, around 1.4% of patients did not respond to FVIIa treatments, and in surgery, it had a 95% efficacy rate.² 

Adverse events were minimally reported, such as excessive clotting. This may have resulted from too large a dosage being prescribed, the patients' already failed kidneys, or sepsis in other patients.² In the UK, National Health Service (NHS) clinical guidelines mandate that the patient’s consultant must seek advice from a consultant haematologist before FVIIa can be prescribed.³

Summary

Activated factor VII FVIIa is a treatment option for Glanzmann's Thrombasthenia (GT), especially in patients who become refractory to platelet transfusions. In GT, the defective GPIIb/IIIa protein impairs platelet function, leading to excessive bleeding. Platelet transfusions can help, but repeated transfusions may cause the immune system to attack donor platelets. FVIIa bypasses the need for functional platelets by activating the extrinsic clotting pathway, allowing clot formation.

Studies show FVIIa is effective in managing bleeding, especially during surgeries and emergencies, with fewer risks like infections or complications during pregnancy compared to platelet transfusions. They are therefore a viable option for GT patient treatment, especially during emergencies.