Introduction

Glanzmann thrombasthenia (GT) is a rare inherited blood clotting disorder characterised by impaired platelet function due to reduced or defective expression of the αIIbβ3 integrin on the platelet surface membrane. This dysfunction prevents proper fibrinogen-mediated platelet aggregation, which is crucial for normal blood clotting.

The condition is genetic, occurs in an autosomal recessive manner, and affects approximately one per million people worldwide. It is however widespread among areas such as Pakistan, Iraqi Jewish communities, nomadic tribes in Jordan, South Indian Hindu communities, and Roma camps in France due to higher consanguinity levels. In the Canadian province of Newfoundland and Labrador, its prevalence could be as high as 1 in 200,000.^1,2

Causes 

GT is an autosomal recessive disorder caused by mutations on chromosome 17, specifically involving the ITGA2B or ITGB3 genes. With hundreds of mutations reported to date, mutations in either of these genes can lead to GT, it also occurs when a patient is either homozygous for the same mutation or compound heterozygous for different mutations. As a result of these genetic mutations variance in the levels at which the αIIbβ3 integrin is expressed and operational ranges occurs. For instance, the Manouche mutation leads to the complete absence of αIIbβ3 integrin expression.

In rare cases, acquired GT can develop due to the presence of an autoantibody against the platelet fibrinogen receptor. Multiple myeloma can trigger the formation of these antibodies, which is a haematological (blood) condition. There has also been a case report of a patient with systemic lupus erythematosus who developed an anti-αIIbβ3 antibody. Despite these rare instances, GT is most commonly used to refer to the inherited form, which is the primary focus of this discussion.³

Pathophysiology 

GT is a rare inherited disorder that affects platelets, the cells in our blood responsible for clotting. Malfunctioning of the GPIIb/IIIa receptor (also known as integrin αIIbβ3), which is found on the surface of platelets, leads to GT. This receptor normally helps in clot formation to stop bleeding by sticking platelets together. GT happens because there’s either a deficiency of receptors or a receptor dysfunction, leading to issues with platelet aggregation and clot formation.

The GPIIb/IIIa receptor (also known as integrin αIIbβ3) is composed of two protein subunits, a larger αIIb subunit and a smaller β3 subunit. Signals are generated within the cell and with the external environment by these two subunits as they work together, and form clots by sticking platelets together. Several substances like fibrinogen and von Willebrand factor (VWF), are crucial for platelet aggregation and clot formation.⁶

On average, a single platelet contains approximately 100,000 copies of the GPIIb/IIIa receptor, although this may not be constant from one person to another. Chromosome 17 contains genes encoding for the αIIb and β3 receptor subunits (ITGA2B and ITGB3, respectively). Various types of GT may arise from mutations within these genes that interfere with receptor production or function; for instance, some mutations prevent receptor synthesis whereas others may cause it to be ineffective.

Depending on how much of the receptor is left and how well it functions, GT is classified into three types:

• Type I GT: Less than 5% of the receptor is present
• Type II GT: Between 5% and 20% of the receptor remains
• Variant GT: More than 20% of the receptor is present, but it doesn’t function properly

The bleeding manifestations are more severe in certain GT genetic mutations, particularly those involving the ITGB3 gene.

In addition to inherited GT, there’s a rare form of acquired GT, which occurs when the body produces antibodies that attack the GPIIb/IIIa receptor, stopping it from working, it appears following conditions such as immune thrombocytopenic purpura or cancers like lymphoma, myeloma, or leukaemia. Autoimmune diseases like systemic lupus erythematosus (SLE) can also trigger acquired GT, as seen in a case where a patient with SLE developed bleeding due to antibodies against GPIIb/IIIa.

Occasionally, medications used to treat cardiac conditions, such as abciximab, eptifibatide, and tirofiban, can transiently inhibit the GPIIb/IIIa receptor, inducing a GT-like state where platelet aggregation is impaired, thereby increasing the risk of bleeding.⁴

History and physical examination

In cases where GT is suspected by medical practitioners, they gather comprehensive information about the patient’s blood makeup and note any bruises. Besides, the presence of a number of bleeding disorders, which run through a relative's generation can help in diagnosis. Epistaxis results in frequent nose bleeds among kids while menorrhagia in girls and gum bleeding are also normal. In some instances, there may be gastrointestinal haemorrhage which is not common. Hence most of the time GT diagnosis is only made possible after an incision has been done or surgery conducted. 

Early diagnosis is common among GT patients – often signs appear in infancy and many before the first year. For instance, significant bleeding post-circumcision could necessitate transfusion. Bleeding symptoms may improve over time in some cases. A bleeding assessment tool can help identify an abnormal bleeding pattern.

Symptoms usually begin at around one year old with many people getting their diagnoses around 5.6 years on average. Most of those with GT find out they have it when they are as young as 14.

Physicians will inquire about episodes of bleeding like ecchymoses (bruises) during physical examination. Given the frequent occurrence of epistaxis (nosebleeds) in patients with GT, a meticulous examination of the nasal cavity is conducted to identify any potential abnormalities.

This comprehensive approach helps doctors identify GT and manage its symptoms effectively.³

Diagnosis

In GT, patients typically present with a normal platelet count but experience prolonged bleeding due to impaired platelet aggregation, which hinders effective clot formation. Diagnosis of GT involves platelet aggregation studies to demonstrate functional deficiencies.

A definitive diagnosis is established through assays that detect deficiencies in the αIIbβ3 (GPIIb/IIIa) receptor, essential for platelet function. These diagnostic tests commonly employ techniques such as monoclonal antibody detection and flow cytometry. It is also possible to use genetic testing to look for the mutations in the ITGA2B and ITGB3 genes that cause GT.

If we know the mutations that are specific to a particular family, carrier and prenatal testing may be accomplished through DNA analysis; otherwise, the amount of αIIbβ3 receptor in the foetus can be checked during prenatal testing so that we can know whether the disorder is present.²

Management of Glanzmann thrombasthenia 

Patients with GT can seek benefits from specialised care centres equipped with the management of bleeding disorders. There should be medical alerts and emergency contact details for healthcare providers unfamiliar with the patient's condition along with 24/7 consultation regarding treatment and other lifestyle modifications should be provided by experts.

Education on avoiding medications like non-steroidal anti-inflammatory drugs (NSAIDs) including ibuprofen and aspirin, which increase bleeding risk, is crucial, and prescribed medications affecting clotting should be monitored.⁵

Managing bleeding

Managing the bleeding associated with GT entails not only addressing acute episodes but also preventing complications during surgical interventions. The option for GT therapy depends on the severity of the bleeding as well as previous reactions to interventions.

Key treatments

Desmopressin (DDAVP), commonly used in other bleeding disorders, has only limited effectiveness for GT.⁵ Recombinant activated factor VII (rFVIIa) is approved for treating GT and has significantly improved outcomes, especially for patients unresponsive to platelet transfusions. The dosing pattern of 90 µg/kg IV every 2-6 hours is used until the bleeding stops. It is also effective during surgeries and generally safe, though rare cases of blood clots have been reported.

Platelet transfusions

GT patients are at high risk of developing antibodies against platelets, particularly after transfusions. About 30% of patients develop these antibodies, making future transfusions ineffective. As a result, platelet transfusions are reserved for major surgeries or life-threatening bleeding.⁵

Bone marrow transplant

In severe cases, bone marrow transplants have been used with success. However, challenges like antibodies affecting the graft remain.

Pregnancy

Pregnant women with GT are at higher risk of complications, especially during delivery. 

Most complications arise at delivery, and treatments like rFVIIa and antifibrinolytics are used. Postpartum bleeding is common, often requiring blood transfusions.

Future directions

Evidence-based research is needed to ensure safe gene delivery in humans as progress is being made in various methods because gene therapy can be a potential treatment for GT.⁵

Summary 

Glanzmann Thrombasthenia (GT) is a rare genetic disorder that impairs platelet function due to mutations in the ITGA2B or ITGB3 genes, leading to defective blood clotting and abnormal bleeding. It is more common in populations with high consanguinity and can occasionally be acquired. Platelet function tests and genetic screening are diagnostic parameters, while management options involve therapies like recombinant activated factor VII (rFVIIa) and platelet transfusions. Bone marrow transplants may be needed in case of severity.

Although gene therapy offers potential for a cure, challenges remain, including antibody development against transfused platelets and limited access to specialised care. Pregnancy with GT faces high risks during delivery and requires careful monitoring. Global initiatives aim to improve treatment options with evidence-based research for this rare condition.