Introduction

Glanzmann thrombasthenia (GT) is a rare, inherited blood disorder that involves excessive bleeding due to failure in blood clotting by platelets. Platelets are produced from division and differentiation of unspecialised cells (known as stem cells) in the bone marrow. Therefore, bone marrow transplantation (BMT)-injecting affected people with stem cells that have the normal genetic makeup-can potentially cure GT. If you or your loved ones are unfortunately affected by GT, a thorough understanding of the disease and how BMT can potentially provide a cure can be invaluable.

Glanzmann Thrombasthenia

The cause of GT - the inheritance of ITGA2B and ITGB3 genes

Glanzmann Thrombasthenia is genetic, which means it runs in families. Each human cell contains two sets of genes. One set comes from the mother and another from the father. There are two genes associated with GT: ITGA2B and ITGB3, both are responsible for producing the platelet protein required for blood clotting. To be specific, its inheritance pattern is autosomal recessive. Autosomal means the defective gene is present on non-sex chromosome. Hence, the probability of being affected is equal in males and females. Recessive means GT occurs only when both copies of the ITGA2B or ITGB3 gene received from each parent are defective. 

If each parent has only one copy of the defect variant of either gene, they do not exhibit GT, but there is a 25% chance that their child will be affected. Therefore, if you have a family history of GT (any relatives exhibit GT), seek a genetic counsellor for suggestions regarding whether to have a child.

How do the defect variants of ITGA2B and ITGB3 lead to excessive bleeding?

Normally, blood from a wound such as a cut, slash, or laceration stops soon after the initial leak because it clots. This is important because it prevents excessive blood loss which can be lethal and reduces the chance of infection by blocking pathogens out of the bloodstream. However, blood clotting does not occur in people with GT.

An essential step of blood clotting is platelets binding to fibrin mesh in order to aggregate. This requires an integrin protein synthesised from ITGA2B and ITGB3 genes. In GT, the lack of normal variant(s) of ITGA2B and/or ITGB3 prevents the production of functional integrins. Thus, the platelets fail to bind to the fibrin mesh and aggregate.¹ Consequently, blood fails to clot and bleeding continues.

Symptoms of GT due to excessive bleeding

Apart from skin wounds, you may also experience excessive bleeding in other body parts. These include blood vessels beneath the skin (purpura; purple patches under the skin), nose (epistaxis) and the gum. Female patients may experience heavy menstrual bleeding (known as menorrhagia). Although these symptoms seem common, complications may arise in the case of large wounds, such as surgeries and childbirth. Because clotting is a complex process, other clotting disorders may have similar symptoms. Therefore, obtaining an accurate diagnosis from your consultants is essential to get appropriate treatment.

Treatment options for GT

There are various treatments available for GT. You may apply pressure to the area around the wound to reduce the blood flow or use medications that promote blood clotting, such as antifibrinolytics, in cases of mild bleeding. In severe cases, you may need a transfusion of normal platelets that can aggregate to allow clotting. However, such treatment can only temporarily stop bleeding instead of enabling blood clotting in the long term.

To cure GT, the person must have correct variants of both ITGA2B and ITGB3 genes so that platelets can aggregate. BMT achieves this by inserting stem cells from a donor containing the normal variants into the patient.²

BMT as a Treatment

How are our platelets produced?

Before understanding BMT, let’s understand how platelets are produced. 

Initially, there is only one embryonic stem cell. Gradually, it produces a set of adult stem cells, each capable of producing a specific set of body cells. Among the adult stem cells are hematopoietic stem cells, which are responsible for making all blood cells. After birth, they reside in the bone marrow. To produce platelets, one hematopoietic stem cell differentiates into several components required for platelet functioning These components give rise to platelets.³

How can BMT cure GT?

For people with GT to produce normal platelets, precursor stem cells of this lineage containing the normal variants of ITGA2B and ITGB3 genes must be present. These stem cells can be taken from a healthy donor, whose stem cells can differentiate into normal platelets. By injecting the stem cells into the bone marrow of the affected individual, the production of functional platelets can thus take place in people with GT.

How is BMT carried out?

Finding a matching donor

Identifying the correct source of stem cells is probably the most challenging step. For BMT for GT, two requirements have to be met: first, the donor must have normal variants of both ITGA2B and ITGB3 genes; second, the donor’s white blood cell antigen profile (known as HLA) must match that of the recipient—otherwise, adverse immune responses can lead to an unsuccessful transplantation.

Close relatives can easily meet the second requirement because they are very likely to inherit the same HLA profile, and are more willing to help the patient. However, since GT is also a genetic disorder, close relatives also have a higher chance of having GT. If no close relatives can be donors, unrelated people who registered at stem cell banks will be evaluated. During registration, volunteers have their HLA profile recorded in the system. Compatible volunteers will be contacted for their consent to donate stem cells.

Harvesting stem cells from the donor

Instead of collecting directly from the bone marrow, haematopoietic stem cells can also be harvested from peripheral blood. This is achieved by connecting a vein of the donor to a machine that selectively filters out stem cells. Compared to harvesting from the bone marrow, due to its lower invasiveness and greater ease, it is a common collection method. But this method requires the donor to take drugs that boost peripheral stem cell count one week in advance.

Infusion of stem cells into the recipient

The term "bone marrow transplantation" may sound daunting to you. But instead of being injected directly into the bone marrow, stem cells are injected into your veins using a central vein catheter. The catheter is inserted from veins close to the heart to the vena cava, the vein connected to the heart. The vein of insertion is commonly the jugular vein (lower neck), the subclavian vein (in the upper chest), or the femoral vein (in the groin area). The exact site is chosen based on the likelihood of potential risks, including infections, lung collapsing, and arterial punctures; the likelihoods are different for each patient due to their previous surgeries and other factors.⁴

These stem cells enter the blood microcirculation of the bone marrow, take around 2-4 weeks to exit the blood flow, reside in the bone marrow, and start dividing to produce normal, functional platelets.^5,6

Post-transplant care

Risks and complications

Although maximum attention has been devoted to reducing adverse outcomes, potential risks and complications necessitate an inpatient stay between a few weeks and months following the transplantation. 

The surgical process may lead to certain complications that must be addressed immediately, especially unintentional punctures in other vital organs, such as arteries, lungs, and nerves, with their respective symptoms being swelling, breathing difficulties, and numbness. Tell your surgeons immediately if you experience any of these because they can be life-threatening.

In cases of imperfect HLA matching, adverse immune responses may still occur. This can be more severe for BMT than for transplantation of other body parts because the introduced stem cells can differentiate into white blood cells that can attack all host organs. This is known as graft vs host disease (GVHD). GVHD can lead to symptoms like rashes and diarrhoea, which can be life-threatening if very severe. Your consultants will administer immunosuppressants to prevent adverse immune responses in GVHD. Your new immune cells will typically "adapt" to your body after some time.

Since the procedure is invasive, infections may occur if pathogens enter the bloodstream during or after surgery. The immunosuppressants against GVHD also increase the chance of infections, which can also be life-threatening if left unattended. Therefore, you must follow your consultants’ guidance regarding disinfection and tell them about any discomfort, such as fever and pain, which can be signs of an infection.⁶ Depending on your condition, your consultant may administer suitable antibiotics.

Treatment outcome

BMT for GT is reported to have a high success rate of around 94%, and the few who failed later succeeded after retransplantation.⁷ Therefore, the post-treatment stay also monitors whether the BMT is successful, and if not, retransplantation through another site is done.

After returning home, try to maintain a healthy diet and lifestyle, which can counteract possible side effects. You may contact a dietician for advice. Further, remember to keep an eye on any discomfort; contact your consultants immediately if you are in doubt since it can be a sign of severe, unexpected side effects.

Whether you should choose BMT

Currently, BMT is the only long-term cure for GT. If you want to enjoy life as if you have never had GT, BMT is the only choice. However, financial costs and geographical inconvenience to BMT centres make it less accessible. Contact your consultants for potential support.

The risks and complications vary according to the individual. Experts will evaluate your health conditions, medical history, and other factors to determine whether BMT is suitable. If you have a close relative who is an eligible and willing donor, the whole process may be easier for you.

If you, unfortunately, cannot find a donor, do not be discouraged. Ongoing research is exploring whether certain HLA mismatches can be deemed safe, potentially allowing donors with partial matches to be accepted. Additionally, another potential cure, gene therapy, is under research and shows promising results.⁸ If you want your GT to be urgently treated, you may volunteer for clinical trials of this new approach, which may lead to success but may also be associated with unexpected risks.

Summary

Glanzmann Thrombasthenis (GT) is a rare, inherited blood disorder that involves excessive bleeding due to failure in blood clotting by platelets. It is caused by defective gene variants that lead to non-functioning platelets. BMT, the only treatment to cure GT, introduces foreign stem cells with the correct gene versions. Therefore, it is worth considering BMT if you have access to it. With the improvements and growing prevalence of stem cell transplantation technology, BMT will be more accessible to all GT patients.