Glanzmann thrombasthenia: an editorial perspective

KEYWORDS:

• Glannzmann thrombasthenia
• diagnosis
• management
• novoseven
• allogenic bone marrow transplantation
• gene therapy
• misecellaneous therapy
• bispecific antibody
• polyphosphates
• DDAVP
• prenatal diagnosis
• rare bleeding patient registry

Glanzmann’s thrombasthenia (GT) is a rare recessively inherited disorder of platelet function due to absence or abnormal structure of one of the two important platelet glycoproteins (GPIIb and GPIIIa which in activated platelet heterodimerizes and forms high affinity receptor for fibrinogen). Platelet count and morphology in this disease is normal and a patient with this disease can have a variety of bleeding from mucosal surfaces of nose, oral cavity, gastrointestinal tract, and genitourinary tract. In severe cases, this bleeding could be life threatening and may involve vital organs like brain or structures which can cause respiratory difficulties like retropharyngeal bleeding. In a recent issue of this journal, Poon and colleagues extensively reviewed the science and art of management of this relatively rare congenital platelet integrin defect called GT [1]. The review is mainly restricted to diagnosis of the disease by platelet function tests and by flow cytometry, while its management was discussed in terms of advances with the use of recombinant factor VIIa under various situations and also allogeneic stem cell transplantation in a few cases across the world.

Data from GT registry using recombinant activated factor VII (rVIIa) was robust. Poon et al. have shown in this extensive review that factor VIIa infusion is safe and effective in both surgical and nonsurgical cases. The effectiveness varied from 80% to 100% and was not much altered by additional use of antifibrinolytics or platelet concentrates. Recombinant VIIa was used in higher concentration for surgical cases and the medicine was used every 2.5 h by injection. Some of the local measures for local bleeds were also highlighted. The data are robust as it is reviewed from GT registry incorporating a large number of patients with this rare disorder. Recombinant VIIa infusion was generally well tolerated.

Poon’s paper [1] consolidates the findings on recombinant VIIa infusion in the management of bleeding in this disorder as was reviewed previously in this journal [2].

However, there are several areas of management and possible advances in the disease which needs to be highlighted as also some of the possible application from further research in the management of the disease.

GT is considered to be relatively rare in western world though continued to be seen not infrequently in the major populous parts of the world where good diagnostic facilities are not extensively available [3] and consanguinity is common. Molecular pathology of GT is now well understood, in terms of lack of normal function of GPIIa (i.e. ITGA2B) or GPIIIa (i.e. ITGB3) receptors on platelets [4,5]. Defects in activation or its intracellular processing can cause rare forms of GT like defect as exemplified by Talin or Kindling 3 defect. These molecules are involved in inside out activation pathway of platelet integrin activation [1,6].

Diagnosis of a platelet function defect is suspected from platelet defect-like bleeding, for example, mucosal, skin, and superficial bleeding in the patient. Although inherited through recessive inheritance, a strong family history helps in the diagnosis as carriers of this disease may be concentrated in those parts of the world where consanguineous or endogamous marriage is common. Hence consanguinity in the family is important but is not a must for diagnosis. Patients with the abovementioned history and normal plasmatic phase of coagulation work up including factor assay, normal platelet counts, and morphology requires work up for congenital platelet defect by platelet aggregation or flow cytometry tests. Relevant drug and diet history may be important in excluding acquired causes of platelet function defects.

Other tests like defective clot retraction which is corrected by addition of platelet from normal healthy volunteer is helpful in those areas of the world where platelet aggregometry or platelet flow cytometry is not readily available. Generally GT platelets have normal morphology in contrast to macrothrombocytopenia and severe bleeding diathesis seen in another platelet function disorder called Bernard–Soulier syndrome [7] which can be suspected from history of bleeding and morphology of platelets in peripheral smear alone.

A simple spot test for severe (Type I) GT as well as for GT with functional defect in the platelet glycoproteins preventing their association during platelet activation has also been developed [8].

This spot test can be more extensively used in the remotest parts of the world or in technically less advanced areas of the world where GT may not be uncommon. Hence in short platelet aggregometry, flow cytometry, and molecular testing would be available for diagnosis of GT in advanced laboratories but there is an unmet need for developing or popularizing simple/near-patient testing for this disorder. Development of a bleeding disorder registry/rare bleeding disorder registries across the world will be of great help in understanding natural history and outcome of many rare bleeding disorders including GT [9].

Like any other genetic disorder, counseling about the disease and prenatal diagnosis in severe cases along with educating the patient about the nature and plan of management strategies for the disorder is an important part of total management of the condition. As menorrhagia is a common complaint in this condition, judicious use of oral contraceptives, antifibrinolytics, and counseling on pregnancy is also an important component of this management. Use of recombinant factor concentrates, platelet concentrates, and antifibrinolytics can be helpful in managing delivery and postdelivery bleeding. Antifibrinolytics like tranexamic acid and EACA can be used in all cases of minor bleeds except genitourinary bleeding. Chronic blood loss should also be made good by regular iron replacement therapy. Nowadays iron replacement can be given both orally and with newer iron preparations parenterally safely.

Rationally, management of severe bleeding due to a platelet defect should either be platelet or platelet substitute infusion in adequate doses. Adequate therapeutic dose of platelets for severe bleeding should raise the platelet count at least by 50,000/ul (i.e. 6–10 units of random donor platelets or one unit of apheresis platelet daily till the bleeding is controlled). If recombinant factor VIIa is available, then of course that drug should be used preferentially as suggested in Poon’s paper [1]. Some medicines are to be avoided (e.g. NSAIDs like acetyl salicylic acid and other antiplatelet drugs) and intramuscular injections need to be avoided. Local hemostatic agents like human thrombin, certain snake venom preparations like Bothorps atrox (Botropase®), Gel foam soaked in hemostatics etc. for controlling local and surface bleeds. A herbal preparation called Ankaferd® blood stopper popularized in Turkey as a local styptic is also effective [9]. This product has also been used in GT to stop GI bleed [10].

Infusion of allogeneic platelets are effective but carries with it a multitude of complications which has been well described in the review [1], but in all preoperative and perioperative preparation of GT patients platelet concentrates given through leukocyte filters is to be considered if the bleeding is likely to be severe and proves ineffective then rVIIa in adequate dose and frequency should be used and this may be more effective in combination with antifibrinolytics as discussed in the review.

Whether prior irradiation by gamma ray or UV-A radiation will reduce alloimmunization sufficiently needs to be seen. Development of alloantibodies against HLA antigens or platelet glycoprotein antigens may cause future platelet refractorioness hence should be used when absolutely necessary, that is, platelet infusion should only be used to control severe bleeds when other measures fail.

There is continuing search for safer medical alternative for management of bleeding in GT. Novoseven, that is, recombinant factor VIIa was found to be effective for 84% of the bleeds in GT patients [1]. Hence combining antifibrinolytics with rVIIa is at present an acceptable therapeutic approach for this difficult condition especially for minor bleeding to avoid the risk of early platelet alloimmunization and if it fails platelet concentrates need to be used.

rVIIa is extremely costly medicine and has only 2–2.5 h of half life. It may be possible to improve the half life of this medicine using technologies similar to that used for factor IX concentrates [11]. Recombinant factor Xa is also on the pipeline and may give similar out come like rVIIa for this condition [12]. Similarly organic polyphosphates commonly present inside the platelets can also be tried as potential general purpose systemic coagulant molecule in this condition [13].

Red cell which has been cross-linked with fibrinogen has been tested as a platelet substitute in experimental condition, and quite a few other similar platelet substitute has been described and reviewed, in future some of them may find its use for GT patients [14] and once the product is improved it can work as out of shelf medication.

Targeted gene therapy using CRISPR(Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9(CRISPR associated Nuclease 9) or similar technology is possible in future [1,15] to correct the genetic defect in this disease. However, one should keep in mind the possibility of developing alloantibody against absent platelet glycoproteins that was originally missing in GT but now replaced with gene therapy.

Allogeneic stem cell transplant can cure GT and has achieved 84% success in the patients so transplanted and this has been adequately discussed in the review [1].

However, stem cell transplantation is a very aggressive procedure and is associated with substantial mortality and morbidity. So it should be used with the caution and obviously not as a first-line therapy. In future if this procedure becomes safer, simpler, and more user friendly, then the treatment can find more extensive application.

Can we think of any other drug currently used for therapy in other conditions for repurposing it for GT patients? For many genetic disorders, chain termination mutations constitute around 15% of all mutations and can be overcome by small molecule nonsense suppressors. Such a molecule is already being used for cystic fibrosis with chain termination mutation in cystic fibrosis gene. Hence this drug called Ataluren® has very good chance of being effective in severe GT caused by chain termination mutations [15].

Bifunctional monoclonal antibodies are increasingly entering in modern therapeutics. Drugs like emicizumab or concizumab for hemophilia A [16] are being used successfully. Similar kind of bifunctional antibodies or even some of the small molecules which can form a bridge between platelet collagen receptor or TSP1 molecule with subendothelial collagen, exposed after endothelial injury could be developed as candidate molecules to treat various congenital platelet disorders. As these monoclonals need to be injected less frequently, some times once every 3–4 weeks, convenience of using such therapy if found to be effective in GT is obvious.

GT patients cannot attach fibrinogen molecule with glycoprotein receptors because of their absence or functional defect. However, platelets can attach to subendothelial collagen or other connective to tissues using other glycoproteins like GP1bIX and von Willebrand factor (vWF). High molecular weight vWF is an efficient molecule for such bridging. Either high molecular vWF concentrates alone or in connection with antifibrinolytic drug may work for moderate bleeding complications of GT.

Many GT patients are females and they have moderate-to-severe menorrhagia. In old days, this was controlled by ovarian irradiation or endometrial ablation or by hysterectomy which is at present performed rarely and in highly selected cases. Moreover, we have in our armamentarium oral contraceptives, other hormonal techniques to control menstrual blood loss.

In the present era, laser endometrial ablation in selected cases could also be used. We must not forget to replacement of iron in many of such patients to improve their quality of life and improve hemostasis by improving hemoglobin levels and blood viscosity [17] which improves ability of the platelets to injured endothelial surfaces and can have close interaction with leukocytes assisting in clot formation.

Finally prenatal counseling and prenatal diagnosis [18] followed by counseling should form part and parcel of overall management of GT patients as has already been described.

The paper by Poon et al. [1] gives us a very important insight about diagnosis and management of GT. With the current advancement in medicine it is quite possible that we will have several options to treat this rare but often severe bleeding disorder with multiple options to suit different occasions.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.