Natural history & quality of life in Glanzmann thrombasthenia & Bernard Soulier syndrome: An observational study from India

Materials & Methods

This observational study was conducted by the department of Haematology, K.J. Somaiya Hospital & Research Center, Mumbai, Maharashtra, India between November 2023 and April 2025. The study was approved by the Institutional Ethics Committee.

Data were collected retrospectively from registered patients and also from new patients registered prospectively in the Hospital Registry. The eligibility criteria for enrolment were confirmed laboratory diagnosis of GT or BSS by platelet aggregometry and flow cytometry. The study included both paediatric and adult patients. Overall, 76 study participants (64 GT, 12 BSS) were included in the present analysis. An informed consent was taken from all study participants or their guardians.

Results

Demographic profile of the study participants are shown in table I.

Bleeding manifestations

The mean ABR in this study cohort over the preceding 24 months was 11.85 while in BSS it was much lower i.e., 1.85. Only one individual with GT, who was six-yr-old, did not have any bleeding episode at the time of enrolment. The mean ISTH - BS was 10.5 in GT and 6 in BSS cases. The unpaired t-test showed statistically significant differences both in ABR (P=0.015) and ISTH-BAT scores (P=0.006) between individuals with BSS and GT (Figs. 1 and 2). Majority of the study participants had the three classical platelet related clinical manifestations i.e., epistaxis, ecchymosis and gum bleed followed by soft tissue bleed and GI bleed. Menorrhagia and postpartum bleed were the common clinical manifestations in all women in the reproductive age group in both BSS and GT (Table II).

Table II. Bleeding data of 76 study participants with Glanzmann thrombasthenia (GT) and Bernard Soulier syndrome (BSS)

Type of bleed	GT, n (%)	BSS, n (%)
Epistaxis	45 (70.3)	7 (58.3)
Ecchymosis	44 (68.8)	7 (58.3)
Gum bleed	37 (57.8)	6 (50)
Haematuria	7 (10.9)	0 (0)
Gastrointestinal bleed	19 (29.7)	4 (33.3)
Intracranial bleed	2 (3.1)	0 (0)
Soft tissue bleed	26 (40.6)	2 (16.7)
Joint bleed	2 (3.1)	0 (0)
Menorrhagia	15 (88.2)	4 (100)*
Post-partum bleed	2 (40)	1 (25)*
No bleed	1 (1.6)	0 (0)
Circumcision	10 (29.4)	0 (0)
Other bleed	17 (26.6)	0 (0)

^* The denominator in these cases is the total number of women in the reproductive age group or those who went through post-partal period

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Fig. 1.

Annualised bleeding rate (ABR) in study participants with GT and BSS. The unpaired t-test Box plot shows significantly higher ABR in GT as compared to BSS individuals (P<0.05). ABR, annual bleed rate; GT Glanzmann Thrombasthenia; BSS, Barnard Soulier syndrome.

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Fig. 2.

ISTH-BAT scores in study participants with GT and BSS. The unpaired t-test shows significant differences in ISTH-BAT scores between GT and BSS (P<0.05). ISTH-BAT, International Society on Thrombosis and Haemostasis – Bleeding Assessment Tool.

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QoL

Table IV shows the scores of the EQ-5D-5L for both individuals with GT and BSS as per the EQ-5D-5L questionnaire. Majority of study participants (>90%) reported no mobility problem, self-care and other routine activities, while more than 50 per cent of the cases had no discomfort or anxiety/depression. The ISTH-BAT score in comparison with all the three QoL scores showed weak negative correlation. The correlation matrix representing the data is shown in figure 3.

Table IV. Self- reporting quality of life parameters in study participants with GT and BSS

Severity of reported problems	No Problem, n (%)	Slight Problem, n (%)	Moderate Problem, n (%)
Mobility	68 (89.5)	8 (10.5)	0 (0)
Self-care	75 (98.7)	1 (1.3)	0 (0)
Unusual activity	65 (85.5)	9 (11.8)	2 (2.6)
Pain/ discomfort	40 (52.6)	32 (42.1)	4 (5.3)
Anxiety/ depression	47 (61.8)	24 (31.6)	5 (6.6)

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Fig. 3.

Correlation matrix showing association between ISTH-BAT score and QoL parameters (EQ-5D, SF-36 and FACIT) in GT and BSS cases. A weak negative correlation was seen between ISTH BAT and all three QoL (EQ-5D, SF-36 and FACIT) score. EQ-5D, EuroQol five-dimensional questionnaire; SF-36, Short form-36, FACIT, functional assessment of chronic illness therapy.

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Discussion

The present study is an observational study on the natural history of 76 individuals with GT (n=64) and BSS (n=12). Both GT and BSS are generally associated with mild to severe mucocutaneous bleeding. They make approximately 4-5 per cent of all bleeding disorders diagnosed in any of the comprehensive coagulation laboratories in the country^10,11. However, this may not be the actual prevalence of these disorders, since many of the mild cases do not even report to the hospital. Moreover, since the confirmation of diagnosis requires both platelet aggregometry and flow cytometry which are available only in few select diagnostic centres, GT and BSS patients with mild clinical manifestations are hardly diagnosed. Third, ‘mild’ bleeding in general is considered as ‘normal’ bleeding and they report to the hospital. Thus, substantial number of patients with IPFDs including GT and BSS remains undiagnosed, which in few cases require specialised phenotypic investigations and molecular tools like NextGen sequencing¹².

There is no reported data on the type of bleed, treatment products QoL or mortality in patients with the two commonest IPFDs in India. Present analysis for the first time provides a first-hand information on a sizeable number of patients with GT and BSS. The ISTH-BAT score was first validated in patients with von Willebrand disease (VWD), but subsequently, it is being validated in different types of bleeding disorders including GT and BSS¹³. It is still debated whether it is the most appropriate tool for assessing the bleeding symptoms in patients with GT and BSS. Despite its limitations, the ISTH‐BAT is considered as the best means of assessing bleeding severity as it takes both frequency and severity into consideration. Both ABR and ISTH-BAT score have been applied in this analysis. Previous studies from India have shown that menorrhagia is an important clinical indicator for women with underlying bleeding disorders^14,15. In addition, postpartum bleeding in women with GT and BSS is equally challenging, requiring highly specialised multi-disciplinary medical management^16,17. Unlike haemophilia, intracranial bleeding is rare in patients with GT and BSS. There are only isolated case reports on either intracranial or spinal cord bleeds in patients with GT^18,19. There were 2 GT cases who gave a history of IC bleed in this series. The bleeding severity was milder in BSS as compared to GT patients, which is in line with earlier reports²⁰.

Patients with GT and BSS do not need routine prophylaxis; so the treatment strategies generally should aim at pre-surgery prophylaxis or during severe life-threatening bleeding. Platelet concentrates are always considered as the first line treatment for severe bleeding in inherited platelet function defects like GT and BSS. One of the major concerns with platelet transfusion is the development of platelet antibodies due to alloimmunisation which is reported in as high as 25-70 per cent of the patients^21,22. Though there are protocols for use of leukocyte depleted and human leukocyte antigen (HLA) matched platelets, this is not feasible in most of the clinical settings in India. Though rFVIIa was approved for use in GT patients in 2004 and has been the standard of care for GT patients, none of our patients were treated with this product till date. This is mainly because most of the patients in this series belonged to lower economic strata of the society and could not have afforded the exorbitant cost of the product. Isolated case reports are published on use of rFVIIa in BSS patients^23,24, but it is not licensed to for use in BSS patients. As per the United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) and British Society of Haematology (BSH) guidelines, for mild bleeding manifestations, tranexamic acid or other anti-fibrinolytics may be used, while rFVIIa is the preferred treatment for severe, non-life-threatening bleeding and unselected platelet transfusion is advised only in severe life-threatening bleeding. Use of herbal medicines like Ankaferd blood stopper have also shown promising results when used both as topical haemostatic agent as well as systemically in refractory GT cases^25,26. Mortality in study participants with GT and BSS is hardly reported but the prognosis of these disorders is generally reported to be good. Thirteen deaths were reported due to bleeding and seven of which were solely due to non-availability of treatment products. Though platelet concentrates are available in most of the blood banks, their ready availability in remote parts is uncertain and majority of the individuals in this series may not afford rFVIIa for any acute bleeding episode.

It is always debated whether the ISTH‐BAT is an appropriate measure of the severity of bleeding due to domain saturation. However, this is the only tool available currently for the quantitative measurement of bleeds. The HRQoL is influenced by patient perception of illness²⁷. In our study, we did not find a significant association of ISTH-BAT score with any of the QoL scores. A similar report of negative association of QoL data with ISTH-BAT score has been published by another group²⁸.

The strength of our study is the inclusion of a large number of study participants with GT and BSS. To the best of our knowledge, this is to first study from India assessing the bleeding phenotype, treatment products used and QoL in a large cohort of patients with GT and BSS. Insight into the natural history of these two disorders have far reaching implications in terms of patient counselling about the prognosis and therapeutic strategies to reduce bleeding related mortality. Limitations of the study include its retrospective nature and heterogeneity of patient population. Nonetheless, given the rarity of the condition, this was the most practical approach which enabled us to present this highly valuable data.