Abstract
Factor VIII replacement is the mainstay of treatment in hemophilia A but may lead to the development of inhibitors. While a vexing clinical problem, some observations suggest that the presence of inhibitors may not necessarily portend a higher bleeding risk. Our aim was to assess the prevalence and clinicopathological correlates of inhibitors in a well characterized cohort of Indian patients with HA patients. We retrospectively reviewed the clinical details and laboratory findings of consecutive hemophilia A patients attending a north-Indian tertiary-care center from 2010 to 2020. Among 592 patients with HA, inhibitors were detected in 35 patients (5.9%). Prevalence of inhibitors in moderate and severe hemophilia was 4.2% and 6.7%, respectively. Most patients with inhibitors had history of transfusion with factor VIII alone (54.3%) or a combination of factor VIII concentrate and other blood-products (42.9%). Intracranial bleed was significantly more frequent in patients with inhibitors compared to those without inhibitors (20% vs. 4.1%; p-0.001). Time dependent and immediately acting inhibitors were seen in 60% and 40% patients, respectively. High-titre (> 5 BU) and low-titre inhibitors (< 5 BU) were detected in 28 (80%) and 7 (20%) patients, respectively. Prevalence of inhibitors in our cohort was 5.9% and most had high-titre, time dependent inhibitors. These patients may have a higher risk of intracranial bleeding.
Keywords: Bethesda assay, Factor VIII inhibitors, Recombinant factor VIII, Hemophilia
Introduction
Haemophilia A (HA) is a common inherited bleeding disorder with a global incidence of 1 in 5000 new-born males [1]. Clinically, HA presents with bleeding which may be spontaneous or precipitated by trauma or surgery. It may range in severity from mild bruises to severe internal bleeds in form of joint bleed, intramuscular or soft tissue bleed, and intracranial bleeds. Treatment of HA centres around replacement using plasma derived or recombinant factor VIII (FVIII) concentrates [2]. However, around 25–40% severe HA patients develop neutralizing antibodies following FVIII infusions and it’s a major concern in the management of HA [3, 4].
Geographic variations in the prevalence of inhibitors have been reported which may be attributed to socio-demographic differences, access to FVIII concentrates, type of FVIII replacement, duration and intensity of treatment and possibly ethnic differences [4–9]. Indian data on prevalence of inhibitors in HA and its clinicopathologic correlates is sparse [5–9]. It has been suggested that prevalence of inhibitors among Indian HA patients is lower than that reported globally. In this study, we analysed the prevalence and clinicopathological correlates of inhibitors in a well characterised cohort of HA patients presenting to a high volume north Indian tertiary care hospital.
Materials and Methods
We retrospectively reviewed the data of 600 HA patients investigated at the coagulation laboratory of Department of Haematology from 2010 to 2020. Patients without details of baseline FVIII levels (n = 8) were excluded.
Clinical Assessment
The clinical details of the patients including demographic factors, site and precipitant of bleed, and transfusion history were retrieved from the available records. Details about family history were inferred from analysis of pedigree-chart.
Laboratory Investigations
Investigations performed included prothombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen level, mixing studies, FVIII assay, inhibitor screening test, inhibitor assay and vWF antigen (vWF: Ag) and vWF glycoprotein 1b receptor (vWF:GPIbR) assay. These tests were run on the fully automated coagulation analyzers [STA Compact®, STA-R Evolution® (both, Diagnostica Stago, Asnieres, France) and/or ACL TOP 500 CTS®
(Instrumentation Laboratory, Bedford, MA, USA)] as per manufacturer’s instructions and depending upon the availability of instrument. Inhibitor assay was primarily performed by classical Bethesda assay (CBA).
The PT, aPTT, fibrinogen and mixing studies (both for detection of deficient factors and inhibitor detection) were performed on fresh citrated platelet poor plasma (PPP) samples while the FVIII, vWF: Ag, vWF:GPIbR and inhibitor assay were performed on stored platelet poor plasma (PPP) sample within a month. During the initial years (up to 2015) inhouse pooled normal plasma (PNP) was used and later on the commercial PNP was used in the inhibitor assay. The VWF antigen/vWFGpIbR testing is performed as a routine departmental protocol in all patients with Haemophilia A to differentiate from vWD.
For statistical analysis, the quantitative data between mild, moderate and severe HA groups were compared using Kruskal Wallis test with Dunn’s test for multiple comparisons. Quantitative data between patients with and without inhibitors were compared using t test for parametric data and Mann Whitney test for non-parametric data. Qualitative data was analysed using Chi square test or Fischer’s exact test as applicable.
Results
Our study cohort comprised of 592 HA patients and included 41 (6.9%), 72 (12.2%) and 479 (80.9%) patients with mild, moderate and severe disease, respectively. The demographic and clinicopathologic characteristics of the patients are shown in Table 1. Pedigree analysis revealed positive family history in 333 (56.3%) patients. There was no difference in the proportion of patients with positive family history of HA across the severity spectrum of HA. History of consanguinity was present in 28 (4.7%) patients.
Table 1.
Clinicopathological characteristics of study population
| Clinicopathological parameters | All cases (n = 592) | Mild HA (n = 41,6.9%) | Moderate HA (n = 72, 12.2%) | Severe HA (n = 479, 80.9%) | p value | ||
|---|---|---|---|---|---|---|---|
| Mild versus moderate | Moderate versus severe | Mild versus severe | |||||
| Age at onset of bleeding in years | 3 (2–8) | 8 (4–12) | 6 (3–8) | 2 (1–3) | 0.11 | < 0.001 | < 0.001 |
| Family history of HA | 333 (56.3%) | 23 (56.1%) | 44 (61.1%) | 266 (55.5%) | 0.69 | 0.44 | > 0.99 |
| Consanguinity | 28 (4.7%) | 1 (2.4%) | 2 (2.8%) | 25 (5.2%) | > 0.99 | 0.56 | 0.71 |
| Spontaneous bleeding | 262 (44.2%) | 9 (21.9%) | 30 (41.6%) | 223 (46.6%) | 0.04 | 0.45 | 0.002 |
| Traumatic bleed | 499 (84.3%) | 32 (78%) | 59 (81.9%) | 408 (85.2%) | 0.63 | 0.48 | 0.26 |
| FVIII levels | 0.8 (0.3–0.9) |
10.7 (7.1–16.58) |
1.6 (1.2–2.5) |
0.25 (0.1–0.6) |
< 0.001 | < 0.001 | < 0.001 |
| vWF antigen in % |
147.8 (98.6–192) |
146.0 (104.3–193.1) |
140.8 (99.1–189.5) |
141.1 (98.95–194) |
0.61 | 0.58 | 0.66 |
| vWFGPIbR level |
106.8 (87–187.2) |
107.5 (85.-188.7) |
105.1 (84.5–184.7) | 106.2 (86.4–187) | > 0.99 | 0.72 | 0.35 |
Data expressed as median (interquartile range) or as proportions
All patients in our cohort had history of bleeding. Age at onset of bleeding was significantly lower in patients with severe HA [2 (1–3) years] compared to those with moderate [6 (3–8) years; p < 0.001] or mild [8 (4–12) years; p < 0.001] HA. Spontaneous and traumatic bleeding were reported in 262 (44.2%) and 499 (84.3%) patients, respectively. Spontaneous bleeding was significantly less common in mild HA (21.9%) in comparison to moderate (41.6%, p = 0.04) and severe HA (46.6%, p = 0.002). However, there was no significant difference in the proportion of patients with traumatic bleeding in the three severity subgroups of HA. Overall, the commonest site of bleeding was hemarthroses (n = 526, 88.9%). History of FVIII transfusion was present in 479 (80.9%) patients. These patients had received FVIII on-demand, and none received prophylactic therapy.
The median FVIII, vWF antigen and vWFGP1bR levels in the whole study population were 0.8 (0.3–0.9)%, 127.8 (98.6–172)% and 99.3 (77–120.2)%, respectively. No significant difference was observed in vWF antigen and vWF:GPIbR levels across the various severities of HA.
FVIII Inhibitors in HA
Prevalence
Inhibitor screen was performed in 236 patients in whom the presence of inhibitors was clinically suspected as in refractory bleeding despite factor replacement. Among these HA patients (n = 16, 6.8%) directly came with inhibitor suspicion and rest of the cases (n = 220, 93.2%) came during follow-up. FVIII inhibitors were detected in 35 patients. Among 35 inhibitor positive HA cases 9 (25.7%) patients directly came for inhibitor suspicion and rest 26 patients (74.3%) cases came during follow-up. The overall prevalence of inhibitors in the whole cohort was 5.9% and 14.8% among patients screened for inhibitors. Among patients with severe HA (n = 479), inhibitors were detected in 32 patients with a prevalence of 6.7%. In patients with moderate HA (n = 72), inhibitors were present in 3 patients (4.2%). Inhibitors were not detected in any of the patients with mild HA.
Demographic Characteristics of Patients with Inhibitors
The median age at index detection of inhibitor was 16 (5–30) years. Positive family history of HA and history of consanguinity were noted in 20 (57.1%) and 03 (8.6%) patients with inhibitors, respectively. Besides, family history of inhibitor was noted in 2 patients (5.7%). However, there was no significant difference in the proportion of patients with positive family history or consanguinity among patients with or without inhibitors (Table 2).
Table 2.
Comparison of demographic and clinicopathological parameters in inhibitor positive versus negative HA
| Inhibitor status | Positive (n = 35, 5.9%) | Negative (n = 557, 94.1%) | p value |
|---|---|---|---|
| Age of patients at time inhibitor detection | 16 (5–30) years | – | – |
| Time between 1st dose of FVIII and inhibitor development | 5 (1.25–15.5) years | – | |
| Age at onset of bleeding | 3 (1–12) years | 2 (1–8) years | 0.26 |
| Positive family history of HA (n, %) | 20 (57.1%) | 313 (56.2%) | 0.99 |
| Consanguinity (n, %) | 04 (11.4%) | 24 (4.3%) | 0.08 |
| Spontaneous bleed | 29 (82.9%) | 233 (41.8%) | < 0.001 |
| Traumatic bleed | 32 (91.4%) | 467 (83.8%) | 0.34 |
| Site of bleed | |||
| Hemarthroses | 32 (91.4%) | 494 (88.7%) | 0.79 |
| Gum bleed | 20 (57.1%) | 234 (42%) | 0.11 |
| Ecchymoses | 17 (48.6%) | 320 (57.4%) | 0.38 |
| Hematuria | 14 (40%) | 141 (25.3%) | 0.07 |
| Epistaxis | 12 (34.2%) | 135 (24.2%) | 0.22 |
| GI bleed | 10 (28.6%) | 124 (22.3%) | 0.41 |
| CNS bleed | 7 (20%) | 23 (4.1%) | 0.001 |
| Severe hemophilia (%) | 32 (91.4%) | 447 (80.3%) | 0.12 |
| Type of treatment (n, %) | |||
| FVIII only | 19 (54.3%) | 193 (34.7%) | 0.01 |
| Both FVIII and FFP | 15 (42.9%) | 252 (45.2%) | |
| FFP only | 01 (2.8%) | 112 (20.1%) | |
| FVIII level in % | 0.5 (0.1–0.8) | 0.7 (0.1–0.9) | 0.07 |
| vWF antigen in % | 142.7 (98.84–192.3) | 148.0 (95.8–190.1) | 0.66 |
| vWFGPIbR in % | 102.6 (87.5–189.7) | 107.9 (87.1–187) | 0.77 |
Data expressed as median (interquartile range) or as proportions
Laboratory Parameters in Patients with Inhibitors
Majority of the patients with inhibitors (n = 32, 91.4%) had severe HA. However, there was no significant difference in the proportion of patients with severe HA between patients with or without inhibitors (p = 0.12). There was no significant difference in vWF antigen and vWF: GPIbR levels between inhibitor positive and inhibitor negative HA patients (Table 2).
Time dependent inhibitors (TDI) were seen in 21 (60%) patients while immediately acting inhibitors (IAI) were present in 14 (40%) patients. High titre inhibitors (≥ 5BU) were seen in 28 (80%) patients with a median tire of 35.09 (24–212.4) BU. Average titre of inhibitors in patients with low titre inhibitors (n = 7, 20%) was 2.8 (1.2–4.4). There was no significant difference in age, family history, consanguinity, levels of FVIII, vWF antigen and VWFGP1bR, or type of inhibitor among patients with high and low titre inhibitors (Table 3). Retesting for inhibitors during follow-up was done in 16 inhibitor positive patients and disappearance of inhibitors was documented in 4 of them. In two patients with initial low titre inhibitors, spontaneous resolution of inhibitors was observed at 5–6 months after initial detection. However, in the other two patients with initial high titre inhibitor, disappearance of inhibitors was noted after 3–4 years. In the remaining 12 patients with persistent inhibitors, a change in the type of inhibitor from IAI to TDI and from TDI to IAI were observed in one patient each.
Table 3.
Comparison of HA patients with high and low titre inhibitors
| Parameters | Low Titre (< 5BU) (n = 7, 20%) | High Titre (> 5BU) (n = 28, 80%) | p value |
|---|---|---|---|
| Age in years at the time of inhibitor development | 21 (14–33) years | 13 (4.0–30.7) years | 0.29 |
| Positive Family history (n, %) | 06 (85.7%) | 14 (50%) | 0.19 |
| Consanguinity (n, %) | 0 | 4 (14.3%) | 0.56 |
| Type of treatment | |||
| -FVIII only | 3 (42.85%) | 16 (57.14%) | 0.12 |
| -Both FVIII and blood products | 3 (42.86%) | 12 (42.86%) | |
| Blood products only | 1 (14.29%) | 0 | |
| Inhibitor level in BU | 2.8 (1.2–4.4) | 35.09 (24–212.4) | < 0.0001 |
| Type of inhibitor | |||
| Immediately acting | 1 (14.3%) | 13 (46.4%) | 0.2 |
| Time dependent | 6 (85.7%) | 15 (53.6%) | |
| FVIII levels in % | 0.8 (0.4–2.1) | 0.4 (0.1–0.8) | 0.08 |
| vWF Antigen in % | 143.3 (96–189) | 149.2 (101.5–191.2) | 0.37 |
| vWFGPIbR in % | 101.2 (92.4–174) | 107.0 (81.93–182.4) | 0.68 |
Data expressed as median (interquartile range) or as proportions
Clinical Correlates in Patients with Inhibitors
All except 1 (2.85%) patient with inhibitors had history of FVIII transfusion with (n = 15, 42.9%) or without (n = 19, 54.3%) other blood products. The inhibitor positive patient without history of FVIII transfusion had received multiple transfusions with fresh frozen plasma (FFP) on several occasions. Thus, among the 479 patients with history of FVIII transfusion, inhibitors were seen in 34 (7.1%) patients. A significant difference in the type of replacement products (FVIII or blood product) was observed between HA patients with and without inhibitors (p < 0.001).
History of spontaneous bleeding was present in 29 (82.9%) patients with inhibitors. Proportion of patients with spontaneous bleeding in patients with inhibitors was significantly higher than that in patients without inhibitors (82.9% vs. 41.8%, p < 0.001). However, there was no difference in traumatic bleeding between patients with and without inhibitors (91.4% vs. 83.8%, p = 0.34). Hemarthroses was the commonest site of bleeding both in patients with (91.4%) and without inhibitors (88.7%). Intracranial bleed was reported in 7 (20%) patients with inhibitors which was significantly higher than that in patients without inhibitors (4.1%, p = 0.001). The higher risk of intracranial bleed in inhibitor positive patients viz a viz inhibitor negative patients was confirmed even when the analysis was restricted to patients with severe HA (21.9% vs. 5.1%, p = 0.002). There was no difference in the other sites of bleeding (gum bleed, epistaxis, haematuria, GI bleed, ecchymoses) between patients with and without inhibitors (Table 2).
Discussion
According to the World Federation of Haemophilia (WFH) annual global survey 2018, total number of patients diagnosed with inherited bleeding disorder (IBD) is 3,37,641 of which 1,73,711 individuals have HA. India accounts for 9–10% of the global burden of HA [1, 10]. Management of these patients is often complicated by the development of inhibitors which was the focus of the present study.
Globally, the prevalence of inhibitors in HA has been reported to be 25–40% [4, 11]. The prevalence observed by us was much lower than that reported in the Western literature. We found an overall inhibitor prevalence of 5.9% in our cohort of 592 HA patients and 14.8% among patients screened for inhibitors. The prevalence of inhibitors in moderate and severe HA were 4.2% and 6.7%, respectively, and no patient with mild HA had inhibitors. Similar low prevalence has been reported in previous Indian studies and range from 3.5 to 20.6% (Table 4) [5, 6, 8, 12]. Data suggests that there may be regional variations in the occurrence of inhibitors in Indian patients with a higher risk in southern and western India compared to the rest of the country [5, 7, 9]. Our centre primarily caters to a north Indian population from the union territory of Chandigarh and the neighbouring states of Punjab, Haryana, Himachal Pradesh and Uttarakhand. Our prevalence of inhibitor positive HA was 5.9% which is similar to observations of Pinto et al. who looked at the prevalence in different areas of the county and reported a prevalence of 5.45% in patients from North India [5].
Table 4.
Comparison of clinicopathological parameters of Haemophilia A patients with inhibitors in various Indian studies
| Parameters | Ghosh et al. [8] | Pinto et al. [5] | Shah et al. [7] | Arshad et al. [12] | Present study 2021 |
|---|---|---|---|---|---|
| Total HA patients | 352 | 1285 | 243 | 300 | 592 |
| Patients with inhibitors, n (%) | 26 (7.4%) | 78 (6.07%) | 50 (20.5%) | 29 (9.6%) | 35 (5.9%) |
| Age of diagnosis of inhibitor (years) | 17.7 (6–42) years | 19.3 (3–58) years | Majority (32%) were in the age group of 11–20 years | – | 16 (5–30) years |
| Transfusion history in patients with inhibitors | |||||
| FVIII only | – | 16 (20.5%) | – | 13 (44.8%) | 19 (54.3%) |
| FVIII and blood products | 49 (62.8%) | 16 (55.2%) | 15 (42.9%) | ||
| Blood product only | 13 (16.7%) | 0 | 01 (2.8%) | ||
| Bleeding site in patients with inhibitors | – | – | Hemarthroses: 44 (88%) | Hemarthroses: 27 (93.1%) | Hemarthroses: 32 (91.4%) |
| Hematoma: 32 (64%) | Gum bleed: 17 (58.6%) | Gum bleed: 20 (57.1%) | |||
| Hematuria: 11(22%) | CNS bleed: 6 (20.7%) | Ecchymoses: 17 (48.6%) | |||
| Intracranial bleed: 2 (4%) | Epistaxis: 10 (34.5% | Haematuria: 14 (40%) | |||
| Mucosal bleed: 26 (52%) | GI bleed: 6 (20.7%) | Epistaxis: 12 (34.3%) | |||
| Dental and surgical bleed: 42 (84%) | Hematuria: 14 (48.3%) | GI bleed: 10 (28.6%) | |||
| Ecchymoses: 15 (51.7%) | CNS bleed: 7 (20%) | ||||
| Severity of HA in patients with inhibitors | |||||
| Mild HA | 0 | 0 | 0 | 0 | 0 |
| Moderate HA | 2 (7.6%) | 0 | 2 (4%) | 0 | 03 (8.6%) |
| Severe HA | 24 (92.4%) | 78 (100%) | 48 (96%) | 29 (100%) | 32 (91.4%) |
| Inhibitor titre | |||||
| High titre | – | 37 (47.4%) | 38 (76%) | 17 (58.6%) | 28 (80%) |
| Low titre | 41 (52.6%) | 12 (24%) | 12 (41.4%) | 7 (20%) | |
The discrepancies between the Western and Indian prevalence of FVIII inhibitors may be attributed to several factors [5, 8]. The main reason stated in previous studies is that FVIII concentrate is less commonly used in India compared to the West [10]. Traditionally, cost and limited availability have been significant barriers for the access to FVIII concentrate by the average Indian patients [13]. In recent years, significant funding by the Government and other non-government organisations have substantially improved the availability of FVIII concentrate at reasonable costs [14]. None the less, its usage remains suboptimal as evidenced in our study. Although all patients in our cohort had history of bleeding, only 80.9% of the patients had received FVIII concentrate. Further, FVIII concentrate was received “on-demand” and none of the patients received prophylactic FVIII. Indeed, our observed inhibitor prevalence of 5.9% in the whole cohort and 6.7% in severe HA is reminiscent of the Western literature of the 1970s and early 1980s prior to the introduction of highly purified FVIII concentrates on a wide scale in these countries [4].
Evidence suggests that the prevalence of inhibitors increases with worsening disease severity. [5]. Our observations corroborate this trend of increasing inhibitor prevalence with worsening severity of HA. Most of our patients with inhibitors (91.4) had severe HA like what has previously been reported from India (Table 4).
The median age of patients at index detection of inhibitors in our study was 16 years as opposed to Western patients who usually develop inhibitors in their first decade of life. Our findings are corroborated by other Indian studies which have documented a higher age of inhibitor development in the second and third decades of life. Another intriguing observation in our study was that even among patients who received FVIII concentrate, only 7.1% patients developed inhibitors. Similarly, Pinto et al. and Arshad et al. also reported the development of inhibitors in 6.03% and 10.62% of Indian HA patients with history of transfusion of FVIII (with or without other blood products), respectively [5, 12]. This could be explained by the receipt of suboptimal or infrequent doses of FVIII, on-demand instead of prophylactic dosing, use of predominantly plasma derived FVIII instead of recombinant products, and transfusions of other blood products along with FVIII concentrate [8].
Similar to our observations, hemarthroses has been documented in multiple Indian studies to be the commonest site of bleed in HA patients irrespective of the presence or absence of inhibitors. While the development of inhibitors in HA is a vexing clinical problem, its association with risk or severity of bleeding is less clear [15, 16]. Our data suggests that inhibitors may be associated with increased bleeding severity. Significantly higher number of patients with inhibitors (82.9%) bled spontaneously compared to those without inhibitors (41.8%). Moreover, intracranial bleeding which is associated with high morbidity and mortality was significantly more common in inhibitor positive patients and was seen in 20% patients. Indian data on the risk of bleed from different sites and its correlation with presence of inhibitors is scanty. Higher risk of intracranial bleed and haematuria in HA patients with inhibitors was also reported by Arshad et al. [12].
In our cohort, high titre (> 5BU) and low titre (< 5BU) inhibitors were detected in 80% and 20% HA patients, respectively. Arshad et al. and Shah et al. also reported that high titre inhibitors were more common than low titre antibodies. However, the proportion of inhibitor positive patients with high titre antibodies was reported to be lower (47.4%) in the study by Pinto et al. Low titre inhibitors may spontaneously disappear with time (usually within 6 months). Such transient inhibitors were documented in two of our patients. Two of our patients showed disappearance of inhibitors after 6 months. One of them received recombinant FVII concentrate and the other patient received combination of FVIII concentrate and FFP.
There is a paucity of Indian data on the clinicopathological differences between HA patients with high and low titre inhibitors. We did not observe any significant difference in demographic or clinicopathological parameters between patients with low and high titre inhibitors. However, it is important to emphasize that this distinction is crucial for the optimum management of these patients.
It is noteworthy to evaluate the methods used for inhibitors assay. Suspicion of presence of inhibitors come from clinical and laboratory evidence. Inhibitor negative population is largely defined based on negative screening test. But this clot-based assay may sometimes give false negative results [12]. The widely used Bethesda assay may be unreliable in presence of low titre inhibitors because of its low sensitivity. In these situations, Nijmegen-Bethesda assay (NBA) may be more reliable. In our study, NBA was performed for two patients where there was a clinical suspicion of inhibitors though the screening test was negative. Low titre inhibitors at a level of 1.2 and 2 units were confirmed in both these patients on NBA.
Conclusion
A comparatively low prevalence of inhibitors was observed in our cohort of north Indian patients with HA. Spontaneous and intracranial bleed were significantly more common in patients with inhibitors. Most of the patients had high titre inhibitors. There was no difference in demographic and clinicopathological parameters in patients with high and low titre inhibitors.
Author contributions
DR, AJ and NK have designed the study, retrieved the data, and drafted the manuscript; CH and AJ performed the testing and helped in retrieving the data; RJ, DB, AT, ArJ, PM and JA performed the analytical analysis and helped in drafting of the manuscript. All authors approved the final manuscript.
Funding
Nil.
Declarations
Conflict of interest
All authors declare no competing interests and have no disclosures.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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