European Journal of Cardiovascular Medicine

Hemophilia and rare inherited bleeding disorders (IBDs) comprise a spectrum of inherited coagulation disorders that present significant challenges in diagnosis, treatment, and healthcare delivery. These conditions, marked by impaired clotting function, can result in spontaneous or trauma-induced bleeding that significantly compromises patients’ quality of life and places a considerable burden on health systems [1,2].

Hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) together affect roughly 1 in 10,000 live births worldwide [3]. Clinical manifestations vary with disease severity, and patients with severe forms frequently experience spontaneous joint and muscle bleeds [4]. IBDs including deficiencies of factors I, II, V, VII, X, XI, XIII, and combined factor deficiencies are rarer and often more complex to diagnose and manage due to their heterogeneous clinical features [5].

Global epidemiological studies have reported variation in bleeding manifestations across populations. A European registry-based study found that joint bleeds accounted for 70–80% of serious bleeding episodes in hemophilia, with muscle bleeds and bleeds at other sites comprising 10–20% and 5–10%, respectively [6]. In contrast, studies from Asia have reported increased mucocutaneous bleeding in certain RBDs, reflecting regional variability in presentation [7].

The therapeutic landscape for managing acute bleeding has evolved significantly over the last decade. Factor replacement therapy remains the cornerstone of care, but advances such as extended half-life (EHL) factor products, non-factor therapies (e.g., emicizumab), and gene therapy have shifted treatment paradigms [8,9]. Nonetheless, access to these newer agents remains limited in many resource-constrained settings, necessitating continued evaluation of real-world practices [10].

Specialized comprehensive care centers have been associated with improved patient outcomes. A North American multi-center study found that such centers led to better bleeding control, reduced joint damage, fewer hospitalizations, and enhanced quality of life [11]. However, data from developing countries, particularly in South Asia, remain limited and fragmented.

Kerala, known for its robust healthcare system, has made strides in hemophilia care through prophylactic treatment and comprehensive care models [6].  While existing Indian studies are largely metropolitan-focused, there is a lack of systematic data from Kerala, leading to important knowledge gaps in the regional context [12].

However, regional data on bleeding patterns and management practices are scarce, hindering evidence-based policy development. This study aims to analyze the frequency, nature, and management of acute bleeding events in hemophilia and rare inherited bleeding disorders at a tertiary care center in Kerala, addressing a critical gap in regional epidemiology.

Study Design and Setting

This retrospective observational study was conducted at the Department of Internal Medicine, Government Medical College, Kottayam, Kerala, India, from May 2023 to April 2025, following approval from the Institutional Ethics Committee (IEC).

Study Population

Patients with confirmed diagnoses of hemophilia A, hemophilia B, or Inherited bleeding disorder (IBDs) presenting with acute bleeding events (spontaneous or trauma-related) requiring outpatient or inpatient care were included. Exclusion criteria included incomplete or illegible medical records and bleeding events not requiring medical intervention.

Data Collection

Data were extracted from the institutional hemophilia registry, capturing demographics (age, district), clinical variables (bleeding disorder type, bleed location, inhibitor status, disease severity), management details (outpatient vs. inpatient care, inpatient duration, clotting factor or blood component therapy usage), and temporal patterns (seasonal distribution). Data were de-identified and entered 3 into a Microsoft Excel database.

Statistical Analysis

Descriptive statistics, including frequencies, percentages, means, and medians, were used to summarize data. Comparisons between groups (e.g., outpatient vs. inpatient management) were analyzed using chi-square tests for categorical variables and t-tests for continuous variables, with a significance threshold of p<0.05. No inferential statistical modeling was performed due to the observational design.

Ethical Considerations: Data anonymization ensured participant confidentiality, and IEC approval was obtained prior to data retrieval.

A retrospective analysis was conducted on 214 acute bleeding events in patients with hemophilia and rare inherited bleeding disorders (IBDs) at a tertiary care center in Kerala, India, from May 2023 to April 2025. The findings are presented in alignment with the study objectives, detailing bleeding patterns, management settings, treatment duration, regional distribution, and clotting factor usage.

Frequency and Nature of Acute Bleeding Events

Of the 214 bleeding events, hemophilia A (factor VIII deficiency) accounted for the majority (163 cases, 76%), followed by hemophilia B (factor IX deficiency, 36 cases, 17%), and various rare bleeding disorders. (Figure-1). Joint bleeds were predominant, comprising 137 cases (64%), with knee bleeds being the most common (55 cases, 40.1% of joint bleeds), followed by elbow (35 cases, 25.5%) and hip (15 cases, 10.9%). Muscle bleeds occurred in 18 cases (8.4%), with psoas muscle involvement in 50% of these. Mucosal bleeds were reported in 17 cases (7.9%), primarily gum bleeds (52.9%), while intracranial bleeds were rare (5 cases, 2.3%), with intraparenchymal bleeds constituting 80% of these. Other bleeds, including surgical interventions, accounted for 37 cases (17%), with dental extractions being the most frequent surgical procedure (7 cases, 64% of surgical interventions) (Table 2,Figure 1).

Management in Outpatient versus Inpatient Settings

Of the 214 bleeding events, 143 (66.8%) were managed in outpatient settings, while 71 (33.2%) required inpatient care. Internal and mucosal bleeds were significantly more likely to require inpatient management (85% inpatient vs. 15% outpatient, p=0.036) compared to joint bleeds (18.5% inpatient vs. 81.5% outpatient). Inhibitor status influenced management, with inhibitor-positive cases requiring inpatient care in 44.4% of cases compared to 22.5% for inhibitor-negative cases, though this was not statistically significant (p=0.119) (Table 3).

Duration of Inpatient Care

Duration of inpatient care ranged from 2 days to 22 days , with a median duration of 4.5 days  Total treatment duration for inpatient  was significantly longer (6.5 days) compared to outpatient treatment duration (1.3 days, p<0.001).

Regional Distribution of Referred Cases

Cases were predominantly from Kottayam district (139 cases, 65%), followed by Alappuzha (25 cases, 11.6%), Kollam (17 cases, 8%), Idukki (14 cases, 6.54%), Pathanamthitta (12 cases, 5.6%), Ernakulam (6 cases, 2.8%), and Palakkad (1 case, 0.46%) (Fig: 2). This distribution reflects the proximity of the tertiary care center to Kottayam and highlights regional referral patterns.

Clotting Factor Concentrate and Blood Component Therapy

The median factor concentrate usage was significantly higher for inpatient cases (13,150 units) compared to outpatient cases (1,086 units, p<0.001). The distribution of factor doses showed that 49% of cases required ≤1,000 units, 21.4% required 1,001–2,000 units, 17% required 2,001–5,000 units, 4.2 % required 5,001–10,000 units, and 4.2% required >10,000 units. 30 units of Fresh Frozen Plasma were given for 5 bleeding events (2.3%) and 36 units of Cryoprecipitate were given for 4 bleeding events (1.9%).  (Table 5). Severity of disease (r=0.423, p<0.001) and treatment duration (r=0.836) were strong predictors of higher factor doses. Inpatient cases required approximately 12 times more factor concentrate than outpatient cases, and inhibitor-positive patients required 40% higher doses than inhibitor-negative patients. (Figure 3)

Age Distribution and Temporal Patterns

The age distribution showed that 50% of patients were aged 18–30 years (107 cases), 31% were 31–50 years (67 cases), 13% were >50 years (27 cases), and 6% were <18 years (13 cases) (Table 6). Bleeding events were distributed throughout the year, with slight peaks in July (25 cases, 12%) and August (27 cases, 13%). Seasonally, the monsoon period (June–October) accounted for 47% of bleeds (100 cases), followed by winter (November–February, 69 cases, 32%) and summer (March–May, 45 cases, 21%) (Table 6).

Disease Severity and Influencing Factors

Of the patients, 160 (74.8%) had severe disease, and 3 (1.4%) had moderate disease. Bleed severity, as indicated by the need for inpatient care, was significantly influenced by disease classification, inhibitor status, and bleeding location (p<0.05 for all). However, no significant associations were observed with age or hemophilia type (A vs. B)(Table 8)

Table 1: Types of Acute Bleeding Events

Subdural hematoma

1

20%

Others

26

12% of total cases

Surgical Interventions

11

5% of total cases

Neck of femur Fracture

1

9%

Shaft of Femur

2

18%

Both bone fracture Tibia and Fibula

1

9%

Dental Extractions

7

64%

Table 2: Management Settings by Bleed Type and Inhibitor Status

Table 3: Distribution of Clotting Factor Concentrate Usage

Table 4: Age Group and Seasonal Distribution of Acute Bleeding Events

Table 5- Factors affecting severity of bleed as indicated by IP Care

This retrospective analysis of acute bleeding events in patients with hemophilia and inherited rare bleeding disorders (RBDs) at a tertiary care center in Kerala, India, provides novel insights into the regional epidemiology, management patterns, and treatment outcomes in a resource-limited setting. The findings highlight the predominance of hemophilia A (76%) among bleeding disorders, consistent with global prevalence data indicating that factor VIII deficiency is the most common form of hemophilia [13]. The high proportion of joint bleeds (64%), particularly knee bleeds, aligns with existing literature that identifies hemarthrosis as a hallmark of severe hemophilia, contributing to significant morbidity due to chronic joint damage [1,14].

The observation that 66.8% of bleeding events were managed in outpatient settings underscores the potential for effective ambulatory care in resource-constrained environments. This is particularly relevant in Kerala, where the public-private integrated healthcare system facilitates access to specialized care [12]. However, the significant association between internal/mucosal bleeds and inpatient management (85% inpatient, p=0.036) reflects the increased clinical complexity of these bleeds, often necessitating intensive monitoring and higher doses of clotting factor concentrates [15]. The median inpatient duration of 4.5 days and the 12-fold higher factor concentrate usage in inpatient settings (13,150 units vs. 1,086 units, p<0.001) further emphasize the resource-intensive nature of managing severe bleeding episodes, a finding corroborated by studies highlighting the economic burden of hemophilia care in low-resource settings [16].

The regional distribution of cases, with 65% originating from Kottayam district, likely reflects the proximity of the tertiary care center and established referral networks. This pattern suggests a need for decentralized hemophilia care to reduce geographic disparities in access, particularly for patients from distant districts [17]. The seasonal trend of increased bleeding events during the monsoon period (47%) may be linked to environmental factors, such as increased physical activity or trauma due to slippery conditions, though this requires further investigation [18].

Inhibitor status emerged as a critical determinant of management complexity, with inhibitor-positive patients requiring inpatient care in 44.4% of cases compared to 22.5% for inhibitor-negative patients. Although this difference was not statistically significant (p=0.119), it aligns with evidence that inhibitors complicate treatment by necessitating alternative therapies, such as bypassing agents, which are often cost-prohibitive in resource-limited settings [19]. The strong correlation between disease severity, treatment duration, and factor concentrate usage (r=0.423 and r=0.836, respectively, p<0.001) further underscores the need for tailored therapeutic strategies to optimize resource allocation [4].

The age distribution, with 50% of patients aged 18–30 years, reflects the demographic profile of hemophilia patients in India, where improved survival due to better access to factor replacement therapy has increased the proportion of young adults [20]. However, the limited representation of pediatric patients (<18 years, 6%) may attributed to the prophylaxis in this age group, limiting the acute bleeding events in this age group.[21]

This study’s findings have important implications for policy and practice. The reliance on factor replacement therapy, coupled with limited access to advanced treatments like emicizumab in Kerala, highlights the need for cost-effective strategies to enhance care delivery [8]. The success of outpatient management in two-thirds of cases suggests that strengthening comprehensive care centers, as demonstrated in North American models, could further reduce hospitalizations and improve quality of life [11]. Additionally, the regional data gap addressed by this study emphasizes the importance of localized registries to inform evidence-based guidelines tailored to India’s diverse healthcare landscape [22].

Limitations include the retrospective design, potential selection bias, and lack of inferential modeling. Future prospective studies should incorporate patient-reported outcomes to assess quality-of-life impacts for a more holistic understanding of acute bleeding events [23].

In conclusion, this study provides critical insights into the management of acute bleeding events in hemophilia and rare inherited bleeding disorders within a unique regional context. By highlighting the predominance of joint bleeds, the feasibility of outpatient care, and the challenges posed by inhibitors and resource constraints, these findings contribute to the growing body of evidence needed to optimize hemophilia care in resource-limited settings

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