Navigating Haemophilia in Dental Practice: Practical Insights and Updates

1.1. Pathophysiology of Haemophilia

The pathophysiology is directly linked to the deficiency of clotting factors. In HA, mutations occur in the F8 gene, which encodes factor VIII, a crucial protein in the coagulation cascade that facilitates blood clot formation. Its absence or dysfunction leads to impaired thrombin generation and fibrin formation, which are critical for adequate hemostasis [6]. In contrast, HB results from mutations in the F9 gene, which is responsible for producing factor IX, another essential clotting factor; its absence disrupts the intrinsic pathway [3, 4]. Both types are X-linked recessive conditions, meaning they predominantly affect males, as the gene mutations are located on the X chromosome. The disease exhibits a crisscross inheritance pattern in which females can be carriers, often exhibiting milder symptoms or none due to the presence of a second, normal X chromosome [7].

The severity of haemophilia is classified based on the level of clotting factor activity. Severe haemophilia has factor levels of less than 1% of normal; moderate haemophilia ranges from 1% to 5%; and mild haemophilia is characterized by factor levels between 5% and 40%, as per standard medical practice [8]. Mild haemophilia is usually diagnosed in adulthood, where patients generally experience their first bleeding episode due to injury, surgery, or tooth extraction. Patients with moderate haemophilia usually experience bleeding even due to minor trauma and injuries, along with occasional spontaneous bleeding episodes. On the other hand, severe haemophilia patients frequently suffer abnormal bleeding in response to injuries, and there is also a likelihood of spontaneous, unexplained bleeding.

1.2. Clinical Presentation and Diagnostic Criteria

haemophilia presents with prolonged bleeding after injuries, easy bruising, and spontaneous bleeding, particularly in joints (hemarthrosis) and muscles, leading to joint damage and chronic pain [3, 6, 9]. Diagnosis involves clinical history, physical examination, and laboratory tests showing prolonged aPTT with normal PT [10]. Definitive diagnosis requires specific assays measuring factor VIII or IX activity levels [10].

1.3. Impact of Haemophilia on Oral Health

The most predominant oral features of haemophilia include gingival bleeding, either unprompted or during brushing, post-extraction hemorrhage from minor trauma or contusions, as well as oral ulcerations, ecchymosis, and hematomas in the lips and tongue. Likewise, unusual features may include TMJ hemarthrosis, triggering pain and swelling, and even bleeding into soft tissues such as the tongue, buccal mucosa, and palate without any apparent signs of injury.

Preventive dental care is crucial to prevent complications associated with dental treatments [11]. Regular check-ups and oral hygiene education significantly reduce dental issues, decreasing the need for extensive interventions [12]. Patients often exhibit a higher prevalence of dental caries and periodontal disease due to fear of bleeding, leading many to avoid flossing and necessary treatments, which creates a vicious cycle requiring more invasive future treatments for improving outcomes and quality of life [13, 14].

1.4. Challenges Faced in Managing Hemophilic Patients in the Dental Operatory

Managing hemophilic patients in the dental operatory presents several challenges. Many practitioners lack training, leading to hesitation and treatment delays [14, 15]. Multidisciplinary collaboration between dentists and hematologists is essential but complex, requiring careful planning for clotting factor replacement therapy before procedures [16]. Many practitioners are unfamiliar with local hemostatic measures such as fibrin glue and gelatin packing [17]. The lack of standardized protocols results in inconsistent practices across dental settings [17].

1.5. Management of Haemophilia

The medical, dental, and bleeding risk assessment is crucial for tailoring treatment plans and ensuring the safety of dental procedures (Fig. 1). The evaluation begins by confirming the specific type and its severity to assess bleeding risk and management needs [18]. Family history provides insights into potential complications and identifies comorbidities, such as liver disease, as they complicate management strategies [17, 19]. A thorough review of current medications, including over-the-counter drugs and supplements, is necessary to assess their impact on bleeding risk [18]. In terms of dental history, documenting previous dental treatments that resulted in bleeding complications can forewarn future treatment planning, while concurrently assessing the current state of oral health [12, 20]. Understanding the patient's attitude towards dental care is essential, as anxiety or fear may lead to avoidance of necessary treatments [21]. Collaboration with hematologists enhances confidence and acceptance of dental care, minimizing risk [21]. Risk assessment tools specifically designed for patients with bleeding disorders, such as the Dental Bleeding Risk Assessment and Treatment Tool (DeBRATT), help further categorize patients based on their bleeding risk during dental procedures [17].

1.6. Laboratory Investigations

Laboratory investigations are crucial in diagnosing, managing, and monitoring haemophilia (Table 1). The primary goal is to assess the levels of specific clotting factors, which directly influence treatment strategies [22, 23].

1.7. Preoperative Hemostasis Optimization

Preoperative hemostasis optimization is critical for patients with haemophilia undergoing surgery.

1.8. Factor Replacement Therapy

Factor replacement therapy is essential before surgery to raise plasma levels of the missing clotting factor and prevent bleeding . Factor concentrates are given shortly before surgery to ensure peak levels during the procedure. WFH guidelines recommend a loading dose within three days before surgery, with preoperative and postoperative monitoring to ensure adequate hemostasis [25].

1.9. Recombinant Factors

Advances in recombinant factor therapies have enhanced treatment safety and effectiveness. Recombinant factor VIIa can be used to develop inhibitors, providing an alternative approach to restoring hemostasis.

1.10. Antifibrinolytics

Antifibrinolytic agents (TXA and EACA) are lysine analogs that inhibit plasminogen activation, preventing fibrin clot breakdown and maintaining hemostasis [25, 26]. Systematic reviews show that they significantly decrease hemorrhage [27].WFH recommends combining antifibrinolytics with factor replacement therapy. TXA should be given preoperatively and continued briefly postoperatively [26].

1.11. Intraoperative Management of Haemophilia

Intraoperative management is critical to minimize the risk of bleeding during surgical procedures. It involves several key considerations, including anesthesia techniques, local hemostatic measures, minimizing trauma, and pharmacological support.

1.12. Anesthesia Considerations

Anesthesia should avoid techniques that could cause significant bleeding. Nerve blocks in vascular areas should be avoided due to hematoma risk [28]. General or local anesthesia with careful technique minimizes tissue trauma [29]. The anesthesiology team must ensure appropriate factor replacement therapy before the procedure [30].

1.13. Local Hemostatic Measures

1.14. Pharmacological Support

Use of Local Vasoconstrictors: Local vasoconstrictors, such as epinephrine, can be used in conjunction with local anesthetics to reduce blood flow to the surgical site. However, caution should be exercised to avoid excessive vasoconstriction, which could compromise tissue perfusion.

1.15. Minimizing Trauma

Surgical techniques should prioritize gentle tissue handling and be minimally invasive [29]. This approach reduces trauma, shortens recovery time, and minimizes the risk of complications [29, 31].

1.16. Postoperative Care for Hemophilic Patients

Postoperative care is critical to ensure optimal recovery and minimize the risk of complications. This care involves several key components, including hemostasis monitoring, appropriate medication management, patient instructions for postoperative care, and emergency protocols for managing delayed bleeding.

1.17. Advances and Updates in Management

Recent advancements aim to improve treatment adherence, reduce infusion frequency, and enhance patients' overall quality of life. The introduction of long-acting recombinant factor products has reduced the frequency of spontaneous bleeds [33, 34]. However, the presence of inhibitor antibodies that neutralize the effectiveness of factor replacement therapy complicates treatment and can lead to increased morbidity and mortality in affected patients [34].

1.18. Extended Half-Life Clotting Factors

Recombinant factor VIII was the first to be developed, followed by the successful replication of factor IX. Recombinant factor VIII products can be categorized by their production method: animal or human cell culture. Initial products used animal proteins along with human serum albumin, whereas newer drugs use human-origin proteins in a culture medium without albumin. Modern protein production has successfully eliminated the addition of either animal or human proteins in its ingredients. One key area of experimentation has been modeling recombinant proteins with extended half-lives. This is because the required infusion time to sustain clotting factor levels greater than 1% is quite long: approximately 12 hours for factor VIII and 16–18 hours for factor IX [35]. This places an additional burden on patients, particularly children and adults, while simultaneously increasing the cost of the procedure. To address this problem, modifying coagulation factors, such as PEGylation or cross-linking with the Fc fragment of antibodies, has been proposed [36]. Extended half-life recombinant FVIII and FIX concentrates have been developed to prolong the duration of action and allow less frequent dosing than traditional factor replacement therapies, thereby significantly reducing the treatment burden [36]. These factors have shown promising results in clinical trials, demonstrating effective hemostatic control with fewer infusions per week, which is beneficial for patients with severe haemophilia who require prophylactic treatment to prevent bleeding episodes [36]. This has also raised awareness of the potential discordance between one-stage activated partial thromboplastin time (aPTT)-based assays and chromogenic factor assays, necessitating careful monitoring and adjustment of treatment protocols [35].

1.19. Non-replacement Therapy for Haemophilia

Antibody-based therapies offer an alternative to EHL drugs by reducing injection frequency. Emicizumab, a humanized bispecific monoclonal antibody (IgG4), mimics factor VIII activity by binding factors IX and X, accelerating their activation. Concizumab, a humanized IgG4 antibody binding the Kunitz-2 domain, modulates thrombin generation and induces procoagulant effects [30, 37].

1.20. Gene Therapy

Gene therapy addresses the underlying genetic defect by delivering a functional copy of the deficient gene, enabling endogenous production of the deficient clotting factor [30]. Early clinical trials show sustained increases in factor levels, reducing bleeding episodes and the need for factor replacement [30]. Adeno-associated virus (AAV) vectors are commonly used for gene delivery. Challenges remain for patients with inhibitors, who have been excluded from studies [30]. Ongoing research focuses on optimizing delivery methods for long-term safety and efficacy [37].

1.21. Treatment of Haemophilia using Blood-purified Factors VIII and IX

In the 1950s and 1960s, whole blood plasma transfusions were the prevailing mode of treatment for haemophilia until cryoprecipitation technology emerged in the second half of the 1960s, enabling the precipitation of necessary blood proteins under a specific thawing regimen for fresh-frozen plasma. In this manner, it is feasible to obtain concentrated clotting factors, thereby significantly reducing the infusion volume.

1.22. Cellular Therapy of Haemophilia

Patients undergoing cell therapy have their endothelial progenitor cells and stem cells transformed in vitro to express coagulation factors before transplantation. Numerous studies have demonstrated successful transplantation of transformed hematopoietic stem cells expressing FVIII or FIX using retroviral or lentiviral vectors. Research on induced pluripotent stem cells (iPSCs) for haemophilia treatment has also been conducted, as the pool of cells expressing coagulation factors is larger [38].

1.23. Role of Dental Lasers in Minimizing Bleeding

Dental lasers minimize bleeding by precisely targeting soft tissues and promoting coagulation while minimizing surrounding damage. Studies show diode lasers significantly decrease intraoperative bleeding and postoperative discomfort, contributing to quicker recovery and less pain [39].

1.24. Updated Guidelines and Consensus Statements

Recent guidelines emphasize individualized treatment plans considering patient needs, including EHL factors and gene therapy where appropriate [35, 38, 39].

1.25. Interdisciplinary Collaboration

Interdisciplinary collaboration is essential; the involvement of various healthcare professionals ensures that patients receive holistic and coordinated care [39]. The management often necessitates surgical interventions, which require careful perioperative planning. Integrating different specialties enables a more comprehensive assessment of the patient's health status and facilitates the development of individualized treatment plans that address both medical and psychosocial aspects of care. Collaborative efforts enhance patient education and improve adherence to treatment regimens [34, 40].

1.26. Challenges in Interdisciplinary Collaboration

Despite the recognized benefits of interdisciplinary collaboration, several challenges persist. One significant barrier is the lack of awareness and understanding of haemophilia among healthcare providers outside specialized centers. This can lead to inconsistent care and management practices, particularly in emergencies requiring immediate intervention [40]. Additionally, communication gaps across specialties can hinder the timely exchange of critical information in patient care. Another challenge is the need for ongoing education and training for healthcare professionals who care for patients with haemophilia. Continuous professional development ensures that all team members are up to date with the latest treatment protocols and management strategies [39]. Patients can receive comprehensive care through a team-based approach that involves multiple healthcare professionals.

1.27. Clinical Perspective: What Dentists Need to Know Today?

With the advent of extended half-life clotting factors, non-factor therapies such as emicizumab, and gene therapy trials, the dental management of patients with haemophilia is evolving. For dentists, this means risk assessment must include not only bleeding history but also the specific therapy regimen, since newer agents may reduce spontaneous bleeding while altering the response to factor replacement in cases of surgical bleeding. Coordination with hematologists is critical to understand whether the patient is on prophylaxis, requires factor supplementation, or is receiving non-factor therapy that modifies coagulation pathways. In preoperative planning, dentists should adopt a tailored approach. Postoperatively, these therapies may reduce the duration of bleeding risk, but vigilant monitoring and patient education remain essential, particularly for invasive procedures. Table 3 presents a dental management quick clinical decision table for haemophilia patients.