Management of dental extraction in patients with Haemophilia A and B: A report of 58 extractions

Objectives: Patients with inherited bleeding disorders are at high risk of bleeding following oral surgery and present challenges to the oral surgeons. Aim of this study was to report our experience in dental extraction in patients exhibiting Haemophilia A and B between 2007 and 2012. Patient and Methods: 58 dental extractions in 15 patients during 19 interventions were performed. Replacement therapy with recombinant and plasma-derived factor VIII and IX was applied systematically in combination with antifibrinolytic treatment and local haemostatic measures. The following data were recorded: type of surgery, applied local haemostatic measures, general substitution, systemic antifibrinolytic agents and occurrence of postoperative bleeding complications. Results: Two patients presented postoperative bleeding. One had secondary bleeding requiring additional injection of factor concentrates. The other one presented epistaxis which was managed conservatively with a nasal tamponade. Conclusions: Excellent haemostasis is achievable after dental extractions in patients with Haemophilia A and B by following a protocol using defined pre- and postoperative doses of factor concentrates in combination with haemostatic measures. Key words:Antifibrinolytic treatment, dental extraction, Haemophilia, inherited bleeding disorders, local haemostatic measures.


Introduction
Haemophilia is a common hereditary bleeding disorder. More than 400,000 people are affected worldwide (1). The X-linked recessive chromosomal bleeding disorder is caused by a variety of mutations in the factor VIII (Haemophilia A) or factor IX (Haemophilia B) gene. As a result men are expressing the disease, meanwhile women are typically asymptomatic carriers. One third of all cases of Haemophilia are the result of spontaneous mutations. Two thirds have a prior family history. Haemophilia A is the most common form of this disorder. Approximately 1:5,000 males are affected. In comparison Haemophilia B is less often, 1:30,000 males are affected (2). Haemophilia is summarized as follows: mild when plasma activity is between 6 and 40 % of normal; moderate if it ranges between 1-5 % and severe if it is <1 % (3). Patients with Haemophilia are at high risk of intra-and postoperative bleeding when oral surgery has to be performed. Therefore management of patients with hereditary bleeding disorders requires close cooperation between oral surgeons and a comprehensive Haemophilia treatment center. The use of clotting factor replacement therapy for all invasive surgical interventions is required (4,5). Successful treatment protocols are described in the current literature using systemic treatment, antifibrinolytic agents and local haemostatic measures (6,7). Purpose of the presented study was to report our experience in dental extractions and to evaluate the efficacy of a systematic protocol involving systemic treatment combined with local haemostatic techniques to prevent bleeding after dental extraction in patients with Haemophilia.

Patient and Methods
The study includes results of 58 extractions in 15 patients. General anesthesia was performed if necessary. Articain with Adrenaline 1:100,000 (Ultracain D-S forte, Sanofi-Aventis, Paris, France) was used for local anesthesia. Recombinant and plasma-derived factor In all cases injection was administered half-hour before surgery. The clotting factor level was planned to increase from 50-100 IU/dL of normal preoperatively. The postoperative factor trough levels were aimed to remain above 30 % (Table 1). Further doses of clotting factor were applied in the next days.
Tranexamic acid (Cyklokapron, Meda Pharma, Bad Homburg, Germany) was used systematically in 16 interventions. It was administered intravenous and orally at a dose of 20 mg/kg of body weight every eight hours for seven days. Due to cardiovascular contraindications it was not used in three cases. Furthermore gauzes saturated with tranexamic acid were applied in all patients during the first three days after surgery. Patients with contraindications for systemic antifibrinolytic agents received tranexamic acid only topical. e57

Discussion
Patients with Haemophilia are at high risk of secondary bleeding following oral surgery. Close cooperation between haematologists and oral surgeons is necessary to prevent excessive haemorrhage. International guidelines strongly recommend the use of clotting factor replacement therapy for all invasive surgical interventions (5). The World Federation of Haemophilia (WFH) advises the use of factor concentrates to cryoprecipitate or fresh frozen plasma for the replacement therapy in patients with Haemophilia. Factor VIII and IX concentrates may be divided into two categories, recombinant and plasma-derived factor. There are no statements from the WFH for a preference for recombinant over plasmaderived concentrates. The level of factor required for surgical procedures in haemophiliacs is given in table 1. In this study we used native plasma derived concentrates in 10 cases and recombinant concentrates in four cases. One unit of infused recombinant factor VIII per kilogram of body weight should lead to a rise of plasma factor VIII level of approximately 2% in patients with Haemophilia A and in absence of an inhibitor. The halflife of factor VIII is approximately 8-12 h. On the other side, one unit of infused plasma-derived concentrates of factor IX per kilogram of body weight will raise the plasma factor IX activity by approximately 1% in pa-tients with Haemophilia B in absence of an inhibitor (8). In contrast to the native plasma-derived factor, the recombinant factor IX has a lower recovery. One unit of infused factor IX per kg body weight should raise the plasma factor IX level approximately 0.8% in adults and 0.7 % in children (9). The half-life of factor IX is approximately 18-24 h (10).
The conventional replacement therapy is not effective in patients with antibodies to factor VIII and IX. Approximately 8 to 20% of the patients with severe Haemophilia A and 2.5 to 16% of those with severe Haemophilia B are affected (11). A variety of genetic and immunologic factors are responsible in inhibitor development (12)(13)(14)(15)(16).
However an activated prothrombin complex concentrate or a recombinant activated factor VII concentrate can be used to this patients (17). Factor replacement therapy carries a risk of transmission of viruses or new pathogens and may lead to develop inhibitors. Therefore reducing the number of patients and times requiring factor replacement therapy is helpful. DDAVP may be the treatment of choice for patients with mild or moderate Haemophilia A (18,19). A preoperative single dose of 0.3 µg/ kg of body weight can increase the factor VIII level three-to sixfold in good responders (20). It is much less expensive than coagulation factor concentrates.
There is no risk of transmission of infections and no risk of immunization. Because of the significant differences between individuals, a prior testing of patient's response a few weeks before surgery is necessary in these cases. Various reports have described dental extractions under DDAVP in patients with bleeding disorders (21,22). The antifibrinolytic treatment with tranexamic acid prevents postoperative bleeding by inhibiting the activation of plasminogen to plasmin and promoting the clot stability. It is usually given as an oral tablet three to four times or by intravenous infusion two to three times daily. Tranexamic acid should be prescribed for seven days following dental extractions in patients with intrinsic bleeding disorders (23). Furthermore various reports referred the successful local use of tranexamic acid for the reduction of oral bleeding (22,24).
Oral surgeons have to use all techniques to minimise the probability of intra-and postoperative bleeding. Local haemostatic measures are obligate following dental extraction in these patients. Typical agents are sutures (22), collagen vlies (21), oxycellulose (25), gelatine (26), a fibrin glue (27) and cyanoacrylate (28). In this study all mentioned local measures were used according to surgeon preference and practice pattern. Furthermore the different agents were combined with each other to potentiate the haemostatic effect. Wagner et al. compared often used topical haemostatic agents in terms of their ability to mediate platelet aggregation, deposi-tion and activation in a series of in vitro tests. He presented an overall activity ranking of the materials used: collagen>gelatine>oxidized regenerated cellulose (29).
In this report we could not note a different efficacy between the various local haemostatic measures. To prevent late bleeding we used absorbable sutures in order to avoid suture removal. For pain control non-steroidal anti-inflammatory drugs and aspirin which affect platelet function must be avoided. Paracetamol is a safe alternative to prevent postoperative pain.
The current literature reports successful treatment protocols to prevent bleeding complications following oral surgery procedures. The results are similar to our report. Frachon (21). Zanon et al. registered two bleeding complications after dental extraction in 75 procedures. Clotting factor concentrates to obtain a plasma peak level of 30% were given. Fibrin sponges, primary suture and tranexamic acid were used for local measures (30). In our study sample secondary bleeding occurred in two patients surprisingly exhibiting mild form of Haemophilia A. This is an indication that postoperative bleeding after oral surgery in patients exhibiting Haemophilia is difficult to predict also if defined treatment protocols are used. Postoperative monitoring of these patients is necessary to prevent excessive haemorrhage.

Conclusion
Considering an individual haemostaseological protocol in consultation with a hematologist helps to prevent bleeding complications in haemophiliacs undergoing dental extractions. Local haemostatic measures have to be used whenever possible following a dental extraction to reduce the need of factor concentrates. A specialist dental service in consultation with a Haemophilia treatment centre should perform these procedures.