- Email: [email protected]
Ten-year study of postoperative complications following dental extractions in patients with inherited bleeding disorders
YIJOM-3677; No of Pages 4
Int. J. Oral Maxillofac. Surg. 2017; xxx: xxx–xxx http://dx.doi.org/10.1016/j.ijom.2017.04.016, available online at http://www.sciencedirect.com
Clinical Paper Oral Surgery
Ten-year study of postoperative complications following dental extractions in patients with inherited bleeding disorders
J.-T. Hsieh1, K. Klein2, M. Batstone3 1 Department of Maxillofacial Surgery, Royal Brisbane & Womens Hospital, Brisbane, Australia; 2Clinical Trials and Biostatistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia; 3Department of Maxillofacial surgery, Royal Brisbane & Womens Hospital, University of Queensland, Brisbane, Australia
J.-T. Hsieh, K. Klein, M. Batstone: Ten-year study of postoperative complications following dental extractions in patients with inherited bleeding disorders. Int. J. Oral Maxillofac. Surg. 2017; xxx: xxx–xxx. Crown Copyright ã 2017 Published by Elsevier Ltd on behalf of International Association of Oral and Maxillofacial Surgeons. All rights reserved.
Abstract. Dental extractions challenge the body’s haemostatic mechanism. Postoperative bleeding from dental extraction can be prolonged, or even life threatening in patients with inherited bleeding disorders. Pre- and postoperative clotting factor replacements or systemic desmopressin (ddAVP) have been advocated at our institution to prevent bleeding complications in these patients. This study aimed to assess the postoperative bleeding rate in patients with inherited bleeding disorders that underwent dental extractions at our institution between 2003 and 2012. Patients with inherited bleeding disorders such as haemophilia A, haemophilia B, and von Willebrand’s disease were included. Retrospective chart review was conducted. The result showed 53 extraction events occurred in 45 patients over the 10-year period. Ten out of 53 extraction events (18.9%) had postoperative bleeding requiring further factor replacement or ddAVP. Postoperative bleeding in one patient with mild haemophilia A was complicated by the development of inhibitors. Type and severity of bleeding disorder, bone removal, and use of a local haemostatic agent did not have any significant effect on postoperative bleeding. Despite the use of perioperative factors and desmopressin, the postoperative bleeding rates remain high for patients with inherited bleeding disorders. More studies are required to assess the safety and effectiveness of using local haemostatic control to achieve haemostasis following extractions.
Dental extractions challenge the body’s haemostatic mechanism. Postoperative bleeding from extraction sockets can be prolonged, or even life threatening in 0901-5027/000001+04
patients with inherited bleeding disorders. Haemophilia A, haemophilia B, and von Willebrand disease are the most common inherited bleeding disorders.
Key words: haemophilia; von Willebrand disease; dental extraction; factor replacement; desmopressin. Accepted for publication 19 April 2017
There have been no controlled trials to date to define the optimal haemostatic therapy for patients with inherited bleeding disorders undergoing oral surgery.
Crown Copyright ã 2017 Published by Elsevier Ltd on behalf of International Association of Oral and Maxillofacial Surgeons. All rights reserved.
Please cite this article in press as: Hsieh JT, et al. Ten-year study of postoperative complications following dental extractions in patients with inherited bleeding disorders, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.04.016
YIJOM-3677; No of Pages 4
2
Hsieh et al.
Published data are based on retrospective series describing routine practice at single institutions1–3. The World Federation of Haemophilia published its second edition of guidelines for the management of haemophilia patients4. Dental extractions should be carried out with a plan for haemostasis management, in consultation with the haematologist; however, the guidelines did not specify if factor level should be increased with systemic therapy. They acknowledged the use of tranexamic acid or aminocaproic acid after dental procedures can reduce the need for replacement therapy, and that local haemostatic measures, such as oxidized cellulose and fibrin glue, may also be used whenever possible. Traditionally at our institution, patients with inherited bleeding disorders undergoing dental extractions are admitted for perioperative systemic factor replacement or desmopressin (ddAVP) infusion depending on their haematological diagnosis. This approach can be time consuming, expensive, and limits patients to receiving extractions as an inpatient in hospital setting. If human-derived blood products are to be used, there are also the potential risks of viral and prion transmission. Of most concern among risks associated with factor replacement therapy is the development of immunoglobulin (Ig)G antibodies or inhibitors, which neutralize the already low level of endogenous clotting factors, making the patient prone to spontaneous bleeds and a challenge to achieve haemostasis in a trauma or surgery setting. Practices at individual institutions can vary from the guidelines. A recent study based in the Royal Alfred Haemophilia Center in Victoria by Hewson et al.5 suggested that no extra factor support in addition to the patient’s usual prophylaxis was required for patients with inherited bleeding disorders undergoing dental extractions. In this study, an emphasis was placed on local haemostatic measures, which included the use of topical tranexamic acid and oxidized cellulose within the extraction sockets, careful surgical techniques, closure over sockets with sutures, and postoperative tranexamic acid mouthwash. Their postoperative bleeding rate was 8% (4 out of 50 patients) and all bleeding responded to replacement of factors or desmopressin. Given the added cost and risks associated with perioperative factor/desmopressin replacement, one would expect a better outcome in bleeding complications after dental extractions for these patients. The objective of our study was to examine the complication rate at our institution for patients with inherited bleeding disorders undergoing dental extractions. We also aimed to iden-
tify factors that may be associated with increased risk of postoperative bleeding. Materials and methods
All patients 18 years or older with haemophilia A, haemophilia B, or von Willebrand disease requiring one or more dental extraction treated at our institution during a 10year period (January 2003 to December 2012) were included in our study. The patients’ charts were reviewed and this included inpatient admission notes, maxillofacial and haematology outpatient progress notes, as well as any records on emergency department presentations. The following details were recorded: -
type of inherited bleeding disorder number of teeth extracted if removal of bone was required if sectioning of teeth was required if haemostatic agent was placed in the socket - pre- and postoperative haemostatic therapy prescribed, including intravenous, oral or topical therapies - postoperative bleeding or other complications. These variables were then examined to see if they were significantly associated with increased postoperative bleeding. All procedures were performed by a maxillofacial surgery trainee or a consultant. If performed by a trainee, an experienced maxillofacial surgery consultant was either scrubbed or present in theatre. All patients were treated as inpatients with at least an overnight stay. The majority of patients were treated under general anaesthesia. These precautionary measures were taken, as this allows for monitoring of any immediate postoperative bleeding and better support in terms of medications, recombinant factors, and personnel, if significant bleeding was to occur. Statistical methods
The types of bleeding disorders are divided into nine groups: haemophilia A mild, moderate, or severe; haemophilia B mild, moderate, severe; and von Willebrand disease types 1, 2, and 3. Mild haemophilia is defined by a factor
level above 5%. Moderate haemophilia has a factor level between 1% and 5% and severe haemophilia is when the factor level is less than 1%. The number of teeth extracted was classified into single tooth extractions or multiple teeth extractions. The potential association between the outcome (postoperative bleeding requiring treatment other than applying pressure) and the risk factors were explored, firstly, using univariate logistic regression. Then with significant variables, a multivariate logistic regression was performed with an Akaike information criteria-based covariate searching method. The significance level was set to be P < 0.05. R (version 3.1.1; https://cran.r-project.org) was used for data management and statistical analysis.
Results
A total of 57 extraction events occurred in 49 patients during the study period. Four extraction events in four patients were excluded from the study as their charts had been destroyed or were missing, making a total of 53 extraction events in 45 patients. The types of inherited bleeding disorder are presented in Table 1. There were two patients with severe haemophilia A who are on regular three times weekly prophylactic factor VIII replacements. Inhibitor screens were performed on these two patients preoperatively to ensure there would be an adequate response to factor VIII perioperatively. The remaining patients were not on any regular prophylaxis. Inhibitor screens were not performed on these patients as they were at low risk of developing inhibitors without exposure to factor VIII followed by a clinical alteration to their bleeding tendency. The male to female ratio was 36:9. A male predominance was expected as haemophilia has an X-linked inheritance. Of the intraoperative variables, 22.6% of patients had a single tooth extraction, 58.5% required bone removal, and 49% of patients had local haemostatic agents placed in the extraction socket. Local haemostatic agents used were Gelfoam1 (Pfizer), Surgicel1 (Ethicon, JohnsonJohnson Corporation), or Floseal1 (Baxter International Inc.). The decision to use
Table 1. Distribution of types of inherited bleeding disorder in 45 patients. Haemophilia A
Haemophilia B
Von Willebrand disease
Mild
Moderate
Severe
Mild
Moderate
Severe
Type 1
Type 2
Type 3
18
0
2
9
0
0
13
3
0
Please cite this article in press as: Hsieh JT, et al. Ten-year study of postoperative complications following dental extractions in patients with inherited bleeding disorders, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.04.016
YIJOM-3677; No of Pages 4
Complications following dental extraction Table 2. Correlation of intraoperative variables to postoperative bleeding. Intraoperative variable
Odds ratio
P-value
Single tooth vs. multiple teeth extraction Bone removal required vs. not required Haemostatic agent placed in socket vs. none Diagnosis (reference = mild haemophilia A) Severe haemophilia A Mild haemophilia B von Willebrand type 1 von Willebrand type 2
0.95 3.48 2.68
0.66 0.14 0.19
2.4 2.4 0.79 <0.001
0.52 0.33 0.80 0.99
local haemostatic agents or not was made clinically at the time of surgery by the operator. All patients had preoperative intravenous factor support or desmopressin, and the majority (84.9%) were followed by a further dose of factor or desmopressin in the postoperative period. Postoperative bleeding requiring further intravenous factor replacement or desmopressin was 18.9% (10 out of 53 extraction events). One patient with mild haemophilia A had significant postoperative bleeding after surgical removal of the bilateral mandibular third molars and developed inhibitors to factor VIII. Statistics about intraoperative variables and correlation with postoperative bleeding are presented in Table 2. Patients who had bone removed were 3.48 times more likely to have postoperative bleeds than those who did not require bone removal; however, the P-value was not significant. Patients who had haemostatic agents placed in the socket were 2.68 times more likely to have postoperative bleeds than those who did not have haemostatic agents, but this again was not statistically significant (P = 0.19). Single tooth extractions appeared to have similar postoperative bleeding rates to multiple teeth extractions (OR 0.95; P = 0.66). In fact, none of the intraoperative variables examined showed statistical significance. Compared with patients with mild haemophilia A, patients with severe haemophilia A or mild haemophilia B were 2.4 times more likely to have postoperative bleeding, but this was not statistically significant. Discussion
Traditionally, pre- and postoperative clotting factor replacements have been advocated to prevent bleeding complications in these patients. However, this approach can be time consuming, expensive, and limits patients to receiving extractions as an inpatient in a hospital setting. If human-derived blood products are to be used, there are also potential risks of viral and prion transmission. Of most concern among the risks associated with factor replacement therapy
is the development of IgG antibodies or inhibitors, which neutralize the clotting factors. The lifetime risk of inhibitor development in severe haemophilia A ranges between 20–30% and 5–10% in moderate or mild haemophilia A6,7. The mean age of development of inhibitors in mild haemophilia A is 30 and often occurs with intensive factor VIII exposure during perioperative periods8,9. Inhibitors are much less common in haemophilia B, occurring in less than 5% of these patients. In our study, one patient with mild haemophilia A developed inhibitors to factor VIII postoperatively. This patient only exhibited symptoms consistent with mild haemophilia preoperatively, for example increased bleeding only on injury or surgical insult; therefore, he was not on any regular factor VIII prophylaxis. He had further two hospital admissions for administration of factor VIIa to help control his postoperative bleeding. The development of inhibitors reduced his already low endogenous factor VIII level and this led him to behave clinically similar to someone with severe haemophilia A. He also had a spontaneous bleed into his thumb requiring evacuation of haematoma under general anaesthesia a few weeks later. This patient went on to receive immunosuppressive therapy in an attempt to clear the inhibitors to factor VIII. Although this is a rare event, development of inhibitors carries significant implications for haemophilia patients. In our study, the use of haemostatic agents in extraction sockets had more of a tendency towards increased postoperative bleeding than those who did not have haemostatic agents placed. This finding appears counterintuitive at first, but may be explained by the decisions for use of haemostatic agents being made clinically, that is on those patients whom the operators deemed to have excessive bleeding at the time of surgery. Therefore, this represents a confounder, which may have contributed to the tendency to increased postoperative bleeding. Postoperative bleeding requiring additional factor replacement or desmopressin
3
infusion was surprisingly high at 18.9% (10 out of 53 extraction events) in our study. Objective quantification of any postoperative bleeding from intraoral wounds is difficult as bleeding is mixed with saliva. None of the 10 cases that had postoperative bleeding requiring further systemic therapy had clear documentation on the severity and quantity of bleeding. Local measures such as tranexamic acidsoaked gauze packs, local anaesthetic with adrenalin, and suturing were not always trialled prior to the administration of additional systemic medications or factors. Perhaps simple local haemostatic measures were overlooked as these patients had a known inherited bleeding disorder and therefore were more likely to be offered systemic therapy to control postoperative bleeding. We acknowledge that this study included only a small and heterogeneous group of patients. Some patients have conditions that do not require factor VIII replacement; therefore, the risk of developing inhibitors did not apply to them. There are still costs associated with inpatient management and administration of systemic therapies that applied to all patients. Despite the use systemic therapies, the postoperative bleeding rate was higher in our study, 18.9% vs. 8%, compared with the study by Hewson et al.5, who employed local haemostatic measures only, without any additional systemic therapy, in their management of patients with inherited bleeding disorders requiring dental extractions. Although the distributions of patients with haemophilia A, haemophilia B, and von Willebrand’s disease were similar in both studies, there was a slightly higher rate of non-surgical extractions (64% vs. 41.5% of patients) and single tooth extractions (40% vs. 22.6% of patients) in Hewson’s study. These may partly explain the lower postoperative bleeding rate in their study. Perhaps the use of systemic therapy provided the operator with a false sense of security and masked the bleeding tendency at the time of the operation. Bleeding then occurred after the effect of systemic therapy had lapsed. On the other hand, if no systemic therapy is given preoperatively, bleeding at the time of operation will prompt the operator to use and combine different local haemostatic measures in order to achieve haemostasis. A literature review showed other studies1–3,10, mostly retrospective, reporting the incidence of postoperative bleeding following dental surgery in patients with inherited bleeding disorder ranging from 2% to 31.6%. It is difficult to com-
Please cite this article in press as: Hsieh JT, et al. Ten-year study of postoperative complications following dental extractions in patients with inherited bleeding disorders, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.04.016
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Hsieh et al.
pare the studies because of variation in the definition on high-risk dental procedures, patient demographics including type and severity of bleeding disorder, the use of factor replacement or antifibrinolytic therapies perioperatively, and whether or not local haemostatic agents were used. A recent Cochrane review in 2015 attempted to assess the efficacy of systemic antifibrinolytic therapy in the prevention of bleeding in patients with haemophilia or von Willebrand disease undergoing minor oral surgery or dental extractions identified only two eligible trials for patients with haemophilia11. Both trials were published in the 1970s. Although there were some benefits in systemically administered antifibrinolytic therapy demonstrated in the trials, the authors could not conclude definite efficacy for their use in dental procedures in patients with haemophilia because of the limited number of randomized controlled trials identified, small sample sizes, and heterogeneity in regards to standard therapy and treatment regimens between the two trials. There are many positive implications if dental extractions can be carried out safely in patients with inherited bleeding disorder using local haemostatic measures only. Firstly, patients will be able to have extractions in an outpatient setting and will not be exposed to the risks of systemic therapy. Secondly, the cost of providing care for these patients will be reduced. Thirdly, the treatment process is simplified, as there is no need to coordinate the timing of systemic therapy with the extractions. Further studies are required to assess the safety and effectiveness of performing dental extractions in patients with inherited bleeding disorder without additional systemic therapy. The findings of this study and the literature review have prompted us to conduct a prospective study on the use of Floseal within extraction sockets in patients with inherited bleeding disorders without the use of perioperative systemic therapy. The result will hopefully support our view that additional emphasis should be placed on minimally traumatic surgical techniques and local haemostatic control in patients with inherited bleeding disorder requiring dental extractions.
Funding
None. Competing interests
None. Ethical approval
Ethic approval was granted by the Royal Brisbane & Women’s Hospital Human Research Ethics Committee. HREC/14/ QRBWH/41. Patient consent
Not required. Acknowledgement. The authors would like to acknowledge Beryl Zeissink, Clinical Nurse Consultant, Queensland Haemophilia Centre for her support and maintenance of clinical records.
References 1. Zanon E, Martinelli F, Bacci C, Zerbinati P, Girolami A. Proposal of a standard approach to dental extraction in haemophilia patients. A case-control study with good results. Haemophilia 2000;6:533–6. 2. Franchini M, Rossetti G, Tagliaferri A, Pattacini C, Pozzoli D, Lorenz C, Del Dot L, Ugolotti G, Dell’aringa C, Gandini G. Dental procedures in adult patients with hereditary bleeding disorders: 10 years experience in three Italian hemophilia centers. Haemophilia 2005;11:504–9. 3. Frachon X, Pommereuil M, Berthier AM, Lejeune S, Hourdin-Eude S, Quero J, Me´zie`re X, De Mello G, Garnier J. Management options for dental extraction in hemophiliacs: a study of 55 extractions (2000-2002). Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;99:270–5. 4. Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, Ludlam CA, Mahlangu JN, Mulder K, Poon MC, Street A, Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Guidelines for the management of hemophilia. Haemophilia 2013;19: e1–47.
5. Hewson I, Makhmalbaf P, Street A, McCarthy P, Walsh M. Dental surgery with minimal factor support in the inherited bleeding disorder population at the Alfred Hospital. Haemophilia 2011;17:e185–8. 6. Astermark J, Altisent C, Batorova A, Diniz MJ, Gringeri A, Holme PA, Karafoulidou A, Lopez-Ferna´ndez MF, Reipert BM, Rocino A, Schiavoni M, von Depka M, Windyga J, Fijnvandraat K, European Haemophilia Therapy Standardisation Board. Non-genetic risk factors and the development of inhibitors in haemophilia: a comprehensive review and consensus report. Haemophilia 2010;16:747–66. 7. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003;9:418–35. 8. Eckhardt CL, Menke LA, van Ommen CH, van der Lee JH, Geskus RB, Kamphuisen PW, Peters M, Fijnvandraat K. Intensive peri-operative use of factor VIII and the Arg593!Cys mutation are risk factors for inhibitor development in mild/moderate hemophilia A. J Thromb Haemost 2009;7: 930–7. 9. Kempton CL, Soucie JM, Miller CH, Hooper C, Escobar MA, Cohen AJ, Key NS, Thompson AR, Abshire TC. In non-severe hemophilia A the risk of inhibitor after intensive factor treatment is greater in older patients: a case-control study. J Thromb Haemost 2010;8:2224–31. 10. Givol N, Hirschhorn A, Lubetsky A, Bashari D, Kenet G. Oral surgery-associated postoperative bleeding in haemophilia patients – a tertiary centre’s two decade experience. Haemophilia 2015;21:234–40. 11. van Galen KP, Engelen ET, MauserBunschoten EP, van Es RJ, Schutgens RE. Antifibrinolytic therapy for preventing oral bleeding in patients with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions. Cochrane Database Syst Rev 2015;(12):CD011385.
Address: Jen-Ti (Rachel) Hsieh Department of Maxillofacial surgery Royal Brisbane & Womens Hospital Herston Queensland 4029 Australia E-mail: [email protected]
Please cite this article in press as: Hsieh JT, et al. Ten-year study of postoperative complications following dental extractions in patients with inherited bleeding disorders, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.04.016
Int. J. Oral Maxillofac. Surg. 2017; xxx: xxx–xxx http://dx.doi.org/10.1016/j.ijom.2017.04.016, available online at http://www.sciencedirect.com
Clinical Paper Oral Surgery
Ten-year study of postoperative complications following dental extractions in patients with inherited bleeding disorders
J.-T. Hsieh1, K. Klein2, M. Batstone3 1 Department of Maxillofacial Surgery, Royal Brisbane & Womens Hospital, Brisbane, Australia; 2Clinical Trials and Biostatistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, Australia; 3Department of Maxillofacial surgery, Royal Brisbane & Womens Hospital, University of Queensland, Brisbane, Australia
J.-T. Hsieh, K. Klein, M. Batstone: Ten-year study of postoperative complications following dental extractions in patients with inherited bleeding disorders. Int. J. Oral Maxillofac. Surg. 2017; xxx: xxx–xxx. Crown Copyright ã 2017 Published by Elsevier Ltd on behalf of International Association of Oral and Maxillofacial Surgeons. All rights reserved.
Abstract. Dental extractions challenge the body’s haemostatic mechanism. Postoperative bleeding from dental extraction can be prolonged, or even life threatening in patients with inherited bleeding disorders. Pre- and postoperative clotting factor replacements or systemic desmopressin (ddAVP) have been advocated at our institution to prevent bleeding complications in these patients. This study aimed to assess the postoperative bleeding rate in patients with inherited bleeding disorders that underwent dental extractions at our institution between 2003 and 2012. Patients with inherited bleeding disorders such as haemophilia A, haemophilia B, and von Willebrand’s disease were included. Retrospective chart review was conducted. The result showed 53 extraction events occurred in 45 patients over the 10-year period. Ten out of 53 extraction events (18.9%) had postoperative bleeding requiring further factor replacement or ddAVP. Postoperative bleeding in one patient with mild haemophilia A was complicated by the development of inhibitors. Type and severity of bleeding disorder, bone removal, and use of a local haemostatic agent did not have any significant effect on postoperative bleeding. Despite the use of perioperative factors and desmopressin, the postoperative bleeding rates remain high for patients with inherited bleeding disorders. More studies are required to assess the safety and effectiveness of using local haemostatic control to achieve haemostasis following extractions.
Dental extractions challenge the body’s haemostatic mechanism. Postoperative bleeding from extraction sockets can be prolonged, or even life threatening in 0901-5027/000001+04
patients with inherited bleeding disorders. Haemophilia A, haemophilia B, and von Willebrand disease are the most common inherited bleeding disorders.
Key words: haemophilia; von Willebrand disease; dental extraction; factor replacement; desmopressin. Accepted for publication 19 April 2017
There have been no controlled trials to date to define the optimal haemostatic therapy for patients with inherited bleeding disorders undergoing oral surgery.
Crown Copyright ã 2017 Published by Elsevier Ltd on behalf of International Association of Oral and Maxillofacial Surgeons. All rights reserved.
Please cite this article in press as: Hsieh JT, et al. Ten-year study of postoperative complications following dental extractions in patients with inherited bleeding disorders, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.04.016
YIJOM-3677; No of Pages 4
2
Hsieh et al.
Published data are based on retrospective series describing routine practice at single institutions1–3. The World Federation of Haemophilia published its second edition of guidelines for the management of haemophilia patients4. Dental extractions should be carried out with a plan for haemostasis management, in consultation with the haematologist; however, the guidelines did not specify if factor level should be increased with systemic therapy. They acknowledged the use of tranexamic acid or aminocaproic acid after dental procedures can reduce the need for replacement therapy, and that local haemostatic measures, such as oxidized cellulose and fibrin glue, may also be used whenever possible. Traditionally at our institution, patients with inherited bleeding disorders undergoing dental extractions are admitted for perioperative systemic factor replacement or desmopressin (ddAVP) infusion depending on their haematological diagnosis. This approach can be time consuming, expensive, and limits patients to receiving extractions as an inpatient in hospital setting. If human-derived blood products are to be used, there are also the potential risks of viral and prion transmission. Of most concern among risks associated with factor replacement therapy is the development of immunoglobulin (Ig)G antibodies or inhibitors, which neutralize the already low level of endogenous clotting factors, making the patient prone to spontaneous bleeds and a challenge to achieve haemostasis in a trauma or surgery setting. Practices at individual institutions can vary from the guidelines. A recent study based in the Royal Alfred Haemophilia Center in Victoria by Hewson et al.5 suggested that no extra factor support in addition to the patient’s usual prophylaxis was required for patients with inherited bleeding disorders undergoing dental extractions. In this study, an emphasis was placed on local haemostatic measures, which included the use of topical tranexamic acid and oxidized cellulose within the extraction sockets, careful surgical techniques, closure over sockets with sutures, and postoperative tranexamic acid mouthwash. Their postoperative bleeding rate was 8% (4 out of 50 patients) and all bleeding responded to replacement of factors or desmopressin. Given the added cost and risks associated with perioperative factor/desmopressin replacement, one would expect a better outcome in bleeding complications after dental extractions for these patients. The objective of our study was to examine the complication rate at our institution for patients with inherited bleeding disorders undergoing dental extractions. We also aimed to iden-
tify factors that may be associated with increased risk of postoperative bleeding. Materials and methods
All patients 18 years or older with haemophilia A, haemophilia B, or von Willebrand disease requiring one or more dental extraction treated at our institution during a 10year period (January 2003 to December 2012) were included in our study. The patients’ charts were reviewed and this included inpatient admission notes, maxillofacial and haematology outpatient progress notes, as well as any records on emergency department presentations. The following details were recorded: -
type of inherited bleeding disorder number of teeth extracted if removal of bone was required if sectioning of teeth was required if haemostatic agent was placed in the socket - pre- and postoperative haemostatic therapy prescribed, including intravenous, oral or topical therapies - postoperative bleeding or other complications. These variables were then examined to see if they were significantly associated with increased postoperative bleeding. All procedures were performed by a maxillofacial surgery trainee or a consultant. If performed by a trainee, an experienced maxillofacial surgery consultant was either scrubbed or present in theatre. All patients were treated as inpatients with at least an overnight stay. The majority of patients were treated under general anaesthesia. These precautionary measures were taken, as this allows for monitoring of any immediate postoperative bleeding and better support in terms of medications, recombinant factors, and personnel, if significant bleeding was to occur. Statistical methods
The types of bleeding disorders are divided into nine groups: haemophilia A mild, moderate, or severe; haemophilia B mild, moderate, severe; and von Willebrand disease types 1, 2, and 3. Mild haemophilia is defined by a factor
level above 5%. Moderate haemophilia has a factor level between 1% and 5% and severe haemophilia is when the factor level is less than 1%. The number of teeth extracted was classified into single tooth extractions or multiple teeth extractions. The potential association between the outcome (postoperative bleeding requiring treatment other than applying pressure) and the risk factors were explored, firstly, using univariate logistic regression. Then with significant variables, a multivariate logistic regression was performed with an Akaike information criteria-based covariate searching method. The significance level was set to be P < 0.05. R (version 3.1.1; https://cran.r-project.org) was used for data management and statistical analysis.
Results
A total of 57 extraction events occurred in 49 patients during the study period. Four extraction events in four patients were excluded from the study as their charts had been destroyed or were missing, making a total of 53 extraction events in 45 patients. The types of inherited bleeding disorder are presented in Table 1. There were two patients with severe haemophilia A who are on regular three times weekly prophylactic factor VIII replacements. Inhibitor screens were performed on these two patients preoperatively to ensure there would be an adequate response to factor VIII perioperatively. The remaining patients were not on any regular prophylaxis. Inhibitor screens were not performed on these patients as they were at low risk of developing inhibitors without exposure to factor VIII followed by a clinical alteration to their bleeding tendency. The male to female ratio was 36:9. A male predominance was expected as haemophilia has an X-linked inheritance. Of the intraoperative variables, 22.6% of patients had a single tooth extraction, 58.5% required bone removal, and 49% of patients had local haemostatic agents placed in the extraction socket. Local haemostatic agents used were Gelfoam1 (Pfizer), Surgicel1 (Ethicon, JohnsonJohnson Corporation), or Floseal1 (Baxter International Inc.). The decision to use
Table 1. Distribution of types of inherited bleeding disorder in 45 patients. Haemophilia A
Haemophilia B
Von Willebrand disease
Mild
Moderate
Severe
Mild
Moderate
Severe
Type 1
Type 2
Type 3
18
0
2
9
0
0
13
3
0
Please cite this article in press as: Hsieh JT, et al. Ten-year study of postoperative complications following dental extractions in patients with inherited bleeding disorders, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.04.016
YIJOM-3677; No of Pages 4
Complications following dental extraction Table 2. Correlation of intraoperative variables to postoperative bleeding. Intraoperative variable
Odds ratio
P-value
Single tooth vs. multiple teeth extraction Bone removal required vs. not required Haemostatic agent placed in socket vs. none Diagnosis (reference = mild haemophilia A) Severe haemophilia A Mild haemophilia B von Willebrand type 1 von Willebrand type 2
0.95 3.48 2.68
0.66 0.14 0.19
2.4 2.4 0.79 <0.001
0.52 0.33 0.80 0.99
local haemostatic agents or not was made clinically at the time of surgery by the operator. All patients had preoperative intravenous factor support or desmopressin, and the majority (84.9%) were followed by a further dose of factor or desmopressin in the postoperative period. Postoperative bleeding requiring further intravenous factor replacement or desmopressin was 18.9% (10 out of 53 extraction events). One patient with mild haemophilia A had significant postoperative bleeding after surgical removal of the bilateral mandibular third molars and developed inhibitors to factor VIII. Statistics about intraoperative variables and correlation with postoperative bleeding are presented in Table 2. Patients who had bone removed were 3.48 times more likely to have postoperative bleeds than those who did not require bone removal; however, the P-value was not significant. Patients who had haemostatic agents placed in the socket were 2.68 times more likely to have postoperative bleeds than those who did not have haemostatic agents, but this again was not statistically significant (P = 0.19). Single tooth extractions appeared to have similar postoperative bleeding rates to multiple teeth extractions (OR 0.95; P = 0.66). In fact, none of the intraoperative variables examined showed statistical significance. Compared with patients with mild haemophilia A, patients with severe haemophilia A or mild haemophilia B were 2.4 times more likely to have postoperative bleeding, but this was not statistically significant. Discussion
Traditionally, pre- and postoperative clotting factor replacements have been advocated to prevent bleeding complications in these patients. However, this approach can be time consuming, expensive, and limits patients to receiving extractions as an inpatient in a hospital setting. If human-derived blood products are to be used, there are also potential risks of viral and prion transmission. Of most concern among the risks associated with factor replacement therapy
is the development of IgG antibodies or inhibitors, which neutralize the clotting factors. The lifetime risk of inhibitor development in severe haemophilia A ranges between 20–30% and 5–10% in moderate or mild haemophilia A6,7. The mean age of development of inhibitors in mild haemophilia A is 30 and often occurs with intensive factor VIII exposure during perioperative periods8,9. Inhibitors are much less common in haemophilia B, occurring in less than 5% of these patients. In our study, one patient with mild haemophilia A developed inhibitors to factor VIII postoperatively. This patient only exhibited symptoms consistent with mild haemophilia preoperatively, for example increased bleeding only on injury or surgical insult; therefore, he was not on any regular factor VIII prophylaxis. He had further two hospital admissions for administration of factor VIIa to help control his postoperative bleeding. The development of inhibitors reduced his already low endogenous factor VIII level and this led him to behave clinically similar to someone with severe haemophilia A. He also had a spontaneous bleed into his thumb requiring evacuation of haematoma under general anaesthesia a few weeks later. This patient went on to receive immunosuppressive therapy in an attempt to clear the inhibitors to factor VIII. Although this is a rare event, development of inhibitors carries significant implications for haemophilia patients. In our study, the use of haemostatic agents in extraction sockets had more of a tendency towards increased postoperative bleeding than those who did not have haemostatic agents placed. This finding appears counterintuitive at first, but may be explained by the decisions for use of haemostatic agents being made clinically, that is on those patients whom the operators deemed to have excessive bleeding at the time of surgery. Therefore, this represents a confounder, which may have contributed to the tendency to increased postoperative bleeding. Postoperative bleeding requiring additional factor replacement or desmopressin
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infusion was surprisingly high at 18.9% (10 out of 53 extraction events) in our study. Objective quantification of any postoperative bleeding from intraoral wounds is difficult as bleeding is mixed with saliva. None of the 10 cases that had postoperative bleeding requiring further systemic therapy had clear documentation on the severity and quantity of bleeding. Local measures such as tranexamic acidsoaked gauze packs, local anaesthetic with adrenalin, and suturing were not always trialled prior to the administration of additional systemic medications or factors. Perhaps simple local haemostatic measures were overlooked as these patients had a known inherited bleeding disorder and therefore were more likely to be offered systemic therapy to control postoperative bleeding. We acknowledge that this study included only a small and heterogeneous group of patients. Some patients have conditions that do not require factor VIII replacement; therefore, the risk of developing inhibitors did not apply to them. There are still costs associated with inpatient management and administration of systemic therapies that applied to all patients. Despite the use systemic therapies, the postoperative bleeding rate was higher in our study, 18.9% vs. 8%, compared with the study by Hewson et al.5, who employed local haemostatic measures only, without any additional systemic therapy, in their management of patients with inherited bleeding disorders requiring dental extractions. Although the distributions of patients with haemophilia A, haemophilia B, and von Willebrand’s disease were similar in both studies, there was a slightly higher rate of non-surgical extractions (64% vs. 41.5% of patients) and single tooth extractions (40% vs. 22.6% of patients) in Hewson’s study. These may partly explain the lower postoperative bleeding rate in their study. Perhaps the use of systemic therapy provided the operator with a false sense of security and masked the bleeding tendency at the time of the operation. Bleeding then occurred after the effect of systemic therapy had lapsed. On the other hand, if no systemic therapy is given preoperatively, bleeding at the time of operation will prompt the operator to use and combine different local haemostatic measures in order to achieve haemostasis. A literature review showed other studies1–3,10, mostly retrospective, reporting the incidence of postoperative bleeding following dental surgery in patients with inherited bleeding disorder ranging from 2% to 31.6%. It is difficult to com-
Please cite this article in press as: Hsieh JT, et al. Ten-year study of postoperative complications following dental extractions in patients with inherited bleeding disorders, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.04.016
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pare the studies because of variation in the definition on high-risk dental procedures, patient demographics including type and severity of bleeding disorder, the use of factor replacement or antifibrinolytic therapies perioperatively, and whether or not local haemostatic agents were used. A recent Cochrane review in 2015 attempted to assess the efficacy of systemic antifibrinolytic therapy in the prevention of bleeding in patients with haemophilia or von Willebrand disease undergoing minor oral surgery or dental extractions identified only two eligible trials for patients with haemophilia11. Both trials were published in the 1970s. Although there were some benefits in systemically administered antifibrinolytic therapy demonstrated in the trials, the authors could not conclude definite efficacy for their use in dental procedures in patients with haemophilia because of the limited number of randomized controlled trials identified, small sample sizes, and heterogeneity in regards to standard therapy and treatment regimens between the two trials. There are many positive implications if dental extractions can be carried out safely in patients with inherited bleeding disorder using local haemostatic measures only. Firstly, patients will be able to have extractions in an outpatient setting and will not be exposed to the risks of systemic therapy. Secondly, the cost of providing care for these patients will be reduced. Thirdly, the treatment process is simplified, as there is no need to coordinate the timing of systemic therapy with the extractions. Further studies are required to assess the safety and effectiveness of performing dental extractions in patients with inherited bleeding disorder without additional systemic therapy. The findings of this study and the literature review have prompted us to conduct a prospective study on the use of Floseal within extraction sockets in patients with inherited bleeding disorders without the use of perioperative systemic therapy. The result will hopefully support our view that additional emphasis should be placed on minimally traumatic surgical techniques and local haemostatic control in patients with inherited bleeding disorder requiring dental extractions.
Funding
None. Competing interests
None. Ethical approval
Ethic approval was granted by the Royal Brisbane & Women’s Hospital Human Research Ethics Committee. HREC/14/ QRBWH/41. Patient consent
Not required. Acknowledgement. The authors would like to acknowledge Beryl Zeissink, Clinical Nurse Consultant, Queensland Haemophilia Centre for her support and maintenance of clinical records.
References 1. Zanon E, Martinelli F, Bacci C, Zerbinati P, Girolami A. Proposal of a standard approach to dental extraction in haemophilia patients. A case-control study with good results. Haemophilia 2000;6:533–6. 2. Franchini M, Rossetti G, Tagliaferri A, Pattacini C, Pozzoli D, Lorenz C, Del Dot L, Ugolotti G, Dell’aringa C, Gandini G. Dental procedures in adult patients with hereditary bleeding disorders: 10 years experience in three Italian hemophilia centers. Haemophilia 2005;11:504–9. 3. Frachon X, Pommereuil M, Berthier AM, Lejeune S, Hourdin-Eude S, Quero J, Me´zie`re X, De Mello G, Garnier J. Management options for dental extraction in hemophiliacs: a study of 55 extractions (2000-2002). Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;99:270–5. 4. Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, Ludlam CA, Mahlangu JN, Mulder K, Poon MC, Street A, Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Guidelines for the management of hemophilia. Haemophilia 2013;19: e1–47.
5. Hewson I, Makhmalbaf P, Street A, McCarthy P, Walsh M. Dental surgery with minimal factor support in the inherited bleeding disorder population at the Alfred Hospital. Haemophilia 2011;17:e185–8. 6. Astermark J, Altisent C, Batorova A, Diniz MJ, Gringeri A, Holme PA, Karafoulidou A, Lopez-Ferna´ndez MF, Reipert BM, Rocino A, Schiavoni M, von Depka M, Windyga J, Fijnvandraat K, European Haemophilia Therapy Standardisation Board. Non-genetic risk factors and the development of inhibitors in haemophilia: a comprehensive review and consensus report. Haemophilia 2010;16:747–66. 7. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. Haemophilia 2003;9:418–35. 8. Eckhardt CL, Menke LA, van Ommen CH, van der Lee JH, Geskus RB, Kamphuisen PW, Peters M, Fijnvandraat K. Intensive peri-operative use of factor VIII and the Arg593!Cys mutation are risk factors for inhibitor development in mild/moderate hemophilia A. J Thromb Haemost 2009;7: 930–7. 9. Kempton CL, Soucie JM, Miller CH, Hooper C, Escobar MA, Cohen AJ, Key NS, Thompson AR, Abshire TC. In non-severe hemophilia A the risk of inhibitor after intensive factor treatment is greater in older patients: a case-control study. J Thromb Haemost 2010;8:2224–31. 10. Givol N, Hirschhorn A, Lubetsky A, Bashari D, Kenet G. Oral surgery-associated postoperative bleeding in haemophilia patients – a tertiary centre’s two decade experience. Haemophilia 2015;21:234–40. 11. van Galen KP, Engelen ET, MauserBunschoten EP, van Es RJ, Schutgens RE. Antifibrinolytic therapy for preventing oral bleeding in patients with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions. Cochrane Database Syst Rev 2015;(12):CD011385.
Address: Jen-Ti (Rachel) Hsieh Department of Maxillofacial surgery Royal Brisbane & Womens Hospital Herston Queensland 4029 Australia E-mail: [email protected]
Please cite this article in press as: Hsieh JT, et al. Ten-year study of postoperative complications following dental extractions in patients with inherited bleeding disorders, Int J Oral Maxillofac Surg (2017), http://dx.doi.org/10.1016/j.ijom.2017.04.016